breast cancer in research and treatment

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February 2022

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Advances in Breast Cancer

Screening and Treatment Get Personal

Illustration of a doctor showing a female patient a mammogram machine

Breast cancer is the second most common cancer among American women. Breast cancer death rates have been falling over the past 30 years. But nearly 13% of women are still diagnosed in their lifetime. Men can get breast cancer too, although it’s rare.

Cancer is caused by changes to genes Stretches of DNA you inherit from your parents that defines features, like your risk for certain diseases. that control the way our cells function. These changes affect how cells grow and divide. Cancer results when cells divide uncontrollably. In breast cancer, this happens in the breast tissue.

Researchers are studying the risk factors for different types of breast cancer. They’re also searching for more personalized treatments.

Unraveling The Risks

“Breast cancer is caused by a combination of factors,” says Dr. Montserrat García-Closas, a cancer researcher at NIH. Your genes, lifestyle, and environment all contribute to your risk. Researchers are trying to better understand how each plays a role.

People with a family history of breast cancer are at increased risk for the disease. Some are born with rare versions of certain genes that put them at high risk. These include the genes BRCA1 and BRCA2 .

“But the vast majority of patients have no known family history and no known gene that causes cancer,” explains Dr. Margaret Gatti-Mays, a breast cancer treatment specialist at The Ohio State University.

So researchers are also searching for combinations of genes that may lead to breast cancer. “Women can inherit hundreds or thousands of common versions of genes that each have tiny effects, but in combination can put them at substantial risk for developing breast cancer,” García-Closas says. An NIH study called the Confluence Project is trying to unravel these combinations.

Other factors can increase your risk for breast cancer, too. These include your age, whether you’ve had children, alcohol use, and obesity.

Studies are examining how all these factors—genes, medical history, and lifestyle—interact to affect cancer risk. One is called Connect for Cancer Prevention. “It’s recruiting 200,000 people in the U.S. and following them for years to see who develops different types of cancers,” says García-Closas.

Staying Ahead of Breast Cancer

Another study, called the Wisdom Study, is exploring how to best personalize breast cancer screening. Screening tests look for signs of a disease before symptoms appear. Finding cancer early may increase the chance that it can be treated and cured.

If you’re at high risk for breast cancer, your doctor may advise you to get screenings at an earlier age than most, or more often.

“Women from 40 to 50 should talk with their doctor about when they should start screening. And that should be based on their personal risks,” says Dr. Brandy Heckman-Stoddard, an NIH expert on breast cancer.

Mammograms are the most common way to screen for breast cancer. These are X-ray pictures of the breast. An NIH study called TMIST is comparing whether 2D or 3D mammograms are better for screening. 2D mammograms are taken from two sides of the breast. 3D mammograms are taken from different angles around the breast. Then, a computer builds a 3D-like image.

Magnetic resonance imaging (MRI) is sometimes used to screen women at high risk of breast cancer. MRIs can create a clearer image of the breast and don’t use radiation.

Researchers are looking for other ways to detect breast cancer, too. García-Closas’ team is trying to detect cancer using blood samples. These “liquid biopsies” detect DNA from cancer cells, which travel around the body in the bloodstream.

“Liquid biopsies should reflect what’s going on in your whole body,” García-Closas says, “versus when you look at a tissue biopsy, you’re taking a tiny sample of tissue in a particular location.”

Liquid biopsies may one day be able to detect cancer before other clinical tests, she says. “And, they might be able to better monitor what’s happening in your body after cancer has been diagnosed.”

Fighting Back

When breast cancer is found, treatment depends on the type of tumor. Surgery and radiation are common. Chemotherapy may also be used. Doctors might recommend other treatments as well, depending on the type of breast cancer.

“There are three main types of breast cancer,” Gatti-Mays says. “The subtype is determined by the presence or absence of three receptors Molecules that receive and respond to signals, such as hormones. .” These receptors respond to the hormones Substances made in the body’s glands that signal another part of the body to react a certain way. estrogen or progesterone or a protein called HER2.

“If your tumor has estrogen and progesterone receptors, then you can be treated with hormone therapies,” says Heckman-Stoddard. These block the action of hormones that can cause certain cancers to grow.

Hormone treatments can also be used to prevent or lower the risk of cancer for certain women. One such drug is called tamoxifen. But it has side effects that make it unappealing for prevention. Heckman-Stoddard’s team is studying whether using the drug as a gel lessens the side effects.

There are newer treatment options called targeted treatments. These block specific proteins that control how cancer cells grow, divide, and spread. Targeted treatments for HER2-positive cancer have improved survival over the last decade.

The most recent type of cancer treatment is called immunotherapy. It trains your body to fight cancer using your own immune system The system that protects your body from invading viruses, bacteria, and other microscopic threats. .

“Immunotherapy is very promising, but the benefits are still limited to only some patients with triple negative breast cancer,” says Gatti-Mays. These cancers lack all three receptors. But researchers are trying to expand this treatment to more patients with breast cancer. They’re also testing whether using it in combination with other treatments will work better.

Scientists continue to look for ways to improve screening, prevention, and treatment. “In the next five to 10 years, there should be better ways for women to determine their risk of breast cancer,” says García-Closas. “That should help them have a conversation with their physicians on what will be the best tailored prevention strategies.”

No matter what your personal risk of cancer, a healthy lifestyle is the best way to prevent it. Eat a heart-healthy diet, reduce alcohol intake, don’t smoke, and get regular exercise. See the Wise Choices box and talk with your health care provider about ways to lower your risk.

Immunotherapy in breast cancer: an overview of current strategies and perspectives

Véronique Debien 1 ,
Alex De Caluwé ORCID: orcid.org/0000-0001-5989-7017 2 ,
Xiaoxiao Wang 3 ,
Martine Piccart-Gebhart ORCID: orcid.org/0000-0001-9068-8504 4 ,
Vincent K. Tuohy 5 ,
Emanuela Romano ORCID: orcid.org/0000-0002-1574-5545 6 &
Laurence Buisseret ORCID: orcid.org/0000-0002-3751-0819 3 , 7

npj Breast Cancer volume 9 , Article number: 7 ( 2023 ) Cite this article

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Breast cancer

Recent progress in immunobiology has led the way to successful host immunity enhancement against breast cancer. In triple-negative breast cancer, the combination of cancer immunotherapy based on PD-1/PD-L1 immune checkpoint inhibitors with chemotherapy was effective both in advanced and early setting phase 3 clinical trials. These encouraging results lead to the first approvals of immune checkpoint inhibitors in triple-negative breast cancer and thus offer new therapeutic possibilities in aggressive tumors and hard-to-treat populations. Furthermore, several ongoing trials are investigating combining immunotherapies involving immune checkpoint inhibitors with conventional therapies and as well as with other immunotherapeutic strategies such as cancer vaccines, CAR-T cells, bispecific antibodies, and oncolytic viruses in all breast cancer subtypes. This review provides an overview of immunotherapies currently under clinical development and updated key results from clinical trials. Finally, we discuss the challenges to the successful implementation of immune treatment in managing breast cancer and their implications for the design of future clinical trials.

Immunotherapy in triple negative breast cancer: beyond checkpoint inhibitors

Yara Abdou, Atta Goudarzi, … Lisa A. Carey

If we build it they will come: targeting the immune response to breast cancer

Margaret E. Gatti-Mays, Justin M. Balko, … Elizabeth A. Mittendorf

Immunotherapy in hematologic malignancies: achievements, challenges and future prospects

Lu Tang, Zhongpei Huang, … Yu Hu

Introduction

Cancer immunotherapy represents one of the most significant advances in oncology in recent years. It has demonstrated impressive anti-tumor activity and a durable clinical benefit in diverse malignancies with recent success in triple-negative breast cancer (TNBC). Historically considered poorly immunogenic, breast cancer (BC) was initially not extensively investigated for its susceptibility to immunotherapy. However, recent breakthroughs with immune checkpoint inhibitors (ICI) in other cancers coupled with increasing evidence of the influence of the immune system in cancer behavior, have led to the development of clinical trials evaluating different types of immune therapeutic strategies for BC patients. The presence of tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment (TME) reflects a pre-existing anti-tumor immune response and is associated with a better prognosis and response to chemotherapy 1 . The immune response captured through immune-related tumor gene expression in microarray-based analyses also demonstrated that immune gene signatures were associated with a favorable clinical outcome, particularly in TNBC and Human Epidermal Growth factor Receptor 2 (HER2)-positive BC 2 , 3 . In using immunophenotyping analyses or transcriptomic approaches, different immune cell subsets were identified in the TME and their participation in a pro- or anti-tumor immune response has been demonstrated given their influence on BC clinical outcomes 4 . Among CD8+ T cells, the cytotoxic subpopulation is able to kill cancer cells and is associated with improved survival in patients, whereas the presence of immunosuppressive regulatory CD4+ T cells (Tregs) or macrophages is associated with a worse prognosis 4 .

The extent and composition of immune infiltrates are highly variable between BC subtypes and within each subtype 5 , 6 . Therefore, it is expected that not all BC patients would benefit from the same immunotherapeutic strategy to restore or elicit an anti-tumor immune response 5 . Predictive biomarkers are required to select patients and tailor therapies beyond the established BC subtypes. Programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) expression is the most widely used biomarker, but not sufficient, as it only appears to have predictive value in metastatic TNBC (mTNBC). Tumor mutational burden (TMB) is a marker of tumor foreignness and immunogenicity, as mutated antigens are recognized by T cells to initiate a cytotoxic response. Mutational load is highly variable in BC, and tumors that present high TMB may respond more favorably to ICI 7 . Tumor antigens have also been investigated in vaccination strategies, as demonstrated by the increasing number of clinical trials evaluating the preventive and therapeutic effects of cancer vaccines. Emerging modalities such as bispecific antibodies (BsAbs) or adoptive cell therapies involving TILs or chimeric antigen receptor T (CAR-T) cells are an area of current research.

This review describes recent advances in immunotherapy to treat BC and summarizes the challenges of implementing such treatments in a heterogeneous disease. We also present a comprehensive overview of the immunotherapeutic combinations currently investigated in clinical trials.

Clinical landscape and update of early results

The clinical development of immunotherapy in BC started more than 20 years ago, but it is only with the discovery of ICI that number of clinical trials testing immunotherapeutic strategies increased (Fig. 1A ) 8 . In January 2022, 745 immunotherapy-based trials enrolling patients with solid tumors, including BC, were identified on clinicaltrials.gov , with 450 (60.4%) exclusively dedicated to BC. Interestingly, our analysis shows a constant increase in the development of vaccines in the last 20 years, whereas more recent immunotherapeutic approaches increased exponentially since 2015 (Fig. 1A ).

Panels A – C show the number of clinical trials in breast cancer since early 2000, by immunotherapeutic approach ( A ), by trial setting ( B ), and by trial phase ( C ). Panel D shows the major immune targets. Only targets present in two or more trials are represented. The complete list of targets is available in online Supplementary Table 1 . Panel E shows the histogram of combination trials with PD-1/PD-L1 ICI backbone. ADC antibody-drug conjugates, ICI immune checkpoint inhibitors, mAbs monoclonal antibodies, Neo-adj neoadjuvant.

The number of trials is increasing both in the advanced setting and in early BC. In 2018, the number of neoadjuvant trials exceeded the number of adjuvant trials (Fig. 1B ), and a shift of phase 1 trials towards phase 2 and 3 trials is clearly observed (Fig. 1C ). Of note, the large phase 3 trials are sponsored by pharmaceutical companies, whereas the observed rise of phase 2 investigator-initiated studies indicates an enhanced global effort to investigate novel immunotherapy strategies.

The most studied co-inhibitory receptor is programmed death-1 (PD-1). Multiple monoclonal antibodies (mAbs) targeting PD-1 or its ligand PD-L1 have been developed (Fig. 1D ). Other molecules targeting immune checkpoints to prevent the inhibition of T cells (e.g., CTLA-4, LAG3, and TIGIT) or to stimulate T cells and increase their cytotoxic activity (e.g., OX-40 and 4-1BB) are being tested. HER2 represents the most studied target for vaccines but is also used by BsAbs and other directed therapies (Fig. 1D ). Recently, new combination strategies beyond ICI aiming to increase response rates (RR) and clinical benefit have been initiated with the hope of improving survival outcomes (Fig. 1E ).

Immune checkpoint combinations

Metastatic breast cancer.

In early phase trials, PD-1/PD-L1 ICI was primarily evaluated in monotherapy, enrolling heavily pretreated metastatic patients 9 . The response rates (RR) were only 5–20%, with increased efficacy in patients with PD-L1-positive TNBC, lower tumor burden, and non-visceral disease 10 . Nevertheless, few responders achieved long-lasting responses with survival benefit 11 , 12 . However, the KEYNOTE-119 trial, in which pembrolizumab monotherapy was compared to chemotherapy, failed to improve overall survival (OS) beyond the first line in mTNBC (Table 1 ) 13 .

Higher RR were observed with ICI combined with chemotherapy as first-line therapy in advanced TNBC, leading to randomized phase 3 trials in this setting 10 , 14 . The IMpassion130 trial demonstrated a gain of 2.5 months in progression-free survival (PFS) for patients treated with atezolizumab plus nab-paclitaxel whose tumors have PD-L1 ≥1% immune cells with the VENTANA SP142 immunohistochemistry (IHC) assay 15 . Based on these results, atezolizumab received accelerated approval from the United States Food and Drug Administration (FDA) in March 2019. However, FDA approval for atezolizumab was later withdrawn due to a lack of clinical benefit, because the final PFS and first OS interim analyses in the intention-to-treat (ITT) population did not cross the boundary for statistical significance 16 . The initially planned testing procedure was hierarchical, meaning that the analysis in the PD-L1 positive subgroup could be tested only if the primary endpoint in the overall cohort was met. Therefore, the OS results suggesting a survival benefit in the PD-L1 positive subgroup results must be interpreted with caution. Furthermore, the IMpassion131 trial enrolled a similar population but evaluated the combination of atezolizumab with paclitaxel (instead of nab-paclitaxel), and it also failed to demonstrate an improved outcome (neither PFS nor OS) even in the PD-L1-positive subgroup (Table 1 ) 17 . The use of immunosuppressive steroids for premedication to prevent hypersensitivity reactions with paclitaxel has been incriminated in these discordant results. In the ongoing IMpassion132 trial enrolling TNBC patients with early relapses (<12 months), the chemotherapy partners are carboplatin and gemcitabine or capecitabine 18 . In the KEYNOTE-355 trial, pembrolizumab was used in combination with paclitaxel, nab-paclitaxel, or gemcitabine plus carboplatin in first-line therapy for patients with mTNBC. The primary PFS results led to the approval of the drug by the FDA in November 2020 for patients with PD-L1-positive tumors 19 . Recently, the OS benefit was confirmed in patients with a PD-L1 combined positive score (CPS) ≥10 assessed by the IHC 22C3 pharmDx test 20 .

In luminal BC, the first attempts to combine ICI and chemotherapy were disappointing. In initial trials, no improved outcomes were reported, such as in a phase 2 study evaluating eribulin with or without pembrolizumab in metastatic luminal BC 21 . Results are expected from ongoing studies investigating the safety and efficiency of ICI in combination with endocrine therapies and Cyclin D Kinase 4/6 inhibitors (CDK4/6i). In preclinical models, CDK4/6i enhanced tumor antigen presentation, decreased Tregs proliferation, and modulated T cell activation by reducing the expression of inhibitory receptors such as PD-1 22 , 23 . The phase 1b trial, evaluating the combination of abemaciclib with pembrolizumab with or without endocrine therapy in ER-positive metastatic BC, with or without anastrozole, were complicated by increased hepatic toxicity, interstitial lung disease, and two toxic death in the triplet arm 24 . In contrast, the triple association of letrozole, palbociclib, and pembrolizumab was well tolerated in a phase 1/2 trial 25 .

In metastatic HER2-positive BC, the combination of trastuzumab with pembrolizumab showed a 15% RR in patients with trastuzumab-resistant PD-L1-positive tumors 26 . In combination with T-DM1, atezolizumab did not improve PFS but increased toxicity 27 .

Poly ADP ribose polymerase (PARP) inhibitors can lead to DNA damage and genomic instability, which could increase cancer cell immunogenicity and enhance the sensitivity to immunotherapies 28 . In BRCA-deficient BC, the combination of ICI with PARP inhibitors is under investigation. The RR (objective RR or disease control rate) was promising in two phases 2 trials evaluating the combination of durvalumab and olaparib or pembrolizumab and niraparib in first-line or pretreated patients with germline BRCA1 or BRCA2 mutations (Table 1 ) 29 , 30 .

Early breast cancer

Although many questions remain unanswered in the metastatic setting, several trials examined the use of immunotherapy in early BC. In theory, the early setting could be more appropriate for immunotherapy as the tumor burden is more limited, the biological background is more homogeneous, and the TME is less immunosuppressive and unimpacted by previous systemic treatments 31 . The majority of trials in early BC are now conducted in a neoadjuvant rather than in an adjuvant setting (Fig. 1B ) because it offers the advantage of evaluating the clinical and imaging response before surgery and the pathological response after surgery, the latter being a possible surrogate endpoint for the long-term clinical benefit 32 . Moreover, the presence of the primary tumor could serve as a source of neoantigens. Notably, in preclinical models, the neoadjuvant immunotherapeutic approach demonstrated enhanced efficacy compared with the adjuvant setting 33 .

Similarly, as with metastatic disease, the majority of neoadjuvant trials were conducted in the TNBC subtype. In the landmark phase 3 KEYNOTE-522 trial, stage II and III patients received neoadjuvant chemotherapy (NACT) associated with pembrolizumab or placebo concomitant with NACT and then continued in the adjuvant setting 34 . The pathological complete response (pCR) rates were superior in the experimental arm (64.8 vs. 51.2%), and the overall pCR benefit was more significant for patients with node-positive disease (∆ pCR rate of 20.6 vs. 6.3%) (Table 1 ). The estimated event-free survival (EFS) rate at 36 months favored the pembrolizumab-chemotherapy combination (HR = 0.63, 95% CI 0.48–0.82, absolute gain 7.7%) 34 . The combination of neoadjuvant pembrolizumab plus chemotherapy, followed by adjuvant pembrolizumab, is an FDA-approved regimen for early TNBC as of July 2021.

While the KEYNOTE-522 trial used paclitaxel with carboplatin followed by anthracycline with cyclophosphamide every 3 weeks, combined with an anti-PD-1, the neoadjuvant trials IMpassion031 and GeparNUEVO combined nab-paclitaxel with an anti-PD-L1 (atezolizumab or durvalumab) 35 , 36 , 37 . The NeoTRIPaPDL1 trial combined nab-paclitaxel with carboplatin without anthracyclines in the neoadjuvant setting 37 . In IMpassion031, the addition of atezolizumab to nab-paclitaxel followed by dose-dense anthracycline-based chemotherapy resulted in a significant increase in pCR rate: 41 vs. 58%, (∆ pCR rate 17%, 95% CI 6–27, one-side p = 0.0044) (Table 1 ) 35 . However, NeoTRIPaPDL1 and GeparNUEVO trials could not demonstrate a substantial increase in pCR rates, highlighting the complexity of comparing different trials 37 , 38 . Even if there had been no difference in pCR rates in the GeparNUEVO trial, the addition of durvalumab to NACT significantly improved 3-year disease-free survival (DFS) and OS, questioning the validity of pCR as a surrogate endpoint in neoadjuvant immunotherapy trials (Table 1 ) 38 . Interestingly, pCR was only improved in patients treated in the window-of-opportunity part, in which durvalumab was given for 2 weeks before starting chemotherapy. Contrarily to the metastatic setting, PD-L1 IHC expression was not predictive of pCR, while TIL levels and dynamic TILs increase were associated with a better response in the retrospective analyses of KEYNOTE-173, GeparNuevo, and NeoTRIPaPDL1 trials 7 , 37 , 39 .

Less data were available for luminal and HER2-positive BC 40 , 41 , 42 . In phase 2 adaptively randomized I-SPY2 trial, adding pembrolizumab to NACT (weekly paclitaxel followed by doxorubicin-cyclophosphamide) was shown to be beneficial amongst patients with HER2-negative BC 40 . Pembrolizumab increased the pCR rate from 13 to 30% in luminal BC, which is a notable result given that in the metastatic setting, no benefit of ICI was found in this subtype. Nevertheless, compared to TNBC, the chemotherapy-ICI combination seems to generate lower pCR rates in luminal cancer, as expected, given its ‘colder’ immune phenotype. The ongoing phase 3 KEYNOTE-756 trial will shed light on the possible benefit of adding ICI to chemotherapy in grade III luminal BC 42 . The use of priming agents to elicit an immune response might be necessary to turn cold luminal BC into hot tumors 43 . For example, radiation therapy, which is a DNA-damaging agent, can be used to induce T cell priming via antigenic release and MHC-I upregulation. In addition, radiation activates innate immunity through several mechanisms, such as dendritic cells (DCs) activation 44 . This strategy is under evaluation in the Neo-CheckRay trial in luminal B MammaPrint high-risk BC 45 . The neoadjuvant chemotherapy-free strategy with ICI combined with endocrine therapy and CDK4/6i for luminal early BC resulted in increased hepatic toxicity 46 .

In HER2-positive BC, the randomized placebo-controlled phase 3 study IMpassion050 that evaluated the addition of atezolizumab to NACT and dual anti-HER2 blockade did not induce a significant increase in pCR rate in ITT nor PD-L1 positive population 47 . In addition, the median EFS, a secondary endpoint, was not reached in both arms 48 .

Fewer studies are being conducted in the adjuvant and post-neoadjuvant settings (Fig. 1B ). Indeed, larger sample sizes are required as well as a longer follow-up, therefore exposing more patients with potentially curable BC to a hypothetically effective and potentially toxic experimental treatment. Of note, the continuation of ICI after neoadjuvant chemotherapy is still unclear in the context of post-neoadjuvant therapies with capecitabine in TNBC and olaparib for patients with germline BRCA1 or BRCA2 mutations 49 , 50 .

Longer follow-up will help to better delineate the benefit versus harm ratio of ICI, which will ultimately dictate the optimal use of immunotherapeutic approaches in early BC. Although the safety profiles with ICI in BC clinical trials were comparable to clinical trials in other tumor types, the risk of long-term side effects in patients treated with curative intent should be taken into consideration as some immune-related adverse events (irAE) could be responsible for chronic diseases 51 , 52 . Moreover, some irAE should be carefully assessed in the perioperative period, particularly endocrine toxicity such as hypopituitarism with the potential risk of adrenal crisis during or after surgical intervention 51 , 53 .

Breast cancer vaccines

When the FDA approved trastuzumab in 1998 as the first monoclonal antibody for cancer treatment, the entire approach to cancer therapy changed. Ever since, there has been a relentless focus on HER2 as a predominant therapeutic target for HER2-positive cancers. However, despite the effectiveness of HER2 as a target for antibody-mediated receptor antagonism, it has met with conflicting and often perplexing results as a cancer vaccine target.

HER2 is a large molecule; therefore, most of the human HER2 cancer vaccines target one or more of the following three HER2-derived peptides: (1) E75 (Nelipepimut-S, NP-S, HER2 369–377, or NeuVax), an HLA-A2-restricted non-peptide derived from the extracellular domain of HER2 and designed to activate CD8+ T cells; (2) GP2 (HER2 654–662), another HLA-A2-restricted nonapeptide derived from the transmembrane domain of HER2 and also designed to activate CD8+ T cells in an HLA-A2-restricted manner; and (3) AE37 (HER2 776–790) an MHC class-II restricted 12-mer peptide derived from the intracellular domain of HER2 but modified by the addition of the four amino acids long Ii-Key peptide LRMK for enhancing the activation of CD4+ T cells 54 .

The results of phase 1/2 trials involving vaccination of BC patients with one or more of these HER2 peptides showed no significant clinical benefit, but exploratory subgroup analyses surprisingly indicated that patients with HER2-low-expressing tumors, including TNBC patients, may have derived a clinical benefit 55 , 56 . However, a subsequent phase 3 clinical trial involving E75 vaccination of patients, including TNBC patients, with node-positive HER2-low expressing breast tumors was stopped early when an interim analysis of the trial data showed that there was no significant difference in the primary endpoint of DFS between E75 vaccinated and placebo vaccinated subjects 57 .

Despite the confounding use of a HER2 vaccine in patients with HER2-low and HER2-negative BC, treatment of mTNBC with AE37 peptide vaccination has continued (NSABP FB-14). Moreover, a dendritic cell vaccine targeting HER2 and HER3, has been used to treat TNBC patients with brain metastases 58 . Further confusing the area, a recent meta-analysis of 24 clinical studies involving a total of 1704 vaccinated patients and 1248 control subjects found that E75 vaccination caused significant improvement in disease recurrence rate and DFS but no significant difference in OS 59 . One can only speculate how a vaccine targeting HER2 could possibly be effective in treating patients with HER2-negative tumors but not HER2-positive tumors, yet the confounding saga of HER2 vaccination continues.

The HER2 vaccine story certainly reveals the frustration that clinical investigators have had in finding a targeted treatment for TNBC, a BC subtype that expresses none of the traditional targets for BC therapy, including estrogen and progesterone receptors, and HER2. Moreover, TNBCs overexpress several non-HER2 tumor-associated antigens (TAAs), many of which have been the focus of numerous cancer vaccine clinical trials.

Perhaps the most commonly targeted non-HER2 TAAs for cancer vaccination have been the cancer-testis antigens (CTAs). These proteins are normally expressed in embryonic stem cells and testicular germ cells, minimally expressed in most other normal tissues but often expressed at high levels in many different tumors 60 . Several hundred CTAs have been identified, and many have served as targets in vaccination involving patients with TNBC 61 . Perhaps the most notable is cancer/testis antigen 1B (NY-ESO-1) 62 . Several other CTAs have been targeted in the vaccination of TNBC patients, including Wilms’ tumor protein (WT1) 63 , 64 the melanoma antigen gene protein-12 (MAGE-12), the folate receptor alpha (FRα), the T-box transcription factor brachyury 65 and the tumor suppressor transcription factor p53 66 .

One of the more interesting TAAs for targeting TNBC is Mucin 1 (MUC1), a hyperglycosylated, immunologically unavailable protein in many normal epithelial cells but a hypoglycosylated, immunologically available protein in several malignant tumors, including TNBC 67 . Several MUC1 vaccines have been tested in TNBC clinical trials. A number of cancer vaccines that target multiple TAAs have been developed for therapy against TNBC, including the PVX-410 vaccine that consists of peptides derived from the transcription factor X-box binding protein 1 (XBP1), the plasma cell marker syndecan-1 (CD138), and the NK cell receptor CD319 (CS1), as well as STEMVAC, a DNA vaccine encoding multiple peptides of CD105 (Endoglin), Y-box binding protein 1 (Yb-1), SRY-box 2 (SOX2), cadherin 3 (CDH3), and murine double minute 2 (MDM2) proteins. In addition, the vaccine-based immunotherapy regimen-2 (VBIR-2) has been used to treat patients with non-small cell lung cancer (NSCLC) and patients with TNBC, and apparently consists of several immunomodulators as well as multiple vaccinations against prostate-specific antigen (PSA), prostate-specific membrane antigen (PSMA), and prostate stem cell antigen (PSCA). Vaccination against PSMA and the preferentially expressed antigen in melanoma (PRAME) has also been used to treat TNBC patients 68 .

It is important to note that not all TNBC vaccines target TAA proteins. Indeed, tumor-associated carbohydrate (TAC) antigens that are frequently poor immunogens can be targeted using molecular mimic peptides or mimotopes that induce antibodies that cross-react with the human TAC antigen 69 . Such a mimotope vaccine called P10s-PADRE is currently being tested in clinical stage I-III TNBC patients. In addition, a vaccine that targets a non-protein hexasaccharide with a ceramide attached to its terminal glucose ring, the Globo H glycosphingolipid antigen, has reached phase 3 clinical trial status in patients with Globo H+ TNBC tumors 70 .

Despite decades of intense efforts using therapeutic cancer vaccines, the results have been modest or confounding at best. However, much has been learned about immunology in the past several decades, and recent cancer vaccine strategies may prove to be more effective than prior generations of cancer vaccines. Individual tumors have their own set of distinct mutations, many of which have the potential to be highly immunogenic for each individual patient. Such mutated proteins are called neoantigens, and recent clinical trials have focused on isolating these neoantigens and vaccinating individual TNBC test subjects with personalized neoantigen vaccines that include traditional vaccine/adjuvant combinations, vaccination with DNA-based vaccines, vaccination involving autologous dendritic cells, and even mRNA vaccination.

Finally, in light of the very successful prophylactic childhood vaccination program against infectious diseases, one may wonder why TNBC cancer vaccines have long been exclusively treatment vehicles 71 . Even when vaccines are used to prevent the recurrence of pre-existing tumors, they are still treatment vehicles. However, it has recently been proposed that vaccination against the human lactation protein, α-lactalbumin, may provide safe and effective primary prevention of TNBC because α-lactalbumin is a “retired” self-protein that is expressed exclusively in the breast only during late pregnancy and lactation but is expressed in >70% of TNBCs 72 . Thus, preemptive α-lactalbumin immunity provided to women at high risk for developing TNBC due to carrying mutations in their BRCA1 genes 73 may provide safe and effective primary prevention of TNBC as long as lactation is avoided. A phase 1 clinical trial to start this clinical testing process has very recently been initiated, with the first patient vaccinated in 2021. Thus, perhaps the focus of cancer vaccinations in the future may be to provide therapeutic immunity in a personalized manner to multiple neoantigens or to provide neoantigen or ‘retired’ self-protein immunity preemptively for the greatest effectiveness.

Other immunotherapeutic strategies under development

Adoptive cell therapies (ACTs) consist of identifying and isolating peripheral blood or tumor-resident T cells in order to modify, activate and expand these cells ex vivo before transferring them back into the patient 74 . ACTs can be classified into TIL-based therapies, T cell receptor (TCR) gene therapy, and CAR-T cells. The latter technology has already provided prolonged responses and remissions for patients with advanced hematological malignancies 75 .

First attempts to reintroduce autologous lymphokine-activated lymphocytes to treat patients with advanced solid tumors were undertaken years ago without relevant results in BC patients 76 . Of note, clinical trials evaluating ACTs were conducted in early phase trials enrolling a small number of patients, including very few with BC 77 . Recently, infusion of autologous activated lymphocytes against specific tumor antigens was demonstrated able to induce a long-lasting response in a patient with chemotherapy-refractory luminal metastatic BC treated with mutant-protein-specific TILs in conjunction with IL-2 and pembrolizumab 78 . In a study evaluating the feasibility of c-MET CAR-T cells, the best response was a stable disease for only one patient with ER-positive HER2-negative disease among the six patients with metastatic BC 79 . In solid tumors, the development of ACTs has been hampered by the heterogeneity of the antigenic landscape, the hostile TME conditions, and the lack of T cell infiltration in the tumor nests. Several strategies are under development to overcome these issues. Thus, promising CAR-T cell targets like HER2, MUC1, or Mesothelin have been identified for the treatment of BC patients 80 . The identification of neoantigens and the use of other immune cell types, such as NK cells or DCs offer new opportunities for ACTs.

Another challenge to develop ACTs is the toxicities related to lymphodepletion and to immune-mediated side effects such as neurotoxicity and cytokine release syndrome, two potentially lethal conditions. Cytokine release syndrome is a systemic inflammatory response with organ dysfunction that can be reversible if promptly diagnosed and managed 81 . In addition to the management of these toxicities, the complexity of manufacturing ACTs limits the development of cellular therapy programs in specialized cancer centers 82 .

Another type of engineered molecule are BsAbs designed to recognize two different epitopes or antigens on tumor cells and immune cells allowing immune recognition of these cancer cells 83 . A variety of BsAbs relevant to BC are in development 84 . Zanidatamab, BsAb, targets two different HER2 epitopes, in combination with chemotherapy, was well-tolerated, and has shown anti-tumor activity in heavily pretreated HER2-amplified metastatic BC patients 85 . In TNBC, BsAbs from a large panel of tissue agnostic targets such as CD3, CEACAM5, epithelial cell adhesion molecule (EpCAM), epithelial growth factor receptor (EGFR), mesothelin including Trop2 are under investigation 83 .

Conclusions and perspectives

Although the development of cancer immunotherapy in BC began more than 20 years ago, its integration into patient care was slower than in other tumor types. The current extensive clinical research landscape will hopefully change this situation and expand the use of ICI and other immunotherapies in BC beyond the TNBC subtype. As reviewed herein, the number of clinical trials evaluating multiple immunotherapeutic strategies is increasing across all BC subtypes. The FDA approval of ICI plus chemotherapy in TNBC will provide real-world data that will help to better evaluate the benefit of this therapeutic strategy in underrepresented in landmark clinical trials populations, specifically Black patients. Comprehensive translational research and the use of biomarkers will help avoid the development of “add-on designs” which adds a new immune drug to a clinically established modality without leading to the development of adequate strategies for each individual patient. Indeed, the first results from biomarker analyses in immunotherapy TNBC trials highlight the heterogeneity of this disease and the urgent need to better characterize the TME to tailor immunotherapeutic approaches 37 , 86 . The predictive value of several biomarkers, including TIL levels, presence of tertiary lymphoid structures, or expression of immune gene signatures, is under investigation and has already been retrospectively evaluated in some clinical trials 7 , 37 , 87 . Only PD-L1 IHC expression is currently used to select TNBC patients for ICI in the metastatic setting. Moreover, its use in clinical practice remains controversial and complicated by the availability of several mAb and scoring systems and by the limited inter-observer agreement of PD-L1 scoring 88 . Blood-based biomarker research is ongoing, and liquid biopsies may become a noninvasive alternative to tissue biopsies in predicting and monitoring treatment responses.

Immunotherapy is associated with unique and sometimes severe irAEs that will require multidisciplinary collaborative efforts to offer adequate management of the increasing number of patients treated with ICI and to treat emerging toxicity from new immune-modulating agents and ACTs 82 . Another challenge for developing immunotherapy is to define an adequate response assessment, as the pattern of responses to ICI is different from that due to chemotherapeutic agents. Immune Response Evaluation Criteria in Solid Tumors (iRECIST) to better capture the benefit of immunotherapy have been developed, but most trials are still using the conventional RECIST 89 . In BC, pCR after NACT is a surrogate endpoint for a long-term clinical outcome, which might be less appropriate to capture long-term immune memory responses that could sustain therapeutic effects and prevent relapses, as recently suggested by the results of the GeparNUEVO study 32 , 38 . The development of adequate endpoints and new imaging techniques to measure the immune response could refine our approach to tumor response assessment and our criteria predictive of benefit from a given therapy.

Future clinical investigations will also need to address the question of de-escalation strategies for patients with long-term benefits. The excellent outcome observed in the absence of chemotherapy in patients with high TILs, and early-stage TNBC has led to the design of neoadjuvant immunotherapy trials omitting chemotherapy (e.g., NCT04427293) 90 . For non-responders, the improved understanding of tumor-immune interactions and the contribution of the TME, notably with the help of the latest technologies such as single-cell analyses and spatial transcriptomics, may provide new drug targets and strategies to overcome resistance 91 , 92 .

In summary, the clinical research landscape of immunotherapy in BC is expanding with novel investigational therapies aimed at initiating, restoring, or triggering patients’ immune responses against tumor cells. Innovative drugs combinations have already demonstrated an improved outcome for some BC patients, and these new therapeutic strategies will gradually be integrated into clinical treatments.

Reporting summary

Further information on research design is available in the Nature Research Reporting Summary linked to this article.

Data availability

The data used for the Fig. 1 design are available in supplementary table 1 . Data extracted from https://clinicaltrials.gov/ with research terms “breast”, “nivolumab”, “pembrolizumab”, “avelumab”, “atezolizumab”, “durvalumab”, “ipilimumab”, “tremelimumab”, “CAR-T”, “Bispecific”, “Vaccine”, “immunotherapy”, “4-1BB”, “OX-40”, “LAG”, “TIGIT”, “PD-1”, “PD-L1”, and “NK cells”. Data extracted on January 14, 2022.

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The authors thank Prof. Christos Sotiriou for the helpful discussions. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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V.D.: Conceptualization, formal analysis, investigation, resources, writing—original draft, visualization, writing—review and editing, and validation. A.D.C.: Formal analysis, investigation, resources, writing—original draft, data research, writing— review and editing, and validation. X.W.: Formal analysis, investigation, resources, writing—original draft, writing—review and editing, and validation. M.P.-G.: Writing—review and editing and validation. V.K.T.: Investigation, writing—original draft, writing—review and editing, and validation. E.R.: Writing—original draft, writing—review and editing, and validation. L.B.: Conceptualization, writing—original draft, visualization, writing—original draft, and validation. All co-authors, after proofreading, approved the final version of the manuscript.

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V.D. and X.W. declare no competing financial or non-financial interests. The following authors declare no competing non-financial interests but the following competing financial interests: A.d.C.: Investigator-initiated trial (funds paid to institution): AstraZeneca. M.P.-G.: Board Member (Scientific Board): Oncolytics; Consultant (honoraria): AstraZeneca, Camel-IDS, Crescendo Biologics, G1 Therapeutics, Genentech, Huya, Immunomedics, Lilly, Menarini, MSD, Novartis, Odonate, Oncolytics, Periphagen, Pfizer, Roche, Seattle Genetics, Immutep, NBE Therapeutics, SeaGen; Research grants to her Institute: AstraZeneca, Lilly, MSD, Novartis, Pfizer, Radius, Roche-Genentech, Servier, Synthon (outside the submitted work). V.K.T.: Funding from the Department of Defense Breakthrough Award, Level 3 Clinical Trial for Primary Immunoprevention of Triple-Negative Breast Cancer, Anixa Biosciences, Inc. V.K.T. holds personal equity in Anixa Biosciences, Inc. ER: Investigator-initiated trial (funds paid to institution): AstraZeneca, BMS, Roche, Replimmune. Consultancy/advisory board: AstraZeneca, Merck, Roche, Pierre Fabre. L.B.: Investigator-initiated trial (funds paid to institution): AstraZeneca. L.B. is supported by the Belgian “Fondation Contre le Cancer”.

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Debien, V., De Caluwé, A., Wang, X. et al. Immunotherapy in breast cancer: an overview of current strategies and perspectives. npj Breast Cancer 9 , 7 (2023). https://doi.org/10.1038/s41523-023-00508-3

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Cancers (Basel)

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, 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.

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Selective omission of sentinel lymph node biopsy in mastectomy for ductal carcinoma in situ: identifying eligible candidates

Sentinel lymph node biopsy (SLNB) is recommended for patients with ductal carcinoma in situ (DCIS) undergoing mastectomy, given the concerns regarding upstaging and technical difficulties of post-mastectomy SL...

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Metabolomics assisted by transcriptomics analysis to reveal metabolic characteristics and potential biomarkers associated with treatment response of neoadjuvant therapy with TCbHP regimen in HER2 + breast cancer

This study aimed to explore potential indicators associated with the neoadjuvant efficacy of TCbHP regimen (taxane, carboplatin, trastuzumab, and pertuzumab) in HER2 + breast cancer (BrCa) patients.

Chitin-mediated blockade of chitinase-like proteins reduces tumor immunosuppression, inhibits lymphatic metastasis and enhances anti-PD-1 efficacy in complementary TNBC models

Chitinase-like proteins (CLPs) play a key role in immunosuppression under inflammatory conditions such as cancer. CLPs are enzymatically inactive and become neutralized upon binding of their natural ligand chi...

Serum protein profiling reveals an inflammation signature as a predictor of early breast cancer survival

Breast cancers exhibit considerable heterogeneity in their biology, immunology, and prognosis. Currently, no validated, serum protein-based tools are available to evaluate the prognosis of patients with early ...

U2AF2-SNORA68 promotes triple-negative breast cancer stemness through the translocation of RPL23 from nucleoplasm to nucleolus and c-Myc expression

Small nucleolar RNAs (snoRNAs) play key roles in ribosome biosynthesis. However, the mechanism by which snoRNAs regulate cancer stemness remains to be fully elucidated.

Clinical factors associated with patterns of endocrine therapy adherence in premenopausal breast cancer patients

Patients with hormone receptor positive breast cancer are recommended at least five years of adjuvant endocrine therapy, but adherence to this treatment is often suboptimal. We investigated longitudinal trends...

Correction: Mcl-1 confers protection of Her2-positive breast cancer cells to hypoxia: therapeutic implications

The original article was published in Breast Cancer Research 2016 18 :26

Exploring the dynamic interplay between exosomes and the immune tumor microenvironment: implications for breast cancer progression and therapeutic strategies

Breast cancer continues to pose a substantial worldwide health concern, demanding a thorough comprehension of the complex interaction between cancerous cells and the immune system. Recent studies have shown th...

Establishing conditions for the generation and maintenance of estrogen receptor-positive organoid models of breast cancer

Patient-derived organoid models of estrogen receptor-positive (ER+) breast cancer would provide a much-needed tool to understand drug resistance and disease progression better. However, the establishment and l...

Factors associated with overall survival in breast cancer patients with leptomeningeal disease (LMD): a single institutional retrospective review

Breast cancer-related leptomeningeal disease (BC-LMD) is a dire diagnosis for 5–8% of patients with breast cancer (BC). We conducted a retrospective review of BC-LMD patients diagnosed at Moffitt Cancer Center...

Paradoxical cancer cell proliferation after FGFR inhibition through decreased p21 signaling in FGFR1-amplified breast cancer cells

Fibroblast growth factors (FGFs) control various cellular functions through fibroblast growth factor receptor (FGFR) activation, including proliferation, differentiation, migration, and survival. FGFR amplific...

Correction: The novel phosphatase NUDT5 is a critical regulator of triple-negative breast cancer growth

The original article was published in Breast Cancer Research 2024 26 :23

Temporal changes in mammographic breast density and breast cancer risk among women with benign breast disease

Benign breast disease (BBD) and high mammographic breast density (MBD) are prevalent and independent risk factors for invasive breast cancer. It has been suggested that temporal changes in MBD may impact futur...

Expression- and splicing-based multi-tissue transcriptome-wide association studies identified multiple genes for breast cancer by estrogen-receptor status

Although several transcriptome-wide association studies (TWASs) have been performed to identify genes associated with overall breast cancer (BC) risk, only a few TWAS have explored the differences in estrogen ...

BIRC5 expression by race, age and clinical factors in breast cancer patients

Survivin/BIRC5 is a proliferation marker that is associated with poor prognosis in breast cancer and an attractive therapeutic target. However, BIRC5 has not been well studied among racially diverse population...

Factors associated with engraftment success of patient-derived xenografts of breast cancer

Patient-derived xenograft (PDX) models serve as a valuable tool for the preclinical evaluation of novel therapies. They closely replicate the genetic, phenotypic, and histopathological characteristics of prima...

TMEM120B strengthens breast cancer cell stemness and accelerates chemotherapy resistance via β1-integrin/FAK-TAZ-mTOR signaling axis by binding to MYH9

Breast cancer stem cell (CSC) expansion results in tumor progression and chemoresistance; however, the modulation of CSC pluripotency remains unexplored. Transmembrane protein 120B (TMEM120B) is a newly discov...

Breast cancer survivors suffering from lymphedema: What really do affect to corporeality/body image? A qualitative study

Breast cancer-related lymphedema is currently one of the most serious complications that most affect the quality of life of women undergoing breast cancer. The aim of this study was to explore in-depth the exp...

Correction: a phase 1b study of zilovertamab in combination with paclitaxel for locally advanced/unresectable or metastatic HER2-negative breast cancer

The original article was published in Breast Cancer Research 2024 26 :32

Breast composition during and after puberty: the Chilean Growth and Obesity Cohort Study

Breast density (BD) is a strong risk factor for breast cancer. Little is known about how BD develops during puberty. Understanding BD trajectories during puberty and its determinants could be crucial for promo...

UCHL1 contributes to insensitivity to endocrine therapy in triple-negative breast cancer by deubiquitinating and stabilizing KLF5

Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) is a deubiquitinating enzyme that regulates ERα expression in triple-negative cancer (TNBC). This study aimed to explore the deubiquitination substrates of UCHL...

Cell morphology best predicts tumorigenicity and metastasis in vivo across multiple TNBC cell lines of different metastatic potential

Metastasis is the leading cause of death in breast cancer patients. For metastasis to occur, tumor cells must invade locally, intravasate, and colonize distant tissues and organs, all steps that require tumor ...

The role of surgical tissue injury and intraoperative sympathetic activation in postoperative immunosuppression after breast-conserving surgery versus mastectomy: a prospective observational study

Breast cancer is the second most common cause of death from cancer in women worldwide. Counterintuitively, large population-based retrospective trials report better survival after breast-conserving surgery (BC...

HER2-low and tumor infiltrating lymphocytes in triple-negative breast cancer: Are they connected?

Most patients with triple-negative breast cancer (TNBC) are not candidates for targeted therapy, leaving chemotherapy as the primary treatment option. Recently, immunotherapy has demonstrated promising results...

Detection of HER2 expression using 99m Tc-NM-02 nanobody in patients with breast cancer: a non-randomized, non-blinded clinical trial

99m Tc radiolabeled nanobody NM-02 ( 99m Tc-NM-02) is a novel single photon emission computed tomography (SPECT) probe with a high affinity and specificity for human epidermal growth factor receptor 2 (HER2). In thi...

How does weight gain since the age of 18 years affect breast cancer risk in later life? A meta-analysis

Early life factors are important risk factors for breast cancer. The association between weight gain after age 18 and breast cancer risk is inconsistent across previous epidemiologic studies. To evaluate this ...

Clinically relevant gene signatures provide independent prognostic information in older breast cancer patients

The clinical utility of gene signatures in older breast cancer patients remains unclear. We aimed to determine signature prognostic capacity in this patient subgroup.

The FBXW7-binding sites on FAM83D are potential targets for cancer therapy

Increasing evidence shows the oncogenic function of FAM83D in human cancer, but how FAM83D exerts its oncogenic function remains largely unclear. Here, we investigated the importance of FAM83D/FBXW7 interactio...

A risk analysis of alpelisib-induced hyperglycemia in patients with advanced solid tumors and breast cancer

Hyperglycemia is an on-target effect of PI3Kα inhibitors. Early identification and intervention of treatment-induced hyperglycemia is important for improving management of patients receiving a PI3Kα inhibitor ...

Overcoming doxorubicin resistance in triple-negative breast cancer using the class I-targeting HDAC inhibitor bocodepsin/OKI-179 to promote apoptosis

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with a poor prognosis. Doxorubicin is part of standard curative therapy for TNBC, but chemotherapy resistance remains an important cl...

PTHrP intracrine actions divergently influence breast cancer growth through p27 and LIFR

The role of parathyroid hormone (PTH)-related protein (PTHrP) in breast cancer remains controversial, with reports of PTHrP inhibiting or promoting primary tumor growth in preclinical studies. Here, we provide...

Small molecule inhibitor targeting the Hsp70-Bim protein–protein interaction in estrogen receptor-positive breast cancer overcomes tamoxifen resistance

Estrogen receptor (ER) positive patients compromise about 70% of breast cancers. Tamoxifen, an antagonist of ERα66 (the classic ER), is the most effective and the standard first-line drug. However, its efficac...

A phase 1b study of zilovertamab in combination with paclitaxel for locally advanced/unresectable or metastatic HER2-negative breast cancer

Zilovertamab is a humanized monoclonal antibody targeting ROR1, an onco-embryonic antigen expressed by malignant cells of a variety of solid tumors, including breast cancer. A prior phase 1 study showed that z...

The Correction to this article has been published in Breast Cancer Research 2024 26 :46

Augmented interpretation of HER2, ER, and PR in breast cancer by artificial intelligence analyzer: enhancing interobserver agreement through a reader study of 201 cases

Accurate classification of breast cancer molecular subtypes is crucial in determining treatment strategies and predicting clinical outcomes. This classification largely depends on the assessment of human epide...

The prostate-specific membrane antigen holds potential as a vascular target for endogenous radiotherapy with [ 177 Lu]Lu-PSMA-I&T for triple-negative breast cancer

Overexpression of prostate-specific membrane antigen (PSMA) on the vasculature of triple-negative breast cancer (TNBC) presents a promising avenue for targeted endogenous radiotherapy with [ 177 Lu]Lu-PSMA-I&T. Thi...

Metabolic adaptation towards glycolysis supports resistance to neoadjuvant chemotherapy in early triple negative breast cancers

Neoadjuvant chemotherapy (NAC) is the standard of care for patients with early-stage triple negative breast cancers (TNBC). However, more than half of TNBC patients do not achieve a pathological complete respo...

Identification of CD160-TM as a tumor target on triple negative breast cancers: possible therapeutic applications

Despite major therapeutic advances, triple-negative breast cancer (TNBC) still presents a worth prognosis than hormone receptors-positive breast cancers. One major issue relies in the molecular and mutational ...

Contrast-enhanced ultrasound to predict malignant upgrading of atypical ductal hyperplasia

A malignancy might be found at surgery in cases of atypical ductal hyperplasia (ADH) diagnosed via US-guided core needle biopsy (CNB). The objective of this study was to investigate the diagnostic performance ...

MRI-based tumor shrinkage patterns after early neoadjuvant therapy in breast cancer: correlation with molecular subtypes and pathological response after therapy

MRI-based tumor shrinkage patterns (TSP) after neoadjuvant therapy (NAT) have been associated with pathological response. However, the understanding of TSP after early NAT remains limited. We aimed to analyze ...

Are better AI algorithms for breast cancer detection also better at predicting risk? A paired case–control study

There is increasing evidence that artificial intelligence (AI) breast cancer risk evaluation tools using digital mammograms are highly informative for 1–6 years following a negative screening examination. We h...

Prognostic impact of HER2 biomarker levels in trastuzumab-treated early HER2-positive breast cancer

Overexpression of human epidermal growth factor receptor 2 (HER2) caused by HER2 gene amplification is a driver in breast cancer tumorigenesis. We aimed to investigate the prognostic significance of manual sco...

The novel phosphatase NUDT5 is a critical regulator of triple-negative breast cancer growth

The most aggressive form of breast cancer is triple-negative breast cancer (TNBC), which lacks expression of the estrogen receptor (ER) and progesterone receptor (PR), and does not have overexpression of the h...

The Correction to this article has been published in Breast Cancer Research 2024 26 :53

Low-dose acetylsalicylic acid reduces local inflammation and tissue perfusion in dense breast tissue in postmenopausal women

One major risk factor for breast cancer is high mammographic density. It has been estimated that dense breast tissue contributes to ~ 30% of all breast cancer. Prevention targeting dense breast tissue has the ...

Improving lesion detection in mammograms by leveraging a Cycle-GAN-based lesion remover

The wide heterogeneity in the appearance of breast lesions and normal breast structures can confuse computerized detection algorithms. Our purpose was therefore to develop a Lesion Highlighter (LH) that can impro...

TBCRC 039: a phase II study of preoperative ruxolitinib with or without paclitaxel for triple-negative inflammatory breast cancer

Patients with inflammatory breast cancer (IBC) have overall poor clinical outcomes, with triple-negative IBC (TN-IBC) being associated with the worst survival, warranting the investigation of novel therapies. ...

ADAMTS18 deficiency associates extracellular matrix dysfunction with a higher risk of HER2-positive mammary tumorigenesis and metastasis

Human epidermal growth factor receptor 2 (HER2)-positive breast cancer accounts for about 20% of all breast cancer cases and is correlated with a high relapse rate and poor prognosis. ADAMTS18 is proposed as an i...

Development of a machine learning-based radiomics signature for estimating breast cancer TME phenotypes and predicting anti-PD-1/PD-L1 immunotherapy response

Since breast cancer patients respond diversely to immunotherapy, there is an urgent need to explore novel biomarkers to precisely predict clinical responses and enhance therapeutic efficacy. The purpose of our...

Development and prognostic validation of a three-level NHG-like deep learning-based model for histological grading of breast cancer

Histological grade is a well-known prognostic factor that is routinely assessed in breast tumours. However, manual assessment of Nottingham Histological Grade (NHG) has high inter-assessor and inter-laboratory...

A genome-wide association study of contralateral breast cancer in the Women’s Environmental Cancer and Radiation Epidemiology Study

Contralateral breast cancer (CBC) is the most common second primary cancer diagnosed in breast cancer survivors, yet the understanding of the genetic susceptibility of CBC, particularly with respect to common ...

Differential patterns of reproductive and lifestyle risk factors for breast cancer according to birth cohorts among women in China, Japan and Korea

The birth cohort effect has been suggested to influence the rate of breast cancer incidence and the trends of associated reproductive and lifestyle factors. We conducted a cohort study to determine whether a d...

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Breast Cancer Research

ISSN: 1465-542X

Submission enquiries: [email protected]

Patient Care & Health Information
Diseases & Conditions
Breast cancer

Receiving a mammogram

During a mammogram, you stand in front of an X-ray machine designed for mammography. A technician places your breast on a platform and positions the platform to match your height. The technician helps you position your head, arms and torso to allow an unobstructed view of your breast.

Getting a breast MRI involves lying face down on a padded scanning table. The breasts fit into a hollow space in the table. The hollow has coils that get signals from the MRI . The table slides into the large opening of the MRI machine.

Core needle biopsy

A core needle biopsy uses a long, hollow tube to obtain a sample of tissue. Here, a biopsy of a suspicious breast lump is being done. The sample is sent to a lab for testing and evaluation by doctors, called pathologists. They specialize in analyzing blood and body tissue.

Breast cancer diagnosis often begins with an exam and a discussion of your symptoms. Imaging tests can look at the breast tissue for anything that's not typical. To confirm whether there is cancer or not, a sample of tissue is removed from the breast for testing.

Breast exam

During a clinical breast exam, a healthcare professional looks at the breasts for anything that's not typical. This might include changes in the skin or to the nipple. Then the health professional feels the breasts for lumps. The health professional also feels along the collarbones and around the armpits for lumps.

A mammogram is an X-ray of the breast tissue. Mammograms are commonly used to screen for breast cancer. If a screening mammogram finds something concerning, you might have another mammogram to look at the area more closely. This more-detailed mammogram is called a diagnostic mammogram. It's often used to look closely at both breasts.

Breast ultrasound

Ultrasound uses sound waves to make pictures of structures inside the body. A breast ultrasound may give your healthcare team more information about a breast lump. For example, an ultrasound might show whether the lump is a solid mass or a fluid-filled cyst. The healthcare team uses this information to decide what tests you might need next.

MRI machines use a magnetic field and radio waves to create pictures of the inside of the body. A breast MRI can make more-detailed pictures of the breast. Sometimes this method is used to look closely for any other areas of cancer in the affected breast. It also might be used to look for cancer in the other breast. Before a breast MRI , you usually receive an injection of dye. The dye helps the tissue show up better in the images.

Removing a sample of breast cells for testing

A biopsy is a procedure to remove a sample of tissue for testing in a lab. To get the sample, a healthcare professional puts a needle through the skin and into the breast tissue. The health professional guides the needle using images created with X-rays, ultrasound or another type of imaging. Once the needle reaches the right place, the health professional uses the needle to draw out tissue from the breast. Often, a marker is placed in the spot where the tissue sample was removed. The small metal marker will show up on imaging tests. The marker helps your healthcare team monitor the area of concern.

Testing cells in the lab

The tissue sample from a biopsy goes to a lab for testing. Tests can show whether the cells in the sample are cancerous. Other tests give information about the type of cancer and how quickly it's growing. Special tests give more details about the cancer cells. For example, tests might look for hormone receptors on the surface of the cells. Your healthcare team uses the results from these tests to make a treatment plan.

Staging breast cancer

Once your healthcare team diagnoses your breast cancer, you may have other tests to figure out the extent of the cancer. This is called the cancer's stage. Your healthcare team uses your cancer's stage to understand your prognosis.

Complete information about your cancer's stage may not be available until after you undergo breast cancer surgery.

Tests and procedures used to stage breast cancer may include:

Blood tests, such as a complete blood count and tests to show how well the kidneys and liver are working.
Positron emission tomography scan, also called a PET scan.

Not everyone needs all of these tests. Your healthcare team picks the right tests based on your specific situation.

Breast cancer stages range from 0 to 4. A lower number means the cancer is less advanced and more likely to be cured. Stage 0 breast cancer is cancer that is contained within a breast duct. It hasn't broken out to invade the breast tissue yet. As the cancer grows into the breast tissue and gets more advanced, the stages get higher. A stage 4 breast cancer means that the cancer has spread to other parts of the body.

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Breast cancer care at Mayo Clinic

Breast cancer staging
Breast cancer types
3D mammogram
BRCA gene test
Breast cancer risk assessment
Breast self-exam for breast awareness
Chest X-rays
Complete blood count (CBC)
Molecular breast imaging
Positron emission tomography scan
Sentinel node biopsy

Breast cancer treatment often starts with surgery to remove the cancer. Most people with breast cancer will have other treatments after surgery, such as radiation, chemotherapy and hormone therapy. Some people may have chemotherapy or hormone therapy before surgery. These medicines can help shrink the cancer and make it easier to remove.

Your treatment plan will depend on your particular breast cancer. Your healthcare team considers the stage of the cancer, how quickly it's growing and whether the cancer cells are sensitive to hormones. Your care team also considers your overall health and what you prefer.

There are many options for breast cancer treatment. It can feel overwhelming to consider all the options and make complex decisions about your care. Consider seeking a second opinion from a breast specialist in a breast center or clinic. Talk to breast cancer survivors who have faced the same decision.

Breast cancer surgery

A lumpectomy involves removing the cancer and some of the healthy tissue that surrounds it. This illustration shows one possible incision that can be used for this procedure, though your surgeon will determine the approach that's best for your particular situation.

A person who has undergone a total (simple) mastectomy without breast reconstruction

During a total mastectomy, the surgeon removes the breast tissue, nipple, areola and skin. This procedure also is known as a simple mastectomy. Other mastectomy procedures may leave some parts of the breast, such as the skin or the nipple. Surgery to create a new breast is optional. It may be done at the same time as mastectomy surgery or it can be done later.

Sentinel node biopsy identifies the first few lymph nodes into which a tumor drains. The surgeon uses a harmless dye and a weak radioactive solution to locate the sentinel nodes. The nodes are removed and tested for signs of cancer.

Breast cancer surgery typically involves a procedure to remove the breast cancer and a procedure to remove some nearby lymph nodes. Operations used to treat breast cancer include:

Removing the breast cancer. A lumpectomy is surgery to remove the breast cancer and some of the healthy tissue around it. The rest of the breast tissue isn't removed. Other names for this surgery are breast-conserving surgery and wide local excision. Most people who have a lumpectomy also have radiation therapy.

Lumpectomy might be used to remove a small cancer. Sometimes you can have chemotherapy before surgery to shrink the cancer so that lumpectomy is possible.

Removing all of the breast tissue. A mastectomy is surgery to remove all breast tissue from a breast. The most common mastectomy procedure is total mastectomy, also called simple mastectomy. This procedure removes all of the breast, including the lobules, ducts, fatty tissue and some skin, including the nipple and areola.

Mastectomy might be used to remove a large cancer. It also might be needed when there are multiple areas of cancer within one breast. You might have a mastectomy if you can't have or don't want radiation therapy after surgery.

Some newer types of mastectomy procedures might not remove the skin or nipple. For instance, a skin-sparing mastectomy leaves some skin. A nipple-sparing mastectomy leaves the nipple and the skin around it, called the areola. These newer operations can improve the look of the breast after surgery, but they aren't options for everyone.

Removing a few lymph nodes. A sentinel node biopsy is an operation to take out some lymph nodes for testing. When breast cancer spreads, it often goes to the nearby lymph nodes first. To see if the cancer has spread, a surgeon removes some of the lymph nodes near the cancer. If no cancer is found in those lymph nodes, the chance of finding cancer in any of the other lymph nodes is small. No other lymph nodes need to be removed.
Removing several lymph nodes. Axillary lymph node dissection is an operation to remove many lymph nodes from the armpit. Your breast cancer surgery might include this operation if imaging tests show the cancer has spread to the lymph nodes. It also might be used if cancer is found in a sentinel node biopsy.
Removing both breasts. Some people who have cancer in one breast may choose to have their other breast removed, even if it doesn't have cancer. This procedure is called a contralateral prophylactic mastectomy. It might be an option if you have a high risk of getting cancer in the other breast. The risk might be high if you have a strong family history of cancer or have DNA changes that increase the risk of cancer. Most people with breast cancer in one breast will never get cancer in the other breast.

Complications of breast cancer surgery depend on the procedures you choose. All operations have a risk of pain, bleeding and infection. Removing lymph nodes in the armpit carries a risk of arm swelling, called lymphedema.

You may choose to have breast reconstruction after mastectomy surgery. Breast reconstruction is surgery to restore shape to the breast. Options might include reconstruction with a breast implant or reconstruction using your own tissue. Consider asking your healthcare team for a referral to a plastic surgeon before your breast cancer surgery.

Radiation therapy

External beam radiation uses high-powered beams of energy to kill cancer cells. Beams of radiation are precisely aimed at the cancer using a machine that moves around your body.

Radiation therapy treats cancer with powerful energy beams. The energy can come from X-rays, protons or other sources.

For breast cancer treatment, the radiation is often external beam radiation. During this type of radiation therapy, you lie on a table while a machine moves around you. The machine directs radiation to precise points on your body. Less often, the radiation can be placed inside the body. This type of radiation is called brachytherapy.

Radiation therapy is often used after surgery. It can kill any cancer cells that might be left after surgery. The radiation lowers the risk of the cancer coming back.

Side effects of radiation therapy include feeling very tired and having a sunburn-like rash where the radiation is aimed. Breast tissue also may look swollen or feel more firm. Rarely, more-serious problems can happen. These include damage to the heart or lungs. Very rarely, a new cancer can grow in the treated area.

Chemotherapy

Chemotherapy treats cancer with strong medicines. Many chemotherapy medicines exist. Treatment often involves a combination of chemotherapy medicines. Most are given through a vein. Some are available in pill form.

Chemotherapy for breast cancer is often used after surgery. It can kill any cancer cells that might remain and lower the risk of the cancer coming back.

Sometimes chemotherapy is given before surgery. The chemotherapy might shrink the breast cancer so that it's easier to remove. Chemotherapy before surgery also might control cancer that spreads to the lymph nodes. If the lymph nodes no longer show signs of cancer after chemotherapy, surgery to remove many lymph nodes might not be needed. How the cancer responds to chemotherapy before surgery helps the healthcare team make decisions about what treatments might be needed after surgery.

When the cancer spreads to other parts of the body, chemotherapy can help control it. Chemotherapy may relieve symptoms of an advanced cancer, such as pain.

Chemotherapy side effects depend on which medicines you receive. Common side effects include hair loss, nausea, vomiting, feeling very tired and having an increased risk of getting an infection. Rare side effects can include premature menopause and nerve damage. Very rarely, certain chemotherapy medicines can cause blood cell cancer.

Hormone therapy

Hormone therapy uses medicines to block certain hormones in the body. It's a treatment for breast cancers that are sensitive to the hormones estrogen and progesterone. Healthcare professionals call these cancers estrogen receptor positive and progesterone receptor positive. Cancers that are sensitive to hormones use the hormones as fuel for their growth. Blocking the hormones can cause the cancer cells to shrink or die.

Hormone therapy is often used after surgery and other treatments. It can lower the risk that the cancer will come back.

If the cancer spreads to other parts of the body, hormone therapy can help control it.

Treatments that can be used in hormone therapy include:

Medicines that block hormones from attaching to cancer cells. These medicines are called selective estrogen receptor modulators.
Medicines that stop the body from making estrogen after menopause. These medicines are called aromatase inhibitors.
Surgery or medicines to stop the ovaries from making hormones.

Hormone therapy side effects depend on the treatment you receive. The side effects can include hot flashes, night sweats and vaginal dryness. More-serious side effects include a risk of bone thinning and blood clots.

Targeted therapy

Targeted therapy uses medicines that attack specific chemicals in the cancer cells. By blocking these chemicals, targeted treatments can cause cancer cells to die.

The most common targeted therapy medicines for breast cancer target the protein HER2 . Some breast cancer cells make extra HER2 . This protein helps the cancer cells grow and survive. Targeted therapy medicine attacks the cells that are making extra HER2 and doesn't hurt healthy cells.

Many other targeted therapy medicines exist for treating breast cancer. Your cancer cells may be tested to see whether these medicines might help you.

Targeted therapy medicines can be used before surgery to shrink a breast cancer and make it easier to remove. Some are used after surgery to lower the risk that the cancer will come back. Others are used only when the cancer has spread to other parts of the body.

Immunotherapy

Immunotherapy is a treatment with medicine that helps the body's immune system to kill cancer cells. The immune system fights off diseases by attacking germs and other cells that shouldn't be in the body. Cancer cells survive by hiding from the immune system. Immunotherapy helps the immune system cells find and kill the cancer cells.

Immunotherapy might be an option for treating triple-negative breast cancer. Triple-negative breast cancer means that the cancer cells don't have receptors for estrogen, progesterone or HER2 .

Palliative care

Palliative care is a special type of healthcare that helps you feel better when you have a serious illness. If you have cancer, palliative care can help relieve pain and other symptoms. A team of healthcare professionals provides palliative care. The team can include doctors, nurses and other specially trained professionals. Their goal is to improve quality of life for you and your family.

Palliative care specialists work with you, your family and your care team to help you feel better. They provide an extra layer of support while you have cancer treatment. You can have palliative care at the same time as strong cancer treatments, such as surgery, chemotherapy or radiation therapy.

When palliative care is used along with all of the other appropriate treatments, people with cancer may feel better and live longer.

Brachytherapy
Breast cancer supportive therapy and survivorship
Chemotherapy for breast cancer
Hormone therapy for breast cancer
Precision medicine for breast cancer
Radiation therapy for breast cancer
Common questions about breast cancer treatment
Paulas story A team approach to battling breast cancer

Clinical trials

Explore Mayo Clinic studies testing new treatments, interventions and tests as a means to prevent, detect, treat or manage this condition.

Alternative medicine

No alternative medicine treatments have been found to cure breast cancer. But complementary and alternative medicine therapies may help you cope with side effects of treatment.

Alternative medicine for fatigue

Many people with breast cancer have fatigue during and after treatment. This feeling of being very tired and worn down can continue for years. When combined with care from your healthcare team, complementary and alternative medicine therapies may help relieve fatigue.

Talk with your healthcare team about:

Expressing your feelings. Find an activity that allows you to write about or discuss your emotions. Examples include writing in a journal, participating in a support group or talking to a counselor.
Gentle exercise. If you get the OK from your healthcare team, start with gentle exercise a few times a week. Add more exercise, as you feel up to it. Consider walking, swimming, yoga and tai chi.
Managing stress. Take control of the stress in your daily life. Try stress-reduction techniques such as muscle relaxation, visualization, and spending time with friends and family.

Coping and support

Some breast cancer survivors say their diagnosis felt overwhelming at first. It can be stressful to feel overwhelmed at the same time you need to make important decisions about your treatment. In time, you'll find ways to cope with your feelings. Until you find what works for you, it might help to:

Learn enough about your breast cancer to make decisions about your care

If you'd like to know more about your breast cancer, ask your healthcare team for the details of your cancer. Write down the type, stage and hormone receptor status. Ask for good sources of information where you can learn more about your treatment options.

Knowing more about your cancer and your options may help you feel more confident when making treatment decisions. Still, some people don't want to know the details of their cancer. If this is how you feel, let your care team know that too.

Talk with other breast cancer survivors

You may find it helpful and encouraging to talk to others who have been diagnosed with breast cancer. Contact a cancer support organization in your area to find out about support groups near you or online. In the United States, you might start with the American Cancer Society.

Find someone to talk with about your feelings

Find a friend or family member who is a good listener. Or talk with a clergy member or counselor. Ask your healthcare team for a referral to a counselor or other professional who works with people who have cancer.

Keep your friends and family close

Your friends and family can provide a crucial support network for you during your cancer treatment.

As you begin telling people about your breast cancer diagnosis, you'll likely get many offers for help. Think ahead about things you may want help with. Examples include listening when you want to talk or helping you with preparing meals.

Preparing for your appointment

Make an appointment with a doctor or other healthcare professional if you have any symptoms that worry you. If an exam or imaging test shows you might have breast cancer, your healthcare team will likely refer you to a specialist.

Specialists who care for people with breast cancer include:

Breast health specialists.
Breast surgeons.
Doctors who specialize in diagnostic tests, such as mammograms, called radiologists.
Doctors who specialize in treating cancer, called oncologists.
Doctors who treat cancer with radiation, called radiation oncologists.
Genetic counselors.
Plastic surgeons.

What you can do to prepare

Write down any symptoms you're experiencing, including any that may seem unrelated to the reason for which you scheduled the appointment.
Write down key personal information, including any major stresses or recent life changes.
Write down your family history of cancer. Note any family members who have had cancer. Note how each member is related to you, the type of cancer, the age at diagnosis and whether each person survived.
Make a list of all medicines, vitamins or supplements that you're taking.
Keep all of your records that relate to your cancer diagnosis and treatment. Organize your records in a binder or folder that you can take to your appointments.
Consider taking a family member or friend along. Sometimes it can be difficult to absorb all the information provided during an appointment. Someone who accompanies you may remember something that you missed or forgot.
Write down questions to ask your healthcare professional.

Questions to ask your doctor

Your time with your healthcare professional is limited. Prepare a list of questions so that you can make the most of your time together. List your questions from most important to least important in case time runs out. For breast cancer, some basic questions to ask include:

What type of breast cancer do I have?
What is the stage of my cancer?
Can you explain my pathology report to me? Can I have a copy for my records?
Do I need any more tests?
What treatment options are available for me?
What are the benefits from each treatment you recommend?
What are the side effects of each treatment option?
Will treatment cause menopause?
How will each treatment affect my daily life? Can I continue working?
Is there one treatment you recommend over the others?
How do you know that these treatments will benefit me?
What would you recommend to a friend or family member in my situation?
How quickly do I need to make a decision about cancer treatment?
What happens if I don't want cancer treatment?
What will cancer treatment cost?
Does my insurance plan cover the tests and treatment you're recommending?
Should I seek a second opinion? Will my insurance cover it?
Are there any brochures or other printed material that I can take with me? What websites or books do you recommend?
Are there any clinical trials or newer treatments that I should consider?

In addition to the questions that you've prepared, don't hesitate to ask other questions you think of during your appointment.

What to expect from your doctor

Be prepared to answer some questions about your symptoms and your health, such as:

When did you first begin experiencing symptoms?
Have your symptoms been continuous or occasional?
How severe are your symptoms?
What, if anything, seems to improve your symptoms?
What, if anything, appears to worsen your symptoms?

Living with breast cancer?

Connect with others like you for support and answers to your questions in the Breast Cancer support group on Mayo Clinic Connect, a patient community.

Breast Cancer Discussions

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Cancer facts and figures 2023. American Cancer Society. https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/2023-cancer-facts-figures.html. Accessed Aug. 9, 2023.
Abraham J, et al., eds. Breast cancer. In: The Bethesda Handbook of Clinical Oncology. 6th ed. Kindle edition. Wolters Kluwer; 2023. Accessed March 30, 2023.
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Klimberg VS, et al., eds. Breast cancer diagnosis and techniques for biopsy. In: Bland and Copeland's The Breast: Comprehensive Management of Benign and Malignant Diseases. 6th ed. Elsevier; 2024. https://www.clinicalkey.com. Accessed Aug. 2, 2023.
Palliative care. National Comprehensive Cancer Network. https://www.nccn.org/guidelines/guidelines-detail?category=3&id=1454. Accessed Aug. 2, 2023.
Cancer-related fatigue. National Comprehensive Cancer Network. https://www.nccn.org/guidelines/guidelines-detail?category=3&id=1424. Accessed Aug. 2, 2023.
Breast SPOREs. National Cancer Institute. https://trp.cancer.gov/spores/breast.htm. Accessed Aug. 9, 2023.
Ami TR. Allscripts EPSi. Mayo Clinic. Jan. 31, 2023.
Ami TR. Allscripts EPSi. Mayo Clinic. April 5, 2023.
Member institutions. Alliance for Clinical Trials in Oncology. https://www.allianceforclinicaltrialsinoncology.org/main/public/standard.xhtml?path=%2FPublic%2FInstitutions. Accessed Aug. 9, 2023.
Giridhar KV (expert opinion). Mayo Clinic. Oct. 18, 2023.
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Open access
Published: 09 April 2024

Long-term survival after neoadjuvant therapy for triple-negative breast cancer under different treatment regimens: a systematic review and network meta-analysis

Zhilin Liu 1 na1 ,
Jinming Li 1 na1 ,
Fuxing Zhao 1 na1 ,
Dengfeng Ren 1 ,
Zitao Li 1 ,
Yongzhi Chen 1 ,
Shifen Huang 1 ,
Zhen Liu 1 ,
Yi Zhao 1 ,
Miaozhou Wang 1 ,
Huihui Li 2 ,
ZhengBo Xu 3 ,
Guoshuang Shen 1 &
Jiuda Zhao 1

BMC Cancer volume 24 , Article number: 440 ( 2024 ) Cite this article

229 Accesses

Metrics details

Triple-negative breast cancer (TNBC) is a life-threatening subtype of breast cancer with limited treatment options. Therefore, this network meta-analysis (NMA) aimed to evaluate and compare the effect of various neoadjuvant chemotherapy (NCT) options on the long-term survival of patients with TNBC.

PubMed, Embase, Medline, Cochrane Library, Web of Science, and major international conference databases were systematically searched for randomized controlled trials (RCTs) on the efficacy of various NCT options in patients with TNBC. Searches were performed from January 2000 to June 2023. Study heterogeneity was assessed using the I 2 statistic. Hazard ratios (HRs) and 95% confidence intervals (CIs) were used to evaluate disease-free survival (DFS) and overall survival (OS). Odds ratios (ORs) and 95% CIs were used to evaluate the pathologic complete response (pCR). The primary outcome was DFS.

We conducted an NMA of 21 RCTs involving 8873 patients with TNBC. Our study defined the combination of anthracyclines and taxanes as the preferred treatment option. On this basis, the addition of any of the following new drugs is considered a new treatment option: bevacizumab (B), platinum (P), poly-ADP-ribose polymerase inhibitors (PARPi), and immune checkpoint inhibitor (ICI). Based on the surface under the cumulative ranking curve (SUCRA) values, the top three SUCRA area values of DFS were taxanes, anthracycline, and cyclophosphamide (TAC; 89.23%); CT (84.53%); and B (81.06%). The top three SUCRA area values of OS were CT (83.70%), TAC (62.02%), and B-containing regimens (60.06%). The top three SUCRA area values of pCR were B + P-containing regimens (82.7%), ICI + P-containing regimens (80.2%), and ICI-containing regimens (61.8%).

Conclusions

This NMA showed that standard chemotherapy is a good choice with respect to long-term survival. Moreover, B associated with P-containing regimens is likely to be the optimal treatment option for neoadjuvant TNBC in terms of pCR.

Peer Review reports

Introduction

The latest global cancer burden data released by the World Health Organization International Agency for Research on Cancer in 2020 indicated that the number of new breast cancer cases reached 2.26 million worldwide, exceeding the total number (2.2 million) of lung cancer cases [ 1 ]. Breast cancer has replaced lung cancer to become the world’s most prevalent cancer [ 2 ]. It poses a great threat to the physical and mental health of patients worldwide. Breast cancer treatment is a very long and complex process, and the cost is also very high, and even some patients give up treatment because they cannot afford the treatment cost, and further worsen the condition. Triple-negative breast cancer (TNBC) is a subtype of breast cancer characterized by the lack of receptor-estrogen and progesterone expression and amplification of human epidermal growth factor receptor 2 [ 3 , 4 ]. Clinically, TNBC is one of the most aggressive subtypes of breast cancer, accounting for approximately 15%–20% of all breast cancers [ 5 ]. Endocrine therapy with hormone receptor and targeted therapy to block human epidermal growth factor receptor 2 (HER-2) have proven ineffective for patients with TNBC [ 6 ]. The clinical course of TNBC is aggressive, with a high probability of visceral and brain metastases, and its prognosis is the worst among the breast cancer subtypes [ 7 , 8 ]. The BRCA 1/2 gene is particularly strongly associated with triple-negative breast cancer. In the Chinese population, the BRCA 1/2 mutation rate is less than 1% in the general population and about 3% in all breast cancer patients, and up to 17.3% in triple-negative breast cancer. From another perspective, approximately 60%-80% of breast cancer patients carrying the BRCA 1 mutation are triple-negative breast cancer, while approximately 25% of breast cancer patients carrying the BRCA 2 mutation have triple-negative breast cancer [ 9 , 10 ].

Anthracyclines, cyclophosphamides, and taxanes are the preferred neoadjuvant chemotherapy (NCT) for TNBC [ 11 , 12 ]. NCT can reduce the micrometastasis, shrink the tumor, reduce the stage, and increase the chance of breast preservation treatment, which improve the radical cure and breast preservation rate and obtain the drug sensitivity information [ 13 , 14 ]. Studies confirm that achieving pathological complete response (pCR) after a neoadjuvant treatment with TNBC has a good predictive value for long-term survival benefits [ 15 ]. Currently, platinum (P) and poly-ADP-ribose polymerase inhibitors (PARPi) play important antitumor roles in NCT for TNBC, and their efficacy is significant in young patients, especially with BRCA gene mutations. As a DNA cross-linking agent, P cross-connects with the DNA after entering the tumor cells, which interferes with DNA replication of the tumor cells, leading to double-strand DNA breaks of the tumor cells, and then killing the tumor cells. Several single-arm or randomized controlled clinical studies including GeparSixto, CALGB40603, BrighTNess, NeoCART have confirmed the efficacy and safety of P-containing chemotherapy regimens for the treatment of TNBC [ 16 , 17 , 18 , 19 ].

Immune checkpoint inhibitor (ICI) therapy is directed against the interaction between the programmed death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) [ 20 , 21 ]. PD-1 is a co-inhibitory molecule expressed by activated T cells when antigen-presenting cells or tumor cells are combined with PD-L1, which further lead to inhibiting the T-cell activation and suppressing the body’s antitumor immune response. Moreover, the view of PD-1/PD-L1 ICI can improve the suppressed antitumor immune response to relieve the body’s immune response inhibition state, further realizing the antitumor effects [ 22 , 23 ]. ICI may enhance the endogenous anticancer immunity after increasing the release of tumor-specific antigens through chemotherapy. Most current studies show that ICI treatment has a better therapeutic effect and lesser toxicity in TNBC [ 24 , 25 ]. Moreover, the vascular endothelial growth factor (VEGF) is an important regulator of tumor angiogenesis and metastasis [ 26 , 27 ]. Bevacizumab (B) is a recombinant human monoclonal antibody against VEGF that plays various roles in the tumor blood vessels by specifically binding to VEGF and blocking its interaction with receptors [ 28 ]. Relevant studies have reported that adding B based on chemotherapeutic drugs can improve the pCR. Antivascular therapy combined with immunotherapy showed an excellent antitumor activity of different cancers [ 29 , 30 ]. Liu et al . showed that antiangiogenic therapy can improve the sensitivity of PD-L1 expression and the infiltration of PD-1/PD-L1 immunotherapy, playing a synergistic sensitization effect and improving the disease-free survival (DFS) and overall survival (OS) of patients with TNBC [ 31 , 32 ].

Although numerous NCT regimens are currently being used for TNBC, the clinical efficacy of different treatment regimens, especially in terms of long-term survival, remains unclear. Therefore, we conducted a Bayesian meta-analysis of randomized controlled trials (RCTs) to evaluate the effectiveness of different treatment regimens (long-term survival and pCR), thereby providing evidence-based medical information on NCT for TNBC in clinical practice.

Search strategy

This network meta-analysis (NMA) was performed according to the preferred reporting items for systematic reviews and meta-analyses statement [ 33 ]. PubMed, EMBASE, Medline, Cochrane Library, Web of Science, main oncology conference of American Society of Clinical Oncology, the European Society of Medical Oncology, and San Antonio Breast Cancer Symposium databases were searched for high-quality RCTs from January 2000 to June 2023. The search was performed using the following keywords without any restrictions: (triple-negative breast cancer OR triple negative breast neoplasm OR er-negative pr-negative her2-negative breast cancer OR TNBC) AND (neoadjuvant therapy OR neoadjuvant treatment OR neoadjuvant chemotherapy OR neoadjuvant chemotherapy treatment) AND (DFS OR disease free survival) AND (OS OR overall survival) AND (pCR OR pathological complete response). The reference lists of relevant studies, reviews, and meta-analyses were manually screened for potentially eligible publications.

Selection criteria

Eligible trials included those that prospectively compared at least two arms of different neoadjuvant chemotherapeutic regimens in patients with TNBC. Inclusion criteria were as follows: patients with pathologically confirmed TNBC; those with clinical stages of II and III (T1c, N1-2 or T2-4, and N0-2); and those who did not receive surgical NCT. The study end-points included event-free survival (EFS) or DFS, OS, and pCR. The exclusion criteria were as follows: studies involving patients with metastatic TNBC; non-RCTs; articles not written in English; and studies with no data regarding EFS or DFS, OS, and pCR. If several publications from the same trial were identified, only the most recent or complete publications were included.

Data extraction

Eight reviewers were divided into four groups to independently screen the articles (ZL and JL, FZ and QX, DR and ZL, and YC and SH), perform data extraction (ZL and JL and LZ and ZY), and assess the risk of bias (ZL and JL and LZ and MW). Disagreements were resolved by discussion, with assistance from a third party (GS or JZ) if necessary. The following information was recorded: study, author–year, journal, country, arms, medicine, clinical stage, trial phase, TNBC definition, sample size, and study outcomes (EFS or DFS, OS, and pCR).

Explanation of treatment regimens and outcome definitions

Currently, the standard treatment options for TNBC are not yet established, and NCT with anthracycline and purple line represents the cornerstone historical standard for TNBC treatment [ 34 ]. Our study defined the combination of anthracyclines and taxanes as the preferred treatment option. On this basis, any addition of other therapeutic drugs is a new treatment option.

Statistical analysis

Hazards ratio (HR) and odds ratio (OR) were used to estimate pooling effect sizes. For pairwise meta-analysis, the Cochrane Q statistic and the I 2 test were used to calculate heterogeneity. Statistical heterogeneity was defined as P of < 0.1 and/or I 2 of > 50%. A pairwise meta-analysis was performed using a random-effects model or a fixed-effect model depending on the presence of statistical heterogeneity. All pairwise meta-analyses were performed using the Review Manager version 5.3. Results are reported as HR, OR, and corresponding 95% confidence intervals (CIs). All P -values were two sided, and differences with P < 0.05 were considered statistically significant. A Bayesian NMA was performed using the Aggregate Data Drug Information System version 1.16.6 ( http://www.drugis.org ). Node splitting analyses were performed to verify the consistency between direct and indirect evidence. If no significant inconsistency was detected, a consistency model was used to analyze the relative effects of the interventions. Otherwise, an inconsistency model was applied. The “gemtc” package of the R (v14.1) software was used for sorting chats and analyze the data. The NMA results are presented as HR and its corresponding 95% CIs. The “network” packages of the Stata (v14.2) software were used for sorting chats and data analysis. The NMA results are presented as OR and corresponding 95% CIs. The rank probability for each treatment was calculated to determine the treatment ranking. When assessing the merit of the drug efficacy, the surface under the cumulative ranking curve (SUCRA) values was used. It has a value of 0 to 1, and higher SUCRA values indicate better efficacy of the agent.

Study selection and characteristics of the included studies

Figure 1 illustrates the study retrieval process. A total of 10,000 results were obtained from the database, and 1500 studies were automatically removed by Zotero. Based on titles and abstracts, 120 suitable full-text studies were screened, and 31 studies were excluded due to the lack of assessment results. Ultimately, 21 studies involving 8873 patients were included in our reticulated meta-analysis [ 16 , 17 , 18 , 19 , 25 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ]. Table 1 summarizes the characteristics of the included RCTs. A total of 18 phase III trials and 3 phase II trials were identified. This study evaluated nine treatment regimens in the form of network maps: standard chemotherapeutic agents, TAC (taxanes, anthracycline, and cyclophosphamide), TC (taxanes and cyclophosphamide), B, P, B + P, P + PARPi, ICI, and ICI + P (Fig. 2 ).

A flowchart of the study selection process

Network plots for eligible comparisons were included in the network meta-analysis. A Network diagram of the disease-free survival (DFS). B Network diagram of the overall survival (OS). C Network diagram of the pathological complete response (pCR)

Of the 21 studies, 20 reported data on DFS, with 3 studies including standard chemotherapy, 8 studies including P-containing regimen, 1 study including B + P-containing regimen, 4 studies including B-containing regimen, 1 study including P + PARPi-containing regimen, 2 studies including ICI-containing regimen, and 1 study including ICI + P-containing regimen, all of which were NCTs. Results showed that CT compared with P (HR, 0.8; 95% CI, 0.68–0.94), B + ICI (HR, 0.29; 95% CI, 0.12–0.73), and B + P (HR, 0.43; 95% CI, 0.23–0.8) had a significant benefit of DFS. Figure 3 A summarizes the results of DFS analysis.

Bayesian network meta-analysis for disease-free survival (DFS). A League comparison table. Data are expressed as hazards ratio (HR) and 95% confidence interval (CI). HR of < 1 supports column definition processing, whereas HR of > 1 supports row definition processing. B Plot of sequencing probabilities for nine DFS schemes. The larger the area of the curve and the X-axis, the higher the recommended treatment

A cumulative ranking of the nine treatment regimens was also analyzed. The results showed that TAC (89.23%), CT (84.53%), B (81.06%), and P (55,30%) ranked first to forth, while ICI (37.86%), ICI + P (30.94%), B + P (15.48%), and B + ICI (5.58%) ranked fifth to eighth (Fig. 3 B).

Of the 21 studies, 17 reported data on OS, with 3 studies including B-containing regimen, 3 studies including standard chemotherapy, 8 studies including P-containing regimen, 2 studies including ICI-containing regimen, and 1 study including PARPi + P-containing regimen, all of which were NCTs. Results showed that PARPi + P-containing regimen compared with B (HR, 0.24; 95% CI, 0.06–0.99), P (HR, 0.24; 95% CI, 0.07–0.89), and standard chemotherapy (HR, 0.21; 95% CI, 0.05–0.8) had a significant benefit of OS. Figure 4 A summarizes the results of OS analysis.

Bayesian network meta-analysis of the overall survival (OS). A League comparison table. Data are expressed as hazards ratio (HR) and 95% confidence interval (CI). HR of < 1 supports the column definition processing, whereas HR of > 1 supports the row definition processing. B Plot of sequencing probabilities for nine OS schemes. The larger the area of the curve and the X-axis, the higher the recommended treatment

A cumulative ranking of the nine treatment regimens was also analyzed. The results showed that CT (83.70%), TAC (62.02%), and B-containing regimens (60.06%) ranked first to third, while P-containing regimens (58.89%), ICI-containing regimens (31.48%), and PARPi + P-containing regimens (3.85%) ranked forth to sixth (Fig. 4 B).

All 21 included trials reported pCR, with 3 studies including standard chemotherapy, 8 studies including P-containing regimen, 1study including B + P-containing regimen, 4 studies including B-containing regimen, 1 study including P + PARPi-containing regimen, 2 studies including ICI-containing regimen, and 2 studies including ICI + P-containing regimen, all of which were NCTs. The incidence of pCR in the PARPi + P-containing regimen (OR, 0.43; 95% CI, − 0.02 to 0.89), P-containing regimen (OR, 0.43; 95% CI, 0.24–0.62), and B-containing regimen (OR, 0.34; 95% CI, 0.06–0.63) was significantly higher than that of standard chemotherapeutic agents. Figure 5 A summarizes the results of pCR analysis.

Bayesian network meta-analysis of pathological complete response (pCR). A The league table of comparisons. Data are presented as odds radio (OR) and 95% confidence intervals (CI). An OR of > 1 favors the column-defining treatment, and an OR of < 1 favors the row-defining treatment. B Cumulative sequence diagram of nine pCR schemes. The higher the SUCRA value, the higher the ranking

A cumulative ranking of the nine treatment regimens was also analyzed. The results showed that B + P-containing regimens (82.7%), ICI + P-containing regimens (80.2%), ICI-containing regimens (61.8%), and P-containing regimens (55.0%) ranked first to forth, while PARPi + P-containing regimens (53.5%), B-containing regimens (44.4%), CT (20.5%), TAC (1.8%), and TC (1.5%) ranked fifth to ninth (Fig. 5 B).

Currently, the combination of P, B, PARPi, and ICI based on anthracyclines, cyclophosphamides, and taxanes has paved a new avenue for TNBC treatment [ 50 , 51 , 52 , 53 , 54 ]. However, the long-term survival after neoadjuvant treatment in patients with TNBC under different treatment regimens remains unclear. Therefore, we conducted a Bayesian meta-analysis of RCTs to evaluate the effectiveness of different treatment regimens (long-term survival and pCR) and provide evidence-based medical information on NCT for TNBC in clinical practice. The results showed that, based on SUCRA values, standard chemotherapy is still a better choice for long-term survival consideration compared with NCT for TNBC, and the B + P-containing regimen is most likely the optimal NCT option for TNBC based on pCR results.

In 2022, Li et al [ 53 ]. published an NMA evaluating eight neoadjuvant treatment options for TNBC. The treatment regimen included the combination of P, B, PARPi, and ICI. In this previous study, the observation indicator was pCR; our study added survival indicators to determine the efficacy ranking of several treatment options for TNBC.

This study included 21 RCTs involving 8873 patients with TNBC. Of these, 20 RCTs reported data on DFS; however, only 7 RCTs reported statistical significance for DFS, with 2 studies using standard chemotherapies, 3 studies using P-containing regimens, 1 using ICI-containing regimens, and 1 trial using B + P-containing regimens. Longer survival was also reported in the remaining 13 trials without significant statistical significance. Due to limited DFS data, we treated data regarding EFS, relapse-free survival, and distant DFS reported in these studies as DFS data; however, the significant DFS data remained somewhat unsatisfactory. It may be related to the small number of patients included in the study or the lack of relevant data. When we summarized 20 studies based on SUCRA values, the proportion of studies using standard chemotherapy was relatively high, and the top three treatment options were standard chemotherapy (89.23%), B-containing regimens (81.06%), and P-containing regimens (55.30%).

In our NMA, 17 of 21 trials reported data on OS, but only 5 of them reported statistical significance for OS, which included 1 study using standard chemotherapy, 2 studies using P-containing regimens, 1 study using ICI-containing regimens, and 1 study using B-containing regimens. Longer survival was also reported in the remaining 12 trials, but without significant statistical significance. This may be related to the small number of patients included in the study or the short follow-up time; however, the addition of P, B, and ICI to the standard chemotherapy can partly prolong the OS of patients with TNBC [ 55 , 56 , 57 , 58 , 59 ]. Further large-scale clinical trials are warranted to confirm their efficacy in the future. In terms of OS, when we summarized 17 studies based on SUCRA values, a high proportion of studies were based on standard chemotherapy, and the top three treatment options were standard chemotherapy (83.70%), B-containing regimens (60.06%), and P-containing regimens (58.89%).

All 21 trials reported pCR data, which were shown to be statistically significant. Compared with standard chemotherapeutic agents alone, P-containing regimens, PARPi-containing regimens, or neoadjuvant regimens based on B or ICI showed significant associations with better pCR. Moreover, a recent paired meta-analysis revealed that NCT based on the above regimens significantly improved pCR in patients with TNBC compared with standard chemotherapy [ 53 ], which is consistent with our findings. The results of reticulation analysis based on SUCRA values suggested that B + P-containing regimens are most likely the optimal NCT option for TNBC. The subsequent regimens were ICI + P (80.2%) and ICI (61.8%), and the final recommendation was standard chemotherapy.

This study has some limitations. First, the small number of clinical patients included in these studies or insufficient follow-up time may have caused a bias on the study results. Second, the RCTs included in this study were mainly based on standard chemotherapy, and the proportion of pairs among nine neoadjuvant regimens was small, which may have led to missing indirect contrast data, resulting in inaccurate estimation of the optimal treatment regimen. Third, although we included survival indicators, survival data of different treatment regimens remained insufficient. However, we believe that the use of our carefully pooled data and statistical methods can overcome these limitations of reticulation analysis.

This NMA demonstrated that standard chemotherapy is a good choice with respect to long-term survival, and B-containing regimens are associated with significantly higher pCR rates among patients with neoadjuvant TNBC. Future research should focus on evaluating larger clinical studies to obtain further survival data to help optimize personalized treatment for patients with TNBC.

Availability of data and materials

All data generated or analysed during this study are included in this published article.

Abbreviations

Triple-negative breast cancer

Network meta-analysis

Neoadjuvant chemotherapy

Randomized controlled trials

Hazard ratio

Confidence interval

Disease-free survival

Overall survival

Odds ratios

Pathologic complete response

Bevacizumab

Poly-ADP-ribose polymerase inhibitors

Immune checkpoint inhibitor

Surface under the cumulative ranking curve

Programmed death protein 1

Programmed death ligand 1

Vascular endothelial growth factor

Event-free survival

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This work was supported by Provincial-Level Clinical Key Specialty Construction in Qinghai Province.

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Zhilin Liu, Jinming Li and Fuxing Zhao are contributed equally.

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Breast Disease Diagnosis and Treatment Center, Affiliated Hospital of Qinghai University, Affiliated Cancer Hospital of Qinghai University, People’s Republic of China, Qinghai Provincial Clinical Research Center for Cancer, Qinghai Provincial Institute of Cancer Research, Xining, China

Zhilin Liu, Jinming Li, Fuxing Zhao, Dengfeng Ren, Zitao Li, Yongzhi Chen, Shifen Huang, Zhen Liu, Yi Zhao, Miaozhou Wang, Guoshuang Shen & Jiuda Zhao

Department of Breast Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China

Qinghai University, Xining, China

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Concept and design: Drs ZL, JL and FZ. Acquisition, analysis, or interpretation of data: Drs DR, ZL and YC. Drafting of the manuscript: All authors. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Drs SH, ZL, YZ and MW. Obtained funding: All authors. Administrative, technical, or material support: All authors. Supervision: Drs GS and JZ. All authors read and approved the final manuscript.

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Liu, Z., Li, J., Zhao, F. et al. Long-term survival after neoadjuvant therapy for triple-negative breast cancer under different treatment regimens: a systematic review and network meta-analysis. BMC Cancer 24 , 440 (2024). https://doi.org/10.1186/s12885-024-12222-9

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DOI : https://doi.org/10.1186/s12885-024-12222-9

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Frenel J , Zeghondy J , Guérin-Charbonnel C, et al. Tucatinib Combination Treatment After Trastuzumab-Deruxtecan in Patients With ERBB2 -Positive Metastatic Breast Cancer. JAMA Netw Open. 2024;7(4):e244435. doi:10.1001/jamanetworkopen.2024.4435

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Tucatinib Combination Treatment After Trastuzumab-Deruxtecan in Patients With ERBB2 -Positive Metastatic Breast Cancer

1 Department of Medical Oncology, Institut de Cancerologie de l’Ouest, Saint-Herblain, France
2 Department of Medical Oncology, Gustave Roussy Cancer Center, Villejuif, France
3 Department of Biostatistics and Analytics, Institut de Cancerologie de l’Ouest, Saint-Herblain, France
4 Department of Medical Oncology, Oscar Lambret Comprehensive Cancer Center, Lille, France
5 Department of Medical Oncology, Oncopôle, Toulouse, France
6 Department of Medical Oncology, Institut de Cancerologie de l’Ouest, Angers, France
7 Department of Medical Oncology Bordeaux, Institut Bergonie, Bordeaux, France
8 Department of Medical Oncology, Centre Antoine Lacassagne, Nice, France
9 Department of Medical Oncology, Centre Eugene Marquis, Rennes, France
10 Department of Medical Oncology, Centre Georges Francois Leclerc, Dijon, France
11 Department of Medical Oncology, Institut Paoli Calmette, Marseille, France
12 Department of Medical Oncology, Montpellier Cancer Institute, Montpellier, France
13 Department of Medical Oncology, Centre Léon Bérard, Lyon, France
14 Department of Medical Oncology, Institut Curie, Paris, France
15 Data Factory, Institut de Cancerologie de l’Ouest, Saint-Herblain, France

Question Is tucatinib combined with trastuzumab and capecitabine (TTC) following treatment with trastuzumab-deruxtecan associated with improved outcomes in patients with ERBB2 -positive metastatic breast cancer (MBC), including patients with and without brain metastasis?

Findings In this cohort study of 101 patients with ERBB2 -positive MBC treated in 12 French comprehensive cancer centers, TTC provided a clinically significant tumor response and progression-free survival after prior exposure to trastuzumab-deruxtecan.

Meaning These findings suggest that TTC therapy was associated with clinically meaningful outcomes in patients with ERBB2 -positive MBC.

Importance Little is known regarding the outcomes associated with tucatinib combined with trastuzumab and capecitabine (TTC) after trastuzumab-deruxtecan exposure among patients with ERBB2 (previously HER2 )-positive metastatic breast cancer (MBC).

Objective To investigate outcomes following TTC treatment in patients with ERBB2 -positive MBC who had previously received trastuzumab-deruxtecan.

Design, Setting, and Participants This cohort study included all patients with MBC who were treated in 12 French comprehensive cancer centers between August 1, 2020, and December 31, 2022.

Exposure Tucatinib combined with trastuzumab and capecitabine administered at the recommended dose.

Main Outcomes and Measures Clinical end points included progression-free survival (PFS), time to next treatment (TTNT), overall survival (OS), and overall response rate (ORR).

Results A total of 101 patients with MBC were included (median age, 56 [range, 31-85] years). The median number of prior treatment lines for metastatic disease at TTC treatment initiation was 4 (range, 2-15), including 82 patients (81.2%) with previous trastuzumab and/or pertuzumab and 94 (93.1%) with previous ado-trastuzumab-emtansine) exposure. The median duration of trastuzumab-deruxtecan treatment was 8.9 (range, 1.4-25.8) months, and 82 patients (81.2%) had disease progression during trastuzumab-deruxtecan treatment, whereas 18 (17.8%) had stopped trastuzumab-deruxtecan for toxic effects and 1 (1.0%) for other reasons. Tucatinib combined with trastuzumab and capecitabine was provided as a third- or fourth-line treatment in 37 patients (36.6%) and was the immediate treatment after trastuzumab-deruxtecan in 86 (85.1%). With a median follow-up of 11.6 (95% CI, 10.5-13.4) months, 76 of 101 patients (75.2%) stopped TTC treatment due to disease progression. The median PFS was 4.7 (95% CI, 3.9-5.6) months; median TTNT, 5.2 (95% CI, 4.5-7.0) months; and median OS, 13.4 (95% CI, 11.1 to not reached [NR]) months. Patients who received TTC immediately after trastuzumab-deruxtecan had a median PFS of 5.0 (95% CI, 4.2-6.0) months; median TTNT of 5.5 (95% CI, 4.8-7.2) months, and median OS of 13.4 (95% CI, 11.9-NR) months. Those who received TTC due to trastuzumab-deruxtecan toxicity-related discontinuation had a median PFS of 7.3 (95% CI, 3.0-NR) months. Best ORR was 29 of 89 patients (32.6%). Sixteen patients with active brain metastasis had a median PFS of 4.7 (95% CI, 3.0-7.3) months, median TTNT of 5.6 (95% CI, 4.4 to NR), and median OS of 12.4 (95% CI, 8.3-NR) months.

Conclusions and Relevance In this study, TTC therapy was associated with clinically meaningful outcomes in patients with ERBB2 -positive MBC after previous trastuzumab-deruxtecan treatment, including those with brain metastases. Prospective data on optimal drug sequencing in this rapidly changing therapeutic landscape are needed.

Recent guidelines have positioned trastuzumab-deruxtecan as the preferred second-line treatment for ERBB2 (previously HER2 )-positive metastatic breast cancer (MBC) except in patients with active brain metastases. 1 , 2 Tucatinib combined with trastuzumab and capecitabine (TTC) has been the preferred third-line treatment for ERBB2 -positive MBC; however, little is known regarding its associated outcomes after trastuzumab-deruxtecan exposure. In this rapidly changing therapeutic landscape, outcome data according to sequencing represents a major issue for standard practice. Few studies have sought to elucidate the mechanisms underlying trastuzumab-deruxtecan resistance, and few clinical data on the outcomes of therapies beyond progression during trastuzumab-deruxtecan treatment have been available. 3 Therefore, we evaluated the outcomes following TTC treatment in patients with ERBB2 -positive MBC who had been previously treated with trastuzumab-deruxtecan.

This cohort study was conducted at 12 cancer centers in France. All patients with ERBB2 -positive MBC who were treated with TTC and had prior exposure to trastuzumab-deruxtecan were included. The TTC regimen included tucatinib (300 mg orally twice daily throughout the treatment period) in combination with trastuzumab (6 mg/kg of body weight intravenously once every 21 days) and capecitabine (1000 mg/m 2 of body surface area orally twice daily on days 1 to 14 of each 21-day cycle). Data were obtained from the patients’ medical records. Clinical end points included progression-free survival (PFS) (Response Evaluation Criteria in Solid Tumors [RECIST] guideline, version 1.1 [RECIST Working Group]) as determined by the local investigator; time to next treatment (TTNT), defined as the duration from TTC initiation to the beginning of the subsequent regimen; response rate in evaluable patients (RECIST guideline, version 1.1); and overall survival (OS). Brain metastases were classified as active (untreated or previously treated and progressing just before TTC initiation) or stable. An independent ethics committee approved our study protocol. Owing to the use of deidentified data, no formal dedicated informed consent was required; however, all patients had provided written approval of the reuse of their electronically recorded data. This study was conducted in accordance with the ethical principles of the Declaration of Helsinki, 4 the Good Clinical Practice guideline, 5 applicable regulatory requirements, and the European General Data Protection Regulation. The Institut de Cancerologie de l’Ouest has made a commitment to the French Commission Nationale de l’Informatique et des Libertés to comply with Reference Methodology 4, and this project is registered in the public directory maintained by the National Institute for Health Data. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology ( STROBE ) reporting guideline.

Survival curves were estimated using the Kaplan-Meier method with 95% CIs. Overall survival was computed from TTC initiation to death or date of last follow-up (censored). Progression-free survival was computed from TTC initiation to progression or death. Patients who started a new treatment without progression and those with ongoing TTC treatment without progression at the time of analysis were censored. Time to next treatment was computed from TTC initiation to the beginning of the subsequent line, with ongoing treatment and deaths being censored. To minimize bias, in cases wherein a gap longer than 60 days with no treatment existed after TTC, the end date of the TTC was taken as a proxy for start date of a new line. We performed all analyses using R software, version 3.6.1 (R Project for Statistical Computing).

We included 101 patients with MBC (median age, 56 [range, 31-85] years); patient characteristics are summarized in Table 1 . Racial and ethnic data were not collected in conformity to French law. These patients were treated between August 1, 2020, and December 31, 2022. Accordingly, the median number of prior treatment lines for MBC at TTC initiation was 4 (range, 2-15), with 82 patients (81.2%) having previously received trastuzumab and/or pertuzumab and 94 (93.1%) having received ado-trastuzumab-emtansine. The TTC regimen was given as a third- or a fourth-line treatment for MBC in 37 patients (36.6%). At TTC initiation, 39 patients (38.6%) had known brain metastases. With a median follow-up of 11.6 (95% CI, 10.5-13.4) months, 76 patients (75.2%) stopped TTC due to disease progression and 25 (24.8%) due to toxic effects. The median PFS in the entire cohort was 4.7 (95% CI, 3.9-5.6) months; median TTNT, 5.2 (95% CI, 4.5-7.0) months; and median OS, 13.4 (95% CI, 11.1 to not reached [NR]) months ( Table 2 ). The overall response rate (ORR) was 32.6% (29 of 89 patients) with 2 complete responses, and disease control rate (DCR) was 64.0% (57 of 89 patients). Patients treated with TTC immediately after trastuzumab-deruxtecan had a median PFS of 5.0 (95% CI, 4.2-6.0) months, median TTNT of 5.5 (95% CI, 4.8-7.2) months, and median OS of 13.4 (95% CI, 11.9-NR) months. Patients who received TTC due to trastuzumab-deruxtecan toxicity-related discontinuation had a median PFS of 7.3 (95% CI, 3.0-NR) months. Two patients without known brain metastases had brain metastases documented as a site of progression during TTC treatment. Patients with active brain metastases (n = 16) had a median PFS of 4.7 (95% CI, 3.0-7.3) months, median TNTT of 5.6 (95% CI, 4.4-NR) months, and median OS of 12.4 (95% CI, 8.3.1-NR) months. The intracranial ORR was 20.0% (3 of 15 patients) with 2 complete responses, whereas the DCR was 66.7% (10 of 15 patients). Details regarding the ORR are presented in Table 3 .

Recent studies have shown that trastuzumab-deruxtecan (an antibody-drug conjugate) and TTC (a combination of tucatinib [a highly selective tyrosine kinase inhibitor (TKI) for ERBB2 ] combined with trastuzumab and capecitabine) outperformed standard chemotherapy for ERBB2 -positive MBC. 6 , 7 Since the results of the DESTINY-Breast03 trial were published, 7 trastuzumab-deruxtecan is the preferred option for the second-line treatment of ERBB2 -positive MBC, except for patients with active brain metastases. However, appropriate sequencing of these drugs has remained challenging given that only 15% of the patients in the DESTINY-Breast03 trial had received a previous TKI, while no patients enrolled in the HER2CLIMB clinical trial had received prior trastuzumab-deruxtecan. Clinical data are even scarcer. In the current study, TTC demonstrated significant activity, although the median PFS is lower than that reported in the registration trial (4.7 [95% CI, 3.9-5.6] vs 7.8 [95% CI, 7.5-9.6] months). The greater median number of previous treatment lines for MBC (4 in our study vs 3 in the HER2CLIMB trial), absence of trastuzumab-deruxtecan exposure, and higher proportion of patients who received lapatinib (another anti- ERBB2 TKI) (33 of 101 [32.7%] vs 6.9%) in the present study may explain these discrepancies. In addition, 25 patients (24.7%) stopped TTC for toxic effects in our population, reflecting a more heavily treated population compared with the HER2CLIMB population, where 5.7% stopped tucatinib treatment and 10.1% stopped capecitabine treatment due to toxic effects.

We also evaluated TTNT, a useful end point for clinical evidence studies, given the lack of a standardized evaluation. Accordingly, we found that the TTNT was 5.2 (95% CI, 4.5-7.0) months. Two prior small studies 8 , 9 had evaluated TTNT with TTC after trastuzumab-deruxtecan exposure. The Flatiron Health Analytic Database study reported a median TTNT of 8.1 (95% CI, 4.0 to NR) months in 29 patients. 8 The second study reported a median TTNT of 7.5 (95% CI, 5.0-13.3) months in 61 patients receiving TTC after trastuzumab-deruxtecan exposure. 9 Importantly, patients in these 2 studies had received a median of 2 previous lines for MBC, with less than 50% of patients previously treated with ado-trastuzumab-emtansine compared with 93.1% in our cohort.

Estimates show that up to 50% of patients with ERBB2 -positive MBC will develop brain metastases. 10 The HER2CLIMB trial has demonstrated that TTC improved OS, including in patients with active brain metastases, while reducing the risk of developing new brain lesions. 10 Despite trastuzumab-deruxtecan preexposure, the present study found a meaningful intracranial DCR of 62.5% based on the RECIST guideline, version 1.1, with an ORR of 18.8%, a median PFS of 4.7 (95% CI, 3.0-7.3) months, and a median TTNT of 5.6 (95% CI, 4.4-NR) months in patients with active brain metastases at TTC initiation.

We acknowledge several limitations of this study, including the retrospective design and potential inclusion bias inherent to the selection of patients who had received this sequence of treatments. Indeed, given the recent approval of these 2 drugs, our cohort may have included patients who experience rapid disease progression during trastuzumab-deruxtecan treatment, potentially explaining the lower PFS with TTC in the present study compared with the HER2CLIMB trial.

In this retrospective cohort study, TTC therapy was associated with clinically meaningful outcomes among patients with ERBB2 -positive MBC who had been previously exposed to trastuzumab-deruxtecan, including those with active brain metastases. Prospective data on optimal drug sequencing in this rapidly changing therapeutic landscape are needed.

Accepted for Publication: February 1, 2024.

Published: April 3, 2024. doi:10.1001/jamanetworkopen.2024.4435

Corresponding Author: Jean-Sebastien Frenel, MD, PhD, Department of Medical Oncology, Institut de Cancérologie de L’Ouest, 11 Boulevard Jacques Monod, 44800 Saint-Herblain, France ( [email protected] ).

Author Contributions: Professor Frenel and Dr Guérin-Charbonnel had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Frenel, Pierga, Bocquet, Larrouquere, Loirat.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Frenel, Zeghondy, Guérin-Charbonnel, Volant, Poumeaud, Cabal, Galland, Bocquet, Larrouquere, Loirat.

Critical review of the manuscript for important intellectual content: Frenel, Zeghondy, Mailliez, Patsouris, Arnedos, Bailleux, Galland, de Nonneville, Guiu, Dalenc, Pistilli, Bachelot, Pierga, Le Du, Bocquet, Larrouquere, Loirat.

Statistical analysis: Frenel, Zeghondy, Guérin-Charbonnel, Le Du, Bocquet, Larrouquere.

Obtained funding: Frenel, Poumeaud, Cabal, Loirat.

Administrative, technical, or material support: Frenel, Zeghondy, Bailleux, Pierga, Bocquet.

Supervision: Frenel, Arnedos, Guiu, Pistilli, Pierga, Bocquet, Larrouquere, Loirat.

Conflict of Interest Disclosures: Professor Frenel reported receiving grant funding from Seagen Inc during the conduct of the study; personal fees from Roche Genentech; and personal fees and nonfinancial support from Seagen Inc, Novartis AG, Pfizer Inc, Eli Lilly and Company, GSK, Clovis Oncology, AstraZeneca, Daiichi Sankyo, Gilead Sciences Inc, MSD, Pierre Fabre, and Amgen Inc outside the submitted work. Dr Mailliez reported receiving consulting or advisory fees from Daichii Sankyo, Pfizer Inc, and Seagen Inc and receiving funding for travel, accommodations, and expenses from AstraZeneca, Eli Lilly and Company, and Pierre Fabre. Dr Patsouris reported receiving funding for travel, accommodations, and expenses from AstraZeneca, Eisai, Novartis AG, Pfizer Inc, and Roche. Dr Arnedos reported receiving funding from Daiichi Sankyo and Pfizer Inc; consulting or advisory fees from Daiichi Sankyo, AstraZeneca, Gilead Sciences Inc, Menarini Group, Pfizer Inc, and Eli Lilly and Company; and funding for travel, accommodations, and expenses from AstraZeneca, Daiichi Sankyo, Eli Lilly and Company, Novartis AG, and Pfizer Inc outside the submitted work. Dr Bailleux reported receiving consulting or advisory fees from Seagen Inc and AstraZeneca and nonfinancial support from AstraZeneca outside the submitted work. Dr de Nonneville reported receiving consulting or advisory fees from Daiichi Sankyo, Gilead Sciences Inc, Eli Lilly and Company, MSD, Novartis AG, Pfizer Inc, and Seagen Inc; receiving research funding to institution from Eli Lilly and Company and Pfizer Inc; and receiving funding for travel, accommodations, and expenses from AstraZeneca, Daiichi Sankyo, Gilead Sciences Inc, MSD, Novartis AG, and Pfizer Inc. Dr Guiu reported receiving consulting or advisory fees from AstraZeneca and funding for travel, accommodations, and expenses from Novartis AG. Dr Dalenc reported receiving consulting or advisory fees from AstraZeneca, Daiichi Sankyo, Gilead Sciences Inc, Novartis AG, Pfizer Inc, and Seagen Inc and funding for travel, accommodations, and expenses from Gilead Sciences and Pfizer Inc. Dr Pistilli reported receiving consulting or advisory fees from AstraZeneca, Daiichi Sankyo/UCB Japan, Myriad Genetics Inc, Novartis AG, Pierre Fabre, and Puma Biotechnology; receiving research funding to institution from AstraZeneca, Daiichi Sankyo, Gilead Sciences Inc, Merus NV, MSD, Pfizer Inc, and Puma Biotechnology; and receiving funding for travel, accommodations, and expenses from AstraZeneca, Daiichi Sankyo, MSD Oncology, Novartis AG, Pfizer Inc, and Pierre Fabre outside the submitted work. Dr Bachelot reported receiving consulting or advisory fees from Daiichi Sankyo/AstraZeneca, Eli Lilly and Company, Novartis AG, Pfizer Inc, Roche, and Seagen Inc; receiving research funding to institution from AstraZeneca, Daiichi Sankyo/AstraZeneca, Novartis AG, Pfizer Inc, Roche, and Seagen Inc; and funding for travel, accommodations, and expenses from AstraZeneca, Pfizer Inc, and Roche outside the submitted work. Professor Pierga reported receiving consulting or advisory fees from AstraZeneca, Daiichi Sankyo, Gilead Sciences Inc, Menarini Group, Novartis AG, Pfizer Inc, Menarini Stemline, Roche, Exact Sciences Corp, Eli Lilly and Company, MSD, and Eisai and funding for travel, accommodations, and expenses from AstraZeneca, Novartis AG, Pfizer Inc, and Gilead Sciences Inc outside the submitted work. Dr Le Du reported receiving consulting or advisory fees from Daiichi Sanyko/AstraZeneca, Eli Lilly and Company, Seagen Inc, Novartis AG, Pfizer Inc, Roche, Gilead Sciences Inc, Sandoz Group AG, and Myriad Genetics Inc, and travel expenses from Daiichi Sanyko/AstraZeneca, Eli Lilly and Company, Seagen Inc, Novartis AG, Pfizer Inc, and Gilead Sciences Inc during the conduct of the study. Dr Loirat reported receiving honoraria from AstraZeneca, Gilead Sciences Inc, Eli Lilly and Company, and MSD; receiving consulting or advisory fees from 4D Pharma, AstraZeneca, Gilead Sciences Inc, Immunomedics, Eli Lilly and Company, MSD Oncology, Novartis AG, Pfizer Inc, and Roche; and funding for travel, accommodations, and expenses from AstraZeneca, Gilead Sciences Inc, MSD, Pfizer Inc, and Roche. No other disclosures were reported.

Funding/Support: This work was supported by the Institut de Cancerologie de l’Ouest and Seagen International GmbH.

Role of the Funder/Sponsor: Both funders assisted in the study design by reviewing the study protocol, assisted with the collection and analysis of data, reviewed and approved the manuscript, and were involved in the decision to submit the manuscript for publication. Neither funder was involved in the conduct of the study, management and interpretation of the data, or preparation of the manuscript.

Meeting Presentation: This work was presented as a poster at the Annual Meeting of the American Society of Clinical Oncology; June 3, 2023; Chicago, Illinois.

Data Sharing Statement: See the Supplement .

Additional Contributions: We thank the French Comprehensive Cancer Centres involved in this study for providing the data and providing each ESME contact for coordinating the project at the local level. We also thank Camille Morisseau and Laetitia Himpe, Institut de Cancerologie de l’Ouest, for their central coordination and ongoing support, for which they were not compensated, and the SIRIC (Site de Recherche Intégré sur le Cancer) Illiad and EPICURE cohort.

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Breast Cancer Research and Treatment

Innovative Concepts

© 2023
Ouissam Al Jarroudi 0 ,
Khalid El Bairi 1 ,
Giuseppe Curigliano 2

Department of Medical Oncology, Mohammed VI University Hospital, Oujda, Morocco

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Division of New Drugs and Early Drug Development, European Institute of Oncology IRCCS, Milan, Italy

Focuses on treatment options for breast cancer, such as radiotherapy, systemic therapy and immunotherapy
Addresses ongoing research in screening, diagnosis and management for all subtypes of breast cancer
Edited and authored by leading experts in the field

Part of the book series: Cancer Treatment and Research (CTAR, volume 188)

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Table of contents (14 chapters)

Front matter, antibody–drug conjugates: a new therapeutic approach for triple-negative breast cancer.

Ouissam Al Jarroudi, Khalid El Bairi, Giuseppe Curigliano, Said Afqir

Immune-Checkpoint Inhibitors: A New Line of Attack in Triple-Negative Breast Cancer

Screening programs for breast cancer: toward individualized, risk-adapted strategies of early detection.

Dario Trapani, Josè Sandoval, Pamela Trillo Aliaga, Liliana Ascione, Pier Paolo Maria Berton Giachetti, Giuseppe Curigliano et al.

Transversal Perspectives of Integrative Oncology Care in Gastric and Lobular Breast Cancer

Emilio Francesco Giunta, Gianluca Arrichiello, Annalisa Pappalardo, Piera Federico, Angelica Petrillo

Assessment and Response to Neoadjuvant Treatments in Breast Cancer: Current Practice, Response Monitoring, Future Approaches and Perspectives

Vincenzo Sabatino, Alma Pignata, Marvi Valentini, Carmen Fantò, Irene Leonardi, Michela Campora

Estimating the Benefit of Preoperative Systemic Therapy to Reduce the Extent of Breast Cancer Surgery: Current Standard and Future Directions

Giacomo Montagna

A Precise Approach for Radiotherapy of Breast Cancer

Samantha Sigurdson, Stephane Thibodeau, Martin Korzeniowski, Fabio Ynoe Moraes

Fast Mimicking Diets and Other Innovative Nutritional Interventions to Treat Patients with Breast Cancer

Federica Giugliano, Laura Boldrini, Jacopo Uliano, Edoardo Crimini, Ida Minchella, Giuseppe Curigliano

Mechanisms of Endocrine Resistance in Hormone Receptor-Positive Breast Cancer

Antonio Marra, Dario Trapani, Emanuela Ferraro, Giuseppe Curigliano

Innovative Therapeutic Approaches for Patients with HER2-Positive Breast Cancer

Beatrice Taurelli Salimbeni, Emanuela Ferraro, Luca Boscolo Bielo, Giuseppe Curigliano

Breast Cancer Brain Metastases: Achilles’ Heel in Breast Cancer Patients’ Care

Emanuela Ferraro, Andrew D. Seidman

New Concepts in Cardio-Oncology

Paola Zagami, Eleonora Nicolò, Chiara Corti, Carmine Valenza, Giuseppe Curigliano

Next-Generation Sequencing for Advanced Breast Cancer: What the Way to Go?

Dario Trapani, Edoardo Crimini, José Sandoval, Giuseppe Curigliano

The Global Landscape on the Access to Cancer Medicines for Breast Cancer: The ONCOLLEGE Experience

Csongor György Lengyel, Baker Shalal Habeeb, Sara Cecilia Altuna, Dario Trapani, Shah Zeb Khan, Sadaqat Hussain
Breast Cancer Treatment
Triple-negative Breast Cancer
Tumor-infiltrating Lymphocytes
Immune Checkpoint Inhibitors
Screening programs for breast cancer
Precision surgery for the treatment of breast cancer
HER2- positive breast cancer
Biomarkers in Breast Cancer
Luminal B breast cancer
Onco-immunology of breast cancer

About this book

Editors and affiliations.

Ouissam Al Jarroudi, Khalid El Bairi

Giuseppe Curigliano

About the editors

Dr. Ouissam Al Jarroudi, MD, is a distinguished medical oncologist practicing in the medical oncology department at Mohammed VI University Hospital in Oujda, Morocco. She holds a position as a professor at the Faculty of Medicine and Pharmacy, affiliated with Mohammed Ist University. Dr. Al Jarroudi has pursued various fellowships at renowned institutions such as the Department of Medical Oncology at Paul Brousse Hospital, Assistance Publique - Hopitaux de Paris, and Léon Bérard Center in France.

Dr. Al Jarroudi's research is primarily focused on prognostic and predictive biomarkers in breast cancer and she is currently a member of the European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO).

Khalid El Bairi is a clinical research fellow and an investigator in OVANORDEST studies. He is currently pursuing clinical and translational research in medical oncology. He has published many peer-reviewedarticles in the field of predictive and prognostic cancer biomarkers to improve survival outcomes in several WoS and Medline-indexed journals. His research focuses particularly on biomarkers for digestive and gynecological cancers such as ovarian and colorectal malignancies. He is currently a member of various international scientific societies such as the European Society for Medical Oncology (ESMO), the American Society of Clinical Oncology (ASCO), the European Society of Gynaecological Oncology (ESGO), and the American Association for Cancer Research (AACR). He is also an editor and reviewer for various journals and a guest editor for several special issues on emerging topics in gynecological cancers such as platinum-resistant ovarian cancer. He is also highly interested in teaching evidence-based medicine, clinical research methods, and publishing ethics to medical and PhD students and was selected for the 70th Lindau Nobel Laureate Meeting as a young scientist. He is also involved in “global oncology” initiatives through providing free training to young researchers across LMICs. He joined the ASCO Trainee & Early Career Advisory Group as a member for the 2022-2024 term and NCODA (National Community Oncology Dispensing Association, Inc.) as an advisory member of its International Executive Council in 2023.

Giuseppe Curigliano, MD PhD, is Associate Professor of Medical Oncology at the University of Milano and the Head of the Division of Early Drug Development at the European Institute of Oncology, IRCCS, Italy. He is a clinician and researcher specializing in early drug development for patients with solid tumors with a special commitment to breast cancer. He has been a member of the Italian National Health Council since 2018 and, in 2019, he served as Chair of the Scientific Committee of The Lega Nazionale Lotta ai Tumori. He has served as a Member of the ESMO Breast Cancer Faculty since 2001 and he is currently the Faculty Coordinator. He has alsoserved on the Scientific Committee for the St Gallen Conference since 2011 and was the Scientific Co-Chair in St Gallen 2017 and 2019. He has been an Editorial Board Member for Annals of Oncology since 2014, and serves as Co-Editor in Chief of The Breast, Co-Editor in Chief of Cancer Treatment Reviews, Associate Editor of the European Journal of Cancer, Editor of the Journal of Clinical Oncology. He also serves on the European School of Oncology (ESO) faculty committee.

Bibliographic Information

Book Title : Breast Cancer Research and Treatment

Book Subtitle : Innovative Concepts

Editors : Ouissam Al Jarroudi, Khalid El Bairi, Giuseppe Curigliano

Series Title : Cancer Treatment and Research

DOI : https://doi.org/10.1007/978-3-031-33602-7

Publisher : Springer Cham

eBook Packages : Medicine , Medicine (R0)

Copyright Information : The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2023

Hardcover ISBN : 978-3-031-33601-0 Published: 05 January 2024

Softcover ISBN : 978-3-031-33604-1 Due: 05 February 2024

eBook ISBN : 978-3-031-33602-7 Published: 04 January 2024

Series ISSN : 0927-3042

Series E-ISSN : 2509-8497

Edition Number : 1

Number of Pages : VIII, 368

Number of Illustrations : 5 b/w illustrations, 28 illustrations in colour

Topics : Oncology , Gynecology , Cancer Research

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New study finds triple-negative breast cancer tumors with an increase in immune cells have lower risk of recurrence after surgery

Kelley Luckstein

Softer tumors fuel more aggressive spread of triple-negative breast cancer, research shows

by Garvan Institute of Medical Research

Softer tumours fuel more aggressive spread of triple-negative breast cancer

Researchers have discovered how the mechanical properties of tumors can prime cancer cells to better survive their spread to other organs.

A metabolic 'survival switch' controlled by the stiffness of triple-negative breast tumors can significantly influence how successfully their cancerous cells spread to other organs, according to new findings from the Garvan Institute of Medical Research.

The study in cell and mouse models showed that softer tumor environments, typical of early-stage cancer, can prime triple-negative breast cancer cells to use an extra energy source for survival during metastasis. The research suggests that drugs targeting this altered cancer cell metabolism could boost treatments for metastatic triple-negative breast cancer.

"Our research suggests triple-negative breast cancer cells in soft tissue environments are 'primed' to better survive the spread to other organs and that they switch on an alternative form of metabolism to do so," says Associate Professor Cox, Head of the Matrix & Metastasis Lab at Garvan and senior author of the study published in Advanced Science .

"This suggests that triple-negative breast cancer cells spreading from softer tumors are more aggressive, and drugs that target cancer cell metabolism may benefit patients with metastatic triple-negative breast cancer treatment."

A metabolic survival advantage

Triple-negative breast cancers are highly aggressive and difficult to treat as they lack three receptors (for estrogen, progesterone and the HER2 protein) that can be targeted in other breast cancers. New treatment options are urgently needed for the 2,500 women diagnosed every year in Australia alone.

Using biomaterials that mimic the properties of tumors, the team investigated how triple-negative breast cancer cells respond to the physical stiffness of their environment. The researchers found the cancer cells were primed to be more resilient when grown in soft environments and, when injected into mouse models, up to 11.8 times more likely to metastasize to new sites compared to those from rigid tumor environments.

The team also discovered that soft environments altered the cancer cells' preference for 'fuel' in a way that enhanced their durability while traveling through the body. These primed cells metabolized glucose—the preferred energy source for cancer cells—but they also stockpiled lipids as internal fuel reserves and in turn ramped up lipid metabolism —a more resilient energy pathway for their journey from a primary tumor site.

"This switch to using both glucose and fats as an energy source equips cells to better survive the mechanical stresses of traveling through the bloodstream and seeding new tumor sites throughout the body," says first author Dr. Elysse Filipe, who completed the study as a postdoctoral researcher at Garvan.

"By blocking lipid metabolism in triple-negative breast cancer cells, we were able to 'starve' their high energy demand and reduce metastasis in a cell model."

A new approach for triple-negative breast cancer

"Our findings highlight that the physical properties of triple-negative breast cancers, which vary dynamically as the cancer progresses, profoundly impact the cancer's ability to spread," says Dr. Filipe. "These findings reveal a vulnerability of triple-negative breast cancers—the metastasizing cells' reliance on diverse fuel sources to meet their high energy demands."

Associate Professor Cox adds, "The study underscores the importance of considering the mechanical diversity within and between tumors when designing new treatments for aggressive cancers. We now plan to explore whether pairing targeted metabolic inhibitors with existing therapies could limit metastasis and improve outcomes for triple-negative breast cancer patients."

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Switching order of breast cancer treatment could lower the need for multiple surgeries, study finds

Experts caution there is still more research that needs to be done.

A study suggests that for some breast cancer patients, something as simple as switching up which treatment comes first - giving radiation before doing surgery - can dramatically improve a patient's quality of life and can reduce the need of multiple surgeries.

The study, published Friday in JAMA Network Open, was preliminary, but experts say if the results hold up on larger studies it could one day lead to updated treatment guidelines that make life easier for breast cancer patients.

"The findings are not only promising but also highly significant, marking a potential paradigm shift," said Dr. Roberto Diaz, a Radiation Oncologist with a focus on breast cancer from the Moffitt Cancer Center in Tampa, Florida.

PHOTO: In this Nov 30, 2016, file photo, a technician carries out a routine mammogram.

MORE: Video New hope for breast cancer patients unable to get surgery

Breast cancer treatment varies from person to person. Some aggressive breast cancers are initially treated with surgery to remove the cancerous breast, a procedure called mastectomy, followed by radiation. This is called "post-mastectomy radiation" and it kills the remaining cancer cells.

Due to the risk of complications, patients must wait six to 12 months after radiation treatment before getting cosmetic reconstruction of the breast tissue. The implant surgery must be delayed to avoid deformities that may occur due to radiation.

MORE: Shannen Doherty talks 'downsizing' amid stage 4 breast cancer battle

PHOTO: In this undated stock photo, a doctor performs a mammogram on a patient.

The current treatment approach has various challenges for patients with breast cancer.

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"Women requiring post-mastectomy radiation, particularly if they desire reconstruction, undergo multiple surgeries… and have poor quality of life while waiting for reconstruction. Despite efforts to minimize long-term toxicity from radiation, cosmetic outcomes are often suboptimal with deformities of the tissue around the implant" said Dr. Ronica Nanda, a Radiation Oncologist at the Moffitt Cancer Center in Tampa, Florida.

Dr. Mark V. Schaverien, faculty in the Department of Plastic Surgery at the University of Texas MD Anderson Cancer Center, conducted a phase two clinical trial of 48 patients with breast cancer that required radiation and desired breast reconstruction and investigated the effects of changing the order of treatment. These patients underwent "pre-mastectomy radiotherapy," or radiation first, followed by surgery to remove the cancerous tissue. Completed radiation meant patients could get reconstruction surgery at the same time without risking implant deformities. This order was found to be feasible and did not result in complications.

Experts are optimistic about the potential benefits these findings suggest. Dr. Clary Evans, Radiation Oncologist from Northwell Health, in New Hyde Park, New York, said that this new treatment sequence has the potential for "better overall cosmetic outcomes, reduced numbers of surgical procedures, and reduced overall treatment time for some patients."

However, experts also caution that this study is small and there is still more research that needs to be done before knowing how this will change current treatment.

"We eagerly await the results of their upcoming Phase 3 study for further validation and insights into long-term outcomes," said Dr. Diaz.

A larger clinical trial with 126 patients started in April 2023 and is ongoing.

Dr. Ashley Yoo, MD is a member of the ABC Medical News Unit and an Internal Medicine Resident at George Washington University Hospital in Washington, DC.

Dr. Camry Kelly, DO is a member of the ABC Medical News Unit and is Chief Resident at Mayo Clinic Family Medicine Residency Program in Rochester, Minnesota.

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Breast Cancer—Patient Version

Breast cancer is the second most common cancer in women after skin cancer. Mammograms can detect breast cancer early, possibly before it has spread. Explore the links on this page to learn more about breast cancer prevention, screening, treatment, statistics, research, clinical trials, and more.

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Texas A&M, University Of Colorado Research Collaboration Wins Federal Grant To Help Turn Off ‘Breast Cancer Switch’

Researchers at the Texas A&M School of Veterinary Medicine & Biomedical Sciences (VMBS) and the University of Colorado Cancer Center have received a $3.3 million grant from the National Institutes of Health to study how a pair of molecules that regulate certain types of metastatic breast cancer interact with a new drug therapy.

One molecule — semaphorin 7A, or SEMA7A — appears to grant drug therapy resistance to some breast cancers; the other — single-minded two, or SIM2 — helps determine whether SEMA7A is switched on or off.

Over the next five years, the researchers hope to combine knowledge of SEMA7A and SIM2 with a new drug to help women with metastatic cancer receive more effective treatment that will prolong their lives.

How Two Molecules Make The ‘Breast Cancer Switch’

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“SEMA7A is a unique gene,” said Dr. Weston Porter , a professor in the VMBS’ Department of Veterinary Physiology & Pharmacology and co-primary investigator on the project. “My colleague at the University of Colorado and lead PI on the grant, Dr. Traci Lyons, discovered that it’s associated with increased metastasis — or cancer spread — especially in postpartum breast cancers, which do not respond to therapy.

“We found that invasive breast cancers are associated with a loss of SIM2, which leads to an increase in the expression of SEMA7A,” he said. “So we started asking whether we could use these molecules to identify patients with metastatic breast cancer and determine the best treatment regimen to use.

“We’ve found that certain cancer drug therapies are less effective when SIM2 is lost and SEMA7A is present. However, we have identified a new drug that we believe can be used instead, and so Dr. Lyons and I are working with Dr. Virginia Borges, a professor of medical oncology at Colorado, to look at patient samples and see how this new drug might be more effective,” he said.

Postpartum breast cancers like the ones affected by SEMA7A and SIM2 are often estrogen receptor positive (ER+) breast cancers, which represent about three-quarters of all breast cancer cases. The name means that the cancer cells have receptors — proteins on the cells — that can respond to estrogen hormones, which tell the cell to grow.

According to Lyons, there are targeted therapies for ER+ breast cancers, yet more than two-thirds of breast cancer deaths are attributed to metastatic ER+ disease, partly because of the therapy resistance promoted by SEMA7A.

“SEMA7A promotes pretty much every hallmark of cancer. It increases cell growth, cell migration, cell invasion, the ability to survive in harsh conditions — such as what a cancer cell will encounter while traveling from one site in the body to the other — and ultimately it promotes metastasis,” she said.

“When SEMA7A is on, it promotes all the things that are advantageous for the tumor and bad for the patient,” she said. “And SIM2s turns it off by preventing SEMA from being made in the first place. So, we’re looking at how we can use the switch to turn SEMA7A off.”

Getting To The Heart Of The Problem

To find out how the two molecules react to the new drug and whether it will be helpful to breast cancer patients, the team will perform laboratory tests to uncover the mechanism behind SEMA7A and SIM2’s interactions in patient samples. Then, they can correlate their findings with data showing how each patient responded to therapy and what the outcome was.

“When someone has ER+ metastatic breast cancer, they are often given a drug that targets one of the mutated proteins caused by the cancer. However, we found that a significant number of women have cancer that isn’t affected by the primary drugs used for this purpose. We wanted to know why,” Porter said.

“What we found when we looked into the details, all the way to the protein level, was that there are actually different variants of this mutated protein, and there are other drugs out there that can target these other variants,” he explained. “The new drug that we’re testing is actually already approved by the FDA for treatment of lymphomas and leukemias, and it can be used for breast cancer treatment.”

The mutated protein targeted by the drug therapies is deeply connected to SEMA7A and SIM2.

“Theoretically, if we can look at a patient’s samples and see their levels for both of these molecules, we would know what kind of treatment that they need much sooner, possibly giving them more time,” Porter said.

Media contact: Jennifer Gauntt, [email protected], 979-862-4216

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Some breast cancer patients could be at risk of another type of cancer, study reveals

Women with breast cancer who have received chemotherapy are at an increased risk of developing lung cancer, a new study suggests.

Epic Research, a health data group based in Delaware, found that women in this category have a 57% higher lung cancer risk than those who received radiation.

In comparison to patients who received endocrine therapy, those who have undergone chemo have a 171% increase in lung cancer risk, the study found.

BREAST CANCER DRUG COULD HAVE POTENTIALLY SERIOUS SIDE EFFECT, NEW RESEARCH REVEALS

In a statement sent to Fox News Digital, the Epic Research team said the key takeaway from their research is that primary lung cancer is more than twice as prevalent in women who were previously diagnosed with breast cancer — compared to those who did not have it.

"Furthermore, women who had breast cancer and received chemotherapy have the greatest risk of subsequent primary lung cancer," the researchers wrote.

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"This suggests that patients diagnosed with breast cancer are at an increased risk of developing second primary lung cancer, especially if their treatment included chemotherapy."

BREAST CANCER BREAKTHROUGH: AI PREDICTS A THIRD OF CASES PRIOR TO DIAGNOSIS IN MAMMOGRAPHY STUDY

The research group studied more than two million women ages 50 to 84 who received a screening mammogram between 2010 and 2023.

Patients with an elevated breast cancer risk due to a previous breast or lung cancer diagnosis, those who had been screened within the past three months and those who started mammogram screenings prior to age 50 were excluded from the study.

"This could potentially limit the generalizability of our findings," the researchers said.

The team encouraged patients with a history of breast cancer — especially those who have had chemotherapy — to monitor for the development of primary lung cancer.

"It is important to remember that while our study found a correlation between breast cancer, its treatments and subsequent primary lung cancer, this does not mean that every woman who has had breast cancer will develop lung cancer," the researchers said.

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Fox News medical contributor Dr. Marc Siegel, clinical professor of medicine at NYU Langone Medical Center, told Fox News Digital that one cancer can cause a " higher genetic risk " for others.

"We don't know the exact etiology, but one cancer puts you in a higher genetic risk pool for other cancers, either because of cancer genes that increase the risk of both, or because of a tendency for mutations that is increased in this pool," he said.

"It could also be because of environmental factors or carcinogens, including diet, or the result of toxicities from the treatment for breast cancer," Siegel added.

Jack Manley, M.D., head of new markets and growth at Viz.ai, a San Francisco-based AI-powered disease detection platform, shared with Fox News Digital that Epic Research’s findings and methodology speak to "the power of incorporating multi-modal data in predictive algorithms."

Said Manley as well, "Companies with capabilities to incorporate both structured and unstructured EHR (electronic health record) data with conventional imaging will have a higher predictive performance than those that don't."

He was not involved in the study.

"Currently, a large majority of patients with pulmonary nodules (a possible indicator of early lung cancer) are missed on conventional imaging, while less than half of these detected patients receive subsequent guideline-recommended follow up," he said.

Artificial intelligence tools are "well-positioned" to address these challenges, Manley noted — but EHR integration is "key to finding those patients at the highest risk."

For more Health articles, visit www.foxnews.com/health .

Original article source: Some breast cancer patients could be at risk of another type of cancer, study reveals

The research group (not pictured) studied more than two million women ages 50 to 84 who received a mammogram screening between 2010 and 2023. iStock

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

Anna Zadrożna Nowak

Hanna Romanowicz

1. Epidemiology

2. Risk Factors

2.3. Degree of Economic Development

2.4. Hormonal Status

2.5. Reproductive and Hormonal Risk Factors in Breast Cancer Patients

2.6. Genetic Factors, Family Occurrence

2.7. Mild Breast Changes

2.8. Ionizing Radiation

2.9. Alcohol Consumption

2.11. Obesity

2.12. Nicotinism

3. Pathomorphology

4. Prognostic and Predictive Factors

4.2. Degree of Histological Malignancy

4.3. Hormonal Receptors

4.4. HER-2 Receptor

4.5. Proliferation Rate Ki67

4.6. Polygenic Prognostic Factors

5. Biological Types of Breast Cancer

6. Breast Cancer Treatment

7. Recent Treatments for Triple Negative Breast Cancer

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

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Author Contributions

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Selective omission of sentinel lymph node biopsy in mastectomy for ductal carcinoma in situ: identifying eligible candidates