The main function of BRCA1 and BRCA2 in the repair of double-strand DNA breaks is through homologous recombination. Thus, they are considered tumor suppressor genes and are associated with an increased risk of cancer including breast and ovarian cancers [1,2]. The pathogenic variants are generally heterozygous, resulting in the loss of function [3]. Phenotypes of breast cancer that are associated with germline BRCA mutations may also be further classified on into germline BRCA1 (gBRCA1) and gBRCA2 pathologic variants, suggesting different mechanisms of homologous recombination [4]. Therefore, we find it useful to further clinically characterize patients with gBRCA1- or gBRCA2-mutated breast cancer with metastasis to the brain as it is a poor prognostic feature that is associated with significant morbidity and shortened survival.

Based on BRCA mutation status, patients with breast cancer may be subdivided into 3 groups: BRCA1 mutation carriers, BRCA2 mutation carriers, and non-BRCA mutation carriers. BRCA1 mutation carriers may, in addition, be further divided into triple-negative (TN), defined as estrogen- and progesterone- negative as well HER-2 negative by IHC <3+ or FISH non-amplified, or non-TN [4]. Additionally, BRCA1- and BRCA2-mutated breast cancers have different clinical differences. First, about 20% of patients with breast cancer carry BRCA1 mutations but only 8% carry BRCA2 mutations, and the majority (72%) do not have BRCA mutations [5]. Compared to patients with BRCA1 mutations, those with BRCA2 mutations tend to be older and have higher incidences of hormone receptor–- or human epidermal growth factor receptor–-positivity [4,6]. Another clinical distinction is the greater prevalence of visceral metastasis in BRCA1 carriers compared to BRCA2 and non-BRCA carriers (70% vs. 9% vs. 37%, respectively). Moreover, Patients with BRCA1-mutated breast tumors have statistically smaller 5-year survival rates compared to those with BRCA2-mutated or with non-BRCA–mutated tumors (73% vs. 96% vs. 92%, respectively with p<0.001) [5]. The use of alkylating agents did not seem to affect the survival of patients with TN breast cancer (TNBC), whether they were gBRCA1 carriers or not [7]. Patients of Ashkenazi descent with BRCA1 mutations had poorer survival outcomes compared to BRCA2-mutated breast cancer patients; however, such differences were abolished with the use of adjuvant chemotherapy [8]. Finally, patients with BRCA1 mutations and metastatic breast cancer have worse outcomes in terms of time to progression and overall survival, compared to other breast cancer clinical entities [6,8,9].

Genetic testing for gBRCA is recommended for patients with metastatic breast cancer, TNBC, and high-risk ER-positive breast cancer in whom the testing could help guide systemic therapy and for patients with any stage breast cancer who are at a substantial risk for hereditary breast cancer based on family cancer history [10]. Genetic testing results inform breast cancer screening, risk reduction strategies, and family counseling, and they are now integral to the treatment of breast cancer, including in the adjuvant and metastatic settings. Testing for BRCA in patients with early breast cancer (eBC) serves to optimize locoregional management and to select patients who may receive help from poly (ADP-ribose) polymerase (PARP) inhibitors in the adjuvant setting. However, the predictive value of BRCA1 vs. BRCA2 regarding patterns of recurrence, particularly that of brain metastasis, is not well understood.

Tumor cells with mutated variants of BRCA1/2 are deficient in DNA double stranded breaks, whose repair is regulated by PARP enzyme. PARP inhibitors cause accumulation of unrepaired DNA damage resulting in cell death. The PARP inhibitors olaparib and talazoparib are shown to improve progression-free survival [11,12] and are United States Federal Drug Association (FDA)–approved options for the treatment of gBRCA-mutated, HER2-negative metastatic breast cancer. In addition, patients with a history of central nervous system (CNS) metastasis (N=63, 14%) benefited more from talazoparip compared to patients with no history of CNS metastasis (n=368, 86%) (hazards ratios of 0.32 and 0.58, respectively), suggesting that talazoparip may have helped control CNS disease, thus reflecting favorably on progression-free survival [11]. In another study of patients with gBRCA-mutated and HER2-negative metastatic breast cancer [13], the combination of chemotherapy with a PARP inhibitor showed improved progression-free survival compared to a placebo; however only 5% of the patients had CNS metastasis and were not analyzed separately for clinical outcomes.

Because of the introduction of various systemic treatment options and improved systemic disease control, askew questioned whether we might see more frequent CNS metastases among patients with gBRCA, particularly if this subgroup has a predilection for brain metastasis [14-17], as was observed with HER2-positive breast cancer patients who showed high rates of CNS metastasis and distinctive clinical features that were eventually associated with gBRCA pathogenic variants. A tucatinib-based therapy has demonstrated clear CNS activity in patients with HER2-positive tumors [18-20], and it may be likely, as well, that other drugs, such as PARP inhibitors, have similar impacts on brain metastasis in patients with gBRCA mutations [21-23].

Therefore, there is a need to figure out the association of brain metastasis and gBRCA in patients witheBC and to explore its potential specific impact of brain metastasis on the survival and be compared to that of non-gBRCA carriers, as well. In addition, there is a need to explore the potential to reduce the risk of developing brain metastasis in patients at high-risk for this metastasis. Therefore, the relatively high incidence of brain metastasis among patients with gBRCA-mutated tumors justifies the suggestion that clinical trials that use agents with CNS activity consider including brain MRIs as part of the evaluation for distant recurrence. This use could promote translational studies to understand the biologic mechanisms of gBRCA-mediated CNS metastasis and subsequently drive the development of clinical trials that aim to prevent brain metastasis in high-risk breast cancer patients with BRCA mutations.

In a recent single-institution study [24], gBRCA1 or gBRCA2 patients with stage I-III breast cancer were evaluated. In this study, several characteristics were identified and differentiated some natural history and clinical outcomes between the 2 groups: Both groups had similar distant recurrence rate (9 years) and 3-year distant metastasis–free survival rate; however, compared to predominant HR-positive gBRCA2 tumors, gBRCA1 tumors have been shown to be more of the TN phenotypes, shorter lead time (2.4 vs 5 years) , and a higher predilection to brain metastasis. Furthermore, patients with gBRCA1 tumors tend to spread to the brain at a younger age compared to patients with gBRCA2 tumors. Finally, patients with gBrRCA2 tumors tend to have a higher incidence of multiple brain lesions (compared to that of solitary lesions) yet a longer overall survival than those with gBRCA1 patients.

Furthermore, distinctions between patients with gBRCA1 mutation carriers and non-gBRCA1 mutation carriers have been documented [7,16]; there is a higher tendency for brain metastasis in gBRCA1 patients compared to non-carriers [[16]. However, when patients with BRCA2 mutations were included in a comparative analyses with patients with BRCA1 mutations or non-carrier [15], BRCA2 were predominantly HR – positive compared to the predominantly TN phenotypes associated with BRCA1 mutated patients, as well as with higher predilection to bone metastasis compared with higher predilection to lung or lymph node recurrences with BRCA1 mutated tumors. In one study, BRCA1 patients with metastatic breast cancer had worse outcomes compared with gBRCA2 patients or gBRCA non-carrier patients; however, brain metastasis was included among the visceral metastasis category and not accounted for separately, although the difference was statistically significant, and the sample size was small [6].

In another study, patients with progressive TN metastatic breast cancer had worse outcomes if they had brain metastasis; however, the relevance of gBRCA was not accounted for as a prognostic feature [26]. Although it is abundantly documented that TN and HER2-positive tumors have a high predilection to brain metastasis [26], but attempts at sub-classifying non–HER-positive cases into BRCA1, BRCA2, and non-BRCA carrier tumors are not clearly characterized. In addition to larger tumor size and poorer nodal status, BRCA1-associated tumors carry poorer prognostic features, and tumor size and nodal status also influence prognosis [27,28]. Furthermore, BRCA1 tumors were characterized to demonstrate high-grade, basal-like phenotypes, HR and HER2-negative, and to express CD5, CD6, and CD14 [27,29-31]. However, timing to brain metastasis is affected by several factors, such as being TN or HER2-positive, being younger than 35 years old, and having luminal A tumors in patients who are older than 60 years [32]. Yet, to our knowledge, BRCA1 or BRCA2 were not separately addressed in the literature until it was first reported that there was no apparent differences in rates of brain metastasis, including CNS parenchymal and leptomeningeal metastasis, in patients with gBRCA1- or gBRCA2-mutated breast tumors [16/30 (53%) vs. 16/32 (50%)], however, with only 67/270 (25%) of the gBRCA non-carriers developed brain metastasis, p<.001 and, with the gBRCA2 seems to be more associated with CNS metastasis when controlling for tumor subtypes, in a multivariate analysis (p=.006) [15]. In contrast, another study [24] reported the frequency of CNS metastasis in the gBRCA1 cohort was higher than that of the gBRCA2 cohort (34/76 [45%] vs. 7/42 [16.7%]) and that of the non–BRCA-carrier patients with TNBC (65/182 [36%]).

Such reported differences may be explained by potential differences in timing to and/or referral biases to different tertiary institutions, for management of diagnosed or suspected brain metastasis. Furthermore, inclusion of leptomeningeal carcinomatosis in the parenchymal brain metastasis group may have, in part, increased the rate of CNS metastasis in the gBRCA2 group. This finding raises an additional question whether gBRCA2 patients have a predilection to leptomeningeal carcinomatosis, which is an issue that has not yet been addressed. It is probably safe to say that there is a higher rate of brain metastasis among gBRCA1 patients and gBRCA non-carrier TNBC patients than in patients with gBRCA2. However, there is no clear clinical signal yet to say that gBRCA breast cancers, particularly gBRCA1 breast cancers, have a unique predilection for CNS metastasis, particularly in the context of patients with TNBC. Small studies of brain metastasis in other BRCA-associated malignancies suggest that gBRCA ovarian cancer patients may have a high risk for brain metastasis, albeit a much lower risk than that of breast cancer patients. An alternative explanation would be the longer overall survival in gBRCA ovarian cancer patients is due to the enhanced chemosensitivity or the effectiveness of the PARP inhibitor maintenance therapy commonly employed with these patients [29,33-37].

Breast cancer brain metastasis shows increased homologous recombination deficiency in relation to the corresponding primary tumor [38,39]. BARD1 and RAD51 are overexpressed as well in metastatic brain lesions, but necessarily so in the paired primary tumor and in a mouse xenograft model [40]. More studies are needed to focus on the molecular features of gBRCA brain metastatic lesions, including but not limited to gBRCA1 or gBRCA2 mutations. In addition, if TNBC BRCA tumors may also benefit from treatment with PARP inhibitors with adequate CNS penetration, as such tumors tend to become more BRCA-like upon seeding the brain. In early 2022, the FDA approved olaparib for the adjuvant treatment of patients with deleterious or suspected deleterious germline BRCA germline-positive mutated high-risk breast cancer. This was based on the adjuvant OlympiA trial that randomized 1,836 HER2-negative high-risk eBC patients who completed definitive local treatment and neoadjuvant or adjuvant chemotherapy to treatment with a placebo or olaparib for 1 year. A statistically significant improvement in invasive disease–free survival and overall survival was seen in patients in the olaparib arm compared to those in the placebo arm. Therefore, it will be important to assess whether olaparib, as evaluated in the phase III OlympiA trial, was effective at preventing both systemic and CNS recurrences [25,39]. Retrospective analysis of the data may help in hypothesis generation that may pave the way for prospective brain metastasis prevention clinical trials in BRCA-mutated eBC.

In conclusion, gBRCA1 patients and gBRCA non-carriers with recurrent TNBC have similar rates of brain metastasis. Breast cancer cells capable of CNS penetration and progression have increased homologous recombination deficiency, a characteristic intrinsic to BRCA1- and BRCA2-deficient tumors. The efficacy of PARP inhibitors for the treatment and therefore, potential prevention, of CNS recurrence in BRCA-mutated (germline or somatic) breast cancer is largely unknown. The prevalence of current published data, therefore, highlights the urgent need for clinical trials with PARP inhibitors and other effective anti–breast cancer tumor drugs with potential therapeutic CNS penetration in the gBRCA-mutated breast cancer brain metastases, particularly in patients with recurrent TNBC, both in gBRCA1 carriers and noncarriers. Such strategy may eventually lead to the use of such proven effective drugs to be implemented in brain metastasis prevention trials.

1. BRCA1 vs. BRCA2 mutation status confers different clinical characteristics in patients with eBC. In addition to the well-documented, different increased risks of developing bilateral and ovarian cancers, other distinguishing clinical characteristics can be listed when comparing eBC and later development of brain metastasis: Age at the time of diagnosis of eBC was younger in BRCA1 carriers compared to BRCA2 carriers.
2. Most BRCA1 carriers with brain metastasis were more likely to be TN, in contrast to BRCA2 carriers, who mostly had HR-positive/HER-negative tumors.
3. The incidence of brain metastasis is higher for BRCA1 carrier patients compared to that for BRCA2 carriers.
4. The incidence of brain metastasis was not different between BRCA1-carrier tumors and TN non-carrier tumors.
5. Patients with BRCA1 mutations displayed a higher incidence rate of brain metastasis at first metastasis, even compared to patients with TNBC.
6. Survival following brain metastasis was significantly shorter for BRCA1 carriers and non-BRCA carrier patients with TNBC compared to that of the BRCA2 carriers.

However, there was a paucity of data to address brain metastasis clinical outcomes among BRCA2 carriers. Although there were “visual” differences between the BRCA1 carriers and non-BRCA1 carriers, such differences are not necessarily statistically different due to the small number of patients.

Despite the small numbers, given the relatively infrequent observations of patients with BRCA1 or BRCA2 mutations, this is the largest amount of published data to date, to our knowledge, which may be used as a base of data to assess the predilection of metastasis to the brain. Therefore, testing for BRCA status as a routine evaluation may help educate patients and clinicians about the likelihood of developing brain metastasis.

We thank Ashli Nguyen-Villarreal, Associate Scientific Editor, and Sarah Bronson, Scientific Editor, in the Research Medical Library at The University of Texas MD Anderson Cancer Center, for editing this article.

This work is supported by the Sheila Wynne philanthropic research fund.

The author declares no competing financial or non-financial Interests.