Abstract
Breast cancer is the most frequent malignancy among young women, with unique challenges particularly for carriers of BRCA pathogenic or likely pathogenic variants (PVs). Among them, the indication for intensive surveillance and risk-reducing surgeries is critical. In addition, special considerations on systemic treatment should be considered, including the use of targeted treatments like poly (adenosine diphosphate (ADP)-ribose) polymerase inhibitors. Moreover, the impact of anticancer treatments and risk-reducing surgeries on their ovarian reserve, pregnancy wish, and breastfeeding is a crucial aspect to be considered. Proper management of long-term toxicities, such as bone and cardiovascular health, as well as menopause-related symptoms, requires proper multidisciplinary care to optimize quality of life. This review examines the biological, clinical, therapeutic, and survivorship implications of breast cancer in young BRCA carriers, emphasizing differences between carriers of PVs in the BRCA1 and BRCA2 genes. Personalized strategies integrating genetic counseling, tailored surveillance and survivorship programs, as well as innovative therapies, are essential for improving prognosis and well-being in these young patients. Multidisciplinary care and further academic research efforts are critical to improve the management of breast cancer in young BRCA carriers.
Introduction
Breast cancer is the most frequent malignancy among women, with different incidence depending on genetic and environmental factors. 1 Among inherited causes, pathogenetic or likely pathogenic variants (PVs) in the BRCA1 or BRCA2 genes are particularly relevant, contributing to a significantly increased risk of developing breast cancer and other neoplasms. 2 BRCA proteins function as tumor suppressors and play a crucial role in repairing double-stranded DNA breaks (DSBs) through homologous recombination (HR) mechanisms. 3 These genes are essential to maintain genomic stability and are central to the HR-mediated repair of DSBs. BRCA proteins support the HR process by facilitating the formation of the RAD51-BRCA2-DSS1 complex, which is crucial for accurate DNA repair. 4 DSBs can arise during DNA replication due to metabolic stress. When such damage occurs, the DNA damage response (DDR) is activated and mediated by key kinases such as ataxia-telangiectasia-mutated (ATM), ataxia telangiectasia-mutated and Rad3-related (ATR), and checkpoint kinases (CHK1/2). 5 This activation triggers cell cycle arrest and initiates DNA repair mechanisms to restore genomic integrity (Figure 1).
DNA repair mechanisms.
Although BRCA PVs are relatively rare in the general population, their prevalence is higher among young women affected by breast cancer.7,8 Between 10% to 15% of young women (defined as ⩽40 years) with newly diagnosed breast cancer are expected to carry a germline BRCA PV. 7 The introduction of large-scale genetic testing has led to the identification of a growing number of individuals at increased cancer risk, guiding preventive strategies, including intensive surveillance and risk-reducing surgeries. 9 At the same time, the peculiarities of breast cancer in BRCA carriers, such as increased sensitivity to DNA-damaging drugs and poly (ADP-ribose) polymerase inhibitors (PARPi), emphasize the need for tailored therapeutic approaches. 10 Moreover, the impact of oncological treatments and risk-reducing surgeries on ovarian reserve, pregnancy wish, and breastfeeding is a critical issue to be considered. 11 Proper management of long-term toxicities, such as bone and cardiovascular health, as well as menopause-related symptoms, requires proper multidisciplinary care to optimize quality of life. 12
The aim of this manuscript is to review the key features of breast cancer management in young BRCA carriers, focusing on its biological, clinical, therapeutic, and survivorship implications. Particular attention is given to the different clinical behaviors of breast cancer according to the specific BRCA gene, thus differentiating between BRCA1 and BRCA2 carriers.
Germline genetic testing and implications on surveillance and preventive strategies
Genetic testing
Sequencing the BRCA genes in the 1990s marked a significant breakthrough in understanding the genetic basis of breast cancer, with subsequent important implications for its clinical management. 13 Since then, indications for genetic testing and guidelines about the management of individuals carrying PVs in the BRCA genes have constantly evolved. 14 Nowadays, 3% of all patients with breast cancer are expected to carry a PV in the BRCA genes.15,16 BRCA1 carriers are estimated to have a 60%–72% chance of developing breast cancer, and, for BRCA2 carriers, the risk is approximately 55%–69%.17,18 Identifying a PV in the BRCA genes offers major implications for these individuals and their family members, opening the door for intensive surveillance programs that include breast magnetic resonance imaging (MRI) and preventive measures such as risk-reducing bilateral mastectomy (RRBM) and risk-reducing salpingo-oophorectomy (RRSO). 19 Moreover, individuals undergoing genetic testing should be informed about the reasons for the test, the potential outcomes, and its possible implications for other family members. 20
According to international guidelines, there is a noticeable trend toward broader access to genetic testing compared to the past. The recently updated guidelines by the American Society of Clinical Oncology (ASCO) recommend performing the test in all newly diagnosed patients with breast cancer younger than or equal to 65 years of age at diagnosis, and in selected patients over 65 years of age based on personal and/or family history, or for those candidates for PARPi. 14 In addition, the test is indicated in patients who develop a second breast cancer in the ipsilateral or contralateral breast. 14 Table 1 shows the main criteria for referring patients with breast cancer for a genetic evaluation according to the American Society of Clinical Oncology, 14 the National Comprehensive Cancer Network (NCCN) guidelines, 21 and the European Society for Medical Oncology (ESMO) guidelines. 19
Criteria for genetic testing according to the main international guidelines.
ASCO, American Society of Clinical Oncology; BC, Breast Cancer; ESMO, European Society for Medical Oncology; NCCN, National Comprehensive Cancer Network; PARPi, poly (ADP-ribose) polymerase inhibitors; PV, pathogenic or likely pathogenic variant; TNBC, Triple-Negative Breast Cancer; VUS, variants of unknown significance.
If we consider only patients with a diagnosis of breast cancer at a young age, genetic counseling should be offered to all of them, regardless of tumor subtype or family history. 22 Current clinical guidelines recommend that BRCA genetic testing should be offered to all individuals, regardless of gender identity, including transgender, nonbinary, and gender-diverse individuals, if they meet personal or family history criteria indicative of hereditary breast cancer, ensuring equitable access to risk assessment and tailored cancer preventive strategies. The testing results should be available before therapy initiation in all cases where the detection of a PV may influence treatment decisions, such as the consideration of risk-reducing surgeries or the use of PARPi.
The importance of knowing the presence of PVs in the BRCA genes in young women with breast cancer has been recently demonstrated by a large analysis within the BRCA BCY Collaboration. In this analysis, almost 5000 young women with breast cancer diagnosed at age 40 years or younger and all BRCA carriers were included. The main aim was to assess the benefit of knowing the presence of BRCA PVs before the diagnosis of breast cancer. Patients who underwent genetic testing before diagnosis had significantly smaller tumors and lower nodal involvement compared to those tested at the time of breast cancer diagnosis. The 8-year disease-free survival (DFS) and overall survival (OS) were 73.3% (95% CI 67.3–78.4) and 90.7% (95% CI 86.5–94.0) in the BRCA test-before-diagnosis group and 70.4% (95% CI 67.5–73.1) and 87.4% (95% CI 85.2–89.4) in the BRCA test-at-diagnosis group, respectively. OS results lost statistical significance after adjustment for potential confounders, including tumor stage (adjusted hazard ratio (aHR), 0.74; 95% CI 0.47–1.15), suggesting that the benefit of knowing the BRCA status is likely associated with the downstaging at diagnosis, thanks to the availability of effective screening measures for breast cancer. 23 This study highlights the critical role of pre-diagnostic awareness of germline BRCA status, particularly in a population of individuals who, due to their young age, would not be qualified for regular screening measures.
In addition to BRCA, other genes are associated with hereditary breast cancer. Recent studies have identified ATM, CHEK2, and PALB2 among the most frequent gene alterations after BRCA in women with a diagnosis of breast cancer before the age of 45 years. 16 Although ordering multigene panel tests that include genes beyond BRCA is becoming more common, particularly in patients diagnosed with breast cancer at a young age, the identification of PVs in other genes can add complexity, as well as the increased risk of identifying variants of unknown significance (VUS), making risk management recommendations more challenging.24,25 The current guidelines underscore the importance of offering a multigene panel test to appropriately selected patients affected by breast cancer to inform them on screening and follow-up procedures, risk-reducing surgeries, and familial risk assessment. However, the guidelines also highlight major clinical challenges, including the complexities of interpreting VUS, the potential for overdiagnosis from moderate-risk gene findings, and the limited availability of genetics expertise to support pre- and post-test counseling. 19
Surveillance and preventive strategies
The primary objectives of risk management in individuals carrying PVs in the BRCA genes are multifaceted. These include reducing the likelihood of cancer development through primary preventive strategies, including risk-reducing surgeries, as well as facilitating early detection of malignancies via secondary preventive measures. 26
In terms of primary prevention of breast cancer, BRCA carriers should be informed first about lifestyle recommendations (Figure 2). In particular, physical activity and weight control should be encouraged; breastfeeding is recommended in women after a pregnancy, while limited alcohol intake should also be suggested.26 –28 The data on the use of hormone-based contraception are mixed: while they may slightly increase the risk of breast cancer, this treatment has been shown to reduce the incidence of ovarian cancer. 26
Clinical, reproductive, and lifestyle implications of carrying germline pathogenic or likely pathogenic variants in the BRCA1 or BRCA2 genes in young women.
Risk-reducing surgeries in young healthy BRCA carriers are the most effective method of reducing the risk of developing breast and/or ovarian cancer (Figure 2). 29 The advantages of undergoing a risk-reducing mastectomy are particularly relevant when performed at around 30 years of age. 30 RRBM has been shown to reduce the lifetime risk of breast cancer by more than 90% in high-risk populations. 31 Over time, several different approaches for RRBM have been developed to improve both aesthetic and survival outcomes, including skin-sparing and nipple-sparing techniques. Risk-reducing nipple-sparing mastectomy is particularly notable for its positive effects on patients’ psychosocial well-being, sexual health, and quality of life.32,33 Although several studies have investigated the potential impact of RRBM on survival, the available data remain controversial. While RRBM significantly reduces the incidence of breast cancer in high-risk individuals, no clear survival benefit has been consistently demonstrated. In individuals already diagnosed with breast cancer, RRBM has shown a dramatic reduction in contralateral cancer risk (91%–93%), but its OS benefits remain debated. 34 In a recent analysis within the BRCA BCY Collaboration, 55.0% of 5290 young BRCA carriers with breast cancer underwent RRBM. RRBM was associated with significantly improved OS (aHR 0.65, 95% CI 0.53–0.78), along with decreased risks of DFS and breast cancer-free interval (BCFI) events. The survival benefit was consistent across BRCA1 and BRCA2 carriers, independent of age at BC diagnosis, tumor subtype, size, or nodal status. In addition, RRSO was associated with overall improved OS (aHR 0.58, 95% CI 0.48–0.71), particularly benefiting BRCA1 carriers and patients with triple-negative breast cancer (TNBC). 35 Although the decision to undergo RRBM remains a complex and highly individualized choice to be guided by an informed discussion between patients and healthcare providers considering both medical evidence and personal preferences, these recent data should be clearly disclosed taking into account the presence of two critical risk factors (i.e. young age at first breast cancer diagnosis and presence of BRCA PVs) for the potential development of a subsequent second primary breast cancer.
For individuals who choose to defer or decline RRBM, in addition to screening strategies, pharmacological risk reduction can be discussed. In premenopausal women, daily treatment with selective estrogen receptor modulators (SERMs) such as tamoxifen or raloxifene represents the only available option.36 –38 These therapies have demonstrated to significantly lower the incidence of breast cancer by targeting the hormonal pathways involved in tumor development, providing a non-surgical yet impactful approach to personalized cancer prevention.36 –40
For secondary prevention, breast cancer screening in BRCA carriers is suggested by all major international guidelines. In particular, ESMO guidelines suggest performing breast cancer screening with imaging evaluations that should begin 5 years before the youngest affected relative, or at the latest at age 30 years (Figure 2). Annual MRI is the imaging of choice because of its greater sensitivity compared to all other exams. 19 Considering the tendency to the rapid development of tumors in patients carrying PVs in BRCA genes, bi-annual screening for BRCA1 carriers and annual screening for BRCA2 carriers is recommended, if possible alternating this examination with breast echography between ages 30 and 39 years or mammography over age 40 years. 19 For the NCCN guidelines, the optimal surveillance for BRCA carriers under 30 years remains uncertain, with a preference for screening with MRI; between 30 and 75 years, annual mammography and MRI are indicated. 9
Features, prognosis, and treatment implications of breast cancer in young BRCA carriers
Breast cancer characteristics and prognosis
Several preclinical and clinical data have shown that breast cancer in BRCA carriers appears to have different features than malignancies arising in patients with sporadic disease. Young BRCA1 carriers are at a significantly increased risk of developing hormone receptor-negative breast cancer, 41 while BRCA2 carriers are more frequently diagnosed with hormone receptor-positive disease. 42 Another study including young women with breast cancer showed that 74.4% of BRCA1 carriers are affected by hormone receptor-negative disease as compared to 15.5% of those harboring BRCA2 PVs. 23
Several studies have shown that the presence of a BRCA PV does not appear to independently influence overall breast cancer prognosis; however, it should be highlighted that among BRCA carriers, clinical outcomes vary depending on the breast cancer subtype. A meta-analysis of 66 studies assessing the survival of patients with breast cancer carrying or not a BRCA PV showed a tendency toward a worse breast cancer-specific survival (BCSS) and OS for BRCA carriers. The pooled 10-year absolute BCSS difference for BRCA1 and BRCA2 carriers compared to wild-type patients was 6.8% (HR 1.12; 95% CI 0.71–1.53) and 4.7% (HR 1.09; 95% CI 0.54–1.65), respectively. However, the results were heterogeneous, and the evidence was judged to be uncertain. 43 The POSH study prospectively included 2733 young patients with breast cancer diagnosed between 2000 and 2008, of whom 338 patients were BRCA carriers (12% of the cohort; 201 with BRCA1 and 137 with BRCA2 PVs). After a median follow-up period of 8.2 years, multivariable analyses revealed no significant differences in OS between patients harboring or not BRCA PVs. 7 Another study evaluated 10-year OS in patients with early-onset breast cancer, with particular attention to BRCA1 carriers. Out of 3345 women diagnosed with stage I–III breast cancer at age 50 or younger, 7.0% were identified as BRCA1 carriers. The 10-year OS for BRCA1 carriers was 80.9%, marginally lower than the 82.2% observed in non-carriers (aHR 1.81; 95% CI 1.26–2.61; p = 0.002). For BRCA1 carriers with small, node-negative tumors, the 10-year OS reached 89.9%. 44
While overall there seems to be no difference between the prognosis of patients harboring BRCA PVs and those with sporadic disease, the prognosis of young BRCA carriers may vary according to the tumor subtype. BRCA carriers with hormone receptor-negative disease tend to experience more favorable outcomes compared to those with sporadic disease, potentially due to the distinct biology and sensitivity of BRCA-associated tumors to DNA-damaging therapies. 45 In contrast, young BRCA carriers affected by hormone receptor-positive breast cancers exhibit features of increased biological aggressiveness and a worse prognosis when compared to the sporadic counterparts. 45 A recent large analysis by Arecco et al., including patients ⩽40 years at diagnosis of breast cancer, evaluated the role of hormone receptor expression in the prognosis of young BRCA carriers. In this analysis, >4500 young BRCA carriers from 78 centers worldwide were included, of whom 2143 (45.5%) had hormone receptor-positive and 2566 (54.5%) hormone receptor-negative disease. Patients with hormone receptor-positive disease had higher rates of distant recurrences (13.1% vs 9.6%, p < 0.01) but lower rates of second primary breast cancer (9.1% vs 14.7%, p < 0.01) compared to those with hormone receptor-negative breast cancer. The 8-year DFS was 65.8% (95% CI 63.4–68.2) for hormone receptor-positive and 63.4% (95% CI 61.2–65.6) for hormone receptor-negative breast cancer, while the 8-year OS was 88.1% (95% CI 86.3–89.7%) in patients with hormone receptor-positive and 87.1% (95% CI 85.5–88.5) in those with hormone receptor-negative disease. 46 Looking specifically at the prognosis according to breast cancer subtypes, 612 (14.0%) patients were classified as having luminal A-like disease, 1038 (23.8%) luminal B-like disease, 2373 (54.4%) TNBC, and 340 (7.8%) HER2-positive disease. Patients affected by luminal A-like breast cancer had the worst DFS (60.8%) compared to all the other breast cancer subtypes (TNBC 63.5%, HER2-positive 65.5% and luminal B-like 69.7%). 46 Previous smaller studies reported similar results, suggesting that breast cancer in young BRCA carriers exhibits different biological characteristics. 47
Given these subtype-specific prognostic differences in young BRCA carriers, further research has examined how BRCA PVs affect survival outcomes in patients treated with neoadjuvant or adjuvant chemotherapy. One study specifically evaluated the prognostic value of BRCA PVs in breast cancer patients treated with chemotherapy in these settings, comparing 266 BRCA carriers (171 BRCA1 and 95 BRCA2 carriers) with 659 noncarriers. Across the entire cohort, BRCA carriers demonstrated a better DFS compared to noncarriers (HR 0.63; 95% CI 0.44–0.90, and HR 0.72; 95% CI 0.47–1.1, respectively). Moreover, in patients with TNBC, BRCA carriers experienced significantly longer DFS (aHR 0.50; 95% CI 0.28–0.89 for BRCA1; and aHR 0.37; 95% CI 0.11–1.25 for BRCA2; p = 0.034) and disease-specific survival (aHR 0.42; 95% CI 0.21–0.82 for BRCA1; aHR 0.45; 95% CI 0.11–1.9 for BRCA2; p = 0.023). However, in the non-TNBC group, having a BRCA PV did not appear to significantly impact survival outcomes. These findings suggest that BRCA germline PVs are associated with improved survival, specifically in women diagnosed with TNBC. 48 De Talhouet et al. reported no significant influence of BRCA PVs on pathological complete response (pCR) rates in HER2-positive or hormone receptor-positive/HER2-negative diseases. In particular, hormone receptor-positive tumors in BRCA2 carriers appeared to be less responsive to chemotherapy, with an observed response rate of only 7%. 48
Genomic testing in BRCA carriers
Since the 2016 guidelines on breast cancer biomarkers, emerging evidence has refined the use of genomic assays, optimizing their application based on menopausal status, age, and tumor characteristics. 49 Shah et al. compared patients with or without BRCA PVs who underwent Oncotype Dx testing, stratifying by age and tumor size. Their findings revealed that BRCA carriers had a higher Oncotype Dx recurrence score (RS) than noncarriers, with a higher proportion of high-risk tumors in the mutated group. 50 A recent meta-analysis by Davey et al. included five studies with 4286 patients to assess the genomic differences in tumors arising in BRCA carriers compared to sporadic diseases. In this analysis, 7.8% of included patients were BRCA carriers (333/4286) and used the Oncotype Dx to calculate the RS. The mean RS in BRCA carriers was 25 (range 10–71) versus 18.4 in cases of sporadic disease (range 0–62). Using Oncotype Dx matching for age and tumor size, BRCA carriers and non-carriers affected by HR-positive node-negative breast cancer, the median RS was higher for cases versus controls (24 vs 16; p < 0.0001). Carriers had more high-risk diseases (28% vs 7%), intermediate-risk diseases (56% vs 36%), and fewer low-risk diseases (16% vs 57%). 51 Kurian et al. analyzed 37,349 patients with hormone receptor-positive/HER2-negative breast cancer, linking germline test results with the 21-gene Oncotype Dx assay. Among them, 714 patients were carriers of PVs in BRCA1, BRCA2, PALB2, ATM, CHEK2, or Lynch Syndrome genes. BRCA1 carriers showed the highest mean RS (26.7 for age ⩾50 years and 36.7 for age < 50 years), followed by BRCA2 carriers (23.3 for age ⩾50 and 24.1 for age <50 years). For patients <50 years of age, 89.4% of BRCA1 carriers had a RS ⩾ 16. BRCA2 and PALB2 carriers showed similar trends but with a lower mean RS than BRCA1 carriers. 52
A retrospective study by Yerushalmi et al. analyzed genomic differences between tumors in BRCA carriers versus sporadic disease in patients with hormone receptor-positive/HER2-negative early breast cancer. A total of 81 BRCA carriers were included and compared to a commercial database of 799,986 samples. With the 21-gene Oncotype Dx assay, the median RS in BRCA carriers was 25 (range 18–35), significantly higher than the median of 16 (range 11–22) observed in sporadic diseases (p < 0.001). Even in this case, BRCA carriers had a higher incidence of high-risk (49.4% vs 16.4%) and intermediate-risk (41.9% vs 47.2%) disease, while low-risk was less common (8.6% vs 36.4%). The expression of 12 out of 16 genes differed significantly between the groups, with a profile characterized by higher proliferation and invasiveness in BRCA carriers. The comparison between BRCA1 and BRCA2 PVs showed a higher median RS in BRCA1 carriers (29 vs 24), but the differences were not statistically significant. 53
Taken together, these results show that hormone receptor-positive breast cancer in BRCA carriers appears to have biological features of greater aggressiveness compared to sporadic disease. However, data on alternative genomic assays such as EndoPredict and Breast Cancer Index (BCI) in BRCA PVs carriers are lacking, highlighting a relevant knowledge gap in assessing endocrine sensitivity and risk of late recurrences in this subgroup.
Treatments
Chemotherapy
BRCA-related tumors are characterized by a high sensitivity to DNA-damaging chemotherapy, especially in hormone receptor-negative tumors. 54
In the neoadjuvant setting, several trials evaluated the role of platinum agents in combination with chemotherapy in BRCA carriers. Three meta-analyses assessed the benefit of platinum agents. The first meta-analysis included nine trials (n = 2109 patients) and examined the impact of adding a platinum agent to neoadjuvant chemotherapy in patients with TNBC. While the inclusion of a platinum agent significantly increased pCR rates in TNBC overall, in BRCA carriers, the addition of carboplatin showed no apparent significant benefit. 55 Similarly, a meta-analysis of 20 studies evaluated the impact of platinum-based chemotherapy in early TNBC, including BRCA carriers. While platinum-based chemotherapy significantly improved DFS and OS in both the neoadjuvant and adjuvant settings, subgroup analyses showed no apparent benefit in DFS in BRCA carriers. 56 Another meta-analysis that included exclusively BRCA carriers from 31 studies (n = 619) showed higher pCR rates when platinum-based chemotherapy was used in combination. Platinum-based agents combined with standard chemotherapy (anthracycline, taxane, and cyclophosphamide) achieved a pCR rate of 62% (95% CI 0.48–0.76). Similarly, the carboplatin and taxane regimen yielded a pCR rate of 63% (95% CI 0.47–0.79) compared to platinum monotherapy, which showed a lower pCR rate of 53% (95% CI 0.30–0.76). 57 Secondary analyses from the BrighTNess trial showed that the pCR benefit of adding carboplatin to standard neoadjuvant chemotherapy in TNBC patients was independent of BRCA status. 58 The INFORM phase II trial compared neoadjuvant cisplatin (CDDP) and doxorubicin-cyclophosphamide (AC) in 117 BRCA carriers with stage I–III HER2-negative breast cancer, of whom 82 had TNBC. pCR rates were 18% for CDDP and 26% for AC. Single-agent CDDP did not show superior efficacy over AC in BRCA carriers with TNBC or hormone receptor-positive/HER2-negative disease. 59 While BRCA carriers are known to have heightened sensitivity to platinum-based chemotherapy, all this evidence suggests that adding a platinum agent to regimens already containing DNA-damaging chemotherapy like anthracyclines and cyclophosphamide may not offer additional benefits.
Patients with BRCA1 PVs and hormone receptor-negative tumors seemed to have a better response to neoadjuvant chemotherapy, as evidenced by higher rates of pCR, and improved long-term survival rates. 60 BRCA carriers are significantly more likely to receive adjuvant chemotherapy than individuals with sporadic breast cancer (85.1% vs 60.0%; p < 0.005). However, despite these treatment differences, multivariable analyses showed no significant differences in the risk of distant recurrence or mortality between BRCA carriers and those with sporadic disease, regardless of chemotherapy treatments. 61 In patients with TNBC, previous studies consistently showed that BRCA1 and/or BRCA2 carriers exhibit higher pCR rates after neoadjuvant chemotherapy.59,62 –65 These findings suggest that tumors associated with BRCA PVs are more sensitive to DNA-damaging chemotherapy, which may explain why the additional benefit of adding a platinum agent is less pronounced for these patients. In other words, the heightened sensitivity of BRCA-associated tumors to DNA-damaging chemotherapy may limit the advantages of adding a platinum agent to standard anthracycline- and taxane-based chemotherapy in these cases.
Notably, in young women, chemotherapy increases the risk of gonadotoxicity. In a study in mice carrying PVs in BRCA or other DNA repair genes, co-administration of carboplatin and paclitaxel caused significant ovarian reserve depletion, revealing potential increased fertility risks. 66
Immunotherapy
Breast cancer in BRCA carriers is known to have an elevated expression of programmed death-ligand 1 (PD-L1), which serves as a compensatory mechanism for inhibiting T-cell activation within tumor sites. 67 This upregulation is linked to genomic instability and the resulting expression of neoantigens on the tumor surface, leading to an increase in tumor-infiltrating immune cells. PD-L1 expression varies between BRCA1 and BRCA2 carriers, being higher in BRCA1 carriers compared to BRCA2 carriers.67,68
Pembrolizumab is now the standard therapy, in combination with chemotherapy, in most patients with early-stage TNBC based on the results of the KEYNOTE-522.69,70 In the KEYNOTE-522 trial, 1174 patients with previously untreated stage II or III TNBC, neoadjuvant and adjuvant pembrolizumab combined with chemotherapy demonstrated a statistically significant improvement in 60-month OS, with an estimated survival rate of 86.6% in the pembrolizumab-chemotherapy group compared to 81.7% in the placebo-chemotherapy group. 71 However, no specific data comparing the clinical efficacy of neoadjuvant and adjuvant pembrolizumab in BRCA carriers versus those with sporadic disease have been reported to date. The lack of this information is particularly critical in a curative-intent setting. Further investigation is warranted to assess the potential benefit of immunotherapy in patients harboring BRCA PVs. 70 Recent real-world data comparing the KEYNOTE-522 trial regimen and standard treatment suggest that BRCA carriers achieve similar pCR rates regardless of the treatment regimen received. 72 The absence of a detectable difference is likely due to the high pCR rate of 75% observed in BRCA carriers receiving chemotherapy only without immunotherapy.
In the metastatic setting, first-line immunotherapy is approved in association with chemotherapy, and different studies evaluated its use in combination with PARPi in BRCA carriers affected by metastatic TNBC. Three small trials (TOPACIO, DORA, and MEDIOLA) tested the combination of an immune checkpoint inhibitor with a PARPi, demonstrating promising efficacy in BRCA carriers with metastatic breast cancer.67,73,74
Target therapy
Homologous recombination deficiency (HRD) causes cells to rely on alternative, error-prone DNA repair mechanisms, which can lead to the accumulation of double-strand breaks. This explains why breast cancer driven by BRCA PVs has enhanced sensitivity to PARPi and DNA-damaging agents. 75 PARPi specifically targets the enzyme responsible for repairing single-strand DNA breaks, leveraging the concept of synthetic lethality in HRD cells, resulting in replication arrest and subsequent tumor cell death. Olaparib is now approved for use in BRCA carriers affected by early HER2-negative breast cancer. 76 In the adjuvant setting, the phase III OlympiA trial established the benefit of olaparib in high-risk, BRCA carriers with HER2-negative early breast cancer. 77 A total of 1836 patients were randomly assigned to receive 1 year of adjuvant olaparib or placebo after local treatment and neoadjuvant or adjuvant chemotherapy. At the last update of the study presented at the San Antonio Breast Cancer Symposium, olaparib showed to significantly improve 6-year invasive DFS from 70.3% to 79.6% (HR 0.65; 95% CI 0.53–0.78), distant DFS from 75.7% to 83.5% (HR 0.65; 95% CI 0.53–0.81), and OS from 83.2% to 87.5% (HR 0.72; 95% CI 0.56–0.93). 78 OS benefit associated with adjuvant olaparib was observed in all pre-specified subgroups, including in patients who had or had not received prior platinum-based chemotherapy, those treated in either the neoadjuvant or adjuvant setting, and among individuals harboring BRCA1 versus BRCA2 germline PVs or being affected by triple-negative or hormone receptor-positive/HER2-negative disease, indicating a broadly applicable therapeutic benefit regardless of baseline treatment characteristics or BRCA variants. 78 These findings support the relevance of BRCA testing also for decisions regarding systemic anticancer therapies.
Notably, a preclinical experiment in mice suggested that olaparib may play a role in gonadal toxicity by significantly depleting primordial follicle oocytes. Olaparib did not exacerbate chemotherapy-induced ovarian follicle loss, suggesting that its impact on ovarian reserve may be independent of cytotoxic treatments. 79
In the neoadjuvant setting, a pilot study of single-agent talazoparib in BRCA carriers showed a reduction in tumor volume after 2 months of treatment (median decrease of 88%). 80 A subsequent phase II trial reported a pCR rate of 45.8% in BRCA carriers with TNBC after 6 months of single-agent talazoparib. 81 Several studies explored the use of currently available PARPi in combination with chemotherapy, with limited success. The phase II GeparOLA trial evaluated olaparib (200 mg/day) with paclitaxel versus carboplatin with paclitaxel, followed by epirubicin and cyclophosphamide in patients with HER2-negative, HRD tumors. 82 Although numerically higher pCR rates and improved tolerability were observed with olaparib-paclitaxel versus carboplatin-paclitaxel, the long-term analysis failed to demonstrate a survival advantage in the overall population. 82 However, in BRCA carriers, the pCR rate was significantly higher than in non-carriers (62.7% and 41.3%, respectively; p = 0.047), regardless of the type of treatment received. 82 In the phase III BrighTNess trial, in patients with stage II–III, high-risk TNBC, the primary analysis did not show a higher pCR rate with the addition of veliparib to carboplatin-paclitaxel compared to chemotherapy alone (in both cases followed by doxorubicin and cyclophosphamide) in the overall population as well as in the subgroup of BRCA carriers. 83 A real-world study investigated the combination of PARPi and chemotherapy in the neoadjuvant setting, failing to demonstrate a benefit in pCR rate compared to chemotherapy alone. 60 In the advanced disease setting, olaparib and talazoparib monotherapies have received approval for the treatment of advanced breast cancer based on the data from the OlympiAD and EMBRACA trials, respectively.84,85
Cyclin-dependent kinase 4/6 inhibitors
CDK4/6 inhibitors have a crucial role in the management of hormone receptor-positive/HER2-negative breast cancer.
In the metastatic setting, palbociclib, ribociclib, and abemaciclib are approved in combination with endocrine therapy as the standard first-line treatment. 86 Emerging data suggest that CDK4/6 inhibitors may have reduced efficacy in BRCA carriers with metastatic breast cancer.87,88 These findings are consistent with retrospective genomic analyses that identified BRCA1 PVs among alterations associated with resistance to CDK4/6 inhibitors in hormone receptor-positive metastatic breast cancer. 89 Moreover, BRCA2 PVs are associated with shorter PFS in patients with breast cancer receiving CDK4/6 inhibitors and endocrine therapy. 90 A strong association was observed between BRCA2 PVs and pathogenic somatic RB1 alterations, which is a known driver of resistance to CDK4/6 inhibitors. 91
In early-stage disease, abemaciclib and ribociclib are approved as adjuvant treatments for patients with hormone receptor-positive/HER2-negative breast cancer at high risk of recurrence. 92 In this setting, there is no clear evidence of a potential lower efficacy of CDK4/6 inhibitors in BRCA carriers. At the ESMO Breast 2024 congress, data in BRCA carriers included in the monarchE trial were presented. A total of 41 (3.5%) BRCA carriers were identified (abemaciclib plus endocrine therapy n = 20; endocrine therapy alone n = 21): despite the limited sample size, the results suggested a benefit of adding adjuvant abemaciclib irrespective of the presence of BRCA PVs. 93
These observations have sparked interest in alternative treatment sequences. Notably, new trials in the metastatic setting, such as EvoPAR-Breast01 (NCT0638075), are exploring the strategy of administering PARPi prior to CDK4/6 inhibitors. Recent data from Safonov et al. 94 have demonstrated that biallelic inactivation of RB1, a known resistance mechanism to CDK4/6 inhibitors, can emerge under selective pressure: upfront use of PARPi may potentially delay this resistance pathway, enhancing the efficacy of subsequent endocrine-based therapies. The differential efficacy of CDK4/6 inhibitors observed between the adjuvant and metastatic settings in BRCA carriers remains not fully understood. While micro-metastatic disease in the adjuvant setting may retain sensitivity to CDK4/6 inhibition, metastatic disease frequently develops primary or acquired resistance mechanisms, such as loss of retinoblastoma protein, upregulation of the cyclin E-CDK2 axis, and hyperactivation of the PI3K/AKT/mTOR signaling pathway, which collectively limit the therapeutic efficacy of CDK4/6 inhibitors. 95 Moreover, in the metastatic setting, resistance may also be driven by tumor evolution and the emergence of adaptive mechanisms, including activation of compensatory signaling pathways and epigenetic reprogramming, which diminish dependence on CDK4/6-mediated cell cycle regulation. 95 However, these data are not specific to BRCA carriers, and further studies are required to elucidate the mechanisms of resistance in this subgroup.
Survivorship
Fertility and pregnancy-related issues in young BRCA carriers
International guidelines recommend that comprehensive oncofertility counseling before starting anticancer treatments should be provided to all patients with cancer diagnosed at reproductive age (Figure 2). 96 BRCA carriers face additional challenges regarding oncofertility.11,97 Specifically, it was shown that BRCA carriers seem to have a reduced ovarian reserve due to their deficient DNA repair mechanisms. This has been shown by indirect ovarian reserve assessments, with reduced anti-mullerian hormone (AMH) levels observed in patients with breast cancer and BRCA carriers versus noncarriers before starting active anticancer treatments. 97 Moreover, the role of DNA repair mechanisms in increasing the susceptibility of these patients to the gonadotoxic effects of treatment remains a topic of debate.98 –100 The main fertility preservation strategies in young women consist of embryo/oocyte cryopreservation or ovarian tissue cryopreservation (OTC) (Figure 2). 11 Embryo/oocyte cryopreservation is considered the standard first option to be discussed with all young BRCA carriers with breast cancer. 97 This technique requires approximately 2 weeks of stimulation with exogenous gonadotropins to achieve ovarian hyperstimulation and follicular maturation. 101 It should be offered to patients preferably under 40 years of age (as the success in older patients is very low), who are post-pubertal, and can delay active anticancer treatment by at least 2 weeks. This technique has proven to be effective and safe, including among young BRCA carriers.102,103 A retrospective analysis by Condorelli et al. among the patients recruited in the BRCA BCY collaboration examined 168 patients harboring a BRCA PV and having a pregnancy after a prior history of breast cancer, of whom 22 underwent assisted reproductive technologies (ART) and 146 conceived naturally. No apparent difference in terms of obstetrical outcomes or the number of DFS events was observed among patients who used ART or had a natural conception. 104 Notably, ART allows for discussing preimplantation genetic testing in BRCA carriers.105,106 Reassuring data were observed in the more recent update of the BRCA BCY Collaboration. 107 Among 543 young BRCA carriers with a pregnancy after breast cancer, 436 conceived naturally and 107 through ART, with ART involving various procedures like oocyte/embryo cryopreservation, in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI), and oocyte donation. At a median follow-up of 9.1 years, ART was not associated with detrimental effects on DFS; pregnancies with ART had higher miscarriage rates (11.3% vs 8.8%) but fewer induced abortions (0.9% vs 8.3%) compared to spontaneous pregnancies. 107 Another multicenter cohort study evaluating the impact of ART in breast cancer survivors included five BRCA carriers out of 39 patients in the ART group and one BRCA carrier out of 79 in the non-exposed group. This study found no significant increase in recurrence risk among those undergoing ART compared to matched controls. In the overall population, despite a higher pregnancy rate in the ART group (59% vs 26%, p = 0.001), the recurrence rate was lower (7.7% vs 20.5%, HR 0.46; 95% CI 0.13–1.62, p = 0.23). 108 Taken together, all these findings provide reassuring data on the feasibility and safety of ART in patients with breast cancer, including BRCA carriers.
Cryopreservation of ovarian tissue is a different technique that consists of the surgical removal of ovarian tissue (in general, fragments of the ovarian cortex) and its cryopreservation before the start of systemic anticancer treatments. This technique has some peculiar differences from embryo/oocyte cryopreservation: it is indicated in younger patients, usually <36 years at diagnosis as the chances of success in older women are limited; it can be proposed to prepubertal patients as it does not require hormonal stimulation. For this reason, this technique can be used in the most urgent situations where it is not possible to wait for the 2-week stimulation time needed for embryo/oocyte cryopreservation before starting anticancer therapies. This technique is challenging in BRCA carriers (especially in BRCA1 carriers) because of the increased risk of ovarian cancer and the indication for RRSO at the age of 35–40 years in BRCA1 carriers and 40–45 years in BRCA2 carriers. 109 Hence, this strategy should not be offered in BRCA carriers unless there is any contraindication to embryo/oocyte cryopreservation and the patient is diagnosed several years before the recommended age of RRSO. 105 In BRCA carriers, the decision to undertake OTC involves a complex risk-benefit evaluation, as the potential for fertility preservation should be carefully balanced against the increased lifetime risk of ovarian cancer and the standard recommendation for risk-reducing salpingo-oophorectomy. While OTC may offer both reproductive and endocrine advantages, concerns remain regarding the overall safety of reimplanting ovarian tissue in this population at higher risk of developing ovarian cancer. In addition to the considerations about the controversial value of OTC in the general breast cancer population, 110 it should be highlighted that the long-term safety and effectiveness of OTC specifically in BRCA carriers remain largely uncharacterized. 111 In BRCA carriers, tissue reimplantation should be performed into the remaining ovary to ensure optimal restoration of ovarian function and facilitate complete removal of all ovarian tissue at the time of RRSO. 111
The administration of a gonadotropin-releasing hormone agonist (GnRHa) during chemotherapy is a standard strategy to preserve ovarian function in young patients receiving chemotherapy. Several randomized studies evaluated the efficacy of this technique in preserving ovarian function in young patients with breast cancer. A meta-analysis based on individual patient-level data showed a reduced risk of premature ovarian insufficiency and increased chances of having a future pregnancies in patients who received a GnRHa during chemotherapy as compared to those who recevied cytotoxic therapy alone. 112 In the PROMISE-GIM6 study, 43 out of 281 recruited patients were BRCA carriers (five with BRCA1 and five with BRCA2 PVs). Among them, the incidence of chemotherapy-induced premature ovarian insufficiency was 0% (0/4) in the GnRHa arm and 33% (2/6) in the chemotherapy alone arm, suggesting a potential protective gonadal effect of GnRHa also in BRCA carriers. 113
The safety of pregnancy after breast cancer has been demonstrated by several studies.114 –116 Recently, specific data in BRCA carriers have become available. The first analysis of the BRCA BCY Collaboration in 2020, including 1252 patients, reported a 10-year pregnancy rate of 19% in young BRCA carriers with a prior history of breast cancer, with no significant differences in DFS and OS between those who conceived and those who did not. 117 A meta-analysis of 39 studies involving 112,840 patients with breast cancer found that survivors were less likely to conceive than the general population. However, no detrimental effect of pregnancy after BC was observed in BRCA PV patients. 116 A subsequent updated analysis of the BRCA BCY Collaboration reported 659 pregnancies after breast cancer diagnosis among 4732 BRCA carriers included in the study. 118 The majority of pregnancies (79.2%) occurred spontaneously, despite over 90% of patients having received prior chemotherapy. Among 470 newborns with available data, the incidence of congenital abnormalities (0.4%) was comparable to that expected in the general population. A significant interaction was observed between pregnancy and BRCA gene status. Specifically, pregnancy was associated with improved outcomes in BRCA1 carriers across all analyses. In contrast, BRCA2 carriers exhibited a potential association between pregnancy and poorer disease-free survival (aHR 1.55; 95% CI 1.12–2.16). 118
Blondeaux et al. 119 have recently reported data on breastfeeding in young BRCA carriers included in the BRCA BCY Collaboration. In this analysis, 659 young BRCA carriers had a pregnancy after breast cancer diagnosis, and 474 delivered a child. After delivery, 23.2% of patients breastfed, 14.4% did not breastfeed, 47.5% underwent RRBM before delivery, and 15.0% had an unknown breastfeeding status. 119 After a median follow-up of 7.0 (interquartile range 3.6–10.5) years after delivery, no difference in cumulative incidence of locoregional and/or contralateral breast cancer events between the breastfeeding and no breastfeeding groups was observed (aHR 1.08, 95% CI 0.57–2.06, p = 0.82). Similarly, no impact of breastfeeding on DFS (aHR 0.83, 95% CI 0.49–1.41, p = 0.49) nor OS (nine OS events in patients that breastfed and three in those that did not breastfeed) was observed. 119 Regarding the possibility of having a pregnancy after hormone receptor-positive disease, the POSITIVE trial reported primary results on the safety of temporarily interrupting adjuvant endocrine therapy to attempt pregnancy; the 3-year incidence of breast cancer events and distant recurrence was comparable between patients who discontinued treatment compared to a control-matched cohort of patients. 120 In this study, 38 BRCA carriers were included; although these patients exhibited a higher number of breast cancer events, this increase was not statistically significant 114 (Figure 2).
Quality of life after treatments
In BRCA carriers, RRSO showed to significantly lower the risk of gynecological cancers, including ovarian, fallopian tube, and primary peritoneal cancers, by 80%–90%, while also reducing all-cause mortality by 77%. 19 However, RRSO has important implications for QoL. Women who undergo RRSO experiencing surgical menopause often report more frequent and severe vasomotor symptoms, sleep disturbances, fatigue, depressive symptoms, and sexual dysfunction compared to those who transition through natural menopause. 121 While vasomotor symptoms in natural menopause typically develop gradually and resolve within 4–5 years in most cases, surgical menopause leads to an abrupt onset of symptoms, which may be more intense. These symptoms could be exacerbated by endocrine therapy in women with hormone receptor-positive disease, leading to early treatment discontinuation. 122 Several pharmacological and non-pharmacological approaches are available to counteract the side effects associated with estrogen deprivation. 123
Conclusion
The management of young BRCA carriers with breast cancer is challenging and requires a personalized and multidisciplinary approach.
The role of genetic counseling and early surveillance remains critical. Expanding access to genetic testing allows for earlier risk assessment, enabling the timely implementation of preventive measures such as risk-reducing surgery and enhanced screening protocols.
Although BRCA carriers do not seem to have a different prognosis than those with sporadic tumors when optimally treated, differences depending on tumor subtype in young BRCA carriers were described. These differences highlight the importance of individualized treatment approaches based on tumor biology.
Platinum-based chemotherapy and PARPi have demonstrated significant efficacy in tumors with HRD. More data are needed to understand the benefit of CDK4/6 inhibitors and immunotherapy in this special patient population.
Beyond oncological treatments, the long-term impact of therapy must be carefully managed. Oncofertility counseling and quality of life considerations play a crucial role in the survivorship care of young BRCA carriers and should be integrated into long-term care planning.
Bridging the gap between clinical research and routine oncology practice will be critical for optimizing patient outcomes, with multidisciplinary models involving oncologists, geneticists, fertility specialists, and psycho-oncologists being increasingly essential to address both the medical and psychosocial challenges faced by young BRCA carriers.
Footnotes
Acknowledgements
Luca Arecco acknowledges the support from the European Society for Medical Oncology (ESMO) for a Clinical Research Fellowship at the Institut Jules Bordet (Brussels, Belgium) during the conduction of this work. Matteo Lambertini acknowledges the support by the Italian Association for Cancer Research (AIRC grant MFAG 2020 ID 24698). Any views, opinions, findings, conclusions, or recommendations expressed in this material are those solely of the author(s) and do not necessarily reflect those of ESMO.
