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Abstract

Background

Breast cancer remains a leading cause of cancer-related morbidity and mortality globally, with BRCA1/2 mutation carriers facing distinct challenges due to aggressive tumor biology and heightened risks of contralateral and secondary cancers.

Purpose

This review synthesizes evidence on managing early-stage breast cancer in BRCA mutation carriers, emphasizing Latin America’s heterogeneous BRCA prevalence (ranging from 5% to 25.7% across countries), which underscores the need for region-specific genetic screening. BRCA-associated tumors exhibit homologous recombination deficiency, informing therapeutic strategies such as PARP inhibitors, which exploit synthetic lethality, as demonstrated by the OlympiA trial showing Olaparib’s sustained survival benefits (28% reduction in mortality risk). Imaging strategies must adapt to BRCA-related tumor phenotypes: BRCA1 carriers often present mammography-elusive tumors, favoring MRI, while abbreviated MRI protocols offer cost-effective alternatives without compromising sensitivity. Surgical decision-making balances breast-conserving surgery (BCS) and mastectomy, with studies showing comparable survival outcomes but elevated contralateral cancer risk post-BCS (10-year risk: 14%), necessitating vigilant surveillance. Contralateral prophylactic mastectomy reduces contralateral cancer risk but requires personalized risk-benefit discussions. Neoadjuvant platinum-based chemotherapy shows higher pathologic complete response rates in BRCA carriers, particularly in triple-negative subtypes, though adjuvant platinum benefits remain under investigation. Emerging immunotherapies, such as pembrolizumab in KEYNOTE-522, show promise but lack BRCA-specific efficacy data. Special considerations for transgender BRCA carriers highlight evolving screening guidelines, including mammography for hormonally treated transgender women and multimodal imaging for non-mastectomized transgender men.

Conclusions

Optimizing outcomes for BRCA mutation carriers demands multidisciplinary, personalized approaches integrating genetic, regional, and clinical factors. Advances in targeted therapies, refined imaging, and risk-adapted surgery emphasize the importance of shared decision-making and ongoing research to address knowledge gaps in survivorship and equitable care.

Keywords

BRCA breast cancer surgery systemic treatment cancer management

Highlights

• The prevalence of BRCA1/2 mutations varies significantly (5-25.7%), highlighting the need for region-specific genetic screening.

• Homologous recombination deficiency in BRCA tumors supports using PARP inhibitors like olaparib, which reduces mortality risk by 28% (OlympiA trial).

• MRI is preferred for BRCA1 carriers due to mammography limitations, with abbreviated MRI protocols offering cost-effective alternatives.

• Evolving guidelines recommend mammography for transgender women on hormone therapy and multimodal imaging for non-mastectomized transgender men.

• While breast-conserving surgery (BCS) and mastectomy offer similar survival outcomes, BCS carries a higher 10-year contralateral cancer risk (14%), warranting personalized surveillance and risk discussions.

• Platinum-based chemotherapy improves pathologic complete response rates in BRCA carriers, especially in triple-negative cases, while BRCA-specific immunotherapy data remain limited.

Introduction

Breast cancer is the most frequently diagnosed malignancy in women globally, contributing significantly to cancer-related morbidity and mortality. With millions of new cases diagnosed annually, it places a substantial burden on healthcare systems. Advances in early detection, such as mammography, and new therapeutic interventions have led to improved survival rates, particularly for early-stage cancers. Early detection typically results in better prognosis and less aggressive treatments. However, certain breast cancer subtypes, particularly those linked to BRCA1 and BRCA2 gene mutations, present unique challenges.

BRCA1 and BRCA2 mutations are associated with a significantly increased lifetime risk of breast and ovarian cancers, often manifesting at a younger age compared to sporadic cases. BRCA1-related tumors tend to be more aggressive, frequently exhibiting triple-negative receptor status, which limits treatment options. Managing these cases requires tailored approaches that go beyond standard treatments, like breast-conserving surgery, due to higher risks of recurrence and secondary malignancies. Preventive strategies, such as prophylactic mastectomy and oophorectomy, are often considered but must be weighed against quality-of-life concerns.

This review focuses on the clinical management of early-stage breast cancer in BRCA mutation carriers, highlighting how genetic insights inform surgical, chemotherapeutic, and surveillance strategies. It also explores emerging therapies, advancements in genetic testing, and the role of personalized medicine in treating this high-risk population. Understanding these genetic factors is crucial for optimizing outcomes and minimizing recurrence risks.

Epidemiology of BRCA Mutations in Breast Cancer Women in Latin America

Estimating the prevalence of BRCA mutations in breast cancer in Latin America is complex due to the diverse nature of breast cancer, varying hereditary statuses, disease stages, and molecular subtypes within the region.¹ The BREAKOUT study, which examined HER2-negative metastatic breast cancer, highlighted considerable geographical variability: 11% in Asia, 18% in Europe, 3% in North America, and 1% in Australia.²

In Argentina, BRCA1 mutations were observed at 1.8% and BRCA2 at 4.5% in a cohort of 112 unselected patients, while a larger study involving 940 familial breast cancer cases showed a prevalence of 11.2% prevalence of BRCA1 mutations and 7.9% for BRCA2.^3,4 Brazil’s studies reported varied results: a prevalence of 12.3% prevalence in 1267 patients referred for BRCA testing and a higher prevalence of 25.7% prevalence in a separate group of 74 patients evaluated for genetic risk.^5,6 In Colombia, genetic risk assessments in 225 women produced a 9.3% prevalence, while a larger study of 853 BRCA patients found a 12.5% prevalence, with 8.1% for BRCA1 and 4.5% for BRCA2.^5,7 Chile’s research on 460 patients showed an 11.4% prevalence of BRCA1/2 mutations.⁸

Mexico’s findings were similarly diverse: 17.4% prevalence in 632 patients, 11.1% prevalence in 252 sporadic cases, and 4.3% prevalence in 810 unselected patients.^5,9,10 In particular, triple-negative breast cancer patients had a 23.2% frequency of BRCA1/2 mutations.¹¹ In Peru, a study of 143 HER2-negative patients found a 14.7% prevalence, with BRCA1 at 9.1% and BRCA2 at 5.6%.¹² Another Peruvian study using the HISPANEL platform reported a lower prevalence of 5% for BRCA1 and 0.8% for BRCA2, reflecting its limited coverage of known variant hotspots.¹³ This variability underscores the importance of region-specific genetic studies to accurately assess the prevalence of the BRCA mutation and tailor screening strategies accordingly.

Biology of BRCA1/BRCA2 Alterations in Breast Cancer

The link between BRCA1 and BRCA2 mutations and heightened susceptibility to breast and ovarian cancer was first established in the mid-1990s, marking a pivotal advancement in cancer genetics.^14,15 These genes are integral to maintaining genomic stability through homology-directed repair, with BRCA1 specifically governing end resection-dependent double-strand break repair. Recent research has revealed that deleterious mutations in BRCA1 and BRCA2 lead to various molecular alterations that disrupt lineage fidelity in both luminal epithelial and myoepithelial cells, contributing to biological aging.¹⁶ Additionally, tumors with BRCA1/BRCA2 mutations display unique changes in homologous recombination pathways, inspiring innovative therapeutic strategies. Notably, the concept of synthetic lethality has emerged, wherein the inhibition of poly (ADP-ribose) polymerases (PARPs) targets single-strand break repair in these genetically predisposed tumors, offering a promising avenue for treatment.¹⁷

Imaging in Patients with Breast Cancer and Mutated BRCA

Current screening guidelines for BRCA1 and BRCA2 mutation carriers recommend annual mammography and MRI. However, tumor characteristics differ between BRCA1 and BRCA2 carriers, raising concerns about using a uniform screening approach. BRCA1 mutation carriers tend to develop more aggressive tumors that can be harder to detect on mammography due to their benign appearance, whereas BRCA2 carriers often have tumors more easily detected by mammography.¹⁸ Additional data is needed to refine guidelines for mammography in BRCA mutation carriers.

Whole-breast ultrasound (US) is generally not recommended for screening BRCA1/BRCA2 carriers, except for those unable to undergo MRI. It has a low cancer detection rate and a high false positive rate. Adding 3D automated breast US to MRI and mammography increased recalls by 39.8% without earlier or additional cancer detection.¹⁹ However, the American College of Radiology (ACR) recommends considering US for supplemental screening in high-risk women who cannot undergo MRI.

MRI screening is highly beneficial for women with BRCA1 or BRCA2 mutations, as it detects earlier-stage disease and fewer interval cancers compared to other methods.²⁰ However, adherence to intensive screening protocols is challenging, and cost-effectiveness studies are still needed. The optimal age to stop MRI screening for BRCA mutation carriers is unclear, requiring further research to determine appropriate guidelines based on age or life expectancy.

Dynamic contrast-enhanced breast MRI (DCE-MRI) is the most sensitive imaging modality for breast cancer detection; however, its widespread implementation is hindered by high costs, lengthy acquisition times, and complex interpretation. To address these limitations, the Abbreviated Protocol Breast MRI (AB MRI) was developed as a streamlined alternative to Full-Protocol MRI (FP MRI), aiming to reduce imaging time and resource utilization while maintaining diagnostic efficacy.²¹

A retrospective cohort study evaluated the clinical performance of AB MRI in a population of 1975 women undergoing high-risk breast cancer screening, including 224 carriers of BRCA1/2 mutations.²² Among BRCA mutation carriers, the cancer detection rate was 28.9 per 1000 examinations, with a sensitivity of 80.0% and a specificity of 90.3%. Additionally, a comparative retrospective analysis of FP MRI and AB MRI in BRCA carriers demonstrated that AB MRI protocols omitting T2-weighted sequences yielded the lowest diagnostic performance.

Given its efficiency and potential cost reduction, AB MRI has been proposed as a complementary screening tool within a biannual MRI-based surveillance strategy. Specifically, alternating AB MRI with FP MRI may offer a balanced approach to mitigate the financial and logistical burden associated with intensive breast cancer screening while preserving diagnostic accuracy. Further prospective studies are warranted to optimize protocol selection and validate long-term clinical outcomes.

Contrast-enhanced mammography (CEM) is an emerging technique that uses iodinated contrast to detect breast cancers. It involves taking dual-energy mammograms after the injection of contrast material. Several studies have shown that CEM performs better than standard digital mammography (DM). A retrospective study found that while CEM led to more biopsies than DM, it had a higher positive predictive value (PPV3) of 29.4%.²³ The authors suggested that replacing DM with CEM may be more effective for BRCA mutation carriers. The ACR has recommended CEM as a supplemental screening option for high-risk women who cannot undergo MRI.

These findings underscore the need for tailored screening strategies in BRCA1/2 carriers, particularly in light of varying tumor characteristics and the effectiveness of different imaging techniques. Further research is needed to refine screening guidelines, optimize detection, and reduce the burden of intensive screening regimens on patients.

Special Considerations

Limited data exist regarding optimal breast cancer screening strategies for transgender individuals carrying BRCA gene mutations. While existing guidelines primarily address cisgender populations, the American College of Radiology (ACR) has issued recommendations tailored to transgender patients at elevated risk.²⁴

For transgender women with BRCA mutations who have undergone at least five years of hormone therapy, annual mammographic screening is advised beginning at age 25. Similarly, cisgender male BRCA2 carriers are recommended to initiate screening mammography at age 50 or 10 years before the earliest known male breast cancer diagnosis within their family. The efficacy of mammographic screening in high-risk males is supported by research from Gao et al, reinforcing the benefit of early detection in this population.²⁵

Transgender women carrying BRCA2 mutations are also advised to begin annual mammographic screening at age 50 or 10 years before the earliest familial male breast cancer case.²⁶ However, current guidelines do not recommend high-risk MRI screening for this group. In contrast, transgender men with BRCA mutations who have not undergone prophylactic mastectomy should undergo annual screening with both mammography and MRI, commencing between ages 25 and 30.

Given the evolving landscape of transgender healthcare, further research is warranted to optimize risk-stratified screening protocols and assess the long-term outcomes of these recommendations.

Surgical Management in Patients with Early-Stage Breast Cancer and Mutated BRCA

The surgical management of patients diagnosed with breast cancer who also present with a mutated BRCA gene has been a topic of controversy over the years, ever since the discovery of this germline genetic disorder. The approach we will present below is based on two clear scenarios: one where we must review the evidence regarding decision-making for the breast with the malignant tumor, focusing on total or purely organ-preserving surgery; and the other scenario, where the decision must be made whether to preserve the contralateral breast, given the origin of the current neoplasm.

Management of the Breast with Cancer

In a retrospective cohort study published in 2022, the researchers evaluated oncologic outcomes among BRCA mutation carriers diagnosed with breast cancer, leveraging institutional databases to identify cases between 2006 and 2015.²⁷ The study aimed to compare local-regional recurrence (LRR), distant recurrence, contralateral breast cancer (CBC), breast cancer-specific survival (BCSS), and overall survival (OS) across different surgical approaches.

The cohort comprised 395 BRCA mutation carriers with a total of 424 breast cancers. Among these, 99 cancers were managed with breast-conserving surgery (BCS), while 325 underwent mastectomy. Patients who opted for mastectomy were more likely to present with bilateral breast cancer, be younger or premenopausal, have prior knowledge of their genetic status before surgery, and were less likely to receive adjuvant radiation therapy (P < 0.001).

After a median follow-up of 7.9 years, no significant differences were observed between the surgical groups in terms of LRR, distant recurrence, BCSS, or OS. However, the incidence of CBC was higher among patients who underwent unilateral surgery, with five cases reported in this group, whereas no CBC cases occurred in patients who received bilateral mastectomy. This translated to an estimated 10-year risk of CBC of 14% among those undergoing unilateral surgery (P < 0.001).

The findings suggest that while BCS and mastectomy yield comparable survival and recurrence outcomes in BRCA mutation carriers, unilateral surgery is associated with an increased risk of CBC. The authors concluded that BCS remains a viable option for BRCA mutation carriers who prefer breast conservation while adhering to intensive surveillance protocols for early detection of subsequent malignancies. A table has been prepared that summarizes the aforementioned recommendations (Table 1).

Table 1.

Comparison Between Breast Conserving Surgery and Mastectomy

Parameter	Breast-conserving surgery (BCS)	Mastectomy (unilateral/bilateral)
Local recurrence rate (LRR)	Slightly higher (9.7%), though not statistically significant (emiroglu et al, 2023)	6.8%, with no significant difference vs BCS
Distant recurrence	No significant difference (Shubeck et al, 2022)	Comparable outcomes
Breast cancer-specific survival (BCSS)	Slightly superior in some reports; not statistically significant	Equivalent to BCS (Shubeck et al, 2022)
Overall survival (OS)	No significant differences compared to mastectomy	Bilateral mastectomy did not significantly improve OS over BCS (Metcalfe et al, 2024)
Contralateral breast cancer (CBC)	Increased risk: 10-year cumulative incidence of 14% after unilateral surgery	Significantly reduced; near 0% after bilateral mastectomy (Metcalfe et al, 2024)
Common tumor subtypes	More frequent in BRCA2; luminal subtypes	More frequent in BRCA1; high-grade and triple-negative tumors
Clinical indications	Small, unifocal tumors; patients prioritizing breast preservation with access to close surveillance	Multifocal tumors, young age, positive family history, known genetic status
Adjuvant radiotherapy	Usually required	Less frequently indicated, especially in bilateral mastectomy
Psychological impact	Lower physical burden; some anxiety related to CBC risk	Reduced anxiety in many cases; risk of body image concerns or regret (Benedict et al, 2017)
Quality of life (QoL)	Often favorable due to less invasive nature	Mixed outcomes; satisfaction with risk reduction vs physical and emotional consequences (Pesce et al, 2021)
Impact of risk-reducing mastectomy (RRM)	Not applicable	Associated with improved OS, DFS, and BCFI in young BRCA carriers (Lambertini et al, 2025)
Role of contralateral prophylactic mastectomy (CPM)	Not typically performed	Reduces CBC risk; potential psychological and QoL benefits in selected patients
Current recommendation	Safe and effective with strict surveillance; requires individualized assessment	Recommended in high-risk settings; requires shared decision-making based on personal risk profile and patient preference

In their 2023 publication, a group of investigators reported on a cohort of seventy-five patients with breast cancer, all of whom carried BRCA1 or BRCA2 mutations, undergoing breast-conserving surgery (BCS) or mastectomy between 2006 and 2017.²⁸ The study aimed to evaluate the impact of surgical intervention and clinicopathological characteristics on surgical outcomes, local recurrence (LR) rates, and overall survival, while also detailing the distribution of BRCA1 and BRCA2 germline mutations within the cohort. The findings revealed that 46 patients (61.3%) had BRCA1 mutations, while 29 patients (38.7%) had BRCA2 mutations. Notably, BRCA1 mutation carriers exhibited higher-grade tumors compared to BRCA2 carriers (84.8% vs 44.8%; P = 0.001) and a greater prevalence of non-luminal subtypes (67.4% vs 13.8%; P = 0.001). Among the participants, 44 patients (58.7%) underwent unilateral mastectomy, while 31 patients (41.3%) received BCS. After a median follow-up duration of 60 months (range: 12-240 months), LR was observed in six patients, with an equal distribution between the BCS and mastectomy cohorts. LR rates were marginally higher following BCS compared to mastectomy (9.7% vs 6.8%). Furthermore, statistical analysis revealed no significant differences in 10-year disease-free survival (DFS) and breast cancer-specific survival (BCSS) between the BCS and mastectomy groups (P = 0.117 and 0.109, respectively), although DFS and BCSS were slightly superior in the BCS cohort. The authors concluded that BCS presents a viable alternative to mastectomy for patients with BRCA1 or BRCA2 mutations. They also emphasized the importance of considering tumor size, lymph node positivity, and TNM staging to optimize surgical decision-making. A chart has been prepared that summarizes the aforementioned recommendations (Figure 1).

Figure 1.

Surgical Management in Patients with Early-Stage Breast Cancer and Mutated BRCA

Contralateral Prophylactic Mastectomy

Contralateral prophylactic mastectomy (CPM) has emerged as a focal point of extensive research and substantial debate, particularly among BRCA mutation carriers diagnosed with breast cancer. The decision to pursue contralateral prophylactic mastectomy is influenced by the significant lifetime risk of developing contralateral breast cancer, estimated to be, among those who had a unilateral mastectomy or lumpectomy according to the latest work of a working group in Canada, at 20 years was 27.5%. Factors such as age, family history, and individual patient circumstances play a crucial role in determining the appropriateness of this intervention.²⁹

The evidence related to risk reduction indicates that CPM effectively reduces the risk of contralateral breast cancer among BRCA mutation carriers, reinforcing its role as a preventive strategy. However, the substantial lifetime risk underscores the necessity for informed patient decisions.

Survival outcomes are important for such matters and investigations into the survival implications of CPM have yielded mixed results. Although some studies suggest potential improvements in survival rates, particularly in younger patients with unilateral breast cancer, other analyses indicate that such benefits may not be universally applicable, advocating for alternative surveillance strategies in specific populations. A team devoted to this matter published research on survival benefits in younger women with unilateral breast cancer, showing that CPM may offer survival advantages, particularly for those at high genetic risk (eg, BRCA1/2 mutations).³⁰ This study highlights that CPM could be associated with lower breast cancer-specific mortality in these subgroups. Another group of researchers examined decision analyses and outcomes, indicating that while some younger women may benefit, the overall survival advantage for CPM varies significantly based on factors like age, genetic risk, and tumor biology.³¹

The psychological ramifications of undergoing CPM warrant considerable attention. While patients opting for CPM often report decreased anxiety regarding the recurrence of breast cancer, some individuals experience regret or altered body image post-surgery. In 2017, a working group explored motivations and outcomes, finding that patients often perceive a reduced risk of recurrence as a primary reason for choosing CPM, which in turn decreases their cancer-related worry and anxiety.³² This highlights the need for comprehensive psychosocial support during the decision-making process. Now, when describing chemotherapy in breast cancer with anxiety or psychological distress, an important team of investigators in 2010 explored how chemotherapy can exacerbate psychological stress, particularly anxiety and depressive symptoms, in breast cancer patients.³³ Their findings showed that many patients experience increased anxiety during chemotherapy, which can also impact their quality of life (QoL).

Recent assessments of quality-of-life outcomes demonstrate variability among patients’ post-CPM. While many report satisfaction with their surgical choice, others experience adverse effects, necessitating a nuanced understanding of the quality-of-life implications associated with CPM. Investigators in 2021 conducted a systematic review of studies on QoL outcomes following CPM. Their findings demonstrated a spectrum of responses, with many patients reporting satisfaction due to reduced cancer worry, while others reported negative impacts on QoL, often related to physical complications and mental health.³⁴

Current clinical guidelines reflect a trend towards a personalized approach to CPM. Emphasis is placed on shared decision-making between healthcare providers and patients, considering individual risk factors and preferences to tailor treatment options effectively.

Ongoing studies are critical for elucidating the long-term implications of CPM, particularly regarding recurrence rates and overall survival. Investigative efforts continue to refine recommendations based on findings from diverse patient populations, underscoring the importance of individualized care.

Under this scenario, an important team in Canada presented their findings at SABCS 2023.²⁹ This is a prospective study in contrast to the rest of the retrospective evidence in this topic. The objective of their study was to determine the risk of contralateral breast cancer and breast cancer-specific mortality following surgical treatment in women with non-metastatic breast cancer and a BRCA1 mutation. The study included 2482 patients from 26 centers in 11 countries, stratified by age and surgical treatment (breast-conserving therapy, total mastectomy, and bilateral mastectomy).

In terms of results and conclusions, women with BRCA1 mutations who had bilateral mastectomy had significantly lower rates of contralateral breast cancer (P < 0.0001). Women with BRCA1 mutations and contralateral breast cancer had twice the likelihood of dying from breast cancer (HR 2.22, P < 0.0001). Finally, bilateral mastectomy was not significantly associated with reduced mortality compared to BCS (HR 0.83, P = 0.52), reinforcing the evidence mentioned in the previous scenario based on retrospective studies.

While the scientific evidence delineates potential advantages of CPM for BRCA mutation carriers, decisions surrounding the procedure must incorporate a comprehensive review of individual risk, potential benefits, and personal preferences. Patients are strongly advised to engage in discussions with genetic counselors and breast cancer specialists to ensure informed decision-making.

By synthesizing these elements, the debate and ongoing conversation on CPM continues, reinforcing the necessity for individualized patient-centered care while navigating the complexities of breast cancer treatment.

Risk-reducing surgeries, including bilateral risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO), are standard interventions for BRCA mutation carriers. However, their impact on young individuals (≤40 years) with prior breast cancer remains unclear. While RRSO has been associated with improved overall survival (OS), the survival benefit of RRM is still debated. These procedures also carry significant implications for reproductive choices and quality of life. An international, multicenter, retrospective cohort study assessed the relationship between risk-reducing surgeries and survival outcomes in young BRCA carriers with breast cancer.³⁵ The study included 5290 patients from 109 centers across 33 countries, with a median follow-up of 8.2 years. Eligible participants were diagnosed with stage I–III invasive breast cancer between 2000 and 2020, aged ≤40 years, and had pathogenic BRCA1 or BRCA2 mutations. The primary outcome was OS, while secondary endpoints included disease-free survival (DFS) and breast cancer-free interval (BCFI). Cox proportional hazards models, treating RRM and RRSO as time-dependent covariates, were used for analysis. Among participants, 55.0% (n = 2910) underwent RRM, and 52.6% (n = 2782) had RRSO. RRM was associated with improved OS (HR 0.65, 95% CI 0.53-0.78), DFS (HR 0.55, 95% CI 0.48-0.62), and BCFI (HR 0.58, 95% CI 0.52-0.65). Similarly, RRSO conferred a survival advantage (OS: HR 0.58, 95% CI 0.48-0.71; DFS: HR 0.65, 95% CI 0.57-0.74; BCFI: HR 0.68, 95% CI 0.61-0.77). No significant interaction between RRM and RRSO was observed for OS (P = 0.829), though RRSO had a stronger impact on DFS and BCFI in patients who also underwent RRM. These findings support the survival benefits of risk-reducing surgeries in young BRCA carriers with breast cancer, emphasizing the need for individualized counseling. A chart has been prepared that summarizes the aforementioned recommendations (Figure 2).

Figure 2.

Contralateral Mastectomy in Patients with Early-Stage Breast Cancer and Mutated BRCA

Systemic management of patients with early-stage breast cancer and mutated BRCA

The standard treatment paradigm for early-stage breast cancer (BC) primarily consists of surgical resection followed by adjuvant chemotherapy to mitigate the risk of disease recurrence. In cases of inoperable, locally advanced breast cancer, neoadjuvant chemotherapy (NAC) is the preferred approach to downstage the tumor, thereby increasing the feasibility of breast-conserving surgery.

While the administration of preoperative systemic therapy has not demonstrated a significant improvement in disease-free survival (DFS) or overall survival (OS) compared to adjuvant treatment achieving a pathologic complete response (pCR) following NAC has been associated with superior survival outcomes. Specifically, patients who attain pCR exhibit improved prognosis relative to those with residual disease. The prognostic significance of pCR was further substantiated in the CTNeoBC pooled analysis, which confirmed that pCR correlates with enhanced survival outcomes, particularly in triple-negative breast cancer (TNBC) and HER2-positive breast cancer subtypes.³⁶

These findings underscore the importance of pCR as a key prognostic marker in NAC-treated patients and highlight its potential role in guiding therapeutic strategies and risk-adapted treatment approaches.

Chemotherapy neoadjuvant

We know the importance of neoadjuvant treatment in early-stage triple-negative breast cancer, platinum agents have been evaluated in BRCA mutation carriers in the neoadjuvant setting.

Several studies have been conducted in this context, in a prospective study by Dr Byrski on patients with early-stage breast cancer carrying the BRCA1 mutation, although it included only a single arm with cisplatin and lacked a comparator, demonstrated the benefit of this chemotherapy by achieving a pathological complete response (pCR) rate of approximately 61%.³⁷

BRCA mutation carriers with breast cancer are more chemosensitive to anthracyclines compared to non-carriers. This was confirmed in a retrospective study that showed a higher pCR rate in the anthracycline arm compared to the taxane arm.

Two randomized clinical trials have shown that incorporating platinum-based agents into standard neoadjuvant chemotherapy significantly enhances the pathological complete response (pCR) rate in triple-negative breast cancer (TNBC), independent of BRCA mutation status.^38,39 Nevertheless, BRCA status is recognized as a predictive biomarker of chemotherapy response, associated with higher pCR rates and improved disease-free survival in the neoadjuvant setting.

According to results from the Phase II GeparSixto and INFORM studies, patients with gBRCAm, early BC, do not appear to benefit much from platinum-based chemotherapy in terms of pCR when compared to non-platinum-based regimens. Patients with BRCAm in GeparSixto did not have a substantial increase in disease-free survival rates when platinum was added to their treatment regimen. Furthermore, the apparent effect of platinum-based therapy might have been affected by the small number of gBRCAm patients in GeparSixto.

Caramelo’s meta-analysis studying the efficacy of neoadjuvant therapy in TNBC patients with gBRCA mutation concludes that those treated with cisplatin as monotherapy in the neoadjuvant setting have a lower pCR compared to chemotherapy derived from platinum anthracyclines taxanes having a higher pCR.⁴⁰ Tables has been prepared that summarizes the aforementioned recommendations (Tables 2 and 3).

Table 2.

Clinical Trial Neoadjuvant Treatment for Early gBRCAm BC Cisplatin in Monotherapy

Treatment	Clinical trial	Phase	patient population	n	pCR	DFS	OS
Cisplatin 75 mg/m² × 4 cycles	NCT01630226	II	gBRCA1m Stages I-III BC 77% TNBC, 22%HR + HER2-	86	pCR: 61%	No	No
Cisplatin 75 mg/m² × 4 cycles	Byriski 2014	II	gBRCA1m Stages I-III BC 77% TNBC, 22%HR + HER2-	86	(n = 65/107)	No	No
Arm 1: cisplatin 75 mg/m² × 4 cycles	INFORM/NCT01670500	RCT Pase II	gBRCAm HER2-negative	44	pCR rate (primary endpoint): cisplatin, 18% (n = 11/60); doxorubicin + cyclophosphamide, 26% (n = 15/57) (RR 0.70 [90% CI 0.39, 1.2])	No	No
Arm 2: Doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m² × 4 cycles every 2 or 3 weeks	INFORM/NCT01670500	RCT Pase II	Stages I–II	44	pCR is not significantly higher with cisplatin than with AC in BRCA carriers	No	No

Table 3.

Clinical Trial Neoadjuvant Treatment for Early gBRCAm BC Platin Derivates

Treatment	Clinical trial	Phase	Patient population	N	pCR	DFS	OS
18 weeks of epirubicin 150 mg/m² followed by Paclitaxel 225 mg/m² followed by cyclophosphamide 2000 mg/m², each q2w (iddEPC) vs weekly Paclitaxel 80 mg/m² plus non-pegylated liposomal doxorubicin 20 mg/m² plus in TNBC carboplatin (AUC 1.5)(PMCb)	GeparOcto	RCT Phase III	Patients with triple-negative BC randomized to the PM arm received additional carboplatin (PMCb)	914	Overall higher pCR rates were observed in patients with BRCA1/2 variants than in patients without (60.4% vs 46.7%; odds ratio [OR], 1.74	No	No
	Pohl-rescigno 2020		BRCA1/2 mutated TNBC patients: 96		95% CI, 1.13-2.68; P = .01) TNBC,a positive gBRCA1/2 variant status was associated with therapy response in both the PMCb arm (74.3% vs 47.0%; OR, 3.26; 95% CI, 1.44-7.39; P = .005) and the id-dEPC arm (64.7% vs 45.0%; OR, 2.24; 95% CI, 1.04-4.84; P = .04 differences between treatment arms were not significant
	Pohl-rescigno 2020		BRCA1/2 mutated TNBC patients received carboplatin: 35
Arm 1: carboplatin 2AUC + paclitaxel 80 mg/m² + liposomal doxorubicin 20 mg/m² + bevacizumab 15 mg/m² 18 weeks	GeparSixto (TNBC subgroup)/NCT01426880	RCT Phase III	TNBC stages II–II	315	pCR rate: gBRCAm 65.4% for carboplatin (n = 17/26) vs 66.7% non carboplatin(n = 16/24) (odds ratio 0.94 [95% CI 0.29, 3.05]; P = 0.92) pCR rate in patients with non-gBRCAm favoured carboplatin: 55.0% (n = 66/120) vs non carboplatin 36.4% (n = 44/121) (odds ratio 2.14 [95% CI 1.28, 3.58]	With a median follow-up of 35 months	OS was not statistically significant
Arm 2: paclitaxel 80 mg/m² + liposomal doxorubicin 20 mg/m² + bevacizumab 15 mg/m² 18 weeks	Von Minckwitz 2014, Hahnen 2017, Loib Ann 2018		BRCA carriers: 50		pCR rate in patients with gBRCAm: no significant differences for carboplatin vs non-carboplatin	gBRCAm without carboplatin, 82.5% with carboplatin, 86.3%
	Von Minckwitz 2014, Hahnen 2017, Loib Ann 2018		BRCA carriers: 50			In patients with non-gBRCAm favoured without carboplatin, 73.5%; with carboplatin 85.3% (HR, 0.53) P = .04

Immunotherapy

Following the promising results of the Phase III KEYNOTE-522 clinical trial, pembrolizumab received regulatory approval in the United States and Europe for neoadjuvant use in combination with chemotherapy, followed by single-agent adjuvant therapy, in patients with high-risk early-stage triple-negative breast cancer (TNBC).⁴¹ However, the clinical benefit of (neo)adjuvant pembrolizumab in patients with germline BRCA mutations (gBRCAm) compared to those without such mutations has not been specifically evaluated within the KEYNOTE-522 dataset. While BRCA carriers have been analyzed, no direct comparative study of treatment responses has been conducted. Therefore, further research is needed to define the optimal (neo)adjuvant therapeutic approach for patients with gBRCAm in early-stage breast cancer.

The Phase II NeoPACT clinical trial evaluated the efficacy of an anthracycline-free neoadjuvant regimen consisting of pembrolizumab in combination with carboplatin and docetaxel in patients with stage I to III triple-negative breast cancer (TNBC).⁴² Between 2018 and 2022, the study enrolled a cohort of 115 female patients.

8% of the participants had BRCA1 or BRCA2 germline mutations. Although the study did not specifically stratify outcomes based on BRCA status, the inclusion of patients with BRCA mutations suggests the efficacy of the regimen in this subgroup.

Chemotherapy Adjuvant

Adjuvant chemotherapy has demonstrated a higher survival benefit in TNBC than in hormone receptor (HR)-positive breast cancer, and it consistently increased DFS in breast cancer patients. Anthracyclines, taxanes, and alkylating drugs are the foundation of conventional adjuvant chemotherapy. When taxanes were added to anthracycline, the risk of cancer recurrence was lower than in the anthracycline-only group, according to the EBCTCG 2012 meta-analysis.⁴³

Platinum-based agents exert their anticancer effects by forming DNA cross-links, thereby disrupting DNA synthesis and inducing apoptosis in malignancies characterized by defective DNA repair mechanisms. Patients with BRCA1/2 mutations exhibit homologous recombination deficiency (HRD), rendering them particularly susceptible to DNA damage induced by platinum compounds. Notably, a subset of patients with sporadic triple-negative breast cancer (TNBC) who lack BRCA1/2 mutations exhibit a phenotype known as “BRCAness,” which reflects a similar impairment in the DNA repair pathway observed in BRCA1/2-mutated TNBC. Although not all cases of sporadic TNBC present with HRD, the probability of BRCAness varies among patients, influencing their potential responsiveness to platinum-based therapies.

The use of adjuvant platinum in conjunction with conventional regimens based on anthracyclines and taxanes has been examined in a few single-center retrospective investigations, but no therapeutic benefit has been verified. Nevertheless, recent phase II and III trials have demonstrated that adjuvant regimens including platinum are neither inferior nor superior to conventional adjuvant regimens. The effectiveness of adjuvant platinum-based regimens is unknown because of the limited number of prospective trials; prospective continuing adjuvant trials are required to validate this information.

PARP Inhibitors Adjuvant

The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib, taken orally twice daily for a year, is an adjuvant treatment for some high-risk BRCA carriers who have had neoadjuvant or adjuvant chemotherapy. The US Food and Drug Administration has approved olaparib as a treatment adjuvant for adult patients with HER2-negative, high-risk, early breast cancer that has been treated with adjuvant chemotherapy or neoadjuvant chemotherapy and has a deleterious or suspected harmful hereditary BRCA mutation.

Olaparib is recommended for BRCA carriers, especially for those who would rather not experience the side effects of capecitabine (such as stomatitis or plantar-palmar erythrodysesthesia). The OlympiA trial served as the model for this strategy.⁴⁴

Adjuvant olaparib should be recommended for TNBC BRCA carriers who have initial surgical treatment and have positive disease in the axillary nodes or an invasive primary tumor that measures at least 2 cm on pathological analysis If they have already received neoadjuvant treatment and still have residual invasive breast cancer.

In patients with hormone receptor-positive breast cancer undergoing neoadjuvant chemotherapy, prognostication is based on the pretreatment clinical stage and post-treatment pathological stage (CPS score), in addition to estrogen receptor status and tumor grade (CPS + EG score). Among BRCA mutation carriers with residual disease and a CPS + EG score of ≥3, adjuvant treatment with olaparib is recommended to improve clinical outcomes.

In patients with hormone receptor-positive breast cancer who have undergone adjuvant chemotherapy and present with N2 disease, adjuvant treatment with olaparib is recommended to enhance therapeutic outcomes.

The OlympiA trial was a randomized, double-blind study that included 1836 women with high-risk, HER2-negative early breast cancer carrying BRCA1 or BRCA2 mutations. All participants had high-risk clinicopathologic features and had undergone local treatment in conjunction with either neoadjuvant or adjuvant chemotherapy.⁴⁴

Recent updates presented at the San Antonio Breast Cancer Symposium (SABCS) in December 2024 demonstrated sustained and clinically significant benefits with a median follow-up of 6.1 years. The findings revealed a 28% reduction in the risk of death, a 35% reduction in the risk of invasive breast cancer recurrence, second primary malignancies, or mortality, and a 35% decrease in the risk of distant disease recurrence or death.

Notably, the OlympiA trial did not allow post-neoadjuvant capecitabine since, at the time the trial was planned, this treatment was not considered standard of care. A table has been prepared that summarizes the aforementioned recommendations (Table 4).

Table 4.

Clinical Trial Adjuvant Treatment for Early gBRCAm PARP-Inhitors

Treatment	Clinical trial	Phase	BC patient population	N	Selected efficacy endpoints and outcomes
Adjuvant olaparib 1 year of oral olaparib or placebo	Olympia NCT02032823	III	gBRCAm early stages BC 751 TNBC: -Neoadjuvant non pCR -Adjuvant >_pT2 or >_N1 168 HR + HER2- -Neoadjuvant non pCR and CPS + EG score>_3 -Adjuvant>_4LN+	1836	Primary analysis Year3 Invasive disease-free survival (primary endpoint) favoured olaparib vs placebo: 85.9% vs 77.1% (hazard ratio 0.58 [99.5% CI 0.41, 0.82]; P < 0.001) distant disease-free survival favoured olaparib vs placebo: 87.5% vs 80.4% (hazard ratio 0.57 [99.5% CI 0.39, 0.83]; P < 0.001)
Adjuvant olaparib 1 year of oral olaparib or placebo	Olympia NCT02032823	III		1836	Key secondary analysis(OS) OS favoured olaparib vs placebo olaparib reduced the risk of death by 32% vs placebo (hazard ratio 0.68; 98.5% CI 0.47, 0.97; P = 0.009): 3-year survival: 92.8% vs 89.1% 4-year survival: 89.8% vs 86.4%

Conclusions

In conclusion, the management of BRCA-positive breast cancer necessitates a comprehensive, multidisciplinary approach, integrating intensive screening protocols, risk-reducing surgical interventions, and the implementation of targeted therapeutic strategies. Emerging advancements in precision medicine, including improved early detection methodologies and the development of gene-based therapies, hold promise for enhancing patient outcomes. However, significant challenges persist regarding equitable access to these innovations, underscoring the need for continued research and policy efforts to bridge existing disparities and optimize the delivery of personalized care.

Footnotes

Acknowledgement

To our families, for all their support.

ORCID iDs

Roberto Paz-Manrique

Henry L. Gomez

Ethical Considerations

This study was conducted in accordance with the ethical standards of the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The authors affirm that no data were fabricated or manipulated inappropriately. No conflicts of interest exist, and the authors declare full responsibility for the integrity and accuracy of the data.

Author Contributions

Bruno Muñante, Roberto Paz-Manrique, Joseph Pinto, and Henry Gomez contributed equally to the development of this article. All authors participated in the conception and design of the review, data acquisition, data analysis, and interpretation. Each author drafted, revised, and approved the final version of the manuscript and agrees to be accountable for all aspects of the work.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article. The present study was self-funded.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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Clinical Management in BRCA Carriers with Early Breast Cancer

Abstract

Background

Purpose

Conclusions

Keywords

Highlights

Introduction

Epidemiology of BRCA Mutations in Breast Cancer Women in Latin America

Biology of BRCA1/BRCA2 Alterations in Breast Cancer

Imaging in Patients with Breast Cancer and Mutated BRCA

Special Considerations

Surgical Management in Patients with Early-Stage Breast Cancer and Mutated BRCA

Management of the Breast with Cancer

Contralateral Prophylactic Mastectomy

Systemic management of patients with early-stage breast cancer and mutated BRCA

Chemotherapy neoadjuvant

Immunotherapy

Chemotherapy Adjuvant

PARP Inhibitors Adjuvant

Conclusions

Footnotes

Acknowledgement

ORCID iDs

Ethical Considerations

Author Contributions

Funding

Declaration of Conflicting Interests

References