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ORIGINAL RESEARCH article

Clinical characteristics, treatment patterns, and outcomes in adult patients with germline brca1/2 -mutated, her2-negative advanced breast cancer: a retrospective medical record review in the united states.

• 1 Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, United States
• 2 Health Economics, RTI Health Solutions, Research Triangle Park, NC, United States
• 3 Pfizer Inc., Collegeville, PA, United States
• 4 Pfizer Inc., Department of US Oncology Medical Affairs, New York, NY, United States
• 5 Pfizer Inc., Department of HTA, Value and Evidence, New York, NY, United States

Aim: To examine clinical characteristics, real-world treatment patterns, and health outcomes among patients with germline BRCA1/2 -mutated, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer (ABC).

Methods: A retrospective analysis was conducted using medical records from patients with HER2-negative ABC with BRCA1/2 mutation who received cytotoxic chemotherapy. Data were stratified into groups with triple-negative breast cancer (TNBC) or hormone receptor–positive (HR+)/HER2-negative diagnoses. Time-to-event outcomes (i.e., real-world progression-free survival [rwPFS] and overall survival [OS]) were calculated to summarize health outcomes.

Results: When diagnosed with ABC, most patients were younger than 60 years (mean age = 57.3 years), were white (76.4%), and had a family history of BRCA -related cancer (71.5%). A total of 305 patient records were examined; 194 patients (63.6%) had advanced TNBC, and 111 patients (36.4%) had HR+/HER2-negative ABC. Chemotherapy was primarily used as first-line treatment for both subgroups, but the TNBC subgroup received poly (ADP-ribose) polymerase (PARP) inhibitors at triple the rate as a second-line treatment and double the rate as a third-line treatment compared with the HR+/HER2-negative subgroup. Two-year OS rates were similar between the TNBC (73.9%) and the HR+/HER2-negative subgroups (77.0%), and anemia, nausea, and neutropenia were the most commonly reported toxicities across all treatments.

Conclusion: Clinicians should consider the use of targeted agents such as PARP inhibitors in earlier lines of therapy for ABC given the growing evidence that PARP inhibitors may improve PFS compared with chemotherapy while potentially offering a more manageable toxicity profile and improved quality of life.

Introduction

In the United States (US), 1 in 8 women will be diagnosed with breast cancer during their lifetime ( 1 ), and among those, 1 in 3 will develop metastatic disease ( 2 , 3 ). The overall 5-year survival rate for women with localized or regional nonmetastatic breast cancer is approximately 86%-99%, but for those with metastatic breast cancer, the 5-year survival rate drops substantially to 29% ( 4 ). Women with a genetic predisposition, such as those with a germline mutation in the BRCA1/2 genes, have a significantly higher lifetime risk of developing breast cancer. Further, the cumulative lifetime risk of breast cancer for women who carry the BRCA1/2 genes was estimated to be 72% for women who carry the BRCA1 gene and 69% for women who carry the BRCA2 gene, and women who had either BRCA1 or BRCA2 mutations carried greater risk for developing breast cancer if they had a family history ( 5 ). BRCA1 /2 mutations have been shown to impact not only breast cancer risk but also breast cancer outcomes. Women with a BRCA1 mutation and a breast cancer diagnosis have reduced time to progression and survival compared with BRCA2 mutation carriers and noncarriers of BRCA1/2 mutations ( 6 ). Additionally, treatment benefits from therapies such as adjuvant chemotherapy have been shown to be higher in patients without the BRCA1/2 genetic mutations compared with patients with the mutations ( 7 ).

Treatment for advanced breast cancer (ABC) is often tailored based on clinical stage, tumor histology, biomarker expression, prior therapy, and patient performance status ( 8 ). Treatment in earlier stages of breast cancer may include surgical resection, breast- conserving surgery, mastectomy (simple or double mastectomy, and modified radical mastectomy), or radiation therapy in women with BRCA1/2 mutation ( 9 , 10 ). Historically, chemotherapy and/or endocrine therapy were the cornerstone of systemic treatment for patients with human epidermal growth factor receptor 2 (HER2)–negative ABC, but the treatment landscape is changing because of the recent introduction of therapies into the treatment paradigm. Recently, therapies such as poly (ADP-ribose) polymerase (PARP) inhibitors were approved in the US for the treatment of germline BRCA1 /2-associated ABC ( 11 – 14 ). PARP inhibitors have been shown to improve the progression-free survival (PFS) compared with chemotherapy in patients with germline BRCA1/2 -mutated, HER2-negative locally advanced and/or metastatic breast cancer ( 12 , 15 – 17 ). Data from previous studies and the PRAEGNANT registry, which examines genetics and other molecular biomarkers in individuals with metastatic breast cancer, indicate that approximately 5% of patients with metastatic breast cancer carry germline BRCA1/2 mutations ( 18 , 19 ) and thus could potentially derive benefit from a PARP inhibitor. The optimal treatment sequencing in this population has not yet been established. Patient characteristics, prescribing patterns, diverse health care systems, and variable access to care in the clinical practice setting differ from controlled clinical trial environments, which can cause variation in real-world outcomes for patients with germline BRCA1/2 mutations.

In this analysis, clinical characteristics, real-world treatment patterns, and health outcomes among patients with germline BRCA1/2 -mutated, HER2-negative ABC in the US were evaluated in order to contextualize the results of relevant clinical trials and determine the extent of unmet need among these patients in the routine clinical-practice setting.

Materials and methods

Study design.

This study was a noninterventional, retrospective medical record review of adult patients with HER2-negative ABC and germline BRCA1/2 mutations who received cytotoxic chemotherapy. The RTI International Institutional Review Board determined that this study was not human subjects research (STUDY00020382), as the data were unidentifiable. ABC was defined as locally advanced breast cancer that was not amenable to curative radiation or surgery, or as metastatic disease. The sample was further stratified into two groups consisting of patients with advanced triple-negative breast cancer (TNBC) and patients with hormone receptor–positive (HR+)/HER2-negative ABC. Data describing patient and clinical characteristics, treatment patterns, and health outcomes were abstracted directly by eligible oncologists. A purposive, quasi-random sampling method was employed through the selection of medical records for patients whose last names began with a randomly generated letter. The inclusion criteria for oncologists, inclusion criteria for medical records, and exclusion criteria for medical records are presented in Table 1 . Medical record abstraction occurred from July 2019 to May 2020, which allowed for extraction of follow-up data (when available) until May 2020.

Table 1 Inclusion/Exclusion criteria.

Demographics and clinical characteristics

Demographic characteristics, including primary medical specialty, primary practice setting, and geographic region of practice, were collected for the recruited oncologists. For eligible patients, demographic data, as well as baseline clinical characteristics related to their initial breast cancer diagnosis and the diagnosis of ABC, were collected from medical records. Patient demographic data included sex, race, and family history of a BRCA -related cancer. Baseline clinical characteristics included age and Eastern Cooperative Oncology Group (ECOG) performance status at ABC diagnosis.

Treatment patterns

Data measures related to the treatment of breast cancer were collected before and after diagnosis of ABC ( Figure 1 ). Treatment choices before the diagnosis of ABC included neoadjuvant treatment(s), surgery, adjuvant chemotherapy, adjuvant targeted therapy/biologics, adjuvant hormonal therapy, and radiation therapy. Types of treatment approaches, along with total number of systemic lines, collected after diagnosis of ABC included surgery, chemotherapy, targeted therapy/biologics, hormonal therapy, and radiation therapy.

Figure 1 Treatment Pattern Time Period. Patients who were initially diagnosed with advanced breast cancer or were initially diagnosed at an earlier stage and experienced progression to advanced breast cancer were included in the study.

Health outcomes

Health outcomes included time-to-event estimates (i.e., real-world PFS [rwPFS], overall survival [OS]) and prespecified treatment-related toxicities. Dates of progression and death (i.e., whether the patient died during the follow-up period and whether the death was related to breast cancer) were documented. Time-to-event estimates were calculated from the date of ABC diagnosis and the start of each treatment line (received after ABC diagnosis). Several treatment-related hematological (i.e., anemia, neutropenia, thrombocytopenia) and nonhematologic toxicities (i.e., hand-foot syndrome [or palmar-plantar erythrodysesthesia], nausea, vomiting) commonly observed in clinical trials and real-world studies ( 10 , 20 ) were documented for each treatment line received after diagnosis of ABC.

Statistical analysis

Measures were summarized descriptively through tabular and graphical display of mean values, medians, ranges, and standard deviations for continuous variables of interest and frequency distributions for categorical variables. Time-to-event outcomes (i.e., rwPFS, OS) were calculated using Kaplan-Meier methods. All analyses were conducted using SAS (version 9.4 or higher) statistical software. This study was descriptive, with the primary goal of retrospectively summarizing existing treatment patterns and patient outcomes.

A total of 97 oncologists provided abstraction of 305 medical records of adult patients with germline BRCA1/2 -mutated, HER2-negative ABC. The majority were medical oncologists (62.9%) and practiced in a private hospital or clinic (48.5%) ( Supplementary Table 1 ). The geographic locations were approximately evenly distributed among the Southern (30.9%), Northeastern (26.8%), Midwestern (21.7%), and Western US (20.6%).

Patient demographics and clinical characteristics are presented in Table 2 . Of the 305 included medical records, 194 (63.6%) patients had advanced TNBC and 111 (36.4%) patients had HR+/HER2-negative ABC. The median age at ABC diagnosis for the overall patient population with germline BRCA1/2 -mutated, HER2-negative ABC was 57.3 (range, 33.3-79.8) years. Similar median ages at ABC diagnosis were found for the TNBC (57.2 years) and HR+/HER2-negative (58.2 years) subgroups. There was one male patient in the TNBC subgroup. The overall group was mostly white (76.4%); this composition decreased for the TNBC subgroup (71.7%) and increased for the HR+/HER2-negative subgroup (84.7%). The percentages of patients of Ashkenazi Jewish ancestry were similar across the overall group (11.5%), the TNBC subgroup (12.9%), and the HR+/HER2-negative subgroup (9.0%). The percentages of patients with no known family history of a BRCA -related cancer were 24.6%, 27.8%, and 18.9% for the overall group, the TNBC subgroup, and the HR+/HER2-negative subgroup, respectively. The percentage of patients with an ECOG performance status of 0 or 1 at ABC diagnosis was 74.6% for the overall group, 70.2% for the TNBC subgroup, and 83.2% for the HR+/HER2-negative subgroup.

Table 2 Demographics and clinical characteristics in patients with germline BRCA1/2 -mutated HER2-negative advanced breast cancer.

For both the TNBC ( Figure 2 ) and HR+/HER2-negative ( Figure 3 ) subgroups, first-line treatments were similar, with chemotherapy being the most commonly used treatment, but differences in treatments between these subgroups emerged in the second-line setting and beyond. First-line treatment for the TNBC subgroup was composed of mostly nonplatinum-based chemotherapy (60.8%) and platinum-based chemotherapy (39.2%). In second-line treatment, the TNBC subgroup had nearly equivalent rates of nonplatinum-based chemotherapy (40.2%) and PARP inhibitors (42.0%). Third-line treatment in the TNBC subgroup again had similar rates for nonplatinum-based chemotherapy (39.1%) and PARP inhibitors (43.5%). In the HR+/HER2-negative subgroup, first-line treatment consisted of chemotherapy for 78.4% of patients and endocrine-based therapy (EBT) for 19.8% of patients. In second-line treatment, most of the HR+/HER2-negative subgroup received EBT (51.2%), with lower percentages of chemotherapy (31.0%) and PARP inhibitors (13.1%). In third-line treatment for the HR+/HER2-negative subgroup, chemotherapy again became the dominant treatment (50.0%), with decreased use of EBT (27.8%) and increased use of PARP inhibitors (19.4%).

Figure 2 First-, Second-, and Third-Line Treatments Among Patients With Advanced Triple-Negative Breast Cancer. PARPi, poly (ADP-ribose) polymerase inhibitors.

Figure 3 First-, Second-, and Third-Line Treatments Among Patients With HR+/HER2-Negative ABC. ABC, advanced breast cancer; EBT, endocrine-based therapy; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; PARPi, poly (ADP-ribose) polymerase inhibitors.

Efficacy and safety outcomes

During the first-, second-, and third-line treatments, rwPFS was assessed for the TNBC and HR+/HER2-negative ABC subgroups ( Table 3 ). Among patients with TNBC, the median PFS for first-line treatment (n = 190) was 11.6 months (95% confidence interval [CI], 9.9-13.6); for second-line treatment (n = 64), the median PFS was 9.0 months (95% CI, 6.2-11.4); and for third-line treatment (n = 26), the median PFS was 5.9 months (95% CI, 3.5-10.9). Among patients who were HR+/HER2 negative, the median PFS for first-line treatment (n = 110) was 12.1 months (95% CI, 9.1-14.3); for second-line treatment (n = 68), the median PFS was 14.2 months (95% CI, 10.7-29.5); and for third-line treatment (n = 29), the median PFS was 6.5 months (95% CI, 4.4-9.2). Overall survival from index chemotherapy was assessed for the TNBC and HR+/HER2-negative ABC subgroups ( Table 4 ). Patients in the TNBC subgroup had a 2-year OS rate of 73.9%, which decreased to 53.1% at 5 years. The median OS was not estimable during the study follow-up. Patients in the HR+/HER2-negative subgroup had a 2-year OS rate of 77.0%, which decreased to 44.2% at 5 years, and a median OS of 45.9 months.

Table 3 Progression-free survival during first-, second-, and third-line treatment.

Table 4 Overall survival and mortality among patients with germline BRCA1/2 -mutated, HER2-negative advanced breast cancer.

The prespecified treatment-related hematological toxicities and evidence of hand-foot syndrome, nausea, and vomiting during the first-, second-, and third-line treatments were documented for the TNBC and HR+/HER2-negative ABC subgroups ( Table 5 ). For first-line treatment, the most commonly experienced toxicities for both the TNBC (n = 190) and HR+/HER2-negative (n = 110) subgroups were nausea (41.1% and 27.3%, respectively) and anemia (26.3% and 20.9%, respectively). Toxicities were not documented for 24.7% of the patients in the TNBC subgroup and 44.6% of patients in the HR+/HER2-negative subgroup in the first-line setting. For second-line treatment, the TNBC subgroup (n = 64) documented anemia (32.8%) and the HR+/HER2-negative subgroup (n = 68) documented neutropenia (17.7%) as the most commonly experienced toxicities. Toxicities were not documented for 32.8% of the TNBC subgroup and 51.5% of the HR+/HER2-negative subgroup in the second-line setting. For third-line treatment, nearly half (44.8%) of the 29 patients in the HR+/HER2-negative subgroup did not document toxicities, compared with 15.4% of patients who did not document toxicities in the TNBC subgroup (n = 26). However, the small sample sizes for third-line treatment warrant caution in interpretation of the toxicities experienced.

Table 5 Toxicities during first-, second-, and third-line treatment.

The current study involved a relatively large review of medical records that described the clinical characteristics, treatment patterns, rwPFS, and OS of adult patients with HER2-negative ABC with germline BRCA1/2 mutation who had received cytotoxic chemotherapy. At the time of ABC diagnosis, most patients in this sample were younger than 60 years (mean age = 57.3 years), were white (76.4%), and had a family history of BRCA -related cancer (71.5%). Nearly 25% of the patients who were germline BRCA1/2 mutation carriers in this study had no known family history of BRCA -related cancers, thus emphasizing the importance of not limiting BRCA1/2 genetic testing to those who have family history. Two-year OS rates were similar between the advanced TNBC subgroup (73.9%) and the HR+/HER2-negative subgroup (77.0%). Anemia, nausea, and neutropenia were among the most commonly documented toxicities across all treatment lines, although some patients had no documentation of experiencing the prespecified toxicities. Because of our selection criteria, chemotherapy was primarily used as first-line treatment for both TNBC and HR+/HER2-negative subgroups. However, compared with the HR+/HER2-negative subgroup, the TNBC subgroup received PARP inhibitors at triple the rate in the second-line setting and double the rate in the third-line setting. The introduction of PARP inhibitors for second-line treatment of TNBC could be linked to the increased proportion of patients who did not experience toxicities, from 24.7% in the first line to 32.8% in the second line. The relatively higher use of PARP inhibitors in the TNBC subgroup compared with the HR+/HER2-negative subgroup likely reflects that there are limited nonchemotherapy treatment options for patients with triple-negative disease, whereas patients with HR+/HER2-negative ABC have other nonchemotherapy-targeted treatment options, such as CDK4/6 inhibitors, PIK3CA inhibitors, and mTOR inhibitors, combined with endocrine therapy that can be utilized in the second and third lines.

Recent clinical trials have demonstrated that the use of PARP inhibitors—a nonchemotherapy-targeted treatment option—has significantly improved clinical and patient-reported outcomes with a manageable side effect profile in patients with HER2-negative ABC carrying a germline BRCA1/2 mutation ( 12 , 15 , 16 ). OlympiAD, a phase 3 clinical trial of patients with germline BRCA1/2 -mutated, HER2-negative ABC, showed that a significantly longer median PFS was observed in patients who received olaparib (7.0 months; n = 205 patients), a PARP inhibitor treatment, compared with patients who received single-agent chemotherapy (either capecitabine, eribulin, or vinorelbine), for whom PFS was 4.2 months (n = 97 patients, P < 0.001) ( 12 ). Similarly, EMBRACA, a phase 3 clinical trial of patients with germline BRCA1/2 -mutated, HER2-negative ABC, demonstrated significantly longer median PFS in patients who received talazoparib (8.6 months; n = 287 patients), a PARP inhibitor treatment, compared with patients who received 1 of 4 physician’s choice standard chemotherapy options, for whom PFS was 5.6 months (n = 144, P < 0.001) ( 15 ). A safety analysis using the EMBRACA trial data evaluated the safety profile of talazoparib in 286 patients compared with chemotherapy in 126 patients with germline BRCA1/2 , HER2-negative mutation and ABC ( 16 ). While anemia and nausea were commonly experienced adverse events, talazoparib participants experiencing these events had more favorable patient-reported outcomes compared with participants on chemotherapy.

Therefore, an accumulating body of evidence suggests patients who receive PARP inhibitors have better PFS, more favorably reported outcomes, and fewer instances of discontinuation secondary to side effects compared with patients treated with chemotherapy. To date, the sequencing of treatment options, particularly when to introduce PARP inhibitors into the treatment of patients with HER2-negative germline BRCA1/2 ABC, has yet to be explored. Targeted therapy with PARP inhibitors may need to be considered in earlier lines of treatment in patients with ABC. This consideration is especially relevant among patients with TNBC whose alternative treatment options will consist of chemotherapy alone or chemotherapy combined with immunotherapy, which are associated with significant toxicities and limited improvement in breast cancer outcomes (i.e., PFS and/or OS).

Study limitations

This study represents the first dataset to examine real-world treatment patterns and outcomes exclusively among HER2-negative patients with germline BRCA1/2 -mutated ABC and provides valuable findings related to how targeted therapies, such as PARP inhibitors, are being incorporated into real-world practice in this select patient population. However, given that data abstraction occurred between July 2019 and May 2020 (maximum follow-up until May 2020), the incidence of PARP inhibitor therapy may have changed, and PARP inhibitors might be prescribed more often. A limitation of this study is that patients selected for study inclusion represented a purposive sample of medical records obtained from oncologists who were willing to participate in the study. Therefore, study findings may not be generalizable to the overall population of patients with germline BRCA1/2 -mutated ABC. To minimize this limitation and improve generalizability of findings, oncologists were recruited from a variety of geographic regions and practice types. Another limitation was that data were limited to medical records to which oncologists had access. Information on health care services received outside the physician’s care setting that was not recorded in the medical record was unavailable for this study (e.g., treatment for adverse events received through care rather than the abstracting physician specialist). Accordingly, some adverse events may not have been included because they were reported elsewhere and not collected in the medical record. Also, while not all known treatment-related toxicities were evaluated in this study, toxicities commonly observed in clinical trials and real-world studies were assessed. Lastly, to homogenize the sample, patients in this study were required to have initiated at least one cytotoxic chemotherapy for ABC, which may have resulted in selection bias and could be the reason for relatively lower utilization of endocrine or endocrine-based therapies and PARP inhibitors observed in our study population.

Key findings

Given the growing evidence that PARP inhibitors may improve PFS better than chemotherapy while potentially offering a more manageable toxicity profile and improved quality of life, clinicians should consider the use of targeted agents such as PARP inhibitors in earlier lines of therapy for ABC. Further prospective trials examining the sequencing of targeted agents in ABC are needed. Ultimately, the results of this study may contextualize the results of ongoing clinical trials, inform routine clinical-practice, and improve patient lives.

Data availability statement

The datasets presented in this article are not readily available because they are not public. Requests to access the datasets should be directed to [email protected] .

Ethics statement

Ethical approval was not required for the study involving humans in accordance with the local legislation and institutional requirements. Written informed consent to participate in this study was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and the institutional requirements.

Author contributions

EO: Investigation, Supervision, Visualization, Writing – review & editing. RCP: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Visualization, Writing – original draft. EE: Formal analysis, Investigation, Methodology, Software, Supervision, Writing – review & editing. BA: Conceptualization, Funding acquisition, Investigation, Methodology, Writing – review & editing. AH: Formal analysis, Investigation, Methodology, Software, Writing – review & editing. LSA: Funding acquisition, Investigation, Supervision, Writing – original draft, Writing – review & editing. AN: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Visualization, Writing – original draft, Writing – review & editing. KW: Investigation, Supervision, Visualization, Writing – review & editing.

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study received funding from Pfizer Inc. The funder had the following involvement in the study: employees of the funder (Pfizer Inc.) were involved in the research and contributed to this article as authors. RTI Health Solutions, an independent nonprofit research organization, received funding under a research contract with Pfizer Inc. to conduct this study and provide publication support in the form of manuscript writing, styling, and submission.

Acknowledgments

The authors thank Brian Samsell, PhD, and Melissa Mehalick, PhD, of RTI Health Solutions for medical writing assistance. Pfizer Inc. provided funding for publication support in the form of manuscript writing, styling, and submission.

Conflict of interest

EO was employed at Fox Chase Cancer Center at the time of study and is presently employed at John Theurer Cancer Center and Hackensack Meridian Health; has a consulting or advisory role with Pfizer, Foundation Medicine, Puma Biotechnology, Daiichi Sankyo/Astra Zeneca, Ethos Immunomedics, Novartis, and OncLive/MJH Life Sciences; has received honoraria from Guidepoint Global; has received research funding from Merck and Genentech/Roche; has no relationships to disclose for the speakers’ bureau, patents, royalties, or other intellectual property; expert testimony; leadership, or travel accommodations, expenses; and has an immediate family member who holds stock and other ownership interests in Bristol-Myers Squibb and is a Bristol-Myers Squibb/Celgene recipient. RCP, EE, and AH are employees of RTI Health Solutions, an independent nonprofit research organization, which received funding to conduct the study presented here. BA, LSA, and AN are employees of Pfizer Inc., which funded the study presented here. KW was employed at Fox Chase Cancer Center at the time of study, is presently employed at Medstar Georgetown Cancer Institute at Washington Hospital Center, and consults for Novartis.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2024.1341665/full#supplementary-material .

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Keywords: metastatic breast cancer, BRCA1/2 gene mutations, poly (ADP-ribose) polymerase (PARP) inhibitors, human epidermal growth factor receptor 2 (HER2)-negative, hormone receptor-positive (HR+), triple-negative breast cancer (TNBC)

Citation: Obeid E, Parikh RC, Esterberg E, Arondekar B, Hitchens A, Arruda LS, Niyazov A and Whitaker K (2024) Clinical characteristics, treatment patterns, and outcomes in adult patients with germline BRCA1/2 -mutated, HER2-negative advanced breast cancer: a retrospective medical record review in the United States. Front. Oncol. 14:1341665. doi: 10.3389/fonc.2024.1341665

Received: 20 November 2023; Accepted: 08 April 2024; Published: 16 May 2024.

Reviewed by:

Copyright © 2024 Obeid, Parikh, Esterberg, Arondekar, Hitchens, Arruda, Niyazov and Whitaker. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Elias Obeid, [email protected]

† Present addresses : Elias Obeid, John Theurer Cancer Center, Hackensack, NJ, United States and Hackensack Meridian School of Medicine, Totowa, NJ, United States Kristen Whitaker, Medstar Georgetown Cancer Institute at Washington Hospital Center, Washington D. C., United States

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Breast cancer research and treatment, breast cancer research and treatment onlinefirst articles, combined transcriptome and proteome analysis reveals msn and arfip2 as biomarkers for trastuzumab resistance of breast cancer, racial differences in familiarity, interest, and use of integrative medicine among patients with breast cancer, an exploratory clinical trial of preoperative non-invasive localization before breast-conserving surgery using augmented reality technology, the emerging predictive and prognostic role of her2 in her2-negative early breast cancer: a retrospective study, measuring cfdna integrity as a biomarker for predicting neoadjuvant chemotherapy response in breast cancer patients: a pilot study, characterizing “collateral damage” in men and women with metastatic breast cancer (mbc) from diverse racial and ethnic backgrounds in new york city, predictive analysis of breast cancer response to neoadjuvant chemotherapy through plasma metabolomics, ductal carcinoma in situ and cause-specific mortality among younger and older postmenopausal women: the women’s health initiative, current axillary management of patients with early breast cancer and low-volume nodal disease undergoing primary surgery: results of a united kingdom national practice survey, do we need reshape rtnm staging system for ipsilateral breast tumor recurrence of breast cancer a population-based, propensity score matched cohort study, latest issues, breast cancer research and treatment 1/2024, breast cancer research and treatment 2/2024, breast cancer research and treatment 3/2024, breast cancer research and treatment 3/2023, breast cancer research and treatment 1/2023, breast cancer research and treatment 2/2023.

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About this journal

Breast Cancer Research and Treatment provides the surgeon, radiotherapist, medical oncologist, endocrinologist, epidemiologist, immunologist or cell biologist investigating problems in breast cancer a single forum for communication. The journal creates a "market place" for breast cancer topics which cuts across all the usual lines of disciplines, providing a site for presenting pertinent investigations, and for discussing critical questions relevant to the entire field. It seeks to develop a new focus and new perspectives for all those concerned with breast cancer. Oncology is undoubtedly the most rapidly growing subspecialty in the field of medicine, and breast cancer is one of the most serious problems of oncology. It is the leading cause of death of women in many countries, and is truly a multidisciplinary problem without geographic restrictions. Yet this very multidisciplinary aspect accounts for breast cancer literature appearing in any of the dozens of existing medical journals. None of these journals provides a focus on the unique problems of breast cancer. There has been no convenient arena for the discussion and resolution of ongoing controversies in breast cancer treatment, or for the consideration of thoughtful speculation and comments on current work. Breast Cancer Research and Treatment aims to fill this need. Each issue contains several articles dealing with original laboratory investigations and articles dealing with clinical studies. There are sections devoted to review articles, pro and con discussions of controversial subjects, meeting reports, and editorials. The panel discussions encourage experts to consider important topics.There is a section for letters to the editor, which provides for a lively exchange of opinions on previously published articles or other topics of interest. There is also an opportunity to publish the proceedings of special workshops, symposia, etc., devoted to breast cancer. All man uscripts are peer reviewed by a distinguished group of advisory editors from many countries covering all of the various disciplines of breast cancer.

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Breast Cancer Treatment : A Review

• 1 Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
• JAMA Patient Page Breast Cancer Treatment Adrienne G. Waks, MD; Eric P. Winer, MD JAMA
• JAMA Insights Treatment of Nonmetastatic Breast Cancer Kathryn J. Ruddy, MD, MPH; Patricia A. Ganz, MD JAMA

Importance   Breast cancer will be diagnosed in 12% of women in the United States over the course of their lifetimes and more than 250 000 new cases of breast cancer were diagnosed in the United States in 2017. This review focuses on current approaches and evolving strategies for local and systemic therapy of breast cancer.

Observations   Breast cancer is categorized into 3 major subtypes based on the presence or absence of molecular markers for estrogen or progesterone receptors and human epidermal growth factor 2 ( ERBB2 ; formerly HER2 ): hormone receptor positive/ ERBB2 negative (70% of patients), ERBB2 positive (15%-20%), and triple-negative (tumors lacking all 3 standard molecular markers; 15%). More than 90% of breast cancers are not metastatic at the time of diagnosis. For people presenting without metastatic disease, therapeutic goals are tumor eradication and preventing recurrence. Triple-negative breast cancer is more likely to recur than the other 2 subtypes, with 85% 5-year breast cancer–specific survival for stage I triple-negative tumors vs 94% to 99% for hormone receptor positive and ERBB2 positive. Systemic therapy for nonmetastatic breast cancer is determined by subtype: patients with hormone receptor–positive tumors receive endocrine therapy, and a minority receive chemotherapy as well; patients with ERBB2 -positive tumors receive ERBB2 -targeted antibody or small-molecule inhibitor therapy combined with chemotherapy; and patients with triple-negative tumors receive chemotherapy alone. Local therapy for all patients with nonmetastatic breast cancer consists of surgical resection, with consideration of postoperative radiation if lumpectomy is performed. Increasingly, some systemic therapy is delivered before surgery. Tailoring postoperative treatment based on preoperative treatment response is under investigation. Metastatic breast cancer is treated according to subtype, with goals of prolonging life and palliating symptoms. Median overall survival for metastatic triple-negative breast cancer is approximately 1 year vs approximately 5 years for the other 2 subtypes.

Conclusions and Relevance   Breast cancer consists of 3 major tumor subtypes categorized according to estrogen or progesterone receptor expression and ERBB2 gene amplification. The 3 subtypes have distinct risk profiles and treatment strategies. Optimal therapy for each patient depends on tumor subtype, anatomic cancer stage, and patient preferences.

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Waks AG , Winer EP. Breast Cancer Treatment : A Review . JAMA. 2019;321(3):288–300. doi:10.1001/jama.2018.19323

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Advances in the care of breast cancer survivors

Linked editorial.

Understanding inequalities in breast cancer screening uptake

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Effect of invitation letter in language of origin on screening attendance

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• Elizabeth J Cathcart-Rake , medical oncologist ,
• Amye J Tevaarwerk , medical oncologist ,
• Tufia C Haddad , medical oncologist ,
• Stacy D D’Andre , medical oncologist ,
• Kathryn J Ruddy , medical oncologist
• Mayo Clinic, Department of Oncology, Rochester, MN, USA
• Correspondence to: E J Cathcart-Rake Cathcart-rake.elizabeth{at}mayo.edu

Breast cancer survivors may experience significant after effects from diagnoses of breast cancer and cancer directed therapies. This review synthesizes the evidence about optimal management of the sequelae of a diagnosis of breast cancer. It describes the side effects of chemotherapy and endocrine therapy and evidence based strategies for management of such effects, with particular attention to effects of therapies with curative intent. It includes strategies to promote health and wellness among breast cancer survivors, along with data to support the use of integrative oncology strategies. In addition, this review examines models of survivorship care and ways in which digital tools may facilitate communication between clinicians and patients. The strategies outlined in this review are paramount to supporting breast cancer survivors’ quality of life.

Introduction

Breast cancer is the most common cancer in the world, with 2.26 million diagnoses in 2020. 1 People with breast cancer are living longer as a result of improvements in screening and treatment, such that in the US alone the number of survivors of breast cancer is expected to grow by more than 2 million in the next decade. 2 3 Unfortunately, survivors may experience significant after effects from breast cancer diagnoses and cancer directed therapies. Symptoms related to surgery, radiation, and systemic therapies may persist lifelong and limit quality of life.

This review synthesizes the evidence base on optimal management of treatment sequelae in survivors of breast cancer. We describe the side effects of chemotherapy and endocrine therapy and evidence based strategies for management of such effects, with particular attention to effects of therapies with curative intent. We include strategies to promote health and wellness among breast cancer survivors, along with data to support the use of integrative oncology strategies. In addition, we examine models of survivorship care and ways in which digital tools may facilitate communication between clinicians and patients.

Sources and selection criteria

We searched PubMed for the term “breast cancer survivorship” (without restricting the date range) on 17 August 2022 and limited our search to papers designated as randomized controlled trials (RCTs) or meta-analyses. This identified 245 peer reviewed publications, some of which we excluded because they were focused more on disease outcomes than on management of toxicity and models of survivorship care. We supplemented this search strategy by a hand search of the references of key articles. We achieved inclusion of identified articles by assessing a study’s impact and its methods, with preference given to RCTs. When RCT evidence was not available for certain topics, we included other study types, focusing on the highest level of evidence available and excluding lower level evidence. To ensure that we covered all critical data relevant to management of endocrine therapy toxicity, management of long term effects of chemotherapy, new models of care and digital tools to facilitate communication and symptom management, integrative oncology for breast cancer survivors, general health maintenance (including screening for second cancers), genetic testing, and surveillance for recurrence, we also added select additional studies for inclusion on the basis of consensus among our author group (medical oncologists with specific expertise in symptom control (ECR, KR), survivorship (KR, AT), integrative medicine (SD), and digital oncologic tools (TH, AT)).

Epidemiology

Breast cancer is the most commonly diagnosed cancer, accounting for nearly a quarter of all cancer cases globally. 4 More than 2.3 million people worldwide are given a diagnosis of breast cancer annually, and more than 7.8 million women are breast cancer survivors with diagnoses over the past five years, according to 2020 statistics. 4 Although the incidence of and mortality from breast cancer vary from region to region, these numbers are steadily growing, such that more than 3 million new cases of breast cancer are projected to be diagnosed by 2040. 4

Burden and management of long term effects of systemic therapies

Despite recent advances that help us to tailor and de-escalate treatment on the basis of estimates of clinical benefit to limit toxicity, 5 6 many curatively treated breast cancer patients still receive chemotherapy. This is particularly true among patients with triple negative breast cancer, who may receive up to four chemotherapies (anthracycline, cyclophosphamide, taxane, platinum) and an immunotherapy (pembrolizumab) (known as the KEYNOTE-522 regimen), with a fifth chemotherapy agent added if residual disease is present at the time of surgery. 7 The persistent (chronic) and future (late) side effects of these systemic therapies are mediated by a variety of host factors, including age, menopausal status, and existing comorbidities such as diabetes and hypertension. 8 9 10 11 12 13 Moreover, some toxicities, such as cancer related cognitive impairment (also known as “chemo brain”), are broadly linked to the use of cancer therapy but not tied to a particular agent. 14 The robustness of evidence based screening and prevention strategies varies between different treatment sequelae. 15

“Traditional” chemotherapeutic agents

Three chemotherapeutic classes (that is, anthracyclines, alkylating agents, and taxanes) have relatively well understood toxicity profiles in the curative setting based on decades of use in breast cancer ( table 1 ). For instance, anthracyclines increase the risk of cardiovascular events in the short term (for example, arrhythmias) and can cause long term irreversible left ventricular dysfunction. 23 24 Anthracyclines and cyclophosphamide carry a risk of secondary leukemia, although this may be less true for cyclophosphamide at the doses used in breast cancer. 25 26 27 Likewise, anthracyclines and cyclophosphamide are gonadotoxic, 28 29 affecting reproduction, menopausal symptom burden, and potentially bone and cardiac health. Taxanes contribute to chemotherapy induced peripheral neuropathy (CIPN), a primarily sensory peripheral neuropathy involving the feet and hands in a sock and glove-like distribution, which may persist lifelong in a small subset of patients. Although duloxetine can assuage CIPN related burning pain, more information is needed to inform strategies used to prevent CIPN and methods to treat numbness/tingling. 13 30

Chronic and late effects after treatment with common chemotherapeutics, immunotherapeutics, and associated targeted therapeutics used in (neo)adjuvant breast cancer setting

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Capecitabine and platinums —Despite longer track records in other disease settings, capecitabine and platinums (namely, carboplatin) are relatively new additions to the adjuvant breast cancer armamentarium. The persistent and future toxicity profiles, particularly when used in younger patients, are less well characterized. For instance, platinums can cause gonadal failure, 31 although the effect on ovarian function is poorly studied for carboplatin in the breast cancer setting. 16 32 33 34 This is despite routine use of carboplatin in combination with docetaxel and trastuzumab (with or witout pertuzumab) in the TCH(+/−P) regimens for human epidermal growth factor receptor 2 (HER2) positive disease for more than a decade. 35 The effect of platinum dosing (for example, weekly versus every three weeks) on ovarian reserve remains unassessed. 27 Platinums have been shown to increase the risk of secondary leukemia in ovarian cancer 33 ; the additive risk when used with anthracyclines and cyclophosphamide as in the Keynote-522 regimen remains understudied. 33

Targeted therapy and immunotherapy agents

HER2 targeted agents —Trastuzumab has been joined by pertuzumab, ado-trastuzumab emtansine, and neratinib in the adjuvant setting. Studies of these newer agents report lower incidences of cardiotoxicity compared with trastuzumab, but ado-trastuzumab emtansine is more hepatotoxic and carries a risk of persistent neuropathy. 22 36 The degree to which the cardiac effects of HER2 targeted agents are confined to the treatment period is not well studied for the newer agents but is presumably similar to that for trastuzumab. 37 38 Patients who do experience cardiotoxicity during HER2 directed therapy do not seem to develop this later, in the absence of other risk factors such as receipt of anthracycline.

Immunotherapy, PARP inhibitors, and abemaciclib —Routine use of pembrolizumab in higher risk triple negative breast cancer has followed the Keynote-522 results. Most of the available data on chronic and late toxicity profiles come from other disease settings, in which long term immune related side effects occurred in 43.2% of patients and ranged from mild disease, such as hypothyroidism (14.0%), to severely debilitating diagnoses, such as hypophysitis (2.1%), which may necessitate lifelong hydrocortisone treatment. 39 Similarly, the poly ADP ribose polymerase (PARP) inhibitor olaparib has recently emerged as a tool for BRCA carriers with high risk disease or residual disease after neoadjuvant chemotherapy. 40 Most of what is known about the chronic and late toxicity profile comes from patients with ovarian cancer and short term follow-up. 41 Finally, abemaciclib is a recent adjuvant therapy for estrogen sensitive breast cancers with a high risk of recurrence; knowledge of toxicities is largely based on that seen in patients with metastatic breast cancer.

Although many targeted agents have fewer listed side effects than do traditional chemotherapeutic agents, their acute toxicities become subacute and longer lasting problems owing to a longer duration of therapy (for example, two years for abemaciclib in the adjuvant setting). 40 42 Certain toxicities, such as interstitial lung disease from abemaciclib, may even be fatal (albeit rarely). 43 Furthermore, owing to short term follow-up of studies with relatively small numbers supporting the efficacy of these agents, long term toxicities in the adjuvant setting have not yet been fully described.

Endocrine therapy

Endocrine therapies improve survival for people with hormone receptor positive breast cancer. 44 45 46 Endocrine therapy encompasses a range of therapeutics, including oral drugs, such as tamoxifen and the aromatase inhibitors (letrozole, anastrozole, and exemestane), as well as gonadotropin releasing hormone (GNRH) agonists, such as goserelin and leuprolide. Endocrine therapies may be recommended for up to 10 years in people with early stage disease. 47

Whereas some patients report manageable or no side effects from endocrine therapy, other patients experience debilitating prolonged symptoms. 48 49 Because of the duration of endocrine therapy, both on-therapy and long term effects of endocrine therapy are within the scope of this survivorship review. Side effects of endocrine therapy are particularly predominant among premenopausal patients taking GNRH agonists for ovarian suppression. 50 These may worsen quality of life, and severe symptoms may also contribute to non-adherence to and/or early discontinuation of endocrine therapy, in turn worsening breast cancer survival. 51 52 53 54 55 Therefore, control of side effects related to endocrine therapy is essential in people with estrogen receptor positive breast cancer.

Vasomotor symptoms

Vasomotor symptoms have been seen in up to 80% of patients receiving endocrine therapy in population based studies. 56 Patients may experience relief from vasomotor symptoms through use of a variety of strategies, as delineated in table 2 .

Side effects of endocrine therapy

As the efficacies of therapeutic strategies have not been directly compared, individualized evaluations of potential benefits and side effects should be completed on a patient-by-patient basis. For instance, although paroxetine is an effective agent for hot flashes, it has the potential to interact with tamoxifen metabolism contributing to a potential decrease in the efficacy of tamoxifen. 86 Patients treated with gabapentinoids for alternative diagnoses, such as diabetic neuropathy, might see improvements in their hot flashes, but in one randomized, crossover trial of 66 patients assigned to gabapentin or venlafaxine, 68% reported an overall preference for venlafaxine (P=0.01) over gabapentin. In this study, patients randomized to venlafaxine and to gabapentin both had a 66% reduction in hot flash scores, but patients receiving venlfaxine reported greated reduction in severity and frequency of hot flashes and fewer adverse effects. 87 Furthermore, patients who do not experience benefit from one drug may glean benefit from another, so trialing a second drug is worthwhile if the first is ineffective. 88

Finally, although estrogen based hormone replacement therapy should be avoided in this setting, data on the benefit-to-risk ratio of progestin monotherapy are limited. 89 Megestrol acetate was compared with placebo in an RCT including 97 women with breast cancer; 74% of the megestrol acetate group, compared with 20% of the placebo group, had a decrease of 50% or more in the frequency of hot flashes (P<0.001). 90 Medroxyprogesterone seems to be particularly effective; an RCT of 218 women found that a depot injection of medroxyprogesterone versus venlafaxine significantly increased the number of women with >50% reduction in hot flashes (74% v 46%; P<0.001). 91

Genitourinary symptoms

Genitourinary symptoms are related to low estrogenic states and are pervasive among patients receiving aromatase inhibitors and ovarian suppression. 66 67 However, although many patients wish to discuss such problems with clinicians, such symptoms are infrequently discussed in oncology clinics, which exacerbates non-use of safe and evidence based treatments. 92 93 94 Vaginal dryness is commonly experienced, and efficacious treatment options are available; however, dyspareunia, poor libido, and other sexual health concerns are frequently distressing to breast cancer survivors and lack data driven management options ( table 2 ).

Vaginal estrogen is commonly recommended for vaginal dryness and its sequelae in patients with no history of breast cancer, but this approach may carry some risks in patients with a history of estrogen sensitive breast cancers. Systemic estrogen concentrations may be very mildly increased after vaginal estrogen in a dose dependent fashion, but this may or may not be clinically significant. 95 One recent cohort study of 8461 breast cancer survivors in Denmark reported a 39% higher risk of recurrence of breast cancer at a median follow-up of 9.8 years after diagnosis, but no difference in mortality, among patients who received concurrent vaginal estrogen therapy and aromatase inhibitors. 96 This study was non-randomized and therefore different doses of vaginal estrogen may have been used; however, the risk-to-benefit ratio of vaginal estrogen remains controversial. Of note, a topical vaginal androgen, dehydroepiandrosterone, does not seem to raise estrogen concentrations in patients taking aromatase inhibitors. 70

Musculoskeletal symptoms

Approximately half of breast cancer survivors taking aromatase inhibitors experience “aromatase inhibitor associated musculoskeletal symptoms” or AIMSS. 76 Various plausible pathogenic explanations have been proposed as to why AIMSS occurs: aromatase inhibitors have pro-inflammatory properties, estrogen helps to maintain synovial fluid health, and pain sensitivity may be altered by aromatase inhibitors. 97 98 99 Of note, tamoxifen may also contribute to musculoskeletal symptoms, more commonly muscle cramping, but insufficient evidence exists about effective treatments. 100

Both duloxetine and acupuncture have been shown to reduce AIMSS in placebo controlled clinical trials ( table 2 ), 101 but one common first approach to AIMSS is a brief hiatus in treatment to ensure symptom improvement or resolution, followed by a switch from one aromatase inhibitor to another (or to tamoxifen). 77 80 102 One prospective, multicenter, non-randomized study of 179 patients reported that 74% had less severe AIMSS after switching from anastrozole to letrozole. Another open label randomized trial of exemestane versus letrozole in 503 women reported that 39% of patients were able to stay on aromatase inhibitor after switching to a second aromatase inhibitor, whereas all patients who did not switch chose to discontinue therapy; however, complete resolution of AIMSS after such a switch is uncommon. 80 102 This approach is safe and low risk, and it typically does not require additional time or cost. 103

More than a third of breast cancer survivors taking endocrine therapy report hair thinning and loss, described as frontal and parietal hairline recession. 104 105 Prospective investigations into the clinical characteristics and incidence of endocrine therapy related alopecia are ongoing. Minoxidil, a vasodilative agent that causes hair follicles to transition into growth phase and increases the size of hair follicles, offers a promising potential therapy for endocrine therapy related alopecia; the use of topical and low dose oral minoxidil has been supported by early studies. Although this may be offered as an off-label treatment, RCT results are eagerly awaited. 106 107

Osteoporosis

Aromatase inhibitors increase risks for bone thinning, osteoporosis, and fractures, which are major drivers of cost, morbidity, and mortality, particularly in breast cancer survivors. 108 109 Bisphosphonates and receptor activator of nuclear factor-κB ligand (RANKL) inhibitors lessen the risks for bone loss and fractures among both postmenopausal patients and premenopausal patients taking ovarian function suppression or with chemotherapy related ovarian failure. 110 111 112 113 114 115 116 117 118 119 Additionally, these agents decrease risk for bone recurrence and improve breast cancer-free survival. 120 The most recently published double blinded RCT of 3425 postmenoapusal patients compared denosumab with placebo; denosumab improved disease-free survival with a hazard ratio of 0.83 (95% confidence interval 0.71 to 0.97; P=0.016) and reduced fractures with a hazard ratio of 0.76 (0.63 to 0.92; P=0.004) at a median follow-up of eight years. 121

Other important components of survivorship care

Screening for recurrence.

Screening for recurrence relies on regular (usually at least annual) visits with a cancer specialist or primary care provider for physical examination and assessment of symptoms that might indicate that cancer has returned. 122 123 124 Female survivors who have residual breast tissue (because they have not undergone bilateral mastectomy) and no evidence of distant metastases are generally recommended to undergo annual mammography at least until age 75 (unless medical comorbidities substantially limit the projected benefit of early detection of local recurrences and new primaries). 125 Supplemental screening imaging (for example, magnetic resonance imaging of the breast, ultrasonography, or molecular breast imaging) may also be considered for female survivors with dense breast tissue (for whom mammography is less sensitive) or for those with an elevated risk of new primary cancer. 126 127 Male survivors should also consider unilateral surveillance mammography if they had breast conserving therapy (to detect local recurrences). 128

Routine imaging or blood tests to assess for distant recurrence is not recommended by current guidelines. 122 124 If a survivor develops a sign or symptom of possible recurrence on physical examination or history, distant imaging (for example, positron emission tomography, computed tomography, or bone scan) may be warranted.

Genetic testing

For patients who do not meet criteria for genetic testing at the time of the initial cancer diagnosis (or who undergo only limited genetic testing at that time), periodically asking about new cancers diagnosed in family members that might affect the projected yield of genetic testing is important. Survivors who are found to carry pathogenic variants predisposing to cancer may warrant additional screening or risk reducing surgeries.

Financial toxicity

Advances in breast cancer management have enabled more cures; however, they have also contributed to the unsustainable rise in the cost of care, 129 with the overall financial burden disproportionately affecting patients. Financial toxicity has been described as a combination of objective financial burden and subjective financial distress, and this adverse event has a spectrum of severity with 79% of patients with cancer reporting moderate to catastrophic financial burden. 130 131 High costs of cancer care, particularly out-of-pocket costs, are associated with worse patient reported outcomes, lower quality of life, and poor adherence to treatment. 131 132 Several factors have been associated with risk of financial toxicity, including younger age, female sex, non-white race, employment changes, low average household income, increasing distance from treatment centers, and increasing out-of-pocket costs. 133 Furthermore, significant geographic disparities exist in financial burden across the world. Large out-of-pocket costs may be required in some parts of the world (for example, the US, Africa, and Central and South America), whereas other healthcare systems (for example, Canada, the EU, and the UK) protect patients against out-of-pocket costs. 134 Defined risk factors for financial toxicity now exist, along with a validated assessment tool. 135 Globally, cancer practices need to systematically screen patients for financial toxicity or proactively discuss finances associated with care during or after cancer care, notably when options with variable costs are available.

Fear of recurrence

Fear of recurrence is experienced by up to 80% of women with breast cancer. 136 This can lead to worsened quality of life, depression, anxiety, and lack of proper follow-up surveillance. 137 138 139 Assessing patient safety is important, as is consideration of referral to mental health professionals. 140 Cognitive behavioral therapy (CBT), discussed further below, has been shown in multiple trials (and a recent systematic review to decrease fear of recurrence, which assessed the quality of the 17 RCTs). 121 One included study ranodmized 56 patients to a form of CBT, termed cognitively based compassion training, over eight weeks and found reduced fear of cancer recurrence and psychologic stress (significant time × group interaction of 3.521; P<0.05). 141 Cognitive behavioral therapy can be delivered via individual therapy, group therapy, or digitally. 140 An RCT of mindfulness based stress reduction (MBSR; also discussed further, below) included 322 patients with breast cancer who were given a six week MBSR course versus usual care. Patients assigned to the MBSR group had significantly reduced fear of recurrence and anxiety scores (P<0.01), as assessed at baseline/six weeks and 12 weeks. 142

Survivorship care plans

Survivorship care plans were proposed in the 2005 Institute of Medicine report “From Cancer Patient to Cancer Survivor: Lost in Transition” as a potential way to support primary care providers in the provision of survivorship care (in part to control costs and in part to assure that survivors receive all of the non-cancer related care that they need). 143 However, subsequent clinical trials assessing the impact of survivorship care plans have shown mixed effects on a variety of survivorship outcomes. 144 145 A persistent need remains for novel approaches to facilitate dynamic transmission of knowledge between survivors and clinicians. As noted below, digital tools are showing potential in this arena and allow for a shared tool for primary care physicians and sub-specialists to communicate and improve care coordination. However, scaling and disseminating interventions into the “real world” is challenging. When asked about survivorship care plans, breast cancer survivors surveyed in one qualitative study recommended better education and personalization with regard to nutrition, exercise, managing side effects, comorbidities, and provision of resources, such as health coaches. 146 Breast cancer support groups can also help patients to cope with their diagnosis and treatment related side effects.

General health maintenance

Screening for and treating new non-breast cancers and managing other medical conditions are critical components of breast cancer survivorship care. Cardiovascular disease is common, especially in this population, in part as a result of the toxicities of breast cancer therapy. 147 148

Screening for second cancers

Breast cancer survivors face elevated risks of colorectal, ovarian, lung, endometrial, and thyroid carcinomas, as well as sarcoma and non-lymphocytic leukemia. 149 150 151 In addition, they face standard age related risks of many other cancers. For people who are not known carriers of genetic mutations predisposing them to cancer or otherwise at high risk of a second malignancy, guidelines recommend continuing with age appropriate cancer screening as recommended for the general population. 122 152 The primary differences between recommendations in the US and Europe pertain to the age range for screening for colorectal cancer and to the fact that screening for Helicobacter pylori is recommended in some EU countries. 153

Cholesterol, diabetes, and blood pressure monitoring and management

Hypertension, diabetes, coronary artery disease, and cerebrovascular disease share the following risk factors with breast cancer: obesity, metabolic syndrome, age, and lack of physical activity. In addition, certain breast cancer therapies, such as anthracycline based chemotherapies and anti-HER2 therapies, are associated with various cardiovascular toxicities, including heart failure. 154 155 Interestingly, a recent case-control Kaiser Permanente study, including 3642 women with breast cancer and 68 202 matched controls, found that breast cancer survivors were more likely to develop diabetes (subdistribution hazard ratio 1.16, 1.07 to 1.26) but less likely to develop dyslipidemia (0.90, 0.86 to 0.95) than matched women without cancer. 156 Although some early studies suggested that aromatase inhibitors might lead to more cardiovascular disease than tamoxifen, a recent cross sectional evaluation of 569 breast cancer survivors, 40% of whom had used aromatase inhibitors, found no difference in carotid intima media thickness (median 0.63 (interquartile range 0.56-0.71) mm with low exposure to aromatase inhibitors, 0.66 (0.59-0.75) mm with intermediate exposure, 0.64 (0.59-0.73) mm with high exposure), advanced glycation end products (median 2.13 (1.90-2.40) arbitrary units with low exposure to aromatase inhibitors, 2.20 (1.90-2.51) with intermediate exposure, 2.11 (1.90-2.43) with high exposure), or hyperlipidemia (data not provided) by exposure to aromatase inhibitors. 157

Thus, for most breast cancer survivors, a reasonable approach is to follow the United States Preventive Service Task Force (USPSTF) guidelines, which include office blood pressure and weight measurement for all patients aged ≥18; fasting plasma glucose, glycated hemaglobin, or oral glucose tolerance test to screen for diabetes in those aged 35-70; lipid panel to screen for dyslipidemia for those aged 40-70 (plus those aged 21-39 on the basis of clinical judgment); and counseling about smoking cessation for all adults who smoke. Optimal screening intervals for these assessments are unknown, but the USPSTF suggests annual screening for hypertension and weight, screening every three years for diabetes, and screening every five years for dyslipidemia. 158 Guidelines from the European Society of Cardiology are similar.

A meta-analysis that included data from 10 RCTs and 1095 breast cancer survivors found that diet and exercise interventions improved anthropomorphic measurements, systolic blood pressure, and C reactive protein but did not affect cholesterol, glucose, insulin, or leptin. 159 Drugs are often needed to optimize cardiovascular health in survivors with abnormal cholesterol, blood pressure, and/or glucose. Unfortunately, evidence that screening and aggressive management of cardiovascular risk factors improve long term cardiac outcomes in breast cancer survivors is limited.

Integrative oncology approaches to breast cancer survivorship

Exercise is one of the most important lifestyle interventions patients can engage in to prevent recurrence and decrease symptoms associated with breast cancer treatments. Research has shown that exercise reduces both recurrence of and death from breast cancer; one meta-analysis reported that meeting recommended physical activity guidelines (at least eight hours of moderate intesnity aerobic exercise a week) after diagnosis was associated with lower risk of breast cancer related death (hazard ratio 0.67, 95% confidence interval 0.50 to 0.90) during average follow-up periods ranging from 4.3 to 12.7 years. 160 161 162 163 164 Exercise has also been shown to improve fatigue, anxiety, depression, quality of life, physical function, strength, sleep, and bone health. 165 166 167 168 169 170 171 172 173 Resistance training is safe in patients with lymphedema and should be encouraged. 174 Unfortunately, most breast cancer survivors do not meet the recommended goals of 150 minutes of moderate aerobic exercise a week and twice weekly strength training. 175 The American Cancer Society also recognizes that people should move about during the day: “move more and sit less.” 176

The American Society of Clinical Oncology (ASCO) recommends aerobic and strength exercises during active treatment to reduce the side effects of therapy. 177 Exercise in patients undergoing chemotherapy has been shown to improve fatigue and cognition, 168 169 177 178 179 quality of life, depression/anxiety, and sleep quality. 165 180 In people taking aromatase inhibitors, exercise, including aerobic and strength training for a 12 month program, reduced pain scores by 30%. 181 This is important given that many people will stop aromatase inhibitors because of side effects.

Patients with no comorbidities do not need medical clearance before starting an exercise program. However, patients with neuropathy, bone/arthritis problems, or lymphedema should be referred for evaluation by a rehabilitation specialist and can consider medical clearance. Those with serious comorbidities, such as coronary artery disease, chronic obstructive pulmonary disease, recent surgeries, severe nutritional deficiencies, fatigue, or bone metastasis, should undergo medical clearance and rehabilitation evaluation before starting a program. 182

Yoga has additional benefits and is recommended by the Society for Integrative Oncology (SIO)/ASCO. 183 Yoga has been shown to improve quality of life (grade B) and may improve depression/anxiety (grade C) and fatigue (grade C). 183 Gentle yoga can be considered to help with sleep problems (grade C). SIO/ASCO also recommends consideration of yoga for aromatase inhibitor induced joint pain and pain after breast cancer therapy (both low level evidence). Yoga can be adapted for patients with functional limitations and is available in person or online. Patients with limited mobility or serious comorbidities should be evaluated and work with a certified instructor to avoid injury. 184

Dietary factors

No one specific diet is known to improve prognosis or quality of life during or after cancer treatment. However, some general recommendations can be made. The Women’s Health Initiative trial was a dietary prevention trial that randomized 41 835 women to low fat (20%) plus increased fruits/vegetables and whole grains versus a standard diet. Women in the intervention arm who developed breast cancer had improved overall survival compared with the usual diet group (10 year overall survival 82% v 78%; hazard ratio 0.78, 0.65 to 0.94; P=0.01). 185 Whether the observed benefits were due to decreased fat intake or the increase in other healthy foods is unclear. In another trial, 2437 women with early stage breast cancer were randomized to a low fat (20%) diet versus a standard diet. The primary endpoint, relapse-free survival, was improved in those in the low fat diet group (9.8% v 12.4% with events; hazard ratio 0.78, 0.60 to 0.98; P=0.03). This was more pronounced in women with hormone receptor negative tumors. However, the low fat group lost weight, and the benefits may have been just due to weight loss. 186 Other studies have shown increased all cause mortality in breast cancer survivors consuming the highest amounts of saturated/trans fats. 187 188 Therefore, a plant heavy diet (which includes the Mediterranean diet and some Asian diets), incorporating healthy fats and whole grains while avoiding processed meats and carbohydrates, sugar sweetened drinks, and artificial sweeteners, is recommended. 176 A Mediterranean diet containing nuts and extra virgin olive oil has cardiovascular benefits, 189 190 191 and incorporating high fiber foods may also be beneficial. 192

The effects of meal timing has also been studied. For example, data collected from 2413 women from the Women’s Healthy Eating and Living study showed that women who fasted <13 hours per night had increased recurrences of breast cancer compared with those who extended overnight fasting periods (hazard ratio 1.36, 1.05 to 1.76). 193 Longer fasting was also associated with improvement in glycated hemoglobin. Further evidence is needed to know the effect of extended overnight fasting on risk for recurrence.

Recommendations for limiting alcohol consumption for primary and secondary breast cancer prevention vary; however, most evidence suggests that alcohol increases the risk of recurrence, especially after the menopause. A recent review suggests limiting alcohol to less than three drinks a week, 194 whereas the National Comprehensive Cancer Network’s survivorship guidelines take a more stringent view on alcohol and state that women with breast cancer should abstain.

Dietary soy is safe for people with a history of breast cancer and may be beneficial. 195 However, soy supplements are not recommended. 196

Acupuncture

Acupuncture is an ancient Chinese medicine practice of placing fine needles into various points in the body. Heat (moxibustion) or electrostimulation can be added to standard needling. 197 The mechanism of action is not well understood. Traditional Chinese medicine explains acupuncture as a technique for balancing the flow of energy or life force that flows through meridians in the body. 198 Acupuncture may also stimulate nerves, fascia, or muscles to affect its action. 199 200 Sessions are generally weekly and often include other evaluations of the patient’s constitution, lifestyle advice, and herbal therapies. These components of traditional acupuncture are not often included in clinical trials in which only the acupuncture needle part of the treatment is assessed. 201 Studies of acupuncture are challenging to perform and evaluate owing to heterogeneity of providers, difficulty in choosing a control group (waitlist versus sham versus standard of care), not including other components of acupuncture treatment (pragmatic study), and difficulty in double blinding. The placebo effect is well established as playing a significant role in these studies. 202 However, evidence has been mounting, and SIO/ASCO recommends electro-acupuncture for consideration for chemotherapy induced nausea on the basis of RCTs and a consensus conference (in addition to standard drug therapies) (grade B, SIO). 197 203 204 SIO/ASCO guidelines for managing pain recommend acupuncture for aromatase inhibitor related joint pain and general pain/musculoskeletal pain from cancer (both with intermediate level evidence quality) and consideration of acupuncture for CIPN and procedural or surgical pain (both with low quality level evidence). 205 Acupuncture is generally safe but should be avoided in patients with severe cytopenias, and needles should not be inserted into areas of tumors or infections. 206 207 208

Acupressure is another technique in which manual pressure is applied to different body parts to achieve an effect, using pressure from fingers, bands, or beads. This has been most well studied for nausea/vomiting, using a pressure point called Neiguan located on the inner arm near the wrist. 209 210 211 212 This treatment is a grade B recommendation from SIO/ASCO. 183 It may also be useful for other cancer related symptoms, including pain and fatigue. 205 213 214

Cognitive behavioral therapy

CBT is a psychological treatment that treats anxiety/depression and insomnia and improves relaxation and quality of life. 215 216 It may also help people with the fear of recurrence. 121 The techniques included in this form of talking therapy involve trying to change thinking patterns to improve a particular condition; for instance, a therapist treating a patient with anxiety will often identify a patient’s anxious/nervous thought patterns and help to reframe these thoughts so that they are less detrimental. CBT has been shown to improve sleep and anxiety/depressive symptoms and increase quality of life in cancer patients. For instance, among 11 RCTs of patients with breast cancer, the overall effect size of CBT on quality of life of breast cancer survivors was 0.39 (95% confidence interval 0.12 to 0.66; P<0.001, I 2 =83%). 215 216 217 218 219 220 221 222 223 224 225

Insomnia is a common problem for patients with breast cancer, both during and after treatment, owing to direct treatment effects (including tamoxifen or steroids prescribed with chemotherapy), stress of diagnosis and treatment, or other causes. Insomnia often coexists with other symptoms such as pain, anxiety/depression, and fatigue, leading to reduced quality of life. 226 CBT-insomnia is a form of CBT that has been shown to improve insomnia in breast cancer patients for up to 12 months post-intervention 217 223 ; in one systematic review and meta-analysis of 22 studies, CBT-insomnia significantly reduced severity of insomnia (g=0.78). 217 CBT-insomnia involves stimulus control, sleep hygiene, cognitive therapy, and relaxation therapy. 219 227

Mindfulness

Mindfulness practice is a technique used to train attention and awareness to focus on the present moment in a non-judgmental way. 228 Mindfulness practice is recommended by SIO/ASCO for anxiety, depression, and quality of life (grade A). 183 Patients may practice mindfulness in different ways, including meditation, yoga, Tai Chi, breathing techniques, and body scans. Mindfulness practices improve anxiety, depression, sleep, and quality of life in cancer patients. 229 230 231 232 233 234 235 236 MBSR is a more formal program that teaches a variety of meditation practices either in person or online, weekly over six to eight weeks, 228 and may also improve mood, sleep, fatigue, and quality of life. 226 234 235 237 Studies have been mixed regarding the effects of MBSR on cognitive function. 238 The duration of beneficial effects of MBSR may not be long lasting, and more studies are needed to determine whether ongoing practice or repeat courses are needed to maintain benefits. 237 239

Supplements

Guidelines state that dietary supplements are not recommended for the treatment of cancer or prevention of recurrence and are not recommended for cancer survivors in the absence of a documented nutritional deficiency, poor diet, or other medical indication. 183 240 241 However, some dietary supplements may be useful in symptom management. For example, Wisconsin ginseng has been shown to reduce fatigue in breast cancer patients undergoing chemotherapy, 242 and ginger may help with nausea. 243 244 245 Treating vitamin D deficiency may be associated with improved breast cancer outcomes and bone health. 246 247 Dietary soy is safe, but supplements are not recommended or useful for hot flashes. 248 249 250 Some supplements, however, can be harmful and should be avoided. For example, acetyl-L carnitine was shown to worsen taxane induced neuropathy. 251 Vitamin B 12 before/during chemotherapy and iron during chemotherapy were associated with increased recurrence of and death from breast cancer. 252 Patients should also avoid supplemental antioxidants during chemotherapy, as some studies suggest worse cancer outcomes. 253 Supplements/herbal medicines can interfere with cancer treatments, generally, through cytochrome P450/P-glycoprotein interactions, which may increase the toxicity of therapy or decrease its effectiveness. 254 255 Many patients are taking dietary supplements and do not inform their care teams. 256 257 Asking whether patients are taking dietary supplements and assessing for potential interactions are important.

Other integrative modalities

Other therapies that have shown promise in helping patients with breast cancer with a variety of problems are listed in table 3 (adapted from SIO guidelines). 205 240

Level of evidence for integrative medicine strategies used for symptom management.

Digital tools to enhance survivorship care

With the burgeoning population of breast cancer survivors, transformation of delivery models for cancer care has become a necessity. Telehealth and virtual care have been adopted globally, and they may offer solutions to enable the transition of some aspects of survivorship care from the clinic into the home or community environment. Communication with care team members, symptom management, and disease surveillance can be facilitated by digital products and platforms, as summarized in this section.

Electronic/mobile health services

Digital technologies leveraged for electronic health (eHealth) interventions are most commonly mediated through the web or internet, whereas mobile health (mHealth) interventions are mediated through smartphone or tablet devices, most commonly via applications. Digital delivery of educational content for patients and online peer support groups accessible through a web browser or mobile device are a few examples of eHealth/mHealth tools that foster self-management.

A systematic review with meta-analyses (random effects model) of RCTs evaluated the effectiveness of eHealth delivered interventions in patients during and after breast cancer treatment. 258 Most interventions were web based and included videos, forums, and electronic reminder systems. The 32 unique studies (4790 participants) included were conducted within health systems globally, showing the broad reach of these interventions and diversity within the populations represented. A significant effect of eHealth interventions on quality of life (standardized mean difference 0.20, 95% confidence interval 0.03 to 0.36), self-efficacy (0.45, 0.24 to 0.65), distress (–0.41, –0.63 to –0.20), and fatigue (–0.37, –0.61 to –0.13) was seen. They had no effect on anxiety or depression. Studies (78.1%) measuring patient reported experience measures (n=25) found that acceptability (n=9) was high, with high ratings for satisfaction (range 71-100%), usefulness (71-95%), and ease of use (73-92%).

A systematic review of mHealth applications used across the breast cancer continuum was conducted by searching four databases with an objective of providing an overview of available, research tested interventions. Ten of the 29 identified studies targeted breast cancer survivorship (846 patients). 259 All aimed to assess lifestyle changes, and nearly all interventions were mobile applications, some of which included email or SMS text messaging features, as well as video enabled sessions with a healthcare professional. Several of the included studies showed a significant association for weight loss and increased physical activity with the mHealth intervention. 260 261 More high quality research is needed to better understand the effect of mHealth applications on these and other clinical outcomes.

Telehealth services

The electronic health record (EHR) has become the standard for storing and viewing patients’ health data and clinical documentation. A shift has taken place from passively viewing health information to an interactive EHR, and patients report that this facilitates better communication, enables a more effective partnership with providers, and helps to track their health information more proactively. 262

Asynchronous telehealth services are a form of eHealth/mHealth, often mediated respectively through the web or application based EHR patient portals. They can facilitate secure messaging between survivors and their care teams, as well as store-and-forward transmission of data. 263 The latter can be used for electronic patient reported outcomes, such as self-reported symptom assessments, or for patients to send images. The submitted data can be reviewed by a healthcare provider and care recommendations can be returned to patients at a convenient time outside of an in-person assessment,.

Synchronous telehealth services require an interactive audio and/or video telecommunication system to permit real time communication between providers at the distant site and the patient at the originating site. 263 Emerging literature suggests that patients’ acceptance of and satisfaction with video telemedicine visits in the breast surgical oncology practice have been high. 264 265 High patient satisfaction scores were also observed in a multisite, multiregional medical oncology practice. In that study, rates of use of telehealth visits were lower for patients ≥65 years of age and those residing in rural communities than for younger patients and those in urban areas. 266 Breast cancer clinicians have also expressed satisfaction with telemedicine and recognize it as a valuable option to enhance outpatient care and routine follow-up. 267 When appropriate, moving some follow-up care to the home via telehealth visits may improve access to facility based care while still serving the needs of breast cancer survivors.

Remotely delivered rehabilitation, weight loss, and physical activity programs

Beyond episodic visits, entire programs supporting cancer survivors have been transformed for virtual care delivery. As an example, telerehabilitation has been developed and implemented in several cancer practices to facilitate physical therapy for complications of breast cancer treatments, including lymphedema, limited shoulder range of motion, pain, fatigue, and loss of muscle strength. 268 Although remotely delivered physical therapy is a viable model of care delivery for survivors, research is needed to understand patients’ acceptance of and compliance with the telerehabilitation program, as well as its efficacy compared with traditional in-person physical therapy.

Additionally, the feasibility and effectiveness of a remotely delivered weight loss program has been compared with usual care in an RCT of patients who have completed treatment for early stage breast cancer. 269 Compared with usual care, the virtual weight loss program, including telephone calls and optional text messaging, was associated with significantly greater improvements in weight, metabolic syndrome risk score, physical quality of life, musculoskeletal pain, and other variables. Notably, the effects on weight, adiposity, and metabolic syndrome risk scores were sustained at 18 months. Bringing these weight loss programs into the home environment with a goal of improving overall health and wellness may improve patients’ access and adherence to them.

Remotely delivered physical activity programs for breast cancer survivors have also emerged separately or in concert with weight loss programs, and early results have shown their feasibility and acceptance in both older rural and young breast cancer survivors. 270 271 Interventions supporting these programs include the use of video enabled exercise sessions, web based education, wearable devices/accelerometers, and certified instruction or peer coaching. In an RCT of a remotely delivered exercise program versus a waitlist wellness control group of breast cancer survivors, those receiving the intervention had significantly greater reductions in sedentary behavior, and the increase in moderate to vigorous physical activity was inversely proportional to sedentary behavior. As shown in a separate study, remotely delivered programs for cancer survivors, when combined with telecoaching, can improve program retention and adherence enabling improved outcomes for patients. 272

This growing body of evidence supports continued investment in the development and study of remotely delivered programs for breast cancer survivors that foster rehabilitation, weight loss, and increased physical activity. They have the potential to improve health related quality of life and clinical outcomes, and they can furthermore break down barriers to access and adherence to these services that traditionally have been offered at limited institutions through traditional in-person care models.

Cancer treatment delivery at home

Home hospital programs can provide supportive care to patients with cancer in the home environment, and studies have shown the feasibility, safety, and effectiveness of oncology specific home hospital programs. 273 274 Initially developed and adopted several decades ago in single payer health systems globally, 275 276 the programs have expanded to include delivery of systemic cancer treatment in the home. Studies have shown that this is safe, improves patient and care giver experience, and reduces treatment costs. 277 Many breast cancer drugs administered to breast cancer survivors have a low risk for reactions and would be amenable to administration in the home, such as GNRH analogs, biologics, and bone supportive care. This could be transformative for care of breast cancer survivors and warrants investigation.

Emerging treatments

Many emerging treatments for long term toxicities of systemic therapies exist. Two upcoming clinical trials will focus on therapies that might prevent the development of long term peripheral neuropathy, one testing a compound called GM-1 and another a device that provides both cryotherapy and compression therapy (NCT number not yet assigned). For therapy related alopecia, a clinical trial is under way to study the benefits of minoxidil in a randomized controlled fashion ( NCT05417308 ).

Various national and international organizations have issued breast cancer survivorship guidelines, as well as guidelines for the management of specific symptoms facing breast cancer survivors, for integrative medicine approaches, and for surveillance strategies. General survivorship guidelines from the American Cancer Society, American Society of Clinical Oncology, European Society of Clinical Oncology, and National Comprehensive Cancer Network guidelines were reviewed in detail to inform this review.

Conclusions

In general, the complexity of after effects from breast cancer are likely to increase as new therapies are added to our armamentarium and treatment becomes increasingly tailored. As the sections above highlight, survivors and clinicians face challenges in monitoring persistent and late after effects from cancer and its treatment. Following up for multiple aftereffects in trials of cancer directed therapy over the long term can be costly, and many clinical trials may be too small to capture rare side effects. Digital tools may help to engage survivors in long term tracking, but reporting bias will be a potential confounder and care must be exercised to prevent under-representation of populations with lower digital literacy.

Questions for future research

How can we prevent and/or treat many of the challenging long term side effects of systemic therapy, including peripheral neuropathy, therapy related alopecia, and vaginal dryness?

What is the optimal way to help patients to differentiate between evidence based integrative oncology approaches and approaches that may not help and may actually harm patients?

How can digital tools enhance the benefit of survivorship care plans?

How patients were involved in the creation of this article

All of the authors of this manuscript are clinicians who interact with breast cancer survivors regularly. All also engage with patient advocates as part of their research efforts. A team of breast cancer survivors and patient advocates provided feedback on the long term side effects and integrative oncology strategies that are covered in this manuscript; we would personally like to acknowledge the following breast cancer survivors and advocates: Lisa Halverson, Anne Mehnke, Tracee Cole, and Jody Koubsky .

Series explanation: State of the Art Reviews are commissioned on the basis of their relevance to academics and specialists in the US and internationally. For this reason they are written predominantly by US authors

Contributors: KJ was responsible for the original conception and design of the article, with input from all co-authors; all authors were responsible for the acquisition and interpretation of data for the work, drafting the work, revising it critically, and final approval of the version to be published. All authors agreed to be accountable for all aspects of the work and will assure that questions related to the accuracy or integrity of any part of the work will be appropriately investigated and resolved.

Competing interests: We have read and understood the BMJ policy on declaration of interests and declare the following interests: none.

Provenance and peer review: Commissioned; externally peer reviewed.

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Breast Cancer—Epidemiology, Classification, Pathogenesis and Treatment (Review of Literature)

Beata smolarz.

1 Laboratory of Cancer Genetics, Department of Pathology, Polish Mother’s Memorial Hospital Research Institute, Rzgowska 281/289, 93-338 Lodz, Poland; lp.pw@zciwonamor-annah

Anna Zadrożna Nowak

2 Department of Chemotherapy, Medical University of Lodz, Copernicus Memorial Hospital, 93-513 Lodz, Poland; [email protected]

Hanna Romanowicz

Simple summary.

Breast cancer is the most-commonly diagnosed malignant tumor in women in the world, as well as the first cause of death from malignant tumors. The incidence of breast cancer is constantly increasing in all regions of the world. For this reason, despite the progress in its detection and treatment, which translates into improved mortality rates, it seems necessary to look for new therapeutic methods, predictive and prognostic factors. The article presents a review of the literature on breast carcinoma - a disease affecting women in the world.

Breast cancer is the most-commonly diagnosed malignant tumor in women in the world, as well as the first cause of death from malignant tumors. The incidence of breast cancer is constantly increasing in all regions of the world. For this reason, despite the progress in its detection and treatment, which translates into improved mortality rates, it seems necessary to look for new therapeutic methods, and predictive and prognostic factors. Treatment strategies vary depending on the molecular subtype. Breast cancer treatment is multidisciplinary; it includes approaches to locoregional therapy (surgery and radiation therapy) and systemic therapy. Systemic therapies include hormone therapy for hormone-positive disease, chemotherapy, anti-HER2 therapy for HER2-positive disease, and quite recently, immunotherapy. Triple negative breast cancer is responsible for more than 15–20% of all breast cancers. It is of particular research interest as it presents a therapeutic challenge, mainly due to its low response to treatment and its highly invasive nature. Future therapeutic concepts for breast cancer aim to individualize therapy and de-escalate and escalate treatment based on cancer biology and early response to therapy. The article presents a review of the literature on breast carcinoma—a disease affecting women in the world.

1. Epidemiology

Breast cancer is the most common malignant tumor in women in the world. Breast cancer patients account for as much as 36% of oncological patients. An estimated 2.089 million women were diagnosed with breast cancer in 2018 [ 1 , 2 ]. The incidence of this malignant tumor is increasing in all regions of the world, but the highest incidence occurs in industrialized countries. Almost half of the cases on a global scale are in developed countries [ 2 , 3 ]. This trend is mainly due to the so-called Western lifestyle, associated with a poor diet, nicotinism, excessive stress and little physical activity [ 3 ]. In the case of breast cancer, mammography has become recognized as screening. The greatest value of mammography is observed in the group of women aged 50–69 years [ 1 , 3 ]. Classical mammography is characterized by 75–95% sensitivity and specificity at the level of 80–95% [ 4 ]. For women with suspected hereditary breast cancer, magnetic resonance mammography is used as a screening test. If a suspicious lesion is found in mammography, an ultrasound examination is performed and, if necessary, a thick needle biopsy along with a histopathological examination of the tumor.

In 2018, there were 234,087 cases of breast cancer in the United States (crude rate: 85/105), 55,439 in the United Kingdom (crude rate: 94/105), 56,162 in France (crude rate: 99/105), 71,888 in Germany (crude rate: 85.4/105) and 66,101 in Japan (crude rate: 58/105) [ 2 ]. The highest incidence rate in the world is found in Belgium (crude rate: 113/105), and among the continents—in Australia (crude rate: 94/105) [ 2 ]. In Poland, breast cancer is also the most-commonly diagnosed malignant tumor in women. There is a steady increase in cases (1990, 8000 new cases; 2018, 20,203 new cases) [ 2 ]. The average incidence rate in Europe is 84/105 [ 2 ]. The lowest incidence occurs in the countries of Southeast Asia and Africa, where the standardized incidence rate does not exceed 25/105 [ 2 ]. The lowest incidence rates in 2018 were recorded in Bhutan (crude rate: 5/105) and the Republic of The Gambia (crude rate: 6.5/105) [ 2 ]. Despite the greater effectiveness of initial diagnostics or the rapid development of pharmacotherapy in recent years, breast cancer is the first cause of death from malignant tumors in women in the world. In 2018, 626,679 people died from breast cancer. Unlike morbidity, the highest mortality from this malignant tumor is recorded in developing countries [ 2 ] (Fiji, crude rate 36/105, highest rate; Somalia, crude rate 29/105; Ethiopia, crude rate 23/105; Egypt, crude rate 21/105; Indonesia, crude rate 17/105; Papua New Guinea, crude rate 25/105) [ 2 ], in which as much as 60% of all deaths from breast cancer occur. This trend is mainly related to the lack of screening, which is less than in developed countries, the availability of diagnostics and modern methods of treatment [ 5 ]. In contrast, the standardized death crude rate in Belgium 16.3/105, in the United States 13/105, and in Japan 9.3/105 [ 2 ]. The number of breast cancer cases in Poland is much lower than in EU countries (in 2013, the standardized incidence rate for Polish—51.8, for the EU 106.6) [ 6 ]. The incidence of adult premenopausal women (20–49 years) has almost doubled over the past 30 years. Unfortunately, Polish women are still not very sensitive to prevention. They neglect their breasts and underestimate the importance of regular check-ups. Compared to other European countries, Polish women have a low incidence of preventative care—in the Netherlands, 80% of women report free mammogram prevention programs, in England 71%, and in Poland only 44% [ 6 ]. The percentage of 5-year survival due to breast cancer in Poland is 78.5%, differing significantly from, for example, the result of 90% achieved in the United States [ 7 ].

2. Risk Factors

The unambiguous cause of carcinogenesis has not yet been established, but several risk factors conducive to the development of breast cancer are known. One of the most important, as also indicated by the epidemiological data described above, are the gender, age, and degree of economic development of a given country. No less important are hormonal factors, mainly related to the time of exposure to estrogens, procreative factors, including the number of children born, the age of birth of the first child, or breastfeeding. Great importance in the development of breast cancer is attributed to genetic factors, the use of hormone replacement therapy, improper diet, and the resulting obesity. Among the significant risk factors for the development of breast cancer, hormonal contraception, alcohol consumption and exposure to ionizing radiation at a young age are also mentioned. Risk factors for breast cancer are presented in Table 1 .

Risk factors for breast cancer [ 8 ].

The vast majority of cases of breast cancer, reaching 99%, occur in women. Only 1% of cases of this malignant tumor affect men, for which the standardized incidence rate in Poland is 0.4/105. No more than 100 cases are reported each year [ 6 ]. However, the incidence of breast cancer in men, like that in women, shows a steady upward trend, which is most likely associated with obesity and longer survival [ 9 ].

Age is one of the most important risk factors for breast cancer. The global increase in the incidence of breast cancer is observed in all age groups and is highest in women under 50 years of age [ 9 ]. Although this malignant tumor is rare in this age group, it remains a significant clinical and social problem, due to its worse course—numerous studies indicate that breast cancer in young women is characterized by greater histological malignancy, marginal expression of steroid receptors, frequent overexpression of the HER-2 receptor or occurs as a molecular biological subtype “basal-like” (“triple negative”) [ 10 ]. Furthermore, the incidence of breast cancer in premenopausal women is increasing—within 30 years it has increased almost 2-fold [ 6 ].

2.3. Degree of Economic Development

As mentioned in the paragraph on epidemiology, the incidence of breast cancer and mortality from this malignant tumor is related to the economic development of a country. This relationship has been documented in many studies [ 3 , 11 , 12 ].

The incidence of breast cancer is increasing worldwide due to the continuous growth of the population and the ageing of the population [ 11 ]. The highest incidence rates are recorded in developed countries [ 3 , 11 , 12 ]. This phenomenon results from the so-called “Western lifestyle” described above. At the same time, it seems that soon the trend of high morbidity will also occur in developing countries. In these countries, along with economic development, access to public health care becomes easier, prevention and screening programs are introduced (which increases detection), maternal, infant and child mortality decreases [ 12 ]. On the other hand, the importance of factors conducive to the development of breast cancer is growing, such as late first birth, low number of babies born, use of hormone replacement therapy, obesity, lack of physical activity, or improper diet [ 11 , 12 ]. Currently, however, lower middle- and low-income countries are dominated by higher breast cancer mortality rates than in developed countries, despite lower incidence [ 3 , 5 , 11 , 12 ]. This trend is associated with frequent diagnosis of cancer at an advanced stage, which results from the lack of resources for the effective implementation of primary prevention programs, diagnostic tests (primarily mammography), and finally modern methods of treatment [ 5 , 11 , 12 ].

Approximately 645,000 cases of premenopausal breast cancer and 1.4 million cases of postmenopausal breast cancer were diagnosed worldwide in 2018, with more than 130,000 and 490,000 deaths in each menopausal group, respectively. Proportionally, countries with a low UNDP Human Development Index (HDI) faced a higher burden of premenopausal breast cancer for both new cases and deaths compared to higher-income countries [ 13 ]. Countries with very high HDI had the highest incidence of premenopausal and postmenopausal breast cancer (30.6 and 253.6 cases per 100,000, respectively), while countries with low and medium HDI had the highest premenopausal and postmenopausal mortality rates (5 and 53.3 deaths per 100,000, respectively). By studying trends in breast cancer, they noted significantly increasing age-standardized incidence rates (ASIRs) for premenopausal breast cancer in 20 of 44 populations and significantly increasing ASIRs for postmenopausal breast cancer in 24 of the 44 populations. Growth only in premenopausal age occurred mainly in high-income countries, while the increase in the burden of postmenopausal breast cancer was most noticeable in transition countries [ 13 ].

2.4. Hormonal Status

Factors related to a woman’s hormonal status seem to have a huge impact on the risk of developing breast cancer. The results of many studies indicate that the risk of developing breast cancer increases in proportion to the time of exposure to estrogen, which prolongs early menarche, late menopause, the age of birth of the first child and the number of children born [ 9 , 11 , 12 , 13 , 14 ].

Brinton et al. showed that the first menstruation that occurred at or after the age of 15 was associated with a 23% reduction in the risk of breast cancer compared to the first menstruation before the age of 12 (early menarche) [ 15 ]. Currently, it is believed that this reduction is about 30%. In turn, the Collaborative Group on Hormonal Factors in Breast Cancer published in 2012 in The Lancet Oncology the results of a meta-analysis, according to which the relative risk of developing breast cancer increased by 5% with each year of early menarche initiation [ 16 ].

In addition, it was found that early first menstruation was associated with a higher risk of developing breast cancer compared to late menopause—each year of late menopause increased the relative risk by 2.9%, with late menopause being believed to be for, achieved after the age of 54, increases the risk of breast cancer twice compared to the menopause achieved before the age of 45 [ 1 , 16 ].

The meta-analysis also showed that women who had not reached menopause had a higher risk of developing breast cancer compared to postmenopausal women of the same age. In this group of analyzed patients, the effect of the Body Mass Index on the risk of developing the disease was noticed—in premenopausal patients, obesity reduced this risk, and in postmenopausal patients it increased. This metanalysis also found that early menarche was associated with a higher risk of developing lobular breast cancer, as was late menopause [ 16 ]. Late menopause also predisposed to developing steroid-expressed breast cancer [ 16 ].

Other reproductive factors with an effect on breast cancer risk confirmed in numerous studies include the age at which the first child was born, the number of babies born and breastfeeding [ 14 ].

Studies indicate an increased risk of breast cancer in transgender women compared to cisgender men and a lower risk in transgender men compared to cisgender women [ 17 ]. In transgender women, the risk of breast cancer increases during a relatively short period of hormone treatment, and the characteristics of breast cancer are more like a female pattern. The results of the study suggest that guidelines for breast cancer screening for cisgender people are sufficient for transgender people using hormone treatment [ 17 ].

Recent studies indicate that the increased risk of breast cancer is associated with long-term use of estrogen-only therapy and combined estrogen-progestogen therapy [ 18 ]. The combination treatment associated with the least increase in risk is estradiol-dydrogesterone. Research suggests a lower increased risk of breast cancer associated with long-term hormone replacement therapy (HTR) use and a more noticeable decrease in risk after discontinuation of treatment [ 18 ].

2.5. Reproductive and Hormonal Risk Factors in Breast Cancer Patients

Estrogens play an important role in the pathogenesis of the development of breast cancer [ 19 ]. Breast cancer is considered a hormone-dependent tumor in which elevated estrogen levels and longer exposure to this hormone are associated with an increased risk of its development [ 19 ].

This is confirmed by epidemiological studies that increased exposure to endogenous and exogenous estrogens increases the risk of developing breast cancer [ 20 ].

In all postmenopausal women, high serum estrogen levels are associated with an increased risk of breast cancer. Both hormonal factors and reproductive factors are indisputably influencing the increase in the risk of breast cancer [ 20 ]. The duration of exposure to estrogen and the effect of pregnancy determined by parameters such as the age of the first menstrual bleeding, the age of the first pregnancy (especially exposure in women who gave birth to the first child after the age of 30), childlessness, or the age of onset of menopause change the individual risk of breast cancer [ 21 ].

Early onset of menstruation (12 years) and late termination (50 years) increases the risk twice compared to women who started menstruation late (15 years) and ended it early (40 years) [ 22 ].

Also, childlessness and the late age of the first pregnancy (over 30 years of age) are factors associated with prolonged exposure to estrogens [ 23 ].

Nulliparous women and those who became pregnant for the first time after the age of 30 have an increased risk of getting sick 2–5 times more. Spontaneous and artificial miscarriages (incomplete pregnancies) do not confer a protective effect as do full pregnancies, but they may increase the risk due to the lack of protective effect of progesterone in the second phase of pregnancy [ 24 ]. The effect of exogenous estrogen on breast cancer is a controversial issue and continues to be subjected to numerous studies.

The use of HRT is a significant risk factor for breast cancer. The first information on the adverse effects of HRT on the risk of developing breast cancer appeared in the nineteen nineties. In 1997, the Collaborative Group on Hormonal Factors in Breast Cancer published in The Lancet the results of a meta-analysis of 51 studies evaluating the relationship between HRT intake and breast cancer. This meta-analysis found that each year of HRT use increased the risk of breast cancer by 2.7% [ 25 ]. In 2019, the same society republished another meta-analysis in The Lancet, this time of 58 prospective studies evaluating the relationship between the type of HRT and the risk of developing breast cancer. This meta-analysis showed that HRT containing estrogens and progestogens increased the risk of breast cancer to the greatest extent, especially when progestogens were taken daily [ 25 ]. The use of HRT even for a short time (1–4 years) was also associated with an increased risk of breast cancer [ 25 ]. The risk of developing the disease was mainly related to breast cancer with the expression of steroid receptors [ 25 ]. The risk of developing the disease was slightly reduced if HRT was used after the age of 60 [ 24 ]. This risk was also lower for obese women, especially if they took HRT containing only estrogens [ 26 ].

Two-component HRT, used for 5 years from the age of 50, was associated with a 2% increase in the risk of breast cancer over 20 years in patients aged 50–69 (from 6.3% to 8.3%)—it is estimated that 1 in 50 women would develop cancer [ 26 ]. Similarly, the use of HRT with estrogens and progestogens taken intermittently increased the risk of breast cancer from 6.3% to 7.7% (1 in 70 women would get sick). In turn, single-component HRT (only with estrogens) used for 5 years was associated with the lowest increase in the risk of breast cancer in 20 years—from 6.3% to 6.8% (1 in 200 women would get sick) [ 26 ].

The relationship between hormonal contraceptive use and breast cancer risk has been demonstrated in two important papers—a reanalysis of 54 epidemiological studies by the Collaborative Group on Hormonal Factors in Breast Cancer published in The Lancet in 1996, and a prospective cohort study by Mørch et al. presented in the NEJM in 2017 [ 27 , 28 ]. Both studies found that long-term use of hormonal contraception adversely affects the relative risk of breast cancer. This risk was estimated at 1.20 (Danish study) and 1.24 (CGoHFiBC reanalysis). It was higher the longer the subjects took hormonal contraception (1.09 for hormonal contraception used for less than a year vs. 1.38 for women taking contraception for more than 10 years) [ 27 , 28 ].

In addition, this cohort study showed that the relative risk of developing breast cancer was elevated for at least 5 years after the end of hormonal contraception in women who took it for a long time (≥5 years). This trend was not noticed in women who used hormonal contraception for a short time (less than 5 years) [ 28 ].

The relative risk of developing breast cancer was also increased regardless of the type of contraception taken [ 27 ].

2.6. Genetic Factors, Family Occurrence

Only a small group of breast cancer cases (5–10%) are genetic. The best-known genetic mutations associated with this cancer include mutations in the BRCA1 and BRCA2 genes [ 29 ].

The BRCA1 gene, located on chromosome 17, is a suppressor gene that encodes nuclear protein, responsible for maintaining genome stability. Together with the products of other suppressor genes, signal transduction genes and DNA damage detection, this protein co-creates a protein complex that binds to RNA polymerase II and interacts with histone deacetylase, thus affecting the processes of transcription, DNA repair or recombination. The BRCA1 protein, together with the BRCA2 gene product, which is also a suppressor gene located on chromosome 13, is particularly involved in the repair of double DNA strand breaks by homologous recombination [ 30 ].

The presence of mutations in these genes occurs only in 3–5% of breast cancer patients. However, due to the high penetration of BRCA1/BRCA2 genes, these patients should be included in the prophylactic program. Carriers of the BRCA1/BRCA2 mutation are estimated to have a 10-fold higher risk of developing breast cancer [ 27 ]. The presence of BRCA1/BRCA2 gene mutations is associated with a cumulative risk of breast cancer at age of 70 of more than 60%, and the probability of developing this malignant tumor throughout life varies in the range of 41–90%. Mutations in the BRCA1 gene are associated with triple-negative cancer and in the BRCA2 gene for estrogen receptor-expressed breast cancer [ 31 , 32 , 33 ].

Other suppressor genes whose high-penetration mutations predispose to breast cancer are the TP53 (Li-Fraumeni syndrome) and PTEN (Cowden syndrome) genes. The cumulative risk of developing breast cancer at age 70 for women with Li-Fraumeni syndrome is 54%. In patients with Cowden’s syndrome, the risk of developing breast cancer throughout life is in the range of 25–50%. However, both genetic syndromes are very rare [ 34 , 35 ].

Mutations in the ATM , BRIP1 , CHEK2 and PALB2 genes show a moderate predisposition to breast cancer. Carriers of these mutations have a 2–3 times higher risk of developing this malignant tumor [ 35 ].

It is believed that <10% of breast cancers are genetically determined [ 36 ]. More than 90% of breast cancers, on the other hand, are formed because of sporadic somatic mutations. The risk of developing breast cancer increases twice in women whose closest relative (mother, sister) has been treated for the malignant tumor in question and by three to six times if the two closest relatives have been treated [ 1 ]. This risk decreased the older the relative was at the time of diagnosis of cancer [ 1 ].

2.7. Mild Breast Changes

Another factor that increases the risk of developing breast cancer is the presence of benign changes in the mammary glands. Some benign lesions—benign neoplasms, e.g., atypical ductal hyperplasia (ADH) or atypical lobular hyperplasia (ALH), which increase the risk by four or five times, and proliferative (proliferative) lesions without atypia (e.g., stellar scar or fibrotic adenoma) increasing the risk up to two times. The Hartmann et al. cohort study assessed the risk of breast cancer in patients with different types of benign lesions [ 33 ]. The relative risk of developing breast cancer for the entire study cohort was 1.56 (95% CI, 1.45–1.68) [ 37 ]. This risk was elevated for 25 years after the biopsy. For women with benign lesions without proliferation, the relative risk of developing breast cancer was 1.27 (95% CI, 1.15–1.41). In the presence of mild proliferating lesions, but without atypia, it was equal to 1.88 (95% CI, 1.66–2.12). The highest relative risk of developing breast cancer was for women with the presence of benign proliferating lesions with atypia (atypical ductal hyperplasia, atypical lobular hyperplasia, or both), amounting to as high as 4.24 (95% CI, 3.26–5.41). It was also found that the earlier benign changes were diagnosed (<55 years of age), the greater the risk of developing the malignant tumor in question [ 37 ].

In addition, it is believed that in women with atypical hyperplasia, whose first-degree relatives were treated for breast cancer, the risk of developing this malignant tumor is as much as nine times greater [ 38 ].

2.8. Ionizing Radiation

A recognized factor in the development of breast cancer is early exposure to ionizing radiation. In 2007, John et al. published an analysis of data from the Breast Cancer Family Registry assessing the relationship between exposure to ionizing radiation used in diagnosis and treatment and the risk of developing breast cancer [ 39 ]. This analysis showed that an increased risk of breast cancer was in women who had received radiation therapy in the past as part of cancer treatment and in women who underwent a control chest X-ray during treatment for tuberculosis and pneumonia [ 39 ]. The risk of developing breast cancer was highest in young patients whose exposure to ionizing radiation was multiple and in patients who had exposure at a very young age [ 39 ].

In the study Moskowitz et al. published in 2014, the risk of developing breast cancer was assessed depending on the dose and field of radiotherapy in women who were exposed to the chest area due to cancer (leukemia, Hodgkin’s or non-Hodgkin lymphoma, Wilms’ tumor, neuroblastoma, soft tissue sarcoma, bone malignant tumor, tumor of the central nervous system) before the age of 21 [ 39 ]. This study indicated that the highest risk of developing breast cancer was in patients who were treated with radiation therapy at lower doses (14 Gy) but for a large chest area (whole lung field), consequently covering a larger area of breast tissue [ 38 ]. The risk of developing breast cancer in women who received high-dose radiotherapy (30–40 Gy) for a smaller chest area (Mantle field) was comparable or lower (mediastinal field) but elevated compared to women who had not been irradiated in the past [ 39 ]. The risk of developing breast cancer was lower if the radiation field included the ovaries [ 39 ]. It was also shown that the cumulative risk of developing breast cancer at the age of 50 was 30%, with the highest (35%) in patients treated for Hodgkin lymphoma [ 40 ].

In a systematic review by Henderson et al., it was also found that the highest risk of developing breast cancer occurred in patients treated in the past for Hodgkin lymphoma. It was noted that the analyzed studies mostly concerned such patients [ 41 ].

In 2005, a paper by Travis et al. was published assessing only the relationship between breast cancer and radiotherapy received in the chest area for Hodgkin lymphoma. The study showed that the cumulative absolute risk of developing breast cancer increased with the patient’s age, sometimes after the diagnosis of cancer and the dose of irradiation [ 42 ].

It was mentioned above that performing a control chest X-ray during the treatment of tuberculosis and pneumonia increased the risk of developing breast cancer. As for other diagnostic methods, it is also believed that mammography performed in young women significantly increases the risk of breast cancer [ 1 ].

Ionizing radiation (IR) increases the risk of breast cancer, especially in women and when exposed at a younger age, and the evidence generally supports the linear dose-response relationship [ 43 ]. Ionizing radiation directly and indirectly causes DNA damage and increases the production of reactive oxygen and nitrogen species (RONS). The RONS lead to DNA damage and epigenetic changes leading to mutation and genomic instability. Proliferation of RONS enhances the effects of DNA damage and mutations leading to breast cancer. Separately, damage to reactive oxygen and nitrogen species and DNA also increases inflammation. Inflammation contributes to direct and indirect effects (effects in cells unattainable directly by IR) through positive feedback to RONS and DNA damage, and separately increases proliferation of breast cancer through pro-carcinogenic effects on cells and tissues. For example, changes in gene expression alter inflammatory mediators, resulting in improved cancer cell survival and growth and a more hospitable tissue environment [ 43 ]. All these events overlap at multiple points with events characteristic of “basic” breast cancer induction, including hormone-dependent proliferation, oxidative activity, and DNA damage. These overlays make the breasts particularly susceptible to ionizing radiation and confirm that these biological activities are important characteristics of carcinogens [ 43 ].

2.9. Alcohol Consumption

Numerous studies indicate a relationship between alcohol consumption and an increased risk of breast cancer [ 44 , 45 , 46 , 47 , 48 ]. This dependence results from several mechanisms —alcohol contributes to the increase in the concentration of estrogens in the blood by inhibiting their metabolism in the liver and by intensifying the conversion of androgens to estrogens. In addition, it has an inhibitory effect on the immune system, or DNA repair processes, may intensify cellular proliferation and migration. Finally, the metabolites of alcohol themselves are carcinogenic compounds [ 49 ]. It is estimated that for every consumption of 10 g of pure alcohol per day, there is an increase in the risk of breast cancer by 9% [ 1 ].

The influence of the type of diet used on the development of the cancer process has been the subject of numerous studies. The correlation between a low-varied diet, rich in saturated fats, including those of animal origin, and the risk of developing mainly colorectal cancer seems undeniable [ 50 ]. On the other hand, studies assessing the relationship between diet and the risk of breast cancer are not entirely consistent. Dandamudi et al. reviewed systematic studies published between 2013 and 2017. Ten of the seventeen publications evaluated looked at the impact of a so-called “unhealthy” diet on breast cancer risk. The basic products of the diet in question included: sweetened soft drinks, processed fruit juices, red and processed meats, hardened fats, saturated fats, salted products (chips, chips, peanuts), refined grains, sweetened products (sweets, desserts) [ 50 ]. In most, but not all, of the studies analyzed, a significant relationship was found between excessive consumption of the above-mentioned products and an increase in the risk of developing breast cancer. This relationship primarily concerned excessive consumption of red and processed meat, saturated fats, and sodium [ 51 ].

This systematic review also showed that a diet rich in vegetables, fruits, fish, legumes, oils, and vegetable oils reduces the risk of breast cancer [ 51 ].

Research suggests that nutrition affects the prognosis of breast cancer. Nevertheless, the level of evidence on the results is still insufficient to make recommendations. A healthy and balanced diet should be encouraged to reduce mortality in the world [ 52 ].

A healthy diet characterized by a high intake of unrefined grains, vegetables, fruits, nuts and olive oil, and a moderate/low intake of saturated fatty acids and red meat may improve overall survival after a diagnosis of breast cancer. Breast cancer patients undergoing chemotherapy and/or radiation therapy experience various symptoms that worsen patients’ quality of life. Studies on nutritional interventions during breast cancer treatment have shown that nutritional counseling and supplementation with certain dietary components, such as eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids, may be useful in reducing drug-induced side effects as well as increasing therapeutic efficacy. Therefore, nutritional intervention in patients with BC can be considered an integral part of a multimodal therapeutic approach [ 53 ].

The link between breast cancer and diet is known to be complex, multifactorial, and nonlinear. Classical epidemiological studies on nutrition have shown conflicting results, showing little correlation between diet and breast cancer risk (except alcohol) [ 54 ]. It can be speculated that this may be due to the complexity of breast cancer, which is a multifaceted, highly heterogeneous disorder. Histological classifications, and more recently also molecular ones, have contributed to the formation of a rather complex picture.

Nutrigenomics and related disciplines can support advances in knowledge in this field by shedding light on the molecular basis of breast cancer formation and paving the way for personalized therapies.

2.11. Obesity

One of the risk factors for developing breast cancer, confirmed in many studies, is obesity. Jiralerspong and Goodwin compiled a pooled analysis of numerous publications evaluating the relationship between obesity and breast cancer prevalence in premenopausal and postmenopausal women. This analysis found that both overweight and obesity increased the risk of developing breast cancer, particularly steroid-receptor-expressed breast cancer, in postmenopausal women who did not use hormone replacement therapy [ 55 , 56 , 57 ].

Unlike postmenopausal patients, being overweight or obese in premenopausal women reduces the risk of developing hormone-dependent breast cancer. The authors of the analysis point out, however, that literature data indicate a relationship between obesity in premenopausal patients and the risk of developing triple-negative breast cancer [ 55 , 58 ].

This analysis also found that physical inactivity (combined with obesity) increases the risk of developing breast cancer regardless of menopausal status. Furthermore, according to the results of numerous studies, overweight and obesity are associated with a worse prognosis of breast cancer patients before and after menopause [ 55 , 59 , 60 ]. According to the authors, worse survival may be influenced by a greater stage of cancer at the time of diagnosis, as well as a more aggressive course of breast cancer in obese patients [ 51 ]. Obesity promotes the process of cancer through several mechanisms. Overdeveloped adipose tissue is a source of numerous cytokines, chemokines, endocrine factors, in particular proangiogenic and promitogenic leptin, which affects the immune environment of the described tissue [ 61 ]. There is a concentration of cells of the immune system of a pro-inflammatory nature, additionally secreting inflammatory cytokines. Excessive development of adipose tissue promotes the surrounding hypoxia, which leads to an increase in the secretion of leptin and VEGF factor, while inhibits the synthesis of antiangiogenic and antimitogenic adiponectin [ 62 ]. The NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) pathway is responsible for the development and maintenance of the inflammatory process within excessive adipose tissue, which through pro-inflammatory cytokines has an inhibitory effect on the process of apoptosis, and at a later stage promotes the proliferation of breast cancer cells, cancer invasion, angiogenesis, and metastasis [ 63 , 64 ].

Adipose tissue is also the main source of sex hormones in postmenopausal women. In this tissue, estrogens are formed in the process of aromatization of adrenal androgens. The accumulation of pro-inflammatory cytokines in overgrown adipose tissue, activation of the NF-κB pathway within adipose tissue, or dying adipocytes stimulate the activity of the aromatase complex, which in turn leads to excessive estrogen synthesis and promotes the development of breast cancer [ 62 ].

Furthermore, the metabolic syndrome that accompanies obesity is associated with insulin resistance, hyperinsulinemia, increased synthesis of insulin-like growth factor 1 (IGF-1). Studies have shown that insulin resistance and hyperinsulinemia are associated with poorer survival of breast cancer patients [ 65 ]. Breast cancer cells also often overexpress the IGF-1 receptor, making this factor considered their potential mitogen [ 61 ].

Obesity is a recognized risk factor for breast cancer and the development of relapses, even if patients are properly treated [ 66 ]. Obese women are less likely to undergo breast reconstruction than women of normal weight, and those who have undergone surgery experience more surgical complications. In obese women, systemic chemotherapy and hormone therapy are less effective. Obese women are at greater risk of local recurrence than women of normal weight. The effectiveness of cancer treatment is significantly lower in obese women who survive breast cancer [ 66 ].

Given the multidimensional effect of overgrown adipose tissue on the development of breast cancer, the campaign against obesity should form the basis for primary prevention of the malignant tumor in question.

2.12. Nicotinism

Research reports on the impact of chronic nicotinism on the increased risk of breast cancer are contradictory. However, a study by Jones et al. published in 2017 showed that smoking, especially at the beginning of early peripubertal age or adolescence, was associated with a moderate but statistically significant increase in the risk of developing breast cancer. The relative risk of breast cancer was higher with a positive family history [ 67 ]. Nicotine promotes breast cancer metastasis by stimulating N2 neutrophils and generating a pre-metastatic niche in the lung [ 68 ]. Chemoresistance effects of nicotine were demonstrated in breast cancer cells. These findings demonstrated the harmful effects of nicotine following metastasis of cancer, owing to the chemoresistance produced through uninterrupted smoking, which may impact the effectiveness of treatment [ 69 ].

3. Pathomorphology

The basis for the diagnosis of breast cancer remains standard pathomorphological diagnostics [ 70 ]. The result of histopathological examination should include not only the histological type of the tumor, its degree of histological malignancy, the degree of advancement according to the TNM classification, information on the completeness of the procedure, or infiltration by cancer cells of peritugal vessels, but also the expression of steroid receptors—estrogen and progesterone, HER-2 receptor, and cellular proliferation index Ki67 [ 71 ].

A reliable assessment of all the above parameters is possible thanks to the examination of material taken by means of a coarse needle biopsy or intra- and postoperative material [ 72 ]. The examination of the material obtained by fine needle biopsy does not allow to distinguish between infiltrating and pre-invasive cancer, as well as to assess the state of HER-2. The correct protocol of histopathological examination, considering the biological subtype of the tumor, determines the determination of recognized predictive and prognostic factors, and consequently the selection of appropriate, individual treatment for each patient.

A common classification of breast cancer is the WHO classification [ 73 ], for which in 2019, the 5th edition was published. This described cancers, both benign and malignant, of epithelial, mesenchymal, fibroepithelial origin, neuroendocrine neoplasms, breast wart and nipple areola tumors, in addition, breast lymphomas and metastatic changes in the mammary gland.

A simplified classification of epithelial precursor and invasive lesions is presented in Table 2 .

Epithelial precursor lesions and invasive lesions of the mammary gland [ 74 ].

The most common form of infiltrating cancer is cancer without a special type (NST), formerly called wired (70–80%) [ 1 ]. It is characterized by a large diversity in terms of cancer cell morphology and the presence of tubular or glandular structures. The second most common invasive breast cancer is lobular carcinoma (10%) [ 1 ]. This form of cancer is characterized by a small diversity of cancer cells, very frequent expression of steroid receptors and extremely rare overexpression of the Her-2 receptor [ 1 ].

The degree of histological malignancy (G, grade) was introduced due to the significant diversity of biological characteristics of breast cancers within the same histological type in the absence of characteristic morphological features. The classification used to correctly assess the degree of histological malignancy is, recommended by the WHO, the Bloom–Richardson–Scarff classification in Elston–Ellis modification ( Table 3 ).

Assessment of the degree of histological malignancy [ 75 ].

Originally, the assessment of the degree of histological malignancy concerned only invasive cancer without a special type (NST). Currently, it refers to any infiltrating cancer, excluding medullary and microinvasive cancer. In the case of heterogeneous cancer weaving, the fields with the highest degree of malignancy should be noted [ 76 ].

The current VIII edition of the TNM classification was published by the AJCC (American Joint Committee on Cancer) in 2018. According to this classification, histopathological examination should assess the size of the primary tumor (Tumor), the condition of the axillary lymph nodes (Nodes) and the presence of distant metastasis (Metastasis) ( Table 4 ). In the case of the N trait, the location and number of lymph nodes taken should be described, but it must not be less more than 10 nodes, as well as the number of lymph nodes affected by metastases, including micrometastases and isolated cancer cells. Correct assessment of all elements of the TNM classification makes it possible to determine the stage of cancer, which is the most important prognostic factor [ 68 ]. In countries where it is not possible to present a prognostic stage of advancement, containing the state of ER, PR and HER-2 receptors, its anatomical version should be used.

VIII edition of the pTNM classification.

4. Prognostic and Predictive Factors

As mentioned earlier, the stage of breast cancer is the most important prognostic factor. According to SEER data, 98.9% of patients with localized disease, 85.7% with regional advancement, and only 28.1% of patients with distant metastases will survive [ 7 ].

In addition, all the individual features of the TNM classification have a prognostic significance.

One of the most important prognostic factors is the condition of the lymph nodes (N). According to SEER data, the 5-year overall survival (OS) is 92% for patients with unoccupied regional lymph nodes, 81% with 1–3 lymph nodes occupied, and 57% when metastases were found in four or more lymph nodes. The presence of micrometastases and isolated cancer cells in regional lymph nodes is also of unfavorable prognostic importance [ 76 , 77 ].

The dimension of the primary tumor is also an important prognostic factor. SEER data indicate that 99% of women with a disease confined to the mammary gland and a tumor smaller than 1 cm, 89% with a tumor measuring 1–3 cm and 86% with a tumor of 3–5 cm will survive 5 years [ 77 ]. In addition, a tumor with an originally large size predisposes to the involvement of regional lymph nodes.

The current feature of T4 according to the TNM classification, i.e., invasion of the skin or chest wall, is also associated with a worse prognosis.

4.2. Degree of Histological Malignancy

Of slightly less prognostic significance are the histological type and the degree of histological malignancy. Less common cancers, such as tubular, papillary, and medullary, have a better prognosis with a 10% risk of recurrence with prolonged follow-up [ 78 ].

Determining the prognosis in the case of frequent cancers, infiltrating NST cancer and lobular cancer, facilitated the introduction of the degree of histological malignancy. Studies have shown that unfavorable prognostic significance is associated with low tumor differentiation (G3). However, it has not been clearly established what impact moderate differentiation has on the prognosis (G2) [ 79 ].

4.3. Hormonal Receptors

The expression of steroid receptors—estrogenic and progesterone—is particularly important due to the favorable value of both prognostic and predictive value for hormonal treatment. This expression is assessed by immunohistochemical method (IHC) in tissue material fixed in buffered formalin and embedded in paraffin. If tissue material cannot be obtained, the expression of the receptors is assessed in the cytological material fixed in alcohol. The tissue material should come from the infiltrating component of the primary tumor, prior to systemic treatment. Due to the frequent phenomenon of hormonal profile change in metastatic tumors, it is recommended to reassess the expression of steroid receptors in metastatic material.

The scale used to determine the expression of hormone receptors is the Allrad scale, according to which the percentage of stained nuclei of cancer cells (PS 0–5) and the strength of coloration (IS 0–1) should be assessed. The sum of both parameters is the total value of TS (TS = PS + IS 0–8). In practice, however, as justified by the recommendations of the International Breast Cancer Conference of St. Gallen, only the percentage of colored cell nuclei is considered. Any reaction in the ≥1% of cancer cells is considered positive [ 80 , 81 , 82 ].

In every patient with current steroid receptors, hormone therapy should be used, regardless of age, condition of regional lymph nodes or additional indications for chemotherapy. The efficacy of complementary treatment with tamoxifen and aromatase inhibitors in hormone-sensitive patients has been demonstrated in numerous randomized controlled trials. In turn, the first reports on the prognostic value of primarily the estrogen receptor were published in the second half of the twentieth century [ 83 , 84 , 85 , 86 , 87 , 88 , 89 ]. Steroid receptor expression is associated with better prognosis and lower sensitivity to chemotherapy.

4.4. HER-2 Receptor

The prognostic and predictive value for targeted treatment is also the overexpression of the HER-2 receptor or amplification of the HER-2 gene. The HER-2 state should be determined in the histological material. The assessment of the HER-2 status in the cytological material is of lower value because the staining reaction used in the determination of the receptor occurs in the cell membrane, which is easily damaged during a fine needle aspiration biopsy.

Determining the HER-2 status requires the use of two methods—immunopathological at each diagnosis of infiltrating cancer ( Table 5 ) and the method of in situ hybridization in immunohistochemically borderline cases (about 15–20% of cases). About 10% of ambiguous cases show amplification of the HER-2 gene after in situ hybridization (FISH or CISH), which is interpreted as a positive state. The in situ hybridization method involves counting a copy of the HER-2 gene (single probe) or a copy of the HER-2 gene and the number of centromeres of chromosome 17 (double probe). The test result is the average number of copies of the HER-2 gene per cell or the ratio of the number of copies of the HER-2 gene to the number of centromeres. Cases without amplification of the HER-2 gene are treated as negative.

HER-2 receptor IHC rating scale, interpretation.

The HER-2 receptor belongs to the family of four ERBB receptors. The first of these—the EGFR receptor (ERBB1), i.e., the epidermal growth factor receptor with tyrosine kinase properties, is a target for many molecularly targeted drugs. Its ligand is epidermal growth factor (EGF) and TGF-α. The HER-2 receptor (ERBB2), the second in the ERBB receptor family, does not have a specific ligand. Its role is to enhance signal transduction by heterodimerization with other ERBB receptors. Heterodimer with ERBB3 receptor is the strongest signal transducing complex. The presence of overexpression of the HER2 receptor or amplification of its gene is an unfavorable prognostic factor, and the introduction of drugs that block the HER-2 receptor, i.e., trastuzumab, T-DM1, pertuzumab, lapatinib, significantly improved the prognosis of patients. In the meta-analysis of phase III studies, min. HERA studies have shown that the addition of trastuzumab, a monoclonal antibody directed against the HER-2 receptor, to adjuvant chemotherapy is associated with a 40% reduction in the relative risk of recurrence and a relative risk of death of 34% compared to left chemotherapy alone [ 89 ].

Studies have shown that the improvement in prognosis also applies to patients treated palliatively. The best example of studies confirming the effectiveness of adjuvant trastuzumab therapy in patients with early HER2-positive breast cancer are 4 international randomized trials-HERA, NSABP-B31, NCCTG-N98 and BCIRG 00, of which the HERA study became a registration study in the above indication [ 90 , 91 , 92 , 93 , 94 ]. One of the first studies to assess the importance of trastuzumab in the first line of treatment for patients with advanced breast cancer was Slamon et al. [ 89 ]. The study showed that adding trastuzumab to chemotherapy (CHT) in the first line of treatment significantly improved prognosis.

Inhibition of HER2 in breast cancer with HER2 amplification is clinically effective, as demonstrated by the effectiveness of HER kinase inhibitors and HER2 antibody treatment. Although resistance to HER2 inhibition is common in the case of metastasis, specific programs that follow HER2 resistance have not been established. In the work of Smith et al. [ 95 ], through genomic profiling of 733 breast cancers with HER2 amplification, enrichment of somatic changes that promote MEK/ERK signaling in metastatic tumors with reduced progression-free survival after anti-HER2 therapy was identified. These mutations, including NF1 loss and ERBB2 activating mutations, are sufficient to mediate resistance to FDA-approved HER2 kinase inhibitors, including tucatinib and neratinib. Moreover, resistant cancers lose their dependence on AKT, undergoing dramatic sensitization to MEK/ERK inhibition. Mechanically, this driver path switch is the result of the activation of MEK-dependent CDK2 kinase. These results define the genetic activation of MAPK as a recurrent mechanism of resistance to anti-HER2 therapy that can be effectively combated with MEK/ERK inhibitors.

Although rare, HER2 mutations appear as important molecular changes that need to be identified, for example, in patients with metastasis, tumors with HER2 mutations may respond to specific tyrosine kinase inhibitors. HER2 mutation may also be a mechanism of resistance to anti-HER2 therapeutic compounds.

4.5. Proliferation Rate Ki67

The Ki67 protein, used in the evaluation of the cellular proliferation index, is a nuclear protein present in all phases of cell division, except the resting phase of G0, and therefore in all actively proliferating cells. The Ki67 protein is identified by immunohistochemical method. The percentage of colored testicles of cancer cells is the value of the cell proliferation index Ki67. However, the positive reaction criterion has not been fully established. It is assumed that 20% is the limit of low and high proliferation.

Currently, the assessment of the cellular proliferation index Ki67 is an essential element of the pathomorphological study, allowing to determine the final luminal subtype of cancer (A or B) and the degree of histological malignancy (G).

The high proliferation index has an unfavorable prognostic significance not only as a component of histological malignancy, but also as an independent prognostic factor [ 93 ].

4.6. Polygenic Prognostic Factors

The development of molecular biology and genetics allowed for the separation of many new prognostic factors (mainly genes), and the introduction of new technologies to create tools for their determination. These tools are multi-gene predictive tests, currently used to estimate the risk of relapse in individual patients and the benefits of the proposed treatments. In practice, these tests are primarily used to qualify patients with early luminal cancer for adjuvant chemotherapy, in addition to standard hormone therapy. The most well-known tests are Oncotype DX and Mammaprint, of which only Oncotype DX was included in the VIII edition of the TNM classification [ 28 ].

One of the prognostic factors widely commented on recently is the complete pathological response (pCR) obtained through induction chemotherapy. Evaluated in several studies, some contradictory, it has been meta-analyzed by Spring et al. and published in Clinical Cancer Research in 2020. This meta-analysis showed that the achievement of pCR as a result of preoperative systemic treatment was associated with an increase in event-free survival (HR = 0.31; 95% PI, 0.24–0.39), especially in the case of triple-negative cancer (HR = 0.18; 95% PI, 0.10–0.31) and HER2 positive (HR = 0.32; 95% PI, 0.21–0.47), as well as an increase in overall survival (HR = 0.22; 95% PI, 0.15–0.30) [ 86 ]. The results obtained were not dependent on subsequent adjuvant therapy. The pCR obtained through induction systemic therapy was considered a favorable prognostic factor for breast cancer [ 96 ].

5. Biological Types of Breast Cancer

Routinely determined elements of the pathomorphological examination seem insufficient to predict the clinical course of breast cancer, which makes it difficult to make appropriate therapeutic decisions. The diverse clinical course of cancers with similar morphological characteristics is due to their different gene profile.

The study of gene expression allowed the identification of five molecular subtypes of breast cancer, such as: luminal A, luminal B, HER-2 positive non-”luminal”, basal-like and special histological types. These surrogates correspond to the immunophenotypes of cancer cells determined according to pathological criteria.

The luminal type A is characterized by high expression of genes associated with the activity of estrogen receptors and at the same time low expression of genes associated with proliferation and genes associated with expressed by the HER2 receptor.

Luminal type B is characterized by a positive ER status associated with low expression of genes associated with this receptor and higher than in type A expression of genes associated with the assessed proliferation by marking Ki-67. A panel of panelists in St. Gallen recognized the meltdown and expression of the Ki-67 as factors that could be used to differentiate between tumors of luminal type A and subtype B [ 97 ]. This is important in the prognostic assessment, which is better in type A.

The next type is basal-like breast carcinoma, also called triple negative cancer due to the absence of estrogen and progesterone receptors and the lack of expression of the HER2 receptor- consequently, there is no expression of genes associated with these receptors. The group of patients with this type of cancer with metastases to the cerebellum is particularly interesting, in their case the use of biological markers (CK 5/6, HER1, c-KIT) can help in the restoration of the basal subtype similar and dissimilar, nevertheless, their clinical usefulness is ambiguous.

The molecular subtype of breast cancer HER2- positive is characterized by overexpression of HER2 combined with the absence of ER and PR.

Breast cancer is the most common cancer in women. Every year, the results of many clinical trials are published, only some of which cause a change in the standard of conduct. Treatment rules for patients with early breast cancer are updated every two years as part of a consensus set by experts St. Gallen International Breast Cancer Conference. Similarly, the European Society for Medical Oncology (ESMO) is developing its recommendations for the treatment of patients with breast cancer at an early stage. Recent Recommendations from St. Gallen (2019) highlight the progress that has been made, particularly in the management of HER2-positive and triple-negative breast cancers with residual disease after preoperative treatment [ 98 ].

6. Breast Cancer Treatment

The basic types of surgical procedures used in women treated for breast cancer are:

• - tumor excision;
• - mastectomy;
• - excision of the sentinel lymph node;
• - excision of the armpit lymphatic system.

Breast amputation is performed in patients who, due to the severity of the disease, do not qualify for breast-sparing treatment or do not agree to perform breast-sparing surgery. Breast amputation involves the removal of the entire breast and the entire skin covering the mammary gland (the exception is subcutaneous amputation). It is possible to make:

• - simple amputation—this is most often a palliative procedure in patients who are not eligible for radical treatment;
• - subcutaneous amputation, consisting in the removal of breast gland tissue and the nipple-areola complex, but leaving the skin;
• - modified radical mastectomy according to the Patey method, consisting in the removal of the mammary gland, lymph nodes of the axillary fossa, pectoral muscle minor and fascia of the pectoral muscle major;
• - modified radical mastectomy according to the Madden method, consisting in the removal of the mammary gland along with the fascia of the pectoral muscle major and the lymph nodes of the armpit in one tissue block;
• - radical mastectomy according to the Halsted method—performed in patients who have been diagnosed with infiltration of the cancer process on the pectoral muscles, consists in the removal of the mammary gland, lymph nodes of the axillary fossa, pectoral muscle larger. This treatment is currently rarely used [ 99 , 100 ].

Currently, breast conserving therapy (BCT), which is a method used in early forms of cancer, is becoming more and more widely used, and is characterized by the same effectiveness. Patients who meet the criteria for eligibility for sparing treatment, in accordance with the guidelines of the Association of Breast Surgery, should be offered the opportunity to choose between this treatment and mastectomy. Surgical treatment of breast cancer can take the form of sparing treatment consisting of:

• - removal of the tumor along with the margin of healthy tissues;
• - quadrantectomy;
• - surgery within the axillary fossa (all lymph nodes of the axillary fossa—axillary lymphadenectomy or sentinel lymph node).

The main purpose of surgery of patients treated for breast cancer is oncological completeness. Both in the case of radical mastectomy and breast conserving therapy, the appropriate cosmetic effect is important [ 98 ]. In the treatment of breast cancer, in addition to surgical intervention, adjuvant treatment is used consisting in the use of radiotherapy, chemotherapy, hormone therapy and immunotherapy or a combination of these methods. Radiation therapy is used in all patients treated with methods that spare the mammary gland, it reduces the risk of recurrence of the disease process. Indications for the use of adjuvant radiotherapy also include the occurrence of metastases in at least four axillary lymph nodes and the presence of positive tissue margins. The chest area and nodal fields are irradiated. Another type of adjuvant treatment is chemotherapy involving the use of cytostatics. This method is used in case of generalization of the disease process. It can be associated with radiation therapy. In breast amputees with indications for supplemental radiotherapy, it should be performed after the end of adjuvant chemotherapy. Hormone treatment is used in patients with breast cancer with estrogen receptor expression; it is used regardless of age and menopausal state. Another reason for using hormone therapy is to reduce the number of hormones secreted and alleviate the ailments and symptoms associated with cancer [ 101 ].

Thanks to advances in diagnostics, modern oncology can offer a personalized course of treatment—adapted to the characteristics of a given cancer. Doctors gained access to multigene tests, which, when used in a properly selected group of patients, are a valuable diagnostic tool. They help to plan the optimal treatment for a given patient and assess the likelihood of recurrence of the disease.

Diagnostic tests are used to measure the activity of a group of genes in breast cancer cells such as the Oncotype DX Breast Recurrence Score.

Its use was presented in the TAILORx clinical trial [ 102 ]. The study enrolled 10,273 breast cancer patients without lymph node metastases, estrogen receptor expression, and HER2 receptor expression. Based on the Oncotype DX test, patients with an intermediate risk of cancer recurrence were randomly assigned to an arm of the study in which only hormone therapy was used or to an arm in which patients were given chemotherapy together with hormone therapy. It was found that in the studied group of patients, independent hormone therapy is no less effective than combined chemotherapy with hormone therapy. Thanks to the results of a groundbreaking study, it is possible to safely avoid chemotherapy in the case of up to 70% of patients diagnosed with the most common form of breast cancer. The Oncotype DX Breast Recurrence Score is a diagnostic test which, based on the analysis of the expression of 21 genes, distinguishes three prognostic groups: with low, intermediate, and high risk of recurrence. The result of the study may help doctors make decisions about the optimal treatment of patients in the early stages of invasive breast cancer showing estrogen receptor activity (ER+), without expressing epidermal growth factor receptors (HER2-negative). The Oncotype DX test determines in this case the likelihood of a beneficial effect of the use of chemotherapy in combination with hormone therapy on treatment. Genetic tests in Oncotype DX work well in patients with Luminal A and B cancers, i.e., with positive estrogen and progestogen receptors, negative HER 2 and “clean” lymph nodes. Especially patients under 50 years of age are the group that can benefit most from the individualization of treatment. Patients with early breast cancer and good prognostic factors (ER+, PGR+, HER2−) are eligible for surgical treatment in the first place. After excision of the breast tumor and its histopathological evaluation and assessment of sentinel nodes (if there are no metastases in them), there is time to perform tests such as OncotypeDX or Mammaprint. The results of the tests make it easier to decide whether the patient should benefit from hormone therapy or chemotherapy will also be necessary and often put a dot over and in the qualification for treatment and allow the patient to be sure of the correctness of the choice of a specific therapy.

7. Recent Treatments for Triple Negative Breast Cancer

Among breast cancers, triple negative breast cancer (TNBC) is the most aggressive, and for its histochemical and molecular characteristics is also the one whose therapeutic opportunities are most limited. In case of breast cancer, a significant clinical problem is provided by the group of patients with no expression of any receptors, qualifying to hormonal therapy or target therapy against HER2 (the human epidermal growth factor receptor-2). The subtype of the disease, characterized by the lack of expression of estrogen receptors (ERs), the progesterone receptor (PR) and HER2, is referred to as the triple-negative breast cancer (TNBC). The triple-negative subtype constitutes approximately 15–20% of all breast cancer cases, its incidence being higher among younger women and is characterized by different biological features, unfavorable clinical course and poor prognosis. During the recent years, a thesis has been put forward that triple-negative breast cancer is a separate, heterogenic subtype of breast cancer, formed in the mechanism of different oncogenesis pathways, characterized by different prognoses and dependent on various clinical, pathological, and genetic factors. Despite its aggressive clinical course, the triple-negative breast cancer responds to chemical therapy, the response rate being very high. However, the disease recurrences are very frequent, while the lack of targeted therapy makes this cancer subtype very unfavorable from the prognostic point of view. No unequivocal principles of management have till now been proposed in the TNBC subgroup.

PARP inhibitors. So far, the Food and Drug Administration (FDA) has approved olaparib and thalasoparib for use in patients with advanced breast cancer with a germinal BRCA1/2 mutation [ 103 , 104 , 105 ]. The effectiveness of thalasoparib was proven in a phase III study, in which this drug was compared with standard chemotherapy, and its choice depended on the attending physician (in practice, capecitabine, vinorelbine, gemcitabine, eribulin). The I-row endpoint was progression-free survival (PFS). This study showed that thalasoparib was associated with a longer PFS duration (8.6 vs. 5.6 months, p < 0.001), thalasoparib was also better tolerated. Forty-five percent of patients were TNBC; 55% were HR+. Olaparib was validated based on a phase III study, with a very similar design to the EMBRACA study (with thalasoparib). The olaparib study showed that the use of this drug, compared to standard CHT, was associated with statistically significant PFS prolongation (7 vs. 4.2 months, p < 0.001). The tolerability of the treatment was also better. Patients eligible for the study, in addition to the current germline BRCA mutation, had to be HER2-. In both of the above studies, patients were previously treated (with anthracyclines and taxanes) and hormonotherapy [ 104 , 106 ].

Sacituzumab govitecan is a conjugate antibody directed against the surface tropoblast antigen Trop-2 along with the active metabolite irinotecan SN-38 [ 106 ]. A Phase 1/2 study evaluated the safety of sacituzumab govitecan in patients with advanced TNBC who had previously been treated with two chemotherapy (CHT) lines. Other endpoints included objective response rate, length of response, degree of clinical benefit, PFS, and OS. This study showed that the use of the above drug was associated with a benefit in the form of long-term objective responses. The 108 patients with triple-negative breast cancer had received a median of three previous therapies (range, 2 to 10). Four deaths occurred during treatment; three patients (2.8%) discontinued treatment because of adverse events. Grade 3 or 4 adverse events (in ≥10% of the patients) included anemia and neutropenia; 10 patients (9.3%) had febrile neutropenia. The response rate (3 complete and 33 partial responses) was 33.3% (95% confidence interval [CI], 24.6 to 43.1), and the median duration of response was 7.7 months (95% CI, 4.9 to 10.8); as assessed by independent central review, these values were 34.3% and 9.1 months, respectively. The clinical benefit rate was 45.4%. Median progression-free survival was 5.5 months (95% CI, 4.1 to 6.3), and overall survival was 13.0 months (95% CI, 11.2 to 13.7). The main adverse reaction was hematological toxicity.

Immunotherapy as monotherapy. Documented efficacy in TNBC has a doublet of atezolizumab along with nab-paclitaxel-study IMpassion130 [ 107 , 108 ]. Anti-PD-1 or anti-PD-L1 monotherapy is still under investigation, but the U.S. FDA has approved the use of pembrolizumab in previously treated BC patients, after exhaustion of therapy options that have shown microsatellite instability or dMMR (The National Comprehensive Cancer Network (NCCN) recommendations). Recently, the results of meta-analyses and systematic reviews have appeared, which indicate the possible effectiveness of anti-PD1 and anti-PD-L1 antibodies in patients with TNBC. Studies have evaluated the efficacy of pembrolizumab, atezolizumab and avelumab, including their effects on ORR, PFS, OS. The results are promising, mainly in the group of patients expressing PD1 or PD-L1, especially when immunotherapy is used in the 1st line of treatment. It seems important to confirm the effectiveness of immunotherapy in TNBC characterized by a particularly poor prognosis, the treatment of which is currently limited to standard CHT.

In the aforementioned 2019 IMpassion130 study, it was shown that the use of atezolizumab with nab-paclitaxel in 1 line of treatment compared to nab-paclitaxel and placebo in patients with advanced TNBC was associated with an increase in the median PFS from 7.2 to 5.5 months ( p = 0.002) in the ITT population, and in the PD-L1 expressing population 7.5 vs. 5.0 months ( p < 0.001). However, in August 2021, the company producing atezolizumab voluntarily withdrew this drug from the indications for the treatment of TNBC. Currently, the only registered checkpoint inhibitor is pembrolizumab—for neoadjuvant treatment along with CHT TNBC with a high risk of relapse, with follow-up adjuvant therapy—based on the Keynote 522 study, and for the treatment of advanced TNBC with PDL1 expression (CPS > 10) based on the Keynote 355 study, as well as in patients with MSI-H and dMMR. In the latter indication, dostarlimab-gxly is also registered. Research is ongoing on other checkpoint inhibitors, including the previously described monotherapy [ 109 , 110 ].

The work of Spini et al. [ 111 ] provides an overview of all evidence regarding the reuse of old, licensed non-cancer drugs for the treatment of TNBC, ranging from preclinical evidence to current clinical trials.

Beta-blockers (BBs) appear to be promising drugs for reuse in the treatment of TNBC. While BB has been shown to be beneficial in the treatment of TNBC, metformin, a promising molecule in preclinical studies, has shown no efficacy in treating women with TNBC. Metformin does not improve survival outcomes in the female population with TNBC compared to women who do not use TNBC. It is worth noting that two studies are underway on the use of metformin in clinical trials in patients with TNBC.

Articles by Shiao et al. [ 112 ] and Williams et al. [ 113 ] showed conflicting results for aspirin. While the first study showed a significant improvement in survival in Grade II/III women through the use of aspirin, Williams et al. did not demonstrate this benefit in the breast cancer study population (women with operative I-III TNBC at stage).

Recently, one phase II study on omeprazole activity in patients with operative TNBC was presented at the ASCO meeting, regardless of baseline fatty acid synthase expression (FASN) [ 114 ]. In vitro, proton pump inhibitors inhibit FASN activity and induce apoptosis in breast cancer cell lines. In this study, 42 patients were given omeprazole in combination with anthracycline-taxane (AC-T) until surgery and a complete pathological response (pCR) was investigated. A positive FASN score decreased significantly for omeprazole from 0.53 (SD = 0.25) at baseline to 0.38 (SD = 0.30; p = 0.02), and the drug was well tolerated without known Grade 3 or 4 toxicity. In addition, the percentage of pCT was 71.4% (95% CI: 51.3–86.8) in patients with FASN+ and 71.8% (95% CI: 55.1–85.0) in all enrolled patients, indicating that omeprazole, in addition to neoadjuvant AC-T, provides a promising PCR rate without adding toxicity. From the literature obtained, BBs seemed to be more promising drugs for repurposing.

Agents that target angiogenesis have shown limited efficacy for human triple-negative breast cancer (TNBC) in clinical trials [ 113 ]. Considering the recommendations of the National Comprehensive Cancer Network (NCCN), the only drug that improved the endpoints of studies evaluating the effectiveness of anti-VEGF drugs with chemotherapy was bevacizumab. Ramucirumab, sorafenib and sunitinib were also studied [ 115 ].

According to NCCN:

• - study E2100 (more than 700 patients) evaluated the combination of bevacizumab with paclitaxel vs. paclitaxel with placebo in line 1 treatment for breast cancer recurrence/spread. This study showed that the addition of bevacizumab allowed for prolongation of the median PFS;
• - a similar study (more than 700 patients) evaluated the doublet bevacizumab plus docetaxel vs. docetaxel with placebo and in this study also achieved improvements in PFS in the combination group (AVADO study);
• - in the RIBBON-1 study, bevacizumab was attached to capecitabine, to taxane (docetaxel or nab-paclitaxel), to anthracyclines—here also PFS elongation was achieved by adding bevacizumab to CHT (study with 2nd line of treatment; the next study with 2nd line was IMELDA-elongation and PFS and OS were shown)
• - the last study mentioned by the NCCN was the Phase III CALGB 4050 study, which evaluated the addition of bevacizumab to nab-paclitaxel in line 1 of advanced TNBC treatment and achieved a median PFS of 7.4 months. In general, research shows that the addition of bevacizumab has an effect on ORR and PFS, but not OS and QoL.

One study showed that bevacizumab used in neoadjuvant lengthened both PFS and OS slightly (NSABP B-40 study).

8. The Role of Non-Coding RNAs in Breast Cancer

The development of molecular biology has made it possible to conduct research at the level of the human genome. In 2003, its full sequence was published. Subsequently, it was discovered that only 1.2% of human genetic material encodes protein, with 93% of genes being transcribed. The huge pool of non-coding RNA molecules has aroused great interest among scientists. The subject of careful analysis in breast cancer became microRNAs, single-stranded RNA molecules with a length of 21 to 23 nucleotides, regulating the expression of other genes [ 116 , 117 , 118 , 119 ].

The first reports of the possible significance of altered miRNA expression in breast cancer were published in 2005. Over the past decade, several miRNA molecules involved in the initiation, progression, and metastasis of breast cancer have been identified [ 104 ]. The relationship between the expression of individual miRNAs and the clinical-pathological features of breast cancer, or the response to causal treatment of this malignant tumor,” has also been determined [ 115 ]. For example, studies have shown that in triple-negative breast cancer, there is an overexpression of oncogenic molecules miR-21, miR-210, miR-221, which is associated with a shorter disease-free time and worse survival [ 86 ]. Molecules with reduced expression, and therefore suppressor potential, are, for example, miR125-b in the case of HER-2 positive cancers, or miR-520 in hormone-dependent cancers [ 117 , 118 ].

Singh and Mo presented a review article on miRNA families, which play an important role in the course of the discussed malignant tumor. They paid attention to the miR-10 family, from which miR-10a and miR-10b are involved in the development and metastasis of breast cancer [ 116 ]. Overexpression of miR-10b is associated with a higher degree of cancer according to the TNM classification (larger size of the primary tumor, presence of metastases in the lymph nodes), a greater degree of cellular proliferation, overexpression, or amplification of the HER-2 receptor [ 117 ].

However, it is negatively correlated with the presence of steroid receptors and the concentration of E-cadherin, which seems to play a role in the suppression of the metastasis process in the EMT (Epithelial-mesenchymal transition) mechanism [ 105 ]. Metastasis, as well as a worse course of particularly ductal breast cancer and consequently shorter overall survival time is also associated with the oncogenic miR-21 family [ 104 ]. Among the families of suppressor miRNAs, with reduced expression in cancerous breast tissue compared to healthy tissue, the aforementioned authors mentioned the miR-200 family and miR-205 and miR-145.

MiR-200 and miR-205 probably inhibit the metastasis process associated with the EMT mechanism, and miR-145 affects cell apoptosis [ 119 ].

On the other hand, in a 2019 review article by Loh et al., the decisive oncogenic potential of the miR-200 family was described [ 120 ]. Increased concentrations of individual miR-200s were associated not only with breast cancer’s ability to form distant metastases, but also with resistance to chemotherapy [ 121 ].

The relationship between the expression of the rich miRNA family and the cell cycle, including the disturbed tumor cell cycle, certainly requires further analysis. However, there is no doubt that the molecules in question have a huge prognostic, predictive and therapeutic potential. Promising research results have prompted scientists to search for new regulatory molecules.

Of particular recent interest are long non-coding RNAs, or lncRNAs. An extensive description of lncRNA was presented by the authors of this article in a review paper Smolarz et al. [ 122 ].

The assessment of the achievements over recent years in the treatment of patients with breast cancer, with the simultaneous lack of fully satisfactory results and satisfactory solutions, suggests that further progress in the development of new methods of combating cancer will bring us closer to a new era in this field.

Funding Statement

This research has received no external funding.

Author Contributions

Conceptualization, B.S., A.Z.N. and H.R.; writing—original draft preparation, B.S.; writing—review and editing B.S.; revision and proofreading B.S. All authors have read and agreed to the published version of the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Breast Cancer Research Results and Study Updates

See Advances in Breast Cancer Research for an overview of recent findings and progress, plus ongoing projects supported by NCI.

Some people with no evidence of cancer in nearby lymph nodes after presurgical chemotherapy can skip radiation to that area without increasing the risk of the cancer returning, a clinical trial found. But some experts caution that more details are needed.

For women in their 70s and older, the risk of overdiagnosis with routine screening mammography is substantial, a new study suggests. The findings highlight the need for conversations between older women and their health care providers about the potential benefits and harms of continuing screening mammography.

Many young women who are diagnosed with early-stage breast cancer want to become pregnant in the future. New research suggests that these women may be able to pause their hormone therapy for up to 2 years as they try to get pregnant without raising the risk of a recurrence in the short term.

For younger women with advanced breast cancer, the combination of ribociclib (Kisqali) and hormone therapy was much better at shrinking metastatic tumors than standard chemotherapy treatments, results from an NCI-funded clinical trial show.

In a large clinical trial, a condensed course of radiation therapy was as effective and safe as a longer standard course for those with higher-risk early-stage breast cancer who had a lumpectomy. This shorter radiation course makes treatment less of a burden for patients.

Adding the immunotherapy drug pembrolizumab (Keytruda) to chemotherapy can help some patients with advanced triple-negative breast cancer live longer. In the KEYNOTE-355 trial, overall survival improved among patients whose tumors had high levels of the PD-L1 protein.

People with metastatic breast cancer whose tumors had low levels of HER2 protein lived longer after treatment with trastuzumab deruxtecan (Enhertu) than those treated with standard chemotherapy, results of the DESTINY-Breast04 clinical trial show.

NCI researchers have shown that an experimental form of immunotherapy that uses an individual’s own tumor-fighting immune cells could potentially be used to treat people with metastatic breast cancer who have exhausted all other treatment options.

Most breast cancer risk tools were developed with data mainly from White women and don’t work as well for Black women. A new tool that estimates risk for Black women may help identify those who might benefit from earlier screening, enabling earlier diagnosis and treatment.

In people with metastatic HER2-positive breast cancer, the targeted drug trastuzumab deruxtecan (Enhertu) markedly lengthened progression-free survival compared with trastuzumab emtansine (Kadcycla), new study results show.

In a large clinical trial, women with HR-positive, HER2-negative metastatic breast cancer treated with ribociclib (Kisqali) and letrozole (Femara) as their initial treatment lived approximately 1 year longer than women treated with letrozole only.

Women with early-stage breast cancer who had one or both breasts surgically removed (a unilateral or bilateral mastectomy) had lower scores on a quality-of-life survey than women who had breast-conserving surgery, a new study has found.

For women undergoing chemotherapy for breast cancer, meeting the national physical activity guidelines may help alleviate cognitive issues, a new study suggests. The benefits may be even greater for patients who were physically active before treatment.

Sacituzumab govitecan (Trodelvy) now has regular FDA approval for people with locally advanced or metastatic triple-negative breast cancer (TNBC). The update follows last year’s accelerated approval of the drug for people with TNBC.

For some people with ER-positive breast cancer, a new imaging test may help guide decisions about receiving hormone therapy, according to a new study. The test can show whether estrogen receptors in tumors are active and responsive to estrogen.

The test, which helps guide treatment decisions, was not as good at predicting the risk of death from breast cancer for Black patients as for White patients, a new study has found. The findings highlight the need for greater racial diversity in research studies.

The drug abemaciclib (Verzenio) may be a new treatment option for people with the most common type of breast cancer, with new study findings suggesting that it can reduce the risk of the cancer returning.

Fertility preservation for young women with breast cancer doesn’t increase their risk of dying in the ensuing decades, a new study affirmed. Experts said the findings support routinely offering fertility preservation to patients who want it.

Some postmenopausal women with HR-positive, HER2-negative breast cancer may not benefit from chemotherapy and can safely forgo the treatment, according to clinical trial results presented at the San Antonio Breast Cancer Symposium.

A heart-related event, like a heart attack, may make breast cancer grow faster, a new study suggests. In mice, heart attacks accelerated breast tumor growth and human studies linked cardiac events with breast cancer recurrence, researchers reported.

FDA has approved sacituzumab govitecan (Trodelvy) for the treatment of triple-negative breast cancer that has spread to other parts of the body. Under the approval, patients must have already undergone at least two prior treatment regimens.

Women with high-risk breast cancer who engaged in regular exercise before their cancer diagnosis and after treatment were less likely to have their cancer return or to die compared with women who were inactive, a recent study found.

Researchers have developed a “microscaled” approach to analyze the proteins and genetic changes (proteogenomics) of a tumor that uses tissue from a core needle biopsy. The analyses can provide important information that may help guide treatment.

Tucatinib improved survival for women in the HER2CLIMB trial, including some whose cancer had spread to the brain. Trastuzumab deruxtecan improved survival and shrank many tumors in the DESTINY-Breast01 trial, which led to its accelerated approval.

A TAILORx analysis shows women with early-stage breast cancer and high recurrence scores on the Oncotype DX who received chemotherapy with hormone therapy had better long-term outcomes than what would be expected from hormone therapy alone.

Men with breast cancer may be more likely to die of the disease than women, particularly during the first 5 years after diagnosis, a new study suggests. The higher likelihood of death was linked in part to undertreatment and later diagnosis.

In a survey of nearly 600 breast cancer survivors, researchers found that the cost of care factored into the decisions the women made about what type of surgery to get. Many women also reported never discussing costs with their physicians.

FDA has expanded the approved use of the drug ado-trastuzumab emtansine (Kadcyla), also called T-DM1, to include adjuvant treatment in some women with early-stage HER2-positive breast cancer.

Many women diagnosed with ovarian and breast cancer are not undergoing tests for inherited genetic mutations that can provide important information to help guide decisions about treatment and longer-term cancer screening, a new study has found.

FDA has approved atezolizumab (Tecentriq) in combination with chemotherapy for the treatment of some women with advanced triple-negative breast cancer. This is the first FDA-approved regimen for breast cancer to include immunotherapy.

The build-up of connective tissue around some types of cancer can act as a barrier to immunotherapy. A new study uses a bone marrow transplant drug, plerixafor, to break down this barrier and improve the efficacy of immune checkpoint inhibitors in animal models of breast cancer.

A new study in mice shows that disrupting the relationship between breast cancer cells that spread to bone and normal cells surrounding them makes the cancer cells sensitive to treatment.

In women with early-stage breast cancer, two clinical trials have shown that both whole- and partial-breast radiation therapy are effective at preventing the cancer from returning after breast-conserving surgery.

Researchers are testing a topical-gel form of the drug tamoxifen to see if it can help prevent breast cancer as effectively as the oral form of the drug but with fewer side effects.

Findings from a clinical study and a mouse study may shed light on genetic risk factors for developing cancer-related cognitive problems in older breast cancer survivors. The results suggest a gene associated with Alzheimer’s disease may play a role.

Arsenic trioxide and retinoic acid work together to target the master regulator protein Pin1, a new study shows. In cancer cell lines and mice, the drug combination slowed the growth of triple-negative breast cancer tumors.

FDA has expanded the approved uses of ribociclib (Kisqali) for women with advanced breast cancer, including new uses in pre- and postmenopausal women. It’s the first approval under a new FDA program to speed the review of cancer drugs.

Using a liquid biopsy to test for tumor cells circulating in blood, researchers found that, in women with breast cancer, the presence of these cells could identify women at risk of their cancer returning years later.

Findings from the TAILORx clinical trial show chemotherapy does not benefit most women with early breast cancer. The new data, released at the 2018 ASCO annual meeting, will help inform treatment decisions for many women with early-stage breast cancer.

Do cancer study participants want to receive their genetic test results? A recent study involving women with a history of breast cancer tested an approach for returning genetic research results and evaluated the impact those results had on the women.

Researchers compared the risk of death for women with breast cancer who had low skeletal muscle mass, or sarcopenia, at the time of their cancer diagnosis and women who had adequate muscle mass.

Some people who have been treated for breast cancer or lymphoma have a higher risk of developing congestive heart failure than people who haven’t had cancer, results from a new study show.

FDA has approved the CDK4/6 inhibitor abemaciclib (Verzenio) as a first-line treatment in some women with advanced or metastatic breast cancer. Under the approval, the drug must be used in combination with an aromatase inhibitor.

A new study in mice raises the possibility that using microscopic, oxygen-carrying bubbles may improve the effectiveness of radiation therapy in the treatment of breast cancer.

The drug olaparib (Lynparza®) is the first treatment approved by the Food and Drug Administration for patients with metastatic breast cancer who have inherited mutations in the BRCA1 or BRCA2 genes.

Joint pain caused by aromatase inhibitors in postmenopausal women with breast cancer can cause some women to stop taking the drugs. Reducing their symptoms may translate into better adherence to therapy.

A new study suggests that the cells in treatment-resistant tumors in women with metastatic breast cancer share important characteristics that could potentially make tumors vulnerable to therapies that otherwise might not have been considered.

A large nationwide clinical trial called TMIST has been launched to compare two techniques used for mammograms: tomosynthesis, often called 3D mammography, and standard 2D digital mammography.

FDA approved abemaciclib (Verzenio™) for the treatment of some people with advanced or metastatic HR-positive, HER2-negative breast cancer whose disease has progressed after treatment with hormone therapy.

Long-term results from a large clinical trial confirm that, for some women with early-stage breast cancer who have lumpectomy as their surgical treatment, a less extensive lymph node biopsy approach is sufficient.

When given at the same time, two immune checkpoint inhibitors were ineffective against breast cancer growth in mice, a new study found. The combination was more effective and safer if the two inhibitors were given in a specific sequence.

FDA has expanded its approval of fulvestrant (Faslodex®) as a standalone treatment for postmenopausal women with advanced HR-positive, HER2-negative breast cancer who have not previously undergone endocrine therapy.

Many women who receive taxane-based chemotherapy to treat breast cancer experience long-term nerve damage, or peripheral neuropathy, data from a large clinical trial show.

Researchers recognized the potential of endoxifen as a treatment for breast cancer and, with NCI support, developed the compound into a drug now being tested in clinical trials.

Researchers have used modified stem cells to deliver a cancer drug selectively to metastatic breast cancer tumors in mice. The stem cells target metastatic tumors by homing in on the stiff environment that typically surrounds them.

FDA has approved neratinib for patients with early-stage HER2-positive breast cancer who have finished at least 1 year of adjuvant therapy with trastuzumab.

Many survivors of early-stage breast cancer prefer that their oncologist handle aspects of routine medical care usually overseen by primary care practitioners, leading to concerns about gaps in care.

Results from the first large prospective study of breast and ovarian cancer risk in women with inherited mutations in the BRCA 1 or BRCA2 genes confirm the high risks estimated from earlier, retrospective studies.

Two clinical trials show that trastuzumab emtansine (T-DM1) improves survival compared with other standard treatments for patients with HER2-positive metastatic breast cancer that has progressed after treatment with other HER2-targeted drugs.

Using one of the largest collections of tumor samples from African Americans with breast cancer, researchers tried to assess the extent to which the molecular characteristics on these tumors might help to explain breast cancer disparities.

A new study shows that the number of women in the United States living with distant metastatic breast cancer (MBC), the most severe form of the disease, is growing. This is likely due to the aging of the U.S. population and improvements in treatment.

In a randomized trial, low-income women who role-played talking with their doctor about their survivorship care plan in a counseling session reported receiving more of their recommended care than women who did not get counseling.

The FDA has approved a new targeted therapy, ribociclib, and expanded its earlier approval of another targeted therapy, palbociclib, for some women with metastatic breast cancer.

Researchers have found that duloxetine (Cymbalta®), a drug most commonly used to treat depression, may also reduce joint pain caused by aromatase inhibitors in some women being treated for early-stage breast cancer.

Peer support interventions for breast cancer patients: a systematic review

Affiliations.

• 1 School of Nursing, Jilin University, Changchun, 130021, China.
• 2 Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, 130033, China.
• 3 Department of Anesthesiology, The First Hospital of Jilin University, Changchun, 130021, China.
• 4 School of Nursing, Jilin University, Changchun, 130021, China. [email protected].
• 5 Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, 130033, China. [email protected].
• PMID: 30600413
• DOI: 10.1007/s10549-018-5033-2

Purpose: Due to the clear efficacy of peer support as a means of improving emotional well-being and healthy behaviors in a highly cost-effective manner, this program is widely used. Controversy remains, however, with regard to its efficacy in breast cancer patients. Given the heterogeneity of peer support interventions, this review aimed to categorize, assess, and synthesize the existing evidence from randomized controlled trials (RCTs) to clarify the effects of different types of peer support on breast cancer patients.

Methods: We searched Pubmed, EMBase, CENTRAL, CINAHL, PsychINFO, Chinese National Knowledge Infrastructure (CNKI) and Wanfang Data for English and Chinese language RCTs. The Cochrane Collaboration 'risk of bias' tool for systematic reviews was used to assess the methodological quality of each RCT.

Results: Of the 1494 studies screened, 15 studies met eligibility criteria for inclusion, comprising 1695 breast cancer patients. Overall, there were more positive effects than invalid or negative effects across peer interventions, with notable exceptions: unmoderated and unstructured group peer support interventions as well as Internet-based models without peer training had no effect or adverse effects on proximal and distal outcomes. However, adding other peer roles to the peer support structure or using one-on-one models could significantly improve the patients' negative emotions. Peer education showed promising effects on stress management, quality of life, and healthy behaviors.

Conclusions: This systematic review found that different types of peer support have different effects on outcomes for breast cancer patients. Web-based group peer support without peer training must be avoided or used with caution in the future. Peer education is recommended for breast cancer patient support models, given its excellent results and cost-effectiveness.

Keywords: Breast cancer patients; Depression; Peer support; Systematic literature review.

Publication types

• Systematic Review
• Breast Neoplasms / psychology*
• Cost-Benefit Analysis
• Psychotherapy / methods*
• Quality of Life / psychology*
• Social Support

Grants and funding

• 31771093/National Natural Science Foundation of China

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• Review Article
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• Published: 04 May 2024

Clinical Studies

Impact of the COVID-19 pandemic on breast cancer patient pathways and outcomes in the United Kingdom and the Republic of Ireland – a scoping review

• Lynne Lohfeld   ORCID: orcid.org/0000-0003-4711-7305 1   na1 ,
• Meenakshi Sharma 1   na1 ,
• Damien Bennett 2 ,
• Anna Gavin 1 , 2 ,
• Sinéad T. Hawkins   ORCID: orcid.org/0000-0002-3340-2917 1 , 2 ,
• Gareth Irwin 3 ,
• Helen Mitchell 2 ,
• Siobhan O’Neill 3 &
• Charlene M. McShane 1  

British Journal of Cancer ( 2024 ) Cite this article

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• Breast cancer
• Health services

The COVID-19 pandemic brought unplanned service disruption for breast cancer diagnostic, treatment and support services. This scoping review describes these changes and their impact in the UK and the Republic of Ireland based on studies published between January 2020 and August 2023. Thirty-four of 569 papers were included. Data were extracted and results thematically organized. Findings include fewer new cases; stage shift (fewer early- and more late-stage disease); and changes to healthcare organization, breast screening and treatment. Examples are accepting fewer referrals, applying stricter referral criteria and relying more on virtual consultations and multi-disciplinary meetings. Screening service programs paused during the pandemic before enacting risk-based phased restarts with longer appointment times to accommodate reduced staffing numbers and enhanced infection-control regimes. Treatments shifted from predominantly conventional to hypofractionated radiotherapy, fewer surgical procedures and increased use of bridging endocrine therapy. The long-term impact of such changes are unknown so definitive guidelines for future emergencies are not yet available. Cancer registries, with their large sample sizes and population coverage, are well placed to monitor changes to stage and survival despite difficulties obtaining definitive staging during diagnosis because surgery and pathological assessments are delayed. Multisite longitudinal studies can also provide guidance for future disaster preparedness.

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Introduction.

Approximately 60,000 people are diagnosed with breast cancer annually in the United Kingdom (UK) and the Republic of Ireland (RoI) [ 1 , 2 ]. Services for screening, diagnosing, treating and follow up of patients provided through national health care services varied by country. During both the initial phase of the COVID-19 pandemic in 2020 and throughout subsequent peaks in transmission, various restrictions were implemented that limited and/or changed how breast cancer was diagnosed, treated and managed in much of the world [ 3 ], including the UK and RoI. Given the importance of early detection and treatment of cancer, there is concern over how COVID- related service delays may affect cancer patients now and in the future regarding stage at diagnosis, prognosis and mortality [ 4 ]. Because potentially life-changing decisions about cancer patients’ care have been made rapidly without the benefit of prior experience, there has been a sudden increase in studies examining possible pandemic impacts on breast cancer services and patients. To better understand the full impact of the COVID-19 pandemic on breast cancer diagnosis, treatment and patient outcomes in the UK and RoI, we conducted a scoping review that would examine findings from several studies conducted in these countries.

Scoping reviews aim to rapidly map key concepts in a research area that have not been studied comprehensively and identify research gaps in the existing literature [ 5 ].

The present scoping review used Arksey and O’Malley’s [ 6 ] framework, minus the last step of expert validation of findings due to resource constraints. Generally, this type of review does not include a critical appraisal of the constituent material. The Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist was used to report the review findings [ 7 ].

A systematic search was conducted on five electronic databases -- PubMed, Medline, Web of Science, Embase and PyschInfo -- using key words and MeSH headings for breast cancer services and outcomes in the countries of interest (Fig.  1 ). Inclusion criteria were publication in English in a peer-reviewed journal between 1 January 2020 and 31 August 2023, and reporting on primary data collected in the UK or RoI. Papers excluded from this report either did not meet the inclusion criteria or: described an intervention other than healthcare system changes or patient outcomes directly related to breast cancer; provided data from multiple locations without separately identifying results from the UK and/or the RoI; or were systematic reviews, conference abstracts, or proceedings, or unpublished (grey) literature. A hand search of the reference lists of each included paper was done.

Symbols: $ is a wildcard to expand the search term and find both British and American spellings of the same word. .mp. means multi-purpose for an Advanced search without specifying a particular field. / means the term preceding it is from the MeSH headings in MEDLINE.

Results from each electronic database were imported into the Covidence systematic review software [ 8 ], an online tool to support doing systematic reviews that automatically removes duplicate entries. Title and abstract screening was done independently by three reviewers (CM, LL, MS) who discussed differences of opinion about papers’ eligibility until reaching consensus. After removing ineligible studies, the remaining papers were downloaded and independently screened by the reviewers against the inclusion and exclusion criteria. Any differences of opinion were resolved through discussion. The reviewers included a cancer epidemiologist, a public health professional and a medical anthropologist.

Data were extracted from the selected papers and entered into an Excel spreadsheet containing information on the bibliography (authors, title, journal, publication date), study aims and design, geographic location, and key findings (Table  1 , Supplementary Material). Results were then organised thematically to describe the impact of the COVID-19 pandemic on the organisation of breast cancer services, referrals/diagnosis and number of cases, and treatment.

A study protocol was not written and registered. The scoping review is part of a larger study on the impact of COVID-19 on breast cancer services in Northern Ireland.

The electronic database search returned 569 studies. Following duplicate removal ( n  = 228), over half (176/341, 51.6%) of the screened studies were deemed irrelevant, leaving 165 studies for full-text review. Of these studies, 129 were excluded, primarily because they were published as a conference abstract. The remaining 34 papers used in the review included 16 studies conducted in England [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ], four in Scotland [ 25 , 26 , 27 , 28 ], three in [ 29 , 30 , 31 ] Wales, one in Northern Ireland [ 32 ], three in the UK [ 33 , 34 , 35 ], one in Ireland [ 36 ] and six that used data from multiple countries which included at least one site in the UK and/or [ 37 , 38 , 39 , 40 , 41 , 42 ] RoI. No additional studies of interest were identified in the hand search of reference lists (Fig.  2 ).

Prisma flowchart.

Impact of the COVID-19 pandemic on the organisation of breast cancer services

During the first wave of the COVID-19 pandemic (March–April 2020), population-based breast cancer screening programs were paused in many jurisdictions, including the UK and RoI. There were also major changes in how members of multidisciplinary teams (MDTs) met to develop treatment plans for breast cancer patients [ 11 , 37 ]. One study in an English hospital tested the acceptability of video-conferencing MDT meetings with participants attending in person or from a remote location. After overcoming minor technical difficulties (e.g. uninterrupted access to online meetings, ensuring participants had the necessary equipment to attend meetings remotely) all the participants indicated that online meetings were acceptable or their preferred mode of communication [ 11 ]. Another study surveyed breast pathologists in the UK and RoI who reported their MDTs often met in small virtual meetings [ 37 ]. Although nearly three-quarters of them indicated their workload and productivity decreased during the pandemic, 36% reported improved efficiency [ 37 ]. No study reported on the optimal balance between virtual and in-person meetings.

Three studies examined changes made to referral pathways to breast clinics or units in response to the COVID-19 pandemic [ 14 , 19 , 23 ]. One study, using data from England’s National Health Service, reported a 28% decline in referrals for suspected breast cancer during the first six months of 2020 compared to the same period in 2019 [ 14 ]. Another research group reported an even greater decline (−35%) in the number of women attending a one-stop rapid breast clinic in England during the initial lockdown (March-April 2020) compared to June-July that year [ 23 ].

A study reported on rapid adaptations made by a London-based breast cancer service in line with The Royal College of Surgeons guidelines to reduce the risk of COVID-19 [ 19 ]. Examples include providing space to maintain the recommended two metre distance between people; fewer appointments plus longer time between them to allow for thorough cleaning of surfaces; following stricter criteria for urgent referrals; and conducting routine follow-up appointments over the phone. In addition, although diagnostic imaging with ultrasound and mammogram continued to be available, all routine surveillance imaging was deferred for three months. Operations were conducted by small teams of specialists who travelled to a “cold” (free of COVID-19 cases) private hospital [ 19 ]. Virtual appointments quickly became the norm for many patients. However, as noted by one research team [ 14 ] this increased the potential for greater inequality of access to care by the elderly or people of lower socioeconomic status.

Several studies observed smaller-than-expected numbers of attendees at breast cancer screening and treatment centres [ 9 , 23 , 26 , 41 ]. This was noteworthy given the association between early detection through screening and the potential to reduce treatment needed potential to reduce treatment needed with better patient outcomes. Reasons for the downtrend in attendance ranged from centres issuing fewer invitations to ensure adequate time between appointments for cleaning equipment [ 26 ], to women declining invitations to be screened due to fears of being exposed to SARS-CoV-2 when in a healthcare facility [ 9 ].

Other investigators focused on how to effectively restart breast screening programs [ 18 , 26 ]. A Scottish study described the benefits of using a phased approach for this, giving priority to high-risk women, followed by recalling program participants, issuing new invitations to women of screening (age 50–70 years or older) or those who had missed or cancelled earlier appointments [ 26 ]. In another study [ 18 ], researchers in London investigated whether switching from sending women invitations to attend a specific appointment (“timed appointments”) to having them book their sessions (“open appointments”) would reduce the backlog of unscreened eligible women. Both invitation types were used between September 2020 and March 2021, allowing researchers to conduct a natural experiment to examine which approach had the greatest response [ 18 ]. The authors found significantly fewer women responded to the open than to the timed invitation (−7.5%) and estimated that if timed invitations were exclusively used approximately 12,000 more women would have attended screening and about 100 more women with breast cancer would have been detected [ 18 ].

The Impact of COVID-19 on referrals, diagnoses and numbers of patients with breast cancer

A major concern regarding COVID-19 is the possible effect that delaying or modifying diagnosis and treatment would have on patients, including those with symptomatic disease, and the potential for excess breast cancer deaths. An English study used national data to estimate the impact of curtailing screening during the first lockdown on predicted breast cancer deaths from 2020 to 2029. The authors estimated up to 687 additional deaths in that 10-year period [ 13 ]. Routinely collected NHS England data were used to compare referral patterns and time to first treatment for breast cancer during the pandemic (first half of 2020) compared to the same period in 2019 [ 14 ]. Results showed a 28% decrease in diagnostic services and 16% of patients receiving their first treatment. They also noted that hormonal therapy, administered in tablet form, had become a frequent alternative to surgery – the mainstay treatment for breast cancer before the pandemic [ 14 ].

Five studies reported on the number of new breast cancer cases during the pandemic in Wales and England [ 10 , 20 , 22 , 29 , 30 ], with results varying widely by location and time period. For example, a Welsh study [ 29 ] found a 2% reduction of cases in April 2020 compared to the same period in 2019, whereas an English study reported a 17.9% reduction in March-April 2020 versus 2019 [ 20 ]. Three other English studies [ 10 , 22 , 30 ] reported reductions in the number of new diagnoses ranging from 19.1% to 29.5%.

Four studies [ 10 , 22 , 28 , 30 ] reported on changes in disease severity or stage of cancer at diagnosis, finding clear evidence of stage migration to more advanced cases attributed to delayed diagnosis of new cases.

Most breast cancer diagnoses are confirmed through pathology. A study [ 32 ] from Northern Ireland compared the number of pathologically-diagnosed (PD) breast cancer cases before the pandemic (2017–2019) with numbers during the early pandemic. The researchers found 105 fewer breast cancer cases in 2020, with the greatest reductions in the early months (−40% in April, −52% in May) [ 32 ]. A UK-based study [ 39 ] compared population-based cancer registry data from Northern Ireland, Scotland and Wales, with sharp declines in the number of patients with breast cancers in each country (−53.5% in Northern Ireland, −45.3% in Scotland, −43.5% in Wales). The finding of fewer PD-confirmed cases of breast cancer was also reported in a study [ 36 ] conducted in the histopathology departments of two university hospitals in Northwest RoI. The larger hospital reported a decline of 21.5% and 14.4% in the first six months of 2020 compared to 2019 for samples from small biopsy diagnostic procedures and cancer resection cases, respectively [ 36 ].

The Impact of COVID-19 on Treatment: As noted in several studies [ 17 , 21 , 24 , 25 , 31 , 34 , 35 , 40 , 42 ], efforts to reduce the risk of exposure to COVID-19 SARS-CoV-2 for patients and healthcare providers resulted in fewer surgical, radiotherapy or systemic treatments of breast cancer patients. There were also changes to facility procedures used to reduce the amount of time patients were potentially exposed in medical facilities.

Four studies [ 17 , 21 , 40 , 42 ] addressed changes to surgical treatment during the pandemic. One of them reported on an international web-based poll with over 100 oncological surgeons that included practitioners from the UK. In both Scotland and England, surgical priority was given to patients with ER-negative disease first followed by those with HER2-positive disease, and that neoadjuvant chemotherapy was to be given following standard criteria. In England, there was also a recommendation to focus on providing minimal treatment via day surgery, with neoadjuvant chemotherapy to be reserved for patients whose disease was deemed to be inoperable [ 42 ].

Another study found a 34% decline in “radical surgery with curative intent” for breast cancer done in a large London cancer centre from March to September 2020 compared to 2019 [ 40 ]. Surgical practices were also altered, such as having procedures done by only consultant surgeons because junior doctors were redeployed to COVID-19-related duties during the first two months of the pandemic [ 40 ]. Another study [ 21 ], conducted at the Oxford University Hospitals in England, reported the unit followed recommendations from the Association of Breast Surgery and did not perform immediate or delayed breast reconstruction between the start of lockdown (23 March 2020) and the end of May despite the known psychological and physical benefits of immediate reconstruction for many women. In two English hospitals surgical procedures continued during the pandemic but at greatly reduced numbers compared to 2019, with declines in both immediate and delayed reconstructive surgeries. Patients also had significantly shorter hospital stays post-surgery [ 17 ].

Widespread changes to radiotherapy regimens also occurred during the pandemic. Earlier, conventional treatment entailed giving 40–42.5 Gray (Gy) units of radiation divided into 15 treatments or ‘fractions’ (F) over a 3-week period. During the pandemic, this protocol was replaced in many centres with a hypofractionated radiation regimen consisting of a smaller amount of radiation divided into five treatments given over a week (26GyF5). The impetus for this was the publication of guidelines by The Royal College of Radiologists [ 43 ] recommending this shift based on findings from the FAST-Forward non-inferiority trial [ 44 ] and the B-MaP-C study [ 45 ].

Radiation oncology teams quickly complied, reporting increases during the pandemic (up from 13 to 48% in Wales, [ 31 ] and 0.2% to 60.6% in England [ 24 ] and 2.7% to 46.1% in Scotland [ 27 ]), as well as during the pandemic. (up from <1% in February to 70% in April 2020 in a study from England and Wales [ 38 ]).

Another four studies [ 12 , 25 , 34 , 35 ] examined changes in systemic anticancer treatment (SACT), noting this was used as a “bridging” or pre-operative treatment while waiting for breast cancer surgery during the pandemic. One study from England [ 42 ] found a 33% decrease in the number of patients registered for SACT immediately after the initial lockdown (April–June 2020) compared to numbers from September 2019 to February 2020.

Modifying or halting cancer treatments was also identified in the B-Map-C study [ 45 ] -- a multicentre national project involving 64 breast units in the UK – which reported that 59% of all breast cancer patients received a “COVID-altered” management plan (e.g. interrupted neoadjuvant chemotherapy or bridging endocrine therapy instead of surgery) during the initial pandemic period from March 16 to May 8, 2020 [ 34 ]. In contrast, a study conducted in a hospital in England found that 56% of women being treated for breast cancer chose to continue SACT despite clear recommendations from the National Institute for Health and Care Excellence (NICE guidelines) [ 46 ] that such treatment should stop during the pandemic to reduce the risk of exposure to SARS-CoV-2 in a hospital setting. Some authors suggest this indicates that many patients feared the effects of not treating their cancer more than they feared COVID-19 [ 35 ].

The studies included in this scoping review identified unprecedented changes to breast cancer services over a short period of time. During the COVID-19 pandemic people with non-urgent stage disease typically diagnosed via screening (e.g. breast, colorectal or cervical cancer) saw a decrease in the number of new cases due to temporary closures or reduced healthcare facility capacity [ 47 ]. This pattern is borne out by population-based data from national cancer registries reporting 11–21% fewer cases diagnosed during the pandemic in ROI [ 1 ] and the UK [ 47 , 48 , 49 , 50 , 51 ] despite a year-on-year increase in cases.

Evidence exists for both overdiagnosis and benefits from diagnosing breast cancer through screening. [ 52 ] It is inevitable that pauses in population-based screening programs during the pandemic resulted in fewer early-stage cancers being diagnosed. However, the long-term deleterious effects of halting screening programs during health emergencies has yet to be determined. None of the included papers in the review were able to provide evidence of direct harm to patients due to reduced detection rates, despite evidence of more advanced disease on detection. In fact, one study clearly indicated that such delays may have less of an impact than commonly believed for surgeries conducted <12 weeks after diagnosis [ 53 ]. The full extent of harm caused to people with breast cancer can only be answered once enough data comparing outcomes related to delayed services before, during and after the pandemic have been analysed.

The studies examined in this scoping review point to efforts made to continue to offer timely services, including early detection and treatment, with a focus on identifying high-priority patients based on tumour- and patient-related characteristics [ 52 ] taking into account availability of healthcare personnel and services during the pandemic [ 54 , 55 ]. Recovery plans for future emergencies [ 56 ] must help implementers decide whether to prioritise rapid resumption of breast screening programs or preserve symptomatic diagnostic services [ 4 ] while taking measures to minimise the risk of communicable disease transmission for patients and staff in breast clinics [ 33 ].

There are also lessons to be learned about the benefits of rapidly incorporating evidence from high-quality studies, such as the FAST-FORWARD clinical trial demonstrating the effectiveness of hypofractionated radiotherapy for eligible patients, into clinical practice during the pandemic [ 44 ]. Another modification was to preferentially offer neoadjuvant therapy over surgery for triple negative or HER2+ patients during the pandemic. This likely was to reduce through flow in chemotherapy departments, thereby reducing the risk of exposing immunocompromised patients to SARS-CoV-2 [ 28 ], although future studies will be needed to determine the effectiveness and long-term impact of this change.

It is also important to adapt international guidelines to fit local conditions [ 57 ]. Factors to consider would be how to continue providing services while safeguarding patients and staff given local resources, what criteria to use when identifying high-priority patients during times of reduced service availability, ensuring that resources are available for increased use of remote/virtual consultations and MDT meetings, as well as developing locally acceptable approaches to phasing in full services post-emergency [ 58 ].

Other recommendations for breast cancer programs focus on ways to avoid undertreatment with neoadjuvant therapy and, in some cases, providing breast-conserving operations [ 54 ] in “clean” surgical sites even during a health emergency. Benefits from continuing to operate include ensuring that surgical trainees continue developing their skills, and so there will be more clinicians available to help reduce the backlog of patients once operations resume [ 54 ]. Second, it should reduce the number of women experiencing unnecessary anxiety and depression, which have been found in patients waiting considerable time for their breast surgery [ 59 , 60 ]. Third, as recommended by the British Association of Plastic, Reconstructive and Aesthetic Surgeons in the UK [ 61 ], resuming breast reconstruction quickly can help prevent unnecessarily long or repeat procedures due to tissue change that occurs over time after a mastectomy, which increase hospital stay and potentially the risk of exposure to SARS-CoV-2. However, the link between length of stay and infection rates has yet to be proven. It is also important to consider the surgical environment, as noted by The Royal College of Surgeons in May 2020 [ 62 ]. This included guidelines for the “four Ps”: the Place for surgeries should be reconfigured to provide a safe setting for patients and clinicians; People should return to their pre-COVID work in order to reduce the backlog of elective cases; PPE should be made available for all staff; and no major surgery for Positive Tests (i.e. if patients test positive for COVID-19) except for life-, (limb- or sight-saving procedures) [ 21 ]. Future research will determine if these actions are effective in reducing the risk of infection with SARS-CoV-2.

Public awareness campaigns should also be delivered that includes the clear communication [ 55 ] for people with relevant symptoms to seek medical care promptly [ 57 ], even at the height of a pandemic or other emergency.

Looking to the future, it will be important to fund research on the long-term impact of delayed or interrupted breast cancer services on patient outcomes such as cancer incidence, stage, tumour size and ultimately survival [ 15 , 16 , 63 ]. For instance, previous studies have found survival differences for women with breast cancer only if the delay in services was longer than 12 weeks [ 53 , 62 ]. Several of the papers in this review reported results from single-site retrospective studies [ 62 ], which is problematic because it is not possible to generalise their findings to other settings or populations. This problem can be alleviated by using data from multicentre investigations and national cancer registries. However, there are issues with obtaining timely information from registries. First, many registries do not have data on cancer recurrences, which makes it difficult to accurately assess the impact of health emergencies. Efforts to address this gap are being led by the European Network of Cancer Registries [ 58 ]. Second, cancer registries use patient-level data retrospectively after they are received and cleaned. Further delays in producing reports were identified during the COVID-19 pandemic, when monitoring was curtailed due to registry staff working off-site or allocated to pandemic-related duties. This delayed data analysis and report preparation. Several registries have reported they can address such problems in the future by adopting novel methods for more quickly assessing the impact of modified and interrupted services during health emergencies [ 64 ].

Although studies have documented changes in the breast cancer service profile and outcomes during the COVID-19 pandemic, there is no evidence available on whether these measures helped minimise the spread of the SARS-CoV-2 infection. Further research is also needed on the long-term effects of changes to breast cancer services for patients who had advanced disease on initial presentation or whose treatment was delayed [ 65 ]. Findings from such studies can be used to update models that predict the number of excess deaths from breast cancer due to interrupting care [ 66 ].

Studies are needed to provide insights into the following: how health emergencies affect the cost and availability of services while considering how closely they follow disaster preparedness guidelines; more accurate estimates of cancer risks and consequences for designing optimal recovery strategies [ 59 , 60 , 61 ]; and recommendations on how to address the backlog of breast cancer cases requiring surgery or other treatment in a timely and safe manner [ 67 , 68 ].

Perhaps the most important gap in current literature on the impact of COVID-19 on breast cancer services and patients is research to document the patient voice and experience, as well as research to evaluate improvements in service timeliness and efficiency during the pandemic which has not compromised patient satisfaction and safety.

Health emergencies like the COVID-19 pandemic are the norm rather than the exception. There are valuable lessons to be learned from existing studies conducted in the short time since the end of the pandemic. There is also a need to pool data and design future studies to provide more evidence to guide future plans on how to best meet the needs of women (and men) with breast cancer during future emergencies. It is impossible to completely prepare for future health emergencies, especially those involving novel pathogens. Evidence extrapolated from other infectious diseases, and recommendations by experts (e.g. oncologists, pathologists and patients) on how to better manage cancer treatments in future emergencies should be considered [ 69 ].

Strengths and limitations

To our knowledge, this is the first scoping review to examine the published literature on the impact of the COVID-19 pandemic on breast cancer services and patient outcomes in the UK and RoI. The review was conducted following a strict protocol carried out by three reviewers with conflicts resolved by consensus.

Because of the short time since the end of the pandemic, findings from more definitive, longitudinal, population-based studies were not available to include in this review. The authors also chosen not to review the grey literature because there is no established guidelines for producing a rigorous review of material that does not meet the level of evidence expected by healthcare providers, commissioners and policymakers.

Another limitation is the wide variation in study design and context, such as the stage of the pandemic when data were being collected, among the studies included in the review. Of particular concern was the large number of retrospective, single-centre studies with data from a relatively homogeneous population, making it difficult to generalise findings beyond a particular study setting.

This scoping review presents a coherent picture of current published knowledge on the impact of the COVID-19 pandemic on breast cancer services and patient outcomes in the UK and RoI. It also recommends ways to fill current knowledge gaps on this topic, summarising findings from studies documenting changes made to breast cancer services provided during the COVID-19 pandemic in the UK and RoI.

The long-term impact of these changes are still unknown. Lessons for future disaster preparedness will come from large-scale, multisite studies and cancer registries using data collected before, during and after the pandemic. Results will be useful for developing guidelines to help reduce the impact of future medical emergencies on people with breast cancer and on healthcare systems and providers.

Data availability

The dataset generated and/or analysed during the current study is available from the corresponding author on reasonable request.

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Acknowledgements

Our thanks go to Breast Cancer Now, the research and support charity that provided funding for the “Impact of the COVID-19 Pandemic on the Diagnosis and Treatment of Breast Cancer” project, of which this scoping review is a part. We also thank Ms Paula Darragh and Dr Jamie Roebuck (Cancer Intelligence Officers, Northern Ireland Cancer Registry) for their work on the project.

This review was funded by Breast Cancer Now as part of a larger “Understanding the Impact of COVID-19 on Breast Cancer Services in Northern Ireland” study. The funder played no role in the decisions made during this review.

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These authors contributed equally: Lynne Lohfeld, Meenakshi Sharma.

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Queen’s University Belfast, Centre for Public Health, School of Medicine, Dentistry & Biomedical Sciences, Royal Victoria Hospital, 247 Grosvenor Road, Belfast, BT12 6BA, Northern Ireland, UK

Lynne Lohfeld, Meenakshi Sharma, Anna Gavin, Sinéad T. Hawkins & Charlene M. McShane

Northern Ireland Cancer Registry, Centre for Public Health, School of Medicine, Dentistry & Biomedical Sciences, Queen’s University Belfast, Mulhouse Building, Grosvenor Road, Belfast, BT12 6DP, Northern Ireland, UK

Damien Bennett, Anna Gavin, Sinéad T. Hawkins & Helen Mitchell

Belfast Health and Social Care Trust, 51 Lisburn Road, Belfast, BT9 7AB, Northern Ireland, UK

Gareth Irwin & Siobhan O’Neill

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LL conceived and designed the work, acquired the data, played an important role in interpreting the results, drafted and revised the manuscript, approved the final version, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. MS and CMMcS conceived and designed the work, acquired the data, played an important role in interpreting the results, revised the manuscript, approved the final version, and agreed to be accountable for all aspects of the work. DB, AG, STH, GI, HM, and SON conceived the work, played an important role in interpreting the results, revised the manuscript, approved the final version and agreed to be accountable for all aspects of the work.

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Table 1: characteristics of 34 included studies, preferred reporting items for systematic reviews and meta-analyses extension for scoping reviews (prisma-scr) checklist, rights and permissions.

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Lohfeld, L., Sharma, M., Bennett, D. et al. Impact of the COVID-19 pandemic on breast cancer patient pathways and outcomes in the United Kingdom and the Republic of Ireland – a scoping review. Br J Cancer (2024). https://doi.org/10.1038/s41416-024-02703-w

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• Published: 16 November 2023

Breast conserving surgery versus mastectomy: the effect of surgery on quality of life in breast cancer survivors in Malaysia

• Maznah Dahlui   ORCID: orcid.org/0000-0003-4923-9410 1 , 2   na1 ,
• Meram Azzani   ORCID: orcid.org/0000-0002-7939-1539 3 , 4   na1 ,
• Nur Aishah Taib 5 , 6 ,
• See Mee Hoong 5 ,
• Suniza Jamaris 5 &
• Tania Islam   ORCID: orcid.org/0000-0003-3056-7799 5 , 6  

BMC Women's Health volume  23 , Article number:  607 ( 2023 ) Cite this article

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In the competitive health care environment, patient satisfaction and quality of life (QoL) have become the subject of interest to evaluate the efficacy of therapeutic interventions as we experience improved breast cancer survival in modern times. The knowledge of the long-term effects of surgery on the QoL in breast cancer patients is currently limited in the Asian setting. The purpose of this longitudinal study is to evaluate the QoL of early-stage breast cancer patients undergoing mastectomy and breast-conserving surgery (BCS).

In this prospective cohort study, the QoL of 208 patients who underwent mastectomy and the BCS treatment were assessed, using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire. The questionnaire was administered at the baseline, 6 and 12 months following diagnosis. One-way ANCOVA was used for statistical analysis.

A total of 208 female survivors of Stage 0–II breast cancer were included, among them 47.1% underwent BCS and 52.9% underwent mastectomy. Older (63.3%), Chinese women (63.6%), and patients with primary education (71.7%) were more likely to undergo mastectomy. At baseline, no significant differences were observed for QoL in both treatment groups. At 6 months, patients who underwent BCS had better social functioning scales(  P  = 0.006) and worse symptom scales for dyspnoea ( P  = 0.031), compared to mastectomy patients. One year after diagnosis, the role functioning score of the mastectomy group was significantly higher than the BCS group, specifically among patients who had undergone chemotherapy ( P  = 0.034).

Patients who underwent BCS had better social functioning and worse dyspnoea symptoms compared to patients undergoing mastectomy at six months. During one year, there were only significant improvements in the role functioning among the mastectomy groups compared to the BCS groups. After further stratification, only mastectomy patients who received chemotherapy exhibited improved role functioning compared to patients those who did not undergo chemotherapy. Providing social and physical support postoperatively and monitoring patients for cancer worry, or other symptoms in the long-term survivorship period would be important to ensure optimal QoL.

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Globally, breast cancer is the most common cancer among women and is the second leading cause of cancer-related deaths. Encouragingly, improvement to diagnostic and treatment facilities dedicated for breast cancer helped to reduce the mortality rates among patients [ 1 ]. In Malaysia, breast cancer is the most common cancer in women with 32.9% of newly diagnosed cancer cases in 2020 [ 2 ].

In the late 1890s, Halsted established the radical mastectomy as a standard treatment for breast cancer [ 3 ]. Whereas, in the early 1980s, large randomized studies were first proved that breast-conserving surgery (BCS) followed by postoperative radiotherapy was a valid alternative therapeutic to radical mastectomy in women with early breast cancer [ 4 , 5 , 6 ]. This modification was based on the result of prospective randomized studies, whereby survival rate is not correlated with either conserving surgery or mastectomy [ 4 , 5 , 7 ]. BCS is the usual choice for patients with early‐stage breast cancer. While some of the patients prefer mastectomy because of the fear of recurrence [ 6 ]. BCS remains a common choice for patients who prefer conserving treatment to maintain their body image [ 8 , 9 , 10 ].

In current times, within the rising competitive healthcare environment, patients’ satisfaction and quality of life (QoL) have become an area of interest to evaluate the efficacy of therapeutic interventions [ 5 , 11 ]. Similarly, in cancer patients, the psycho-social factors and QoL have become important indicators used by the healthcare providers caring for these patients. The knowledge about QoL in breast cancer patients is derived from provisional studies whose results may differ according to country, culture, ethnicity, and societal relations. To the best of our knowledge, longitudinal studies on the QoL of Malaysian patients treated with BCS or mastectomy have not been reported in the literature. Therefore, this study aims to compare the impact of mastectomy versus the BCS on the QoL of breast cancer patients at different points of time during their survivorship period.

Methodology

Study design and methods.

This study is a part of a prospective cohort study called the Malaysian Breast Cancer Cohort (MyBCC). MyBCC aims to determine the association between socio-demographic, lifestyle, and psychosocial factors, QoL as well as overall survival of multi-ethnic breast cancer survivors. The protocol of the MyBCC study can be found elsewhere [ 12 ].

The MyBCC study is an ongoing hospital-based prospective cohort study of Malaysian women who are newly diagnosed with primary breast cancer (within 3 months of diagnosis), above 18 years old, and able to read and understand Malay, English, Mandarin, or Tamil. The exclusion criteria were patients with a prior history of any other cancer, bedridden at the time of recruitment, and whose attending physician had certified them as unfit as a result of other prevailing medical conditions. Patients were recruited from February 2016 to December 2019.

The objective and details of the research were explained to all participants, and subjects who had provided their written informed consent of participation were included. Purposive sampling was used and a total of 208 MyBCC patients who underwent surgery and with complete information about their QoL, were included. Patients with advanced stages of cancer (3 and 4) and male patients were excluded.

Procedure and measures

All questionnaires administered to the participants were done by trained research coordinators at the time of diagnosis (baseline). Socio-demographic data and clinical information were collected from the breast cancer registry database. The stage of the patient's breast cancer was confirmed by the surgeon using the American Joint Committee on Cancer (AJCC) staging method. The patient's surgical details were retrieved from the UMMC i-Pesakit (electronic database) records. In addition, the QoL was measured again at 6 and 12 months following diagnosis. Six months was chosen because the side effects of chemotherapy and radiation would have diminished, and after 1 year they had settled into long-term survivorship after completion of the cancer treatment.

The QoL was assessed using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30 and EORTC QLQ-BR23). Two modules were translated to the local languages and validated. The validity and reproducibility of the EORTC questionnaire have been proven to be acceptable [ 13 , 14 ]. The EORTC QLQ-C30 comprised 30 items including five functional scales (physical, role, emotional, cognitive, and social), nine symptom scales (fatigue, nausea and vomiting, pain, dyspnoea, insomnia, appetite loss, constipation, diarrhoea, and financial difficulties) and Global health status scale [ 15 ]. The QLQ-BR23 contains of 23 items of functional scale and symptom scale. The four-functional scale evaluates body image, sexual functioning, sexual enjoyment, and future perspective, while the four-symptom scale evaluates systemic therapy side effects, breast symptoms, arm symptoms, and being upset by hair loss [ 16 ]. All the domains except upset by hair loss (number of patients at baseline: 11, 6 months: 45, and 1 year: 18) and sexual enjoyment (number of patients at baseline: 36, 6 months: 26, and 1 year: 24) were not evaluated. This is because a limited number of patients filled out the hair loss and sexual enjoyment questionnaires, primarily due to the fact that the majority of individuals were not experiencing hair loss and were not sexually active during those specific time periods. Information extracted from the questionnaires was scored accordingly. The raw score for each subscale was calculated and subsequently linearly transformed to a level between 0 and 100 (standardized raw score) according to the guidelines of the EORTC scoring manual. A higher score for functional scale scores represents a high/healthy level of functioning [ 17 ]. A high score for the global health status/QoL represents high QoL. However, a high score for a symptom scale represents a higher level of symptom, indicating poor QoL. The scoring approach for QLQ BR 23 is identical in principle to that of the functional and symptom scales of the QLQ-30.

Statistical analysis

Data were checked for the normality using the Shapiro–Wilk test. Descriptive statistics analysis was performed for demographic characteristics and socioeconomic status of cancer patients. The mean and standard deviation for all items in the QLQ-C30 and QLQ BR23 were calculated for the BCS and mastectomy patients. Categorical variables are shown as frequency and percentage, while continuous variables are presented as (mean ± standard deviation). Chi-square test was applied to identify the association between the different socio-demographic factors and types of surgeries. A T-test was conducted to show the mean differences for QoL between both groups (mastectomy vs. BCS) at baseline, 6 months, and 1 year. One-way ANCOVA was used to find the adjusted QoL measures according to type of surgery at 6 months and 12 months following diagnosis. Post hoc tests were carried out to identify which groups differed. Subgroup analysis was carried out for chemotherapy treatment. A P -value of < 0.05 was considered as statistically significant.

Ninety-eight patients who had undergone BCS and one hundred-ten mastectomized patients were included in the final analysis. Background demographic and socio-economical details of the subjects are shown in Table 1 . There were significant differences for many of the socio-demographic factors including age group, ethnicity, marital status and education level, and occupation label based on the two types of surgery ( P  < 0.05). As expected, there was a significant difference between cancer stage and radiotherapy with type of surgery, as BCS patient routinely receive radiotherapy ( P  < 0.005). Chinese (63.6%) and Indian (57.9%), women were more likely to have mastectomy whereas Malay women preferred BCS (70%). Comparing the patients who underwent BCS, those who underwent mastectomy tended to be older, unmarried/widowed, less educated, and were not working.

Table 2 presents the average scores of each QoL domain at different time points by surgery type. From the QLQ-C30 questionnaire, the general health status scores in the mastectomy group were higher than in the BCS group at baseline (74.3 ± 16.6 vs. 73.1 ± 16.3), 6 months (76.2 ± 13. vs.70.4 ± 1 6.4) and 1 year (73.8 ± 15.4 vs. 71.5 ± 15.8). In the functional scale, some of the domains (physical functioning, role functioning, and cognitive functioning), the mastectomy group’s QoL was slightly better than those of the BCS group at 6 months and 1 year. Simultaneously the mean scores for symptoms, particularly nausea and vomiting, insomnia, appetite loss, constipation, and financial difficulty, in the BCS group were higher than those in the mastectomy group during 6 months and 1 year. The scores for fatigue, pain, dyspnoea (except 6 months), and diarrhoea, showed a higher rating on the symptom scale for the patient who had undergone mastectomy than those who had undergone BCS. The QLQ-BR23 functional scales showed the mean scores for body image were higher in the BCS group than the mastectomy group at the baseline but lower than the mastectomy group at 6 and 12 months after diagnosis. Among the symptom scale, the scores for sexual functioning were higher in the mastectomy group at baseline, during 6-month and 1 year time points. In contrast, mean scores for future perspective were comparatively higher among the BCS group in all 3-time points. The mean scores for breast symptoms were higher among the mastectomy group compared to the BCS group at baseline, 6 months, and 1 year after diagnosis.

Table 3 shows the adjusted (age, ethnicity, hormonal therapy, chemotherapy, radiotherapy and the quality of life score at time of diagnosis (baseline)) mean difference of QoL according to the types of surgeries at baseline, 6 and 12 months following diagnosis. The QLQ-C30 questionnaire at baseline showed no significant difference in general health status at different time points. There was no significant difference in QoL between the BCS and mastectomy patients in any of the four functional domains (physical functioning, role, functioning, emotional functioning and cognitive functioning). At 6 months after diagnosis, the BCS group's social functioning score (mean score 97.6 vs 88.6; F = 7.85 and P  = 0.006) were significantly higher than mastectomy patients. However, the dyspnoea symptom scale of the mastectomy group was significantly lower (mean score of 2.5 vs. 12.5, F = 4.76, and P  = 0.031) than that of the BCS, indicating better QoL. At 1 year after diagnosis, the role functioning score of the mastectomy group was significantly higher than the BCS group (mean score 94.8 vs. 85.7; F = 4.89, P  = 0.029). From the QLQ-BR23 feedback, among the functional and symptom scales only sexual functioning was significantly higher among the mastectomy group compared to the BCS group at baseline (mean score 22.2 vs. 10.9; F = 5.2 and P  = 0.027) and during six months (mean score 18.5 vs. 8.7; F = 25.1 and P  = 0.000). Nevertheless during 1 year after diagnosis, there was no significant difference.

Table 4 shows the subgroup analysis outcome based on chemotherapy treatment status (yes, no) of the adjusted mean difference of QoL, according to surgery type at baseline, 6 and 12 months following diagnosis. From the QLQ-C30 questionnaire, at baseline and 6 months after diagnosis there was no significant difference in the QoL functional and symptom scales between the BCS and mastectomy patients except dyspnoea. At 6 months, BCS groups (undergoing chemotherapy) were more dysphonic than mastectomy patients (mean score 15.0 vs. 0.0; F = 6.661, P  = 0.012). However, one year after diagnosis, dyspnoea was insignificant also among the two groups and only the role functioning score of the mastectomy group was significantly higher than the BCS group, among patients undergoing chemotherapy treatment (mean score 95.2 vs. 84.4; F = 4.69, P  = 0.034). For the QLQ-BR23 scoring, at baseline and 6 months after diagnosis among the functional and symptom scales, there was no significant difference except the mean scores of systematic therapy side effects. Patients undergoing chemotherapy BCS groups had more systematic therapy side effects compared to mastectomy patients (mean score 24.1 vs. 11.4; F = 6.5, P  = 0.013). Nevertheless, there was no significant difference in 1 year except mastectomy patients who did not undergo chemotherapy had a higher sexual functioning mean score in contrast to the BCS group (mean score 25.8 vs. 2.4; F = 5.9, P  = 0.02).

The current study found that Chinese (63.6%) and Indian (57.9%) women are more likely to have a mastectomy whereas Malay women received BCS (70%). At baseline, upon adjustment of demographical and clinicopathological factors, no significant difference were for QoL in both treatment groups. At 6 months, patients who underwent BCS had better social functioning scales (mean score 97.6 vs. 88.6 and P  = 0.006). However, the differences in scores became insignificant at 1 year. BCS patients complained of worse symptoms, scoring a high scale for dyspnoea (mean score 12.5 vs. 2.5, and P  = 0.031) at 6 months, compared to mastectomy patients. Even after stratification of chemotherapy, BCS patients who received chemotherapy seemed to experience more dyspnoea than mastectomy patients at 6 month follow-up period only. Although differences were present in social functioning and dyspnoea (symptom) scales at 6 months for both BCS and mastectomy groups, at 1 year, no statistical differences were noted for QoL between both groups. At one year mastectomy patients had better role functioning scores (mean score 94.8 vs.85.7, P  = 0.029) compared to the BCS group. The effect remained even after stratification by chemotherapy treatment, we found mastectomy patients who only received chemotherapy had better role functioning compared to BCS group (mean score 95.2 vs.84.4 P  = 0.034).

Baseline assessment revealed that sexual functioning was notably higher in the mastectomy group compared to the BCS group, with mean scores of 22.2 and 10.9, respectively (F = 5.2, P  = 0.027). This disparity persisted at the six-month, with mean scores of 18.5 and 8.7 for mastectomy and BCS groups, respectively (F = 25.1, P  = 0.000). However, after 1 year post-diagnosis, no significant difference in sexual functioning was observed. Upon further analysis, when stratified by chemotherapy data, mastectomy patients who did not undergo chemotherapy exhibited significantly higher mean scores for sexual functioning compared to the BCS group, but this difference was only apparent at the 1 year (mean score 25.8 vs. 2.4; F = 5.9, P  = 0.02). After stratifying the chemotherapy data, it was observed that six months after diagnosis, BCS group patients experienced a higher occurrence of systemic therapy side effects in comparison to mastectomy patients, with mean scores of 24.1 and 11.4, respectively (F = 6.5, P  = 0.013). However, no significant difference was noted in the 1 year.

The evaluation of the patient’s QoL, since the surgery is becoming progressively important in assisting decision-making concerning the types of management to be carried out, BCS or mastectomy [ 18 ]. The QoL of the study participants had high means functional scores (≥ 75 points) except for the sexual functioning scale (< 10 points) while low scores were recorded for symptom scores (< 26 points) in all time points. A similar trend was previously reported by a study done in Spain [ 19 ]. Breast cancer survivors can adjust well to their treatments and have low symptom scores, as the side effects are reversible [ 20 , 21 ]. Notably at six months, there were insignificant differences in the functional scales between both groups, except for the social functioning scale ( P  < 0.001). Mastectomy patients need a longer time to adjust to their new body habitus, they may feel low self-confidence to return to normal living as seen in other Asian and Western studies [ 10 , 16 , 20 , 21 ].

In contrast, BCS patients had significantly higher symptom scores for dyspnoea than mastectomized patients. After further classification, patients undergone chemotherapy seemed to experience more dyspnoea ( P  < 0.012). The presence of the breast may invoke more anxiety that may manifest as dyspnoea in panic attacks or anxiety attacks [ 22 ] There is evidence that women treated for breast cancer can have ongoing morbidity with symptoms of dyspnea, and reduced physical activity that can result in perceived poor health status [ 23 ].

Although it is a common belief that less-extensive surgeries would result in better cosmetic effects leading to maintenance of QoL and function [ 20 ]. On the other hand, at one year, there was no significant difference in the symptom scale between both groups. Previous literature had reported inconclusive findings related to QoL of breast cancer patients. Similarly, in Germany, a study assessing the QoL during the first 2 years following diagnosis using SF-12, found no difference in the QoL of patients treated with BCS and mastectomy [ 5 ]. Another study in Belgium reported significant benefits of BCS in compared to radical mastectomy surgery and mastectomy with reconstruction based on treatment satisfaction [ 9 ]. A study conducted in the USA found that patients undergoing BCS had better scores for satisfaction of their appearance and physical health (QoL domain) six months after surgery [ 4 ]. A longer follow-up (6–24 months) resulted in all three groups having identical QoL [ 4 ].

Furthermore, a study in Brazil examined clinical and demographic predictors affecting the QoL of breast cancer patients and found that worse QoL scores on physical and psychological scales were related to mastectomy [ 24 ]. In contrast, mastectomized patients undergoing chemotherapy tended to have better role-functioning scores ( P  < 0.034). Differences in QoL by geographical location may suggest different cultural nuances that we could not capture in our study. However, a possibility of diminishing cancer worry in mastectomy patients compared to BCS patients could explain better role functioning and lesser dyspnoea; as seen in a study from Australia that reported worse physical and role functioning scores among patients treated with conserving surgery [ 25 ].

However, in the current study, there was no significant association observed in physical functioning between both groups. Both groups routinely received physiotherapy and rehabilitation postoperatively in UMMC, thus optimal physical functioning was able to be achieved as the scores were quite high and physical functioning is not associated with the type of surgery.

A cross-sectional study done to assess QoL, revealed that women who had breast-conserving surgery reported a higher quality of life, improved sexual functioning, and fewer side effects from systemic therapy when compared to their counterparts who had mastectomy [ 26 ]. Factors such as the type of surgery, the age of the patient, and the time elapsed since the completion of treatment were identified as significant influencers of sexual functioning and quality of life in breast cancer survivors. Another study examining the impact of breast cancer treatments on short- and long-term sexual functioning, sexual enjoyment, and body image, and comparing them with age-matched women in the Norwegian general population [ 27 ], found that the sexual functioning score was notably low among the cancer patients, which aligns with our findings. However, women who had undergone mastectomy exhibited a modest yet significantly lower level of sexual functioning compared to those who had breast-conserving surgery in the long term, and breast cancer survivors who underwent chemotherapy showed decreased sexual functioning in the first year following treatment, which differs from our findings. This discrepancy may be attributed to our BCS group having a lower mean baseline sexual functional score compared to the mastectomy group even before the surgical procedures were performed.

A systematic review also compared the QoL between patients who had undergone BCS and mastectomy. It found that only body image scored significantly better for the BCS patients, while other domains were inconclusive [ 21 ]. A study in Germany reported no difference in QoL domains between both groups (mastectomy versus BCS), but there was a lesser satisfaction for body image in patients who underwent mastectomy [ 28 ]. Although our BCS patients seemed to have better body image for this study at 1 year, the data was statistically insignificant. Another narrative review involved the QoL of patients who underwent radical mastectomy, breast-conserving therapy, or oncoplastic breast surgery and found that oncoplastic breast surgery is associated with better QoL compared to the other two groups [ 20 ]. However, this type of surgery was not included in our study.

Scores for QoL are directly associated to the consequences of treatment among cancer patients, particularly for breast cancer [ 18 ]. Moreover, better levels of QoL (physical and mental domains) tend to be associated with a more encouraging prognosis and survival of patients [ 25 ]. However, QoL tools are not routinely used to evaluate the effects of cancer surgery. In Malaysia, only a few cross-sectional studies have examined QoL among breast cancer patients [ 10 , 16 , 29 ], but none of them has conducted any longitudinal study or evaluated the QoL of patients who underwent different type of surgery. Ganesh et al. found a mean general health status of 65.7 (SD = 21.4) which is lower than that demonstrated in our study. This might be due to the inclusion of patients with late stages of cancer (stage 3 and 4) in their study [ 16 ].

The age of the patients at the time of diagnosis also effects the QoL of breast cancer patients [ 30 ]. Prior studies have revealed variances in the impact of breast cancer on QoL for different age brackets, compared to the current study [ 31 , 32 ]. The variations may be the result of different follow-up durations. In addition, the categorization of the patients based on different age groups before the assessment of QoL would possibly result in variances. However, most studies have also used the EORTC QLQ-C30 and EORTC QLQ-BR23 as tools to measure QoL.

Several methodological strengths and limitations of this study warrant mention. This study is the first longitudinal study in Malaysia that aimed to assess the QoL of patients who underwent mastectomy and BCS. In addition, the prospective design allowed the comparison of QoL before and after surgery, which provided better evidence and understanding of different options for surgery among breast cancer patients. However, the relatively smaller sample size due to the inclusion of only stages 0, 1, and 2 is seen as a limitation. Despite the prospective manner of this study for one year, a longer study period would be more valuable. Another limitation is that due to significant advancements in breast cancer diagnosis and treatment, the EORTC QLQ-BR 30 questionnaire has been superseded by the EORTC QLQ-BR45 tool [ 33 ]. However, since our baseline recruitment began in 2012, it was not feasible to transition to the new questionnaire midway through the study. Lastly, to observe the difference between different types of surgery, other aspects that may affect results such as radiotherapy or socioeconomic conditions and mental health and satisfaction issues were not studied.

Conclusions

Patients who underwent BCS had better social functioning but worse dyspnoea symptoms and sexual functional scores compared to the patients undergone mastectomy at six months. However, there was no significant difference in QoL except for better role functioning among the mastectomy group was seen at one year following diagnosis. After further stratification

BCS group of patients who received chemotherapy experienced increased dyspnea and systemic therapy side effects at 6 months after their diagnosis compared to those who underwent mastectomy. However, 1 year after diagnosis, mastectomy patients who received chemotherapy exhibited improved role functioning, while those who did not undergo chemotherapy treatment appeared to have better sexual functioning compared to patients who underwent chemotherapy. To ensure optimal quality of life for breast cancer survivors need to offer postoperative social and physical support and monitoring for cancer-related concerns and other symptoms.

Availability of data and materials

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

Breast conservative surgery

• Quality of life

European Organization for Research and Treatment of Cancer Core Quality of Life

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Acknowledgements

The authors wish to thank UMMC doctors, nurses, technical staff, hospital administration staff, research assistances, and MyBCC study group who contributed to the project. MyBCC study group consists of Samsinah Hussain, Tin Tin Su, Nirmala Bhoo-Pathy, Ng Chong Guan, Hazreen Abdul Majid, Mohd Nahar Azm i Mohamed from University of Malaya and Marie Cantwell from Queens University Belfast. MyBCC study group has contributed to the conception of MyBCC cohort study.

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Maznah Dahlui and Meram Azzani contributed equally to this work.

Authors and Affiliations

Centre of Population Health, Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, 50603, Malaysia

Maznah Dahlui

Faculty of Public Health, Universitas Surabaya, Surabaya, Indonesia

Department of Public Health Medicine, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh,Selangor, Malaysia

Meram Azzani

Centre of Occupational Safety, Health and Wellbeing, Universiti Teknologi MARA, Puncak Alam, Selangor, Malaysia

Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, 50603, Malaysia

Nur Aishah Taib, See Mee Hoong, Suniza Jamaris & Tania Islam

University Malaya Cancer Research Institute (UMCRI), Kuala Lumpur, Malaysia

Nur Aishah Taib & Tania Islam

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The study was conceived and designed by Maznah Dahlui, Meram Azzani, Tania Islam and Nur Aishah Taib. Data collection was performed by Tania Islam, See Mee Hoong, Suniza Jamaris, and Nur Aishah Taib. Analysis was performed by Maznah Dahlui and Meram Azzani. The first draft of the manuscript was written by Maznah Dahlui and Meram Azzani and all authors revised it critically for important intellectual content, and agreed for all aspects of the work of the manuscript.

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Correspondence to Tania Islam .

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The University Malaya Medical Centre (UMMC) Ethical Committee (MEC number 896.150) approved the study protocol and procedures. We obtained full permission from the European Organization for Research and Treatment of Cancer (EORTC) to use the QoL questionnaires and EORTC QLQ-C30.

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Dahlui, M., Azzani, M., Taib, N.A. et al. Breast conserving surgery versus mastectomy: the effect of surgery on quality of life in breast cancer survivors in Malaysia. BMC Women's Health 23 , 607 (2023). https://doi.org/10.1186/s12905-023-02738-w

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Trajectories and influencing factors of social anxiety in postoperative breast cancer patients

• Shaotong Wang 1 , 2 ,
• Yafang Hua 3 ,
• Yueyue Zhang 1 ,
• Daoxia Guo 2 &
• Li Tian 1 , 2 , 4  

BMC Psychiatry volume  24 , Article number:  357 ( 2024 ) Cite this article

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Social anxiety among postoperative breast cancer patients is a prevalent concern, with its intensity fluctuating throughout the course of treatment. The study aims to describe the trajectory of social anxiety in postoperative breast cancer patients, explore the influencing factors, and provide theoretical support for the construction of future intervention programs.

This study was conducted from June 2022 to January 2023, encompassing 213 breast cancer patients from three first-class hospitals in China. Data collection occurred at four distinct time points. A growth mixture model was employed to identify latent categories representing the trajectories of social anxiety changes among patients. A multiple regression analysis was utilized to explore predictive factors associated with different latent trajectory categories.

The trajectory of social anxiety changes in postoperative breast cancer patients includes five potential categories: maintaining mild social anxiety group, changing from mild to moderate social anxiety group, maintaining moderate social anxiety group, changing from moderate to severe social anxiety group, and maintaining severe social anxiety group. Cluster analysis results indicated three types: positive, negative, and low. Logistic regression analysis revealed that younger age, spouses concerned about postoperative appearance, chemotherapy with taxol-based drugs, opting for modified radical surgery or radical mastectomy surgical approaches, and breast cancer patients with negative rumination were factors that influenced patients’ social anxiety ( P  < 0.05).

The trajectory of social anxiety in postoperative breast cancer patients comprises five potential categories. In clinical practice, it is essential to strengthen the management of high-risk populations susceptible to experiencing social anxiety emotions, including younger age, spouses concerned about postoperative appearance, chemotherapy with taxol-based drugs, opting for modified radical surgery or radical mastectomy surgical approaches, and breast cancer patients with negative rumination.

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Introduction

According to the data released by the International Agency for Research on Cancer (IARC) of the World Health Organization (WHO) in 2020, the number of new cases of breast cancer worldwide was as high as 2.26 million, surpassing the incidence rate of lung cancer and becoming the largest cancer type in the world [ 1 ]. The typical treatment for breast cancer involves surgery, often complemented by radiation therapy, chemotherapy, and other modalities to enhance patient survival rates. However, these treatments also lead to side effects, such as breast loss, hair loss, nausea, and vomiting, which cause patients to develop social anxiety [ 2 ]. Social Anxiety (SA) refers to emotional and behavioral disorders in individuals caused by concerns about negative evaluations from others, leading to a fear of judgment in social situations and a tendency to avoid them actively. If unable to avoid these social situations, individuals may experience physiological reactions such as trembling, stuttering, sweating, blushing, or urgency to urinate. These reactions disrupt interpersonal interactions and affect the individual’s daily life [ 3 ]. Studies by Carver et al. [ 4 ] suggest that breast cancer patients may experience varying degrees of social anxiety following surgery, potentially associated with altered postoperative body image. If not controlled by timely intervention, social anxiety will not only adversely impact the affected individual but also cause distress to others [ 5 ].

Social anxiety is influenced by various factors. Firstly, genetic inheritance is associated with social anxiety. It has been noted that overexpression of genes such as the 5-hydroxytryptamine transporter gene (Solute carrier family 6member4, SLC6A4), catechol-oxygen-site methyltransferase (Catechol-O-methyltransferase, COMT), and Monoamine Oxidase A (MAOA) and other genes may trigger social anxiety in individuals [ 6 ]. Secondly, gender also promotes the development of social anxiety. Research on primary school students showed that the level of social anxiety in girls was higher than that in boys [ 7 ]. Additionally, social support plays a crucial role in influencing an individual’s level of social anxiety [ 8 ]. Rhoten et al. [ 9 ] believe that there is a negative correlation between social support and social anxiety, i.e., the more social support, the lower the level of social anxiety. In a cross-sectional study of rumination and social anxiety among college students, researchers concluded that rumination also has an impact on social anxiety and that rumination can affect social anxiety levels among college students directly or indirectly through feelings of loneliness [ 10 ]. In an intervention study of rumination and social anxiety among undergraduate psychology students, Mellings [ 11 ] revealed that reducing students’ rumination was effective in reducing their focus on negative information about themselves, thereby lowering their levels of social anxiety.

Relevant policies and measures have been implemented to facilitate disease recovery, such as medical insurance coverage for breast cancer patients [ 12 ] and postoperative rehabilitation exercise programs [ 13 , 14 ]. However, specific intervention measures and targeted policies regarding potential social anxiety among patients have not been fully discussed and established. Current research on social anxiety always focuses on healthy populations and is less often applied to diseased groups [ 15 ]. Furthermore, existing studies are predominantly cross-sectional studies [ 16 ], and previous research has not explored the patterns of changes in social anxiety levels over time and the variations between different populations. Therefore, this study aims to use the Growth Mixture Model (GMM) to investigate potential categories of trajectories in postoperative social anxiety levels among breast cancer patients [ 17 , 18 ]. Logistic regression will be employed to analyze the influencing factors on the trajectories of social anxiety changes in different potential categories among breast cancer patients. The study will examine the characteristics of high-risk individuals and relevant modifiable factors aiming to facilitate the early identification of high-risk individuals and the implementation of targeted measures. Ultimately, the goal is to reduce social anxiety levels in this high-risk population.

Participants

Breast cancer patients admitted to the surgery wards of three first-class general hospitals in Suzhou from June 2022 to January 2023 were recruited by convenience sampling. The inclusion criteria were: (i) patients diagnosed with primary breast cancer by pathology report who underwent surgical treatment and chemotherapy after surgery; (ii) female, aged 18–75 years old; (iii) with specific communication and comprehension abilities; (iv) who understood their condition and voluntarily participated in this study. The exclusion criteria were: (i) those suffered from malignant tumors in other parts of the body; (ii) combined with other serious diseases (severe heart disease, hypertension, etc.); (iii) withdrew in the middle of the study or interrupted the treatment for various reasons; (iv) receiving any psychological therapy or counseling intervention during treatment; (v) with a history of mental illness before surgery.

The study was ethically approved by the Ethics Committee of Soochow University (SUDA20230115H05). All patients completed four time-point measurements: the day of admission (T1), seven days postoperative (T2), one month postoperative (T3), and three months postoperative (T4). This study employed a longitudinal research design, estimating the sample size based on the repeated measures design proposed by Barcikovski and Robey [ 19 ]. The sample size was calculated using GPower software, with an effect size of 0.1 [ 20 , 21 , 22 ], a significance level (α) of 0.05, a power (1-β) of 0.95, and a calculated sample size of 431 participants. Because the number of repeated measurements was 4, the number of study subjects was calculated to be 108. Because this study involves fitting a GMM. Research indicates that when using the Bayesian Information Criterion as the primary consideration for model selection, the sample size should be ≥ 200 [ 21 , 23 ]. Therefore, the sample size for this study should be at least 200 cases.

Study measures

General information questionnaire.

Two components were included: socio-demographic information and disease information. Socio-demographic data included age, ethnicity, whether there was religious belief, occupation, work status, marital status, education level, per capita monthly family income, place of residence, whether there were children, and whether the spouse cared about the patient’s image after surgery. Disease and treatment information included the affected side, family history, tumor stage, metastasis, surgical method, chemotherapy medication, and whether other diseases were combined.

Positive and negative rumination scale

It included 23 entries, which were categorized into five dimensions: enjoyment of pleasure, inhibition of pleasure, denial of self, positive coping, and negative attribution [ 24 ]. Enjoyment of pleasure and positive coping constitute the positive rumination degree, whereas the remaining three factors constitute the negative rumination degree. The scale is scored using a four-point scoring system, with options A-D corresponding to scores of 1–4, respectively. The total sum of these scores represents the final score for each dimension [ 24 ]. The internal consistency coefficients of the scale ranged from 0.70 to 0.81, with the internal consistency coefficients for negative and positive rumination being 0.84 and 0.81 and the internal consistency coefficient for the total scale amounting to 0.74 [ 25 , 26 ]. For distinguishing between types of rumination, we followed the approach outlined by Yang et al. [ 27 ]. The specific steps are as follows: (1) Calculate the standard scores, or Z-scores, for the two dimensions of positive and negative rumination; (2) Utilize cluster analysis to determine the number of clusters by assessing the maximum change in the agglomeration coefficient between clusters, using the sum of squared deviations and Euclidean distance. Subsequently, individuals are grouped into several categories based on these clusters.

Interaction anxiety scale

It is mainly used to measure individuals’ perceived social anxiety levels in interpersonal interactions but does not measure specific external social behaviors [ 28 ]. The scale consists of 15 self-report items, with options A-E corresponding to scores of 1–5, respectively. The total sum of these scores represents the final score, which ranges from 15 to 75 points. The scale has high reliability and validity, with Cronbach’s alpha coefficient greater than 0.87 and an 8-week retest correlation coefficient of 0.80. A score of less than or equal to 31 is classified as a low social anxiety group, a score of 32–48 is classified as a medium anxiety group, and a score of more than 48 is classified as a high social anxiety group.

Data analysis

The latent classes of social anxiety trajectories were identified using GMM. The fitting process began with a one-class latent model (1 C), during which relevant fit indices were summarized to determine the most suitable fitting model. Considering group heterogeneity, identifying potential types was followed by exploring the characteristics of each group of patients [ 29 ]. A Robust Maximum Likelihood Estimator (MLR) is used to estimate parameters and handle missing values in the follow-up data, assuming the randomness of missing values did not affect the results. When fitting the GMM model, the metrics for evaluating the goodness-of-fit include (i) loglikelihood value (Loglikelihood, LL), AIC (Akaike Information Criterion), and sample size-adjusted BIC (sample size-adjusted BIC) information indices. These statistics are used to judge the goodness of fit by comparing the expected and actual values, and the smaller the value, the better the fit. (ii) Classification accuracy can be evaluated by entropy, which ranges from 0 to 1. Entropy ≥ 0.80 indicates that the classification accuracy is more than 90%, and the closer the entropy value is to 1, the more accurate the classification is. (iii) In addition, Bootstrapped Likelihood Ratio Test (BLRT) and Vuong-Lo-Mendell-Rubin Likelihood Ratio Test (VLMR) are used to compare the number of different categories of the models. These tests determine whether the difference in fit between a K-category model and a K-1-category model is significant. If the p -values of the BLRT and VLMR tests are insignificant, the K-category model is not better than the K-1-category model [ 30 ]. Cluster analysis was employed to categorize and summarize the types of rumination in breast cancer patients. Normally distributed data were expressed as mean and standard deviation, and multiple comparisons were made using ANOVA. Count data were presented as frequencies and percentages, and chi-square tests were used for multiple group comparisons. Finally, regression analysis was used to explore the effects of socio-demographic, disease-related information, and different types of rumination on the latent categories trajectories of social anxiety changes. Differences were considered statistically significant at P  < 0.05. Mplus 7.4 and SPSS 25.0 were used for data analysis.

In the baseline data survey, a total of 247 patients were enrolled, with 213 ultimately completing all four surveys. During the follow-up process, there were patients lost to follow-up. Reasons for loss to follow-up included patients discontinuing treatment, refusing to fill out forms, and seeking treatment at another hospital. The follow-up process is illustrated in Fig.  1 . The results revealed that the participants had an average age of 47.9 ± 9.70 years old, the youngest being 24 years old and the oldest being 72 years old. (Table  1 )

The enrollment and attrition of patients during the study process

Potential categories of change trajectories in social anxiety in postoperative breast cancer patients

A total of six potential category models were fitted in this study, and the relevant fit indices are in Table  2 . The results showed the best fit to the data for five potential category models, each named according to the characteristics of the trajectory of change in social anxiety, namely Marinating mild SA group (37.95), Changing from mild to moderate SA group (7.2%), Maintaining moderate SA group (31%), Changing from moderate to severe SA group (15.2%), and Maintaining severe SA group (8.8%). (Fig.  2 ).

Distribution of GMM five categories of social anxiety levels in postoperative breast cancer patients

Note: T1: The day of admission; T2: Seven days postoperative; T3: One month postoperative; T4: Three months postoperative

Rumination type in breast cancer patients

Since the total score of the scale used in this study contains both positive and negative aspects and therefore has less significance for its mean value, this study analyzed the positive and negative rumination of 213 patients in a hierarchical cluster analysis to categorize the level of rumination of the included population. The results showed that among the 213 breast cancer patients who completed all the follow-ups, 32.4% of the patients had a positive type, 32.4% had a negative type, and the remaining 35.2% had low type of rumination. (Figures  3 and 4 ).

Cluster analysis of the variation of agglutination index fold plot

Note: Determine the number of categories for rumination. The results showed that the movement of the agglutination index changed most steeply between 2 and 3, so the number of clusters should be between 2 and 3, and synthesizing previous studies, the number of categories was finally set to 3

Final clustering of the three types of rumination

Note: Distinguish between three types of ruminators. The standardized scores (Z-scores) of positive and negative rumination scores were clustered using K-means clustering and clustered into three categories, positive, negative and low. The table shows that the positive ruminator has positive values for their positive rumination and negative values for their negative; on the contrary, the negative ruminator has positive values for their negative rumination and negative values for their positive rumination; whereas the low type indicates that this category is in a neutral state so that they have negative values for both positive and negative aspects

Univariate analysis of factors influencing potential categories of social anxiety change trajectories in postoperative breast cancer patients

The results of the univariate analysis showed that menstrual status, whether the spouse cares about the postoperative image, chemotherapy regimen, surgical approach, and the type of rumination affect the potential categories of social anxiety change trajectories in postoperative breast cancer patients. (Table  3 ).

Logistic regression analysis of factors influencing social anxiety in postoperative breast cancer patients

Statistically significant independent variables identified through univariate analysis included menstrual status, whether the spouse cared about the postoperative image, chemotherapy regimen, surgical approach, and type of rumination. These metrics were subjected to logistic regression analysis to determine the final influences affecting the potential categories of social anxiety change trajectories in postoperative breast cancer patients. The results showed that the younger the age, the more likely their social anxiety trajectory would develop into the changing from moderate to severe SA group; patients whose spouses cared about their postoperative image would develop into the changing from mild to moderate SA group, maintaining moderate SA group, changing from moderate to severe SA group, and maintaining severe SA group; patients whose chemotherapeutic agents contained paclitaxel were more likely to develop a trajectory of social anxiety into changing from moderate to severe SA group and maintaining severe SA group; while patients with breast-conserving surgery were more likely to be in the maintaining mild SA group; breast cancer patients with negative ruminators were more likely to develop changing from mild to moderate SA group, changing from moderate to severe SA group and maintaining severe SA group. (Table  4 ).

This study conducted four follow-up surveys on the level of social anxiety among breast cancer patients three months post-surgery. Results indicated that over half of the postoperative breast cancer patients experienced moderate to severe levels of social anxiety, and the trajectory of social anxiety comprises five potential categories. Additionally, this study revealed that younger age, spouse’s concern about the patient’s postoperative appearance, chemotherapy regimen containing taxane drugs, surgical methods other than breast-conserving surgery, and breast cancer patients with negative rumination tendencies were highly prone to experiencing social anxiety.

This study found the best models after potential category analysis, including maintaining mild SA group (37.95%), changing from mild to moderate SA group (7.2%), maintaining moderate SA group (31%), changing from moderate to severe SA group (15.2%), and maintaining severe SA group (8.8%). The maintaining mild SA group and maintaining moderate SA group demonstrated relatively stable and minor changes in social anxiety levels throughout the entire treatment process. Which may have increased slightly postoperatively but remained below the threshold for moderate or severe social anxiety consistently maintaining a low to remaining moderate social anxiety, similar to the baseline level. The changing from mild to moderate SA group and the changing from moderate to severe SA group exhibited consistently mild to moderate levels of social anxiety before surgery. Due to the psychological impact of the surgery, these patients experienced a significant increase in postoperative social anxiety levels. In some cases, individuals in the moderate social anxiety group reached levels indicative of severe social anxiety. Patients with severe social anxiety, whether preoperative or postoperative, consistently exhibited relatively high levels of social anxiety. The study has confirmed that people with severe social anxiety are susceptible to adverse evaluations. When confronted with negative emotions or evaluations from the external environment, they rapidly perceive and generate anxiety emotions [ 31 ]. In this study, 62% of the patients experienced moderate to high levels of social anxiety, aligning closely with previous research findings [ 32 ].

Age, the spouse’s care about the postoperative image, chemotherapy regimen, surgical modality, and type of rumination are all influential factors in the change of social anxiety in postoperative breast cancer patients. First, younger patients tend to have social anxiety trajectories that are more likely to develop into changing from moderate to severe SA group. Nowadays, the expectations for women are increasing, requiring them to be not only intelligent but also attentive to their appearance. Younger women are becoming increasingly demanding and paying more and more attention to their appearance. The current treatment methods for breast cancer can cause substantial harm to the external appearance of younger women, leading to a sense of shame, which is highly likely to result in social anxiety [ 33 , 34 ]. On the contrary, older individuals have a more negligible probability of developing such negative emotions [ 35 ]. This may be because older people can approach illness more rationally. Therefore, compared to younger women, their changes in social anxiety levels are less noticeable. Research has also confirmed that younger individuals are more prone to social anxiety and sensitive to social relationships [ 36 ]. Despite the favorable prognosis of disease after treatment for younger breast cancer patients, the damage to their appearance caused by the treatment is also very vulnerable to negative evaluation by others, and such negative evaluation leads to an increase in the level of social anxiety in young postoperative breast cancer patients.

Second, patients who believed that their spouses were concerned about their current appearance tend to experience an increase in social anxiety levels as the disease progresses. The results of this study are like those of Li Jianghua [ 32 ]. Such patients who care about their spouse’s perception of their image are more likely to develop social anxiety after breast cancer surgery. Breast cancer is a stressful event experienced by both spouses, and spousal support can help patients reduce psychological pressure [ 37 , 38 ]. Since breast cancer patients are predominantly female, after experiencing postoperative appearance changes, patients will have a psychological burden. Without timely and positive guidance from their spouses, patients may engage in negative behaviors such as avoidance of communication [ 39 ]. Some studies have shown that adequate social support can reduce the level of social anxiety [ 40 ], with family support, particularly spousal support, playing a crucial role in coping with social anxiety emotions [ 41 ]. A qualitative study on breast cancer patients post-surgery suggested that some patients believed their spouses were disgusted with their appearance, leading to feelings of self-loathing and guilt [ 42 ]. Patients’ spouses indicated that the patient was less attractive after surgery, which led to the gradual dissolution of the intimate relationship between the spouses in a vicious circle [ 43 ]. The lack of social support makes patients more prone to negative emotions and inferiority [ 44 ], which makes them reluctant to contact the outside world and close themselves off, leading to social withdrawal and heightened levels of social anxiety [ 45 ].

Patients receiving taxane chemotherapy, such as paclitaxel, are more likely to develop change from the moderate to severe SA group and maintain the severe SA group. This may result from the mechanism of action of taxane drugs on cancer cells. Taxane drugs, including paclitaxel and docetaxel, primarily function by inhibiting the mitosis of tumor cells, thereby suppressing their proliferation [ 46 ]. The main adverse reactions include neurotoxicity, myelosuppression, and allergic reactions. Notably, neurotoxicity is the most prominent, manifesting as peripheral neuropathy, sensory neuropathy, and other symptoms [ 47 ], which can affect patients’ quality of life and social function in severe cases [ 48 ]. Taxane drugs are neurotoxic, causing neurological-related discomfort and producing chronic neurotoxic clinical symptoms, such as unrelenting pain sensation, weakness, and fatigue. This affects patients’ moods and psychological states, leading to negative emotional states such as fear of socialization and depression [ 49 , 50 ].

The surgical procedure is a factor Influencing social anxiety among breast cancer patients. Breast cancer patients treated with breast-conserving surgery were more likely to develop into the maintaining mild SA group. The loss of the breast caused by breast cancer surgery is a significant factor influencing patients’ development of social anxiety. A Greek research study suggested that patients undergoing mastectomy and breast-conserving surgery would experience different emotions. Patients undergoing radical mastectomy were more likely to believe they were unattractive, had increased self-consciousness, were dissatisfied with their appearance, and avoided contact with others compared to those treated with breast-conserving therapy [ 51 ]. Although modified radical mastectomy can achieve radical tumor cure or significantly prolong patient survival time and protect the patient’s physiological function, this procedure cannot maintain the integrity of the breast, leading to negative emotions due to physical damage [ 52 ]. Isabel suggested that patients who undergo mastectomy would experience adverse effects on body perception and social behavior, severely affecting the patient’s quality of life [ 53 ]. Compared to other procedures, only breast-conserving surgery preserves breast morphology, helping patients alleviate postoperative psychological stress and maintaining social anxiety levels postoperatively. Shi et al. [ 54 ] confirmed this viewpoint in a two-year follow-up study involving 172 breast cancer patients. The result showed that patients undergoing breast reconstruction had the highest quality of life scores, followed by patients undergoing breast-conserving surgery, while patients choosing mastectomy had the lowest quality of life scores. Therefore, Shi et al. [ 54 ] concluded that patients undergoing mastectomy for breast cancer would have adverse impacts on their quality of life, leading to an increase in their levels of social anxiety [ 54 , 55 ].

Finally, an individual’s rumination type also affected the social anxiety of the patients. The results showed that negative ruminators showed a gradual increase in their postoperative social anxiety levels, while positive and low ruminators tended to have a more stable trajectory of social anxiety emotions. This may be due to the stability of the memory-refreshing function of such people after being harmed by adverse events or negative emotions in positive and low types, which helps them control the production of negative emotions [ 56 ]. This is consistent with the findings of Yang [ 27 ], who concluded that positive ruminators are predictive of positive psychological indicators and that positive types react quickly when they encounter adverse events to regulate possible negative emotions. In contrast, patients with negative rumination showed an increase in postoperative social anxiety, which is consistent with the results of Jolijn [ 57 ] and Faith A [ 58 ]. Who found that people with high negative rumination also had relatively high social anxiety. Compared to the positive type, negative ruminators will be stuck in a negative emotion that cannot be extricated, and they will keep thinking about every detail after each socialization, which will produce a negative evaluation of themselves and increase the individual’s level of social anxiety [ 59 ]. Research suggests that negative ruminators have weaker emotional regulation abilities, are more susceptible to adverse events, and generate negative emotions [ 60 ].

Limitations

This study was conducted only in first-class hospitals in Suzhou due to epidemic and time factors. In the future, we may further consider expanding the scope of the study, conducting a multicenter, large-sample study, increasing the follow-up time, and including postoperative breast cancer patients with six or eight cycles of chemotherapy to validate the results of this study. Based on the results of this study, a social anxiety management program for postoperative breast cancer patients can be constructed and evaluated for clinical practice.

Conclusions

There are dynamic changes in the level of social anxiety in postoperative breast cancer patients with different potential categories. In clinical practice, we should pay more attention to breast cancer patients who are younger, whose spouses are concerned about the patient’s image, whose chemotherapy regimens contain paclitaxel, whose surgical methods, and who have negative rumination. To help the clinic identify the characteristics of the postoperative population that is prone to social anxiety at an early stage and to provide references for the development of corresponding nursing measures.

Data availability

The authors have full control of all primary data available from the corresponding author ([email protected]) upon request.

Abbreviations

Social Anxiety

Growth Mixture Model

Bootstrapped Likelihood Ratio Test

Vuong-Lo-Mendell-Rubin Likelihood Ratio Test

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Acknowledgements

We would like to express our heartfelt gratitude to the data collectors and study participants. This study would not have been possible without their contributions.

This study was supported by the Major Project of Philosophy and Social Science Research in Colleges and Universities in Jiangsu Province (No. 2023SJZD144). They had no role in the study design, collection, analysis, or interpretation of the data, writing the manuscript, or the decision to submit the paper for publication.

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S.T.W., Y.F.H., and L.T. wrote the main manuscript. S.T.W., Y.F.H., and Y.Y.Z. collected the data, S.T.W., D.X.G., and Y.Y.Z. prepared the figures and tables. All authors reviewed and agreed the final manuscript.

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Wang, S., Hua, Y., Zhang, Y. et al. Trajectories and influencing factors of social anxiety in postoperative breast cancer patients. BMC Psychiatry 24 , 357 (2024). https://doi.org/10.1186/s12888-024-05770-8

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Implementation of a clinical breast exam and referral program in a rural district of Pakistan

• Russell Seth Martins 1 ,
• Aiman Arif 2   na1   na2 ,
• Sahar Yameen 2 ,
• Shanila Noordin 2 ,
• Taleaa Masroor 3 ,
• Shah Muhammad 2 ,
• Mukhtiar Channa 2 ,
• Sajid Bashir Soofi 2 &
• Abida K. Sattar 2 , 4  

BMC Health Services Research volume  24 , Article number:  616 ( 2024 ) Cite this article

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The role of clinical breast examination (CBE) for early detection of breast cancer is extremely important in lower-middle-income countries (LMICs) where access to breast imaging is limited. Our study aimed to describe the outcomes of a community outreach breast education, home CBE and referral program for early recognition of breast abnormalities and improvement of breast cancer awareness in a rural district of Pakistan.

Eight health care workers (HCW) and a gynecologist were educated on basic breast cancer knowledge and trained to create breast cancer awareness and conduct CBE in the community. They were then deployed in the Dadu district of Pakistan where they carried out home visits to perform CBE in the community. Breast cancer awareness was assessed in the community using a standardized questionnaire and standard educational intervention was performed. Clinically detectable breast lesions were identified during home CBE and women were referred to the study gynecologist to confirm the presence of clinical abnormalities. Those confirmed to have clinical abnormalities were referred for imaging. Follow-up home visits were carried out to assess reasons for non-compliance in patients who did not follow-through with the gynecologist appointment or prescribed imaging and re-enforce the need for follow-up.

Basic breast cancer knowledge of HCWs and study gynecologist improved post-intervention. HCWs conducted home CBE in 8757 women. Of these, 149 were warranted a CBE by a physician (to avoid missing an abnormality), while 20 were found to have a definitive lump by HCWs, all were referred to the study gynecologist (CBE checkpoint). Only 50% (10/20) of those with a suspected lump complied with the referral to the gynecologist, where 90% concordance was found between their CBEs. Follow-up home visits were conducted in 119/169 non-compliant patients. Major reasons for non-compliance were a lack of understanding of the risks and financial constraints. A significant improvement was observed in the community’s breast cancer knowledge at the follow-up visits using the standardized post-test.

Conclusions

Basic and focused education of HCWs can increase their knowledge and dispel myths. Hand-on structured training can enable HCWs to perform CBE. Community awareness is essential for patient compliance and for early-detection, diagnosis, and treatment.

Peer Review reports

Introduction

Breast cancer is the most frequently diagnosed malignancy (barring skin cancers) and the fifth leading cause of cancer-related deaths worldwide [ 1 , 2 ]. According to GLOBOCAN 2022, 2.3 million new cases of breast cancer were diagnosed in 2022, with 666,103 patients dying from the disease [ 3 ]. Moreover, the incidence and mortality of breast cancer is expected to increase by 40% and 50% respectively by 2040 [ 3 ]. The rise in incidence is particularly steep in Asia, with these countries also seeing a significantly younger age of onset compared to the Western world [ 4 , 5 ]. In Pakistan, one in every nine women suffers from breast cancer, with the country having one of the highest incidence rates in the region (around 2.5 times higher than neighboring countries such as Iran and India) [ 6 , 7 ]. Breast cancer accounts for more than 20% of all malignancies in Pakistan, and almost half of all cancers in women [ 8 ].

The World Health Organization (WHO) has emphasized the role of early diagnosis of symptomatic breast cancer as a more feasible and economical strategy as compared to screening in resource-constrained countries [ 9 , 10 ]. Screening for breast cancer allows for detection of breast cancer at an earlier stage (especially when small enough to remain undetectable on clinical examination) and leads to significantly better management outcomes and less treatment expenditure [ 1 , 9 ]. While screening aims to identify lesions in asymptomatic and healthy individuals who have yet to develop clinical manifestations of disease, early detection of symptomatic breast cancer seeks to recognize individuals at an earlier stage than when they would otherwise present, allowing for more timely management and potentially better oncologic outcomes [ 9 ].

Early diagnosis and treatment are a cornerstone of efforts to reduce cancer-associated mortality in developed countries. In the United States (US), fewer than 20% of cancers present with advanced disease [ 11 ]. Data from Pakistan presents a stark contrast, with more than half of patients presenting with locally advanced or metastatic disease [ 11 ]. Mammography is the most effective screening modality for breast cancer in high-income countries. Multiple breast cancer screening trials have reported a reduction breast cancer-related mortality up to 25% among women undergoing mammography screening [ 12 ]. However, it remains under-utilized as a screening tool, both in developing and developed countries. Reasons for this range from misconceptions regarding screening methods, techniques, and radiation to lack of insurance or a care provider and fear of recall imaging, overdiagnosis leading to unnecessary biopsies and treatment and side effects [ 13 , 14 ]. In the US, more than 75% of eligible women are screened for breast cancer via mammography [ 15 ]. In a lower-middle-income country (LMIC) like Pakistan, access to investigations such as mammogram, breast ultrasound and needle biopsy is limited due to lack of availability of machines and trained personnel, lack of awareness and financial limitations (75% of healthcare financing in Pakistan is out-of-pocket and over one-third of the population lives below the poverty line) [ 16 , 17 ]. In addition, conservative sociocultural norms and religious factors also prevent women from seeking routine healthcare [ 18 ]. Given the lack of healthcare access coupled with a largely conservative culture, community outreach programs with home visits may be the ideal system for bringing initial breast cancer recognition home to the rural communities, enabling early confirmation of disease and initiation of treatment. Similar outreach programs have met with considerable success in other aspects of healthcare. These include programs improving screening and prevention of malaria, tuberculosis, and HIV and those targeting improvement maternal and neonatal mortality [ 19 , 20 ]. Thus, screening, and early detection interventions implemented in LMICs like Pakistan must take into account the local healthcare systems and social structures.

Clinical breast examination (CBE) is recommended as the preferred approach for early detection of symptomatic and clinically detectable breast cancer in LMICs such as Pakistan. It consists of inspection and palpation of the breasts and regional (axillary, supraclavicular, infraclavicular and cervical) lymph nodes of the patient in a sitting and supine position [ 21 ]. It can be readily performed by a primary care physician to identify abnormal breast findings and determine the need for further evaluation.[ 22 ], [ 23 ] In fact, while mammography is expected to miss over 20% of breast cancers, CBE is able to detect 3–45% of these false negative cases [ 24 , 25 , 26 ].

Due to the aforementioned sociocultural barriers towards mammographic breast screening in Pakistan, it is vital that early detection interventions employ more feasible methods such as CBE. Thus, the objective of this study was to describe the outcomes of a community outreach breast education, home CBE and referral program for early recognition of breast abnormalities and improvement of breast cancer awareness in a rural district of Pakistan. We conducted a community outreach and referral program where home CBE visits were conducted by trained healthcare workers (HCWs) for early detection of breast signs and symptoms, in a rural district of Pakistan. Women who had clinical abnormalities detected upon examination were then referred for further evaluation. During these visits, the women were also educated regarding breast cancer management. In this study, we report our results and experiences with this program. We believe that it is important to reinforce that early detection interventions for breast cancer may be implemented in LMICs like Pakistan using CBE as the preferred approach. Given that most patients with breast cancer present with advanced disease, CBE may be able to identify characteristic breast changes earlier and allow for timely treatment of the tumor at earlier stages [ 27 ].

Materials and methods

Study design and setting.

A quasi-experimental study was carried out over September 2021 - September 2022 in Sindh, Pakistan. The study team was primarily based at Aga Khan University (AKU) in Karachi, Sindh, while the field location where the community outreach program was implemented was situated in the Dadu district of Sindh, Pakistan. The Aga Khan University is an academic tertiary care private hospital and a health services agency of the Aga Khan Development Network (AKDN) in Pakistan. This study featured a collaboration between the Departments of Surgery and Maternal and Child Health at AKU. Ethical approval was obtained from the ethical review committee at AKU.

The Dadu district covers 19,070 km 2 in interior Sindh and is divided into four sub-divisions which are further divided into Union Councils (UC). The UC is the smallest administrative unit of Pakistan. The field location of our study consisted of five UCs within the Johi subdivision of the Dadu district. Some census data of the five included UCs, as collected by the AKU for local projects, are shown in Table  1 . Approximately 48.7% of the population is female. As of 2021, it has 47 Basic Health Units (BHU) and 5 Rural Health Centers (RHC) with a total of 503 beds (BHUs and RHCs are first-level primary healthcare facilities that serve rural populations). The doctor -to-patient ratio is 1:6,030, nurse-to-patient ratio is 1:39,629, and bed-to-patient ratio is 1:3,309 [ 28 ].

Study population and sample size calculation

The total population within the five target UCs was 64,023. Our target sub-population consisted of all adult women ≥ 18 years of age. Using an estimated 20% prevalence of abnormal CBE according to a similar study conducted in Tajikistan [ 29 ], 80% power, 95% confidence level, and design effect of 2, we calculated the minimum required sample size to be 547 individuals. This was inflated by 100% to mitigate against extreme rates of individuals being lost to follow-up, which we anticipated to be a significant real-world challenge, yielding a final minimum required sample size of 1,094. Cluster convenience sampling was used to identify women in the community.

Training workshop and outreach program

The study schema consisted of the following interventions in sequence as described:

Training of Health Care Workers (HCWs) : Non-physician HCWs received training at AKU, Karachi in September – October 2021. This specialized training program was designed to enhance HCWs’ skills in identifying suspicious breast problems, making appropriate and timely referrals, and improving general knowledge regarding breast cancer. This training was conducted and overseen by an attending breast surgeon at AKU. HCWs were taught how to perform clinical breast examinations (CBEs) and engaged in hands-on practice sessions with simulated breast disease models and real patients in clinics. In addition, the HCWs were educated regarding general knowledge regarding breast cancer, with special emphasis on treatment, evaluation and commonly held misconceptions among the public. Pre and post-intervention surveys were administered to evaluate improvement in knowledge.

Community outreach program with home visits : The HCWs were deployed into the community in the Johi subdivision in October 2021. The initial series of home visits took place between October 2021 to February 2022, with the HCWs performing home visits in groups of two. Each visit began with an introductory and informed consent-seeking debriefing, followed by CBE of all consenting adult women belonging to a household, an assessment of baseline breast cancer-related knowledge, and lastly, a brief, standardized educational intervention delivered verbally (Supplement). For each CBE performed, a checklist of examination findings was completed. In the event of any abnormal finding, a referral to a local gynecologist within Johi was made. All interactions during the home visits were conducted in the Sindhi language, which is the native language of the region.

Visit to the local gynecologist : Patients who complied with their referral (for a palpable breast concern) were evaluated by a gynecologist at the local District Health Quarter. The gynecologist repeated a CBE on all referred patients in order to validate the HCWs’ examination findings. All eligible patients were then referred for breast imaging, either mammography or ultrasound, to the nearest facility within Johi.

Follow-up home visits : The HCWs attempted to conduct follow-up home visits for all women who were non-compliant with initial referral to a gynecologist. These follow-up visits took place six months after the initial series of home visits. Patients were questioned as to the reasons for their non-compliance with referral using a self-designed structured questionnaire (Supplement: Sect.  4 ). In addition, the breast cancer-related knowledge survey was re-administered to the women to gauge improvement in knowledge since the educational intervention delivered at the initial home visits. Finally, the importance of complying with referral for future evaluation, diagnosis and management was re-emphasized to all patients.

Validation of Data Collection Tools :

CBE checklist : This was a self-designed checklist (Supplement: Sect.  3 ) that included all the important components of a CBE, including a brief history of relevant symptoms (pain, discharge), breast inspection (skin changes, or changes in breast size, shape, or symmetry, and nipple changes), and breast palpation (presence of lumps in the axilla or breast).

Breast cancer-related knowledge survey : Separate surveys were administered to the HCWs and the women within the general community (Supplement: Sects.  2 and 3 ). Both surveys were designed by faculty within the Section of Breast Surgery at AKU. Prior to its use, the survey for women within the community was pretested amongst 30 local women for content, comprehensibility, and language. Minor adjustments were made on the basis of this pilot procedure.

Statistical analysis

All analyses were performed using SPSS (Statistical Package for Social Sciences) version 23.0 (IBM Corporation, Armonk, New York). Descriptive analysis was performed whereby categorical values were reported using frequencies and percentages. McNemar’s test was used to compare changes in knowledge across the multiple administrations of the breast cancer-related knowledge surveys. A p-value less than 0.05 was considered significant for all the analysis.

Education and training of the HCWs

A total of 8 HCWs were trained. Tables  2 and 3 show the changes in breast cancer-related knowledge after the educational and training intervention for the HCWs. The absolute percentage increase in HCWs who correctly believed that breast cancer can occur in men, and in women despite breast feeding their children, was 50%. In addition, the percentage of respondents who believed that women with a painless lump should visit a healthcare professional increased from 87.5 to 100%. The absolute percentage of HCWs who correctly identified painless lump and bloody nipple discharge as a symptom suspicious of breast cancer increased by 12.5% and those that identified dimpling of skin as a suspicious symptom increased by 25%. The percentage of HCWs who correctly believed that a tissue biopsy could be used to diagnose breast cancer increased from 62.5 to 87.5%.

Implementation of the outreach program

A total of 8,757 women were screened by the HCWs in the field during initial series of home visits. A palpable breast lump was identified in 20/8,757 women, while other palpable or visible breast concerns warranting further evaluation were identified in 98/8,757 women. In addition, HCWs were unsure about the presence of a lump in 51/8,757 women. Keeping a low threshold for seeking a physician’s evaluation and prompt referrals, these 169/8,757 patients were all referred to a gynecologist for further examination. However, only 38/169 patients (ten with a palpable breast lump and 28 for which the HCWs exercised caution-either noted other breast concerns or were unsure) complied with initial referral to the gynecologist. Out of the 28 patients (where HCWs noted breast concerns or were unsure about a lump), none were found to have a lump on the gynecologist’s CBE examination. Out of the ten patients in which the HCWs had positively identified the breast lumps, nine patients (90% concordance) were confirmed to have a breast lump on the gynecologist’s CBE. However, all these ten patients were referred for imaging with only 4 of them complying. Amongst these 4 patients who had breast imaging, one patient had BI-RADS (Breast Imaging Reporting and Data System) category I finding (i.e. negative imaging) and 3 patients had BI-RADS category III findings (Lump with extremely low probability of malignancy). The outcomes of the CBE and referral program are illustrated in Fig.  1 .

Outcomes of community outreach Breast referral program. HCW: Health Care Workers; CBE: Clinical Breast Examination; FNAC: Fine Needle Aspiration Cytology

At the follow-up home visits to the 131 patients who had been non-compliant with initial referral, the most common reasons for non-compliance were assessed by the HCWs ( Table  4 ). The most common reasons for non-compliance were a belief that follow-up was not important (42.0%), lack of money to visit the gynecologist (24.4%), not having anyone to accompany them (9.2%), long distance to travel for the appointment (7.6%).

Increase in community awareness regarding breast cancer

A comparison of the women’s knowledge regarding breast cancer at the time of initial visit and later at follow-up is shown in Table  5 . The percentage of women who had heard of breast cancer increased from 54.6 to 100%, the percentage of women who were aware that breast cancer was treatable increased from 32.8 to 61.3%. The percentage of women understood the need to consult a healthcare professional upon finding a lump increased from 50.4 to 94.1%.

The purpose of this study was to evaluate the feasibility of the real-world implementation of a large-scale clinical breast examination and referral community outreach program in a rural district of Pakistan. Secondarily, we also explored the feasibility of delivering basic breast cancer-related knowledge to the community via non-physician HCWs. This program was the first of its kind for breast cancer detection in the country. The key positive takeaways from our experience were that it is: (i) possible to train non-physician HCWs to perform a comprehensive CBE and identify examination findings warranting referral and further evaluation, (ii) practically feasible to implement a large-scale community outreach program with home-visits for mass detection of breast cancer, (iii) possible to increase community knowledge and awareness for breast cancer by imparting education at the home-visits when CBE was performed. However, we encountered several real-world challenges that precluded the full realization of this outreach program’s impact. Only 50% of women initially identified by the HCWs as having a breast lump followed through with referral to the gynecologist, and only 40% of women followed up with subsequent referral for imaging. None of the patients eventually referred for histopathological evaluation ended up complying with the referral. However, prior experience with a similar program by the AKDN in Tajikistan demonstrated that with appropriate follow-ups, breast cancer may be detected in up to 0.2% of the women in the community [ 29 ]. Although this rate is slightly lower than the reported incidences of mammographic screening-detected breast cancers in the literature (0.5–0.8%), it underscores the potential for success of CBE-based programs as an early detection strategy in low-resource communities [ 30 , 31 ].

Accuracy of CBE by non-physician HCWs and effectiveness of educational interventions

Overall, the theoretical frameworks and foundations of this large-scale clinical breast examination and referral community outreach program were observed to be largely successful. We were able to achieve a high degree of concordance (90%) between the CBE findings of the HCWs and the gynecologist, indicating that it is possible and feasible to leverage HCWs for the early detection of symptomatic breast cancer. Another study carried out in Malawi to train community laywomen to conduct CBE in the community showed 88% concordance between CBE performed by the HCWs and those performed by the physicians [ 32 ]. This is exceedingly important in a LMIC like Pakistan, where the ratio of physicians to population is a major impediment to healthcare access. In Pakistan, there are only 170,000 general practitioners to serve a population of over 230 million individuals. Thus, a major bottleneck for the delivery of high quality breast cancer-related healthcare is the timely initial identification of these patients from the community. Utilizing existing community outreach frameworks, such as the Lady Health Worker (LHW) Program, cite which was in Pakistan in 1994 [ 33 , 34 ]. While the LHW Program was initially developed for promoting family planning and maternal health, the model has been adapted for other major public health interventions such as immunizations and basic preventative healthcare. These LHWs are salaried and recognized as part of the healthcare workforce. Since LHWs are recruited from within the community itself, one of the major strengths of such a program is their ability to deliver culturally appropriate healthcare to populations with limited access to healthcare facilities. Thus, based on the successful training of HCWs in our study, we believe that the LHW Program model can be effectively adapted for the early recognition of breast abnormalities in women who would otherwise go undetected. However, it is important to know that the training of the HCWs in our study was performed by a fellowship-trained breast surgeon at a tertiary care hospital in one of the major cities of Pakistan. To ensure the feasibility, uptake, and growth of our model throughout the underserved regions of the country, it is important that a certain degree of sustainability is achieved. In future iterations of this model, we plan to assess the effectiveness of cascade learning with peer-to-peer teaching. In such a model, HCWs initially trained by a breast surgeon will subsequently assume the role of trainers themselves and teach other HCWs/LHWs how to perform a CBE. Interestingly, the study conducted in Malawi trained non-HCWs to serve as “Breast Health Workers”, highlighting the potential to leverage non-HCW professionals to perform a health-related role in communities with low HCW-to-patient ratios [ 32 ].

Community education and awareness

Despite the successful and rigorous implementation of the CBE and referral community outreach program, the Achilles’ heel of this project was the pervasive lack of community awareness regarding the importance of following up with referrals. This was compounded by other sociocultural barriers such as financial constraints, transportation issues, and a lack of family support to visit the healthcare facility. Thus, it is important that future iterations of similar public health interventions be cognizant of these challenges and seek to mitigate them to the best of their ability. Indeed, the most modifiable of these obstacles is the lack of awareness which can be countered by greater community education during home visits, with a particular focus on emphasizing the potential consequences of non-compliance with diagnostic evaluations. Our results demonstrated the feasibility of educating HCWs to subsequently serve as teachers for the community, and that the newly gained knowledge remained reasonably intact even at a follow-up of six months. A study in Vietnam showed that repeated breast cancer-related educational interventions were successful in increasing compliance with referrals for breast cancer evaluation. [ 35 ] In addition, a more robust follow-up system including frequent interaction and monitoring of patients could help boost compliance with referrals and better continuity of care. For example, routinely scheduled phone calls could be made to the patient as a reminder to follow-up with their referrals. Moreover, for women who are not able to comply with their referrals because of the absence of a family member to accompany them, arrangements may be made whereby LHWs could accompany them as their attendants.

The other challenges, however, harken to well-known and longstanding problems with the healthcare system in Pakistan, where most of the population is unable to afford even basic healthcare. In such a setting, Universal Healthcare Coverage (UHC) emerges as the only viable solution to the masses. An attempt at such a system, the Sehat Sahulat Program (SSP; translates to Health Facility Program) was introduced in 2016 by the provincial government of Khyber Pakhtunkhwa, one of the five provinces of Pakistan [ 36 ]. The SSP was designed to cover a broad range of health conditions and services, including breast cancer diagnosis and evaluation. While the program was met with success in its initial years, and even expanded into some of the other provinces, instability in the political and economic infrastructures of Pakistan have limited its growth, uptake, and effectiveness. Ideally, mass community interventions for early breast cancer detection such as ours could be integrated with UHC programs such as SSP to ensure patient compliance, continuity of care, and maximization of invested resources most effectively.

Limitations

Our study has several limitations that we would like to acknowledge. Firstly, we were unable to calculate a study participation rate as the HCWs did not record the number of informed refusals that they received from women in the community. Secondly, as mentioned earlier, compliance with referrals was exceedingly poor and limited the realization of the true impact of the program. Thirdly, given the limited number of HCWs included, we were unable to perform statistical comparisons to evaluate the improvement in HCWs knowledge. Lastly, the evaluation of the long-term impact and sustainability of the program was limited, presumably due to the influence of sociocultural barriers on the health-seeking behaviors of the women.

This study describes the real-world implementation of a large-scale clinical breast examination and referral community outreach program in a rural district of Pakistan. Our study highlights the importance of CBE programs in early recognition of breast abnormalities/lumps, in regions where mammography is not feasible. Such training programs may lay the foundation for improved provider and community awareness, and examination at the patient’s doorstep and initiate referrals. However, for such programs to ultimately lead to earlier detection of breast cancer/downstaging of disease, community awareness and political buy-in from governmental stakeholders would be critical. Lastly, for such a program to have a truly national impact and be sustainable, more widespread training of HCWs using cascade learning and peer-to-peer teaching models would be necessary.

Data availability

The datasets generated and/or analysed during the current study are not publicly available since the Ethical Review Committee guidelines does not allow institutional data to be dispersed. However, the data is available on reasonable request to the corresponding author.

Abbreviations

Global Cancer Observatory

United States

Lower-Middle-Income Country

World Health Organization

Clinical Breast Examination

Aga Khan University

Union Council

Healthcare Workers

Breast Imaging Reporting and Data System

Lady Health Worker

Universal Health Coverage

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Acknowledgements

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No funding was received for this study.

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Russell Seth Martins and Aiman Arif contributed equally to this work.

Sahar Yameen and Shanila Noordin contributed equally to this work.

Authors and Affiliations

Division of Thoracic Surgery, Department of Surgery, Hackensack Meridian School of Medicine, Hackensack Meridian Health Network, Nutley, NJ, 08820, USA

Russell Seth Martins

Aga Khan University, Karachi, 74800, Pakistan

Aiman Arif, Sahar Yameen, Shanila Noordin, Shah Muhammad, Mukhtiar Channa, Sajid Bashir Soofi & Abida K. Sattar

Department of Surgery, John Hopkins University, Baltimore, MD, 21218, USA

Taleaa Masroor

Department of Surgery, Link Building The Aga Khan University, Karachi, 74800, Pakistan

Abida K. Sattar

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Contributions

AKS was responsible for study conceptualization, design of the study. Project administration was overseen by AKS and SBS. Development of the curriculum and training of healthcare workers was conducted by AKS. Implementation of the study protocols and the acquisition of data was performed by SY, SN, SM, and MC. TM and RSM were responsible for formal analysis and data curation. AA was responsible for writing the original draft of the manuscript. Critical review and editing of the manuscript were conducted by RSM, AKS and AA. SM and MC were responsible for the supervision of the project on the field and AKS and SBS were responsible for the supervision of the entire project. AKS was involved in all aspects from conception and design, through implementation, monitoring, internal audits, study coordination, data analysis, manuscript concept, and critical review. All authors approved the final version to be published and agree to be accountable for all aspects of the work.

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Correspondence to Abida K. Sattar .

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The study was approved by the Institutional Ethical Review Committee at Aga Khan University Hospital, Karachi. Informed consent was taken from all study participants after debriefing them regarding the study. The reference number for the study was 2020-2047-14276.

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Martins, R.S., Arif, A., Yameen, S. et al. Implementation of a clinical breast exam and referral program in a rural district of Pakistan. BMC Health Serv Res 24 , 616 (2024). https://doi.org/10.1186/s12913-024-11051-7

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