BRCA and CDK4/6: allies or antagonists?—efficacy of CDK4/6 inhibitors in HR⁺/HER2⁻ breast cancer with germline BRCA1/2 mutations: a narrative review

Introduction

Breast cancer (BC) remains the most common malignant neoplasm in women worldwide and one of the leading causes of cancer-related mortality in females (1). Within its heterogeneity, the luminal subtype, characterized by the expression of hormone receptor-positive (HR⁺) and the absence of human epidermal growth factor receptor 2-negative (HER2⁻) overexpression, accounts for approximately 70% of diagnosed cases. Over the past two decades, its therapeutic management has seen substantial advances, particularly with the introduction of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), which have significantly improved progression-free survival (PFS) and, in several studies, overall survival (OS) in both early-stage (adjuvant setting) and advanced disease (2-6).

Simultaneously, progress in understanding the molecular biology of BC has enabled the identification of patient subgroups with high-penetrance germline mutations, particularly in the BRCA1 and BRCA2 genes. The incidence of germline BRCA1 and BRCA2 mutations varies significantly by BC subtype. In large unselected cohorts, the overall prevalence of pathogenic BRCA mutations (BRCAm) among BC patients is approximately 5–6% (7-11). However, the incidence of germline BRCAm (gBRCAm) is highly dependent on BC molecular subtype. Triple-negative BC (TNBC) shows the highest incidence, with BRCA1 mutations identified in approximately 8–11% of cases and BRCA2 mutations in 2–3%; notably, TNBC accounts for about 70–75% of BCs occurring in BRCA1 mutation carriers (8-10). In contrast, in estrogen receptor-positive (ER⁺)/HER2⁻ BC, the incidence of BRCA1 mutations is low (generally <2%), whereas BRCA2 mutations are observed in about 2–3% of cases, with BRCA2-associated tumors being predominantly ER⁺ (approximately 76%) (8-10). In HER2-positive (HER2⁺) BC, both BRCA1 and BRCA2 mutations are uncommon, with reported rates generally below 2% (8). Overall, BRCA1 mutations are most prevalent in TNBC, while BRCA2 mutations are more evenly distributed across subtypes but predominate in ER⁺ disease, findings that are consistent across large population-based studies and clinical genetic testing cohorts. This is represented in Figure 1.

Figure 1 Distribution of gBRCAm across BC subtypes. +, positive; −, negative. BC, breast cancer; ER, estrogen receptor; gBRCAm, germline BRCA mutations; gBRCA1m, germline BRCA1 mutations; gBRCA2m, germline BRCA2 mutations; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; PR, progesterone receptor; TNBC, triple-negative breast cancer.

The central role of BRCA1/2, both gBRCAm and somatic BRCAm (sBRCAm), in DNA repair through homologous recombination raises important clinical questions about differential sensitivity to certain treatments. Approximately 20% of BCs in BRCA1 germline mutation carriers and up to 77% in BRCA2 carriers are HR⁺ (12). It is well-established that BRCA1-associated breast tumors, as a group, differ from non-BRCA1 tumors in terms of histological phenotype. BRCA1-mutated tumors tend to be high-grade, with medullary-like features, including high mitotic counts, pushing margins, lymphocytic infiltration, trabecular growth patterns, and necrosis. The tumor phenotype in BRCA2 carriers is less distinct than in BRCA1 carriers. However, immunohistochemical and gene expression analyses have shown that BRCA2 tumors are predominantly luminal B, more likely to be ER⁺, high-grade, with reduced tubule formation and continuous pushing margins (13). Additionally, BRCAm carriers often exhibit a higher cell proliferation index (Ki67) and higher genomic test scores (e.g., Oncotype DX), with over 80% categorized as intermediate or high risk of recurrence (12).

Currently, three CDK4/6i (abemaciclib, palbociclib, and ribociclib) are approved by the United States Food and Drug Administration (FDA) for first-line treatment of HR⁺/HER2⁻ locally advanced BC or metastatic BC (MBC). Abemaciclib and ribociclib are also approved for adjuvant use in high-risk early-stage HR⁺/HER2⁻ disease (14). However, the pivotal clinical trials supporting these indications did not include prespecified subgroup analyses for germline BRCA1/2 mutations (gBRCA1/2m), leaving a lack of robust prospective evidence to guide specific recommendations for this population. In this context, retrospective studies and real-world data suggest that CDK4/6i outcomes may be less favorable in patients with pathogenic BRCAm compared to BRCA wild-type (BRCAwt) carriers (11,12,14). Most published studies and subgroup analyses have not distinguished between germline and somatic BRCA status. One proposed explanation for this reduced efficacy is the presence of concurrent genetic co-alterations, such as retinoblastoma 1 (RB1) mutations, which may interfere with CDK4/6i activity (12). Nevertheless, available evidence remains scarce and often contradictory, making it difficult to draw definitive conclusions about the prognostic and predictive impact of BRCA status in this setting.

Despite these uncertainties, clinical guidelines continue to recommend endocrine therapy combined with CDK4/6i as first-line treatment for HR⁺/HER2⁻ MBC, regardless of BRCA germline status (15). However, the true efficacy of this strategy in gBRCAm carriers has not been adequately characterized. Some retrospective studies report reduced OS and PFS in gBRCA1/2m patients compared to wild-type or untested cases, though findings are inconsistent across studies (7,16,17). This context also highlights a lack of consensus on the sequential positioning of PARPi, underscoring the need for more robust evidence to define their optimal role in the therapeutic algorithm for HR⁺/HER2⁻ MBC patients with BRCAm.

Thus, the objective of this review is to critically analyze available evidence on the efficacy of CDK4/6i in HR⁺/HER2⁻ BC patients with gBRCA1/2m. Additionally, we aim to explore potential biological mechanisms that may explain the reduced efficacy of these agents in this population, with the goal of informing clinical decision-making for a patient subgroup with potentially distinct therapeutic needs. We present this article in accordance with the Narrative Review reporting checklist (available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-46/rc).

Methods

A narrative review was carried out, without a systematic approach. Data was collected through database search using sources from PubMed, Google Scholar, and abstracts from main international congresses [European Society for Medical Oncology (ESMO), American Society of Clinical Oncology (ASCO), and San Antonio Breast Cancer Symposium]. Search was carried out using the free text terms “CDK inhibitors”, “BRCA”, and “breast cancer”. References of all the studies detected were analyzed to detect other manuscripts suitable for the review. The search was initially carried out in April 2025, and a new search was carried out in July to detect new publications if they were available. No timeframe was defined. All studies detected were analyzed to detect data that could possibly be considered in the review, including phase 3 trials, subanalysis of these trials, retrospective, and prospective cohorts. Articles were analyzed independently by two authors (M.F.I. and P.M.), and then the selected ones were presented to all authors, who approved the inclusion. The search strategy is summarized in Table 1.

Prognostic implications of BRCAm in BC

The prognostic impact of BRCAm in BC remains debated. Some cohort studies have found no significant differences in OS between patients with and without BRCAm. However, a meta-analysis of 30 studies involving over 35,000 patients showed a trend toward worse OS in patients with HR⁺/HER2⁻ early and advanced BC, harboring gBRCAm, an effect that was particularly pronounced among BRCA1 mutation carriers and observed across studies evaluating treatments such as PARPi, platinum-based chemotherapy, and CDK4/6i (11,18). Consistently, a study including 1,133 patients reported that carriers of BRCA1/BRCA2 mutations had slightly worse disease-free survival (DFS) and BC-specific survival (BCSS) compared with non-carriers; within the HR⁺ subgroup, relapse occurred 2.3 times more frequently in mutation carriers than in non-carriers [23 of 60 (38.3%) vs. 74 of 445 (16.6%), P<0.001], with a 3.4-fold increased risk of BC-specific mortality [13 of 60 (21.7%) vs. 28 of 445 (6.3%), P<0.001], identifying HR⁺ BC patients with BRCAm as a high-risk population, particularly those harboring BRCA2 mutations (19).

In contrast, the prognosis of mutation carriers with HR-negative (HR⁻) tumors appears comparable to that of non-carriers with HR⁺ disease, suggesting a differential prognostic impact according to HR status. Additional evidence from meta-analyses has shown a decrease in BCSS without significant differences in DFS among gBRCA1/2m carriers (20), as well as a non-significant trend toward worse survival outcomes in this population (21), highlighting the need for further studies to better define the prognostic role of BRCAm across BC subtypes.

Molecular biology of BC and BRCAm

The BRCA1 and BRCA2 proteins play a central role in maintaining genomic stability by facilitating accurate DNA repair through homologous recombination. BRCA1 has an N-terminal RING domain with E3 ubiquitin ligase activity and a C-terminal region involved in double-strand break repair, containing multiple binding sites for phosphoproteins. BRCA2, on the other hand, has an N-terminal transactivation domain and, toward the C-terminus, a DNA-binding domain along with a specific interaction domain for RAD51, a key protein in the homologous recombination process (22-24). Through this interaction, BRCA2 directly regulates RAD51’s function in DNA repair. Loss-of-function (LOF) mutations in BRCA1 or BRCA2, which are widely distributed across both genes, include nonsense mutations, deletions, and insertions, resulting in truncated or inactive proteins that impair their repair function (25). Many of these mutations are located in the C-terminal regions, affecting critical domains for transcriptional activation. Consequently, the functional loss of BRCA1/2 leads to homologous recombination deficiency (HRD), promoting the accumulation of genetic damage and genomic instability, a key event in carcinogenesis (19,22-24,26).

In the context of BRCA-associated BC, it has been suggested that ER⁺ tumors with BRCA1 mutations might be sporadic and not attributable to a functional deficiency of the gene. However, recent studies have shown that most of these tumors exhibit a genomic profile characteristic of “BRCAness”, along with loss of heterozygosity (LOH) of the wild-type BRCA1 allele, suggesting that BRCA1 functional loss actively contributes to their tumorigenesis (27). This genomic profile, which includes specific copy number alterations, is remarkably similar to that seen in ER⁺ tumors with BRCA2 mutations and clearly distinct from that of sporadic ER⁺ tumors. LOH of the wild-type allele is considered the second “hit” required for complete BRCA1 gene silencing in these cases, reinforcing its biological significance. Additionally, BRCA1 promoter methylation has been identified as another mechanism.

BRCA1-type tumors exhibit characteristic and extensive genomic alterations. Genomic analyses reveal a distinct molecular pattern in HRD cancers due to BRCA1 mutations compared to those with BRCA2 mutations and homologous recombination proficiency (28-30). Another prominent feature of BRCA1-type cancers is their high burden of copy number alterations (26). Some studies have begun to describe the molecular differences associated with BRCA1-related HRD, noting that these cancers tend to have a higher mutational burden and specific mutational signatures (28,31,32).

gBRCAm and sBRCAm share similar molecular features in BC. Both types of mutations frequently involve the same inactivating alterations, such as frameshift deletions, single-nucleotide variations, or deletions in exon 11, and exhibit comparably high rates of biallelic inactivation (33,34). These mutations are largely mutually exclusive within individual tumors, underscoring their convergent role in tumorigenesis (34). Functionally, BRCA-mutated tumors, regardless of germline or somatic origin, display HRD phenotypes, including high genomic instability, genome-wide LOH, telomeric imbalance, and large-scale chromosomal alterations (35). This pattern of biallelic BRCA loss and HRD is also observed in BRCA-mutated ovarian cancers, indicating that homologous recombination repair (HRR) deficiency is a consistent outcome of BRCAm, independent of its origin (36). The data are detailed in Figure 2.

Figure 2 Molecular biology of BC and BRCAm. BC, breast cancer; BCCR, breast cancer cluster region; BRCAm, BRCA mutations; BRCT, BRCA1 C-terminal domains; NLS, nuclear localization signals; OB, oligonucleotide/oligosaccharide-binding; OCCR, ovarian cancer cluster region; PCCR, prostate cancer cluster region; RING, really interesting new gene domain; TAD, transactivation domain; TR2, tumor supressor regulator 2 in the C-terminal region of BRCA2.

From a clinical and pathological perspective, BRCA-mutated tumors have distinct features. Tumors with gBRCA2m may show greater lymph node involvement, which could increase the risk of recurrence. Histologically, most BRCA-mutated BCs are invasive ductal carcinomas. Invasive lobular carcinoma is less common, observed in approximately 1% of patients with BRCA1 mutations and 7% of those with BRCA2 mutations (11).

From a therapeutic standpoint, DNA repair deficiencies caused by BRCAm present an attractive target for precision therapies. In HER2⁻ locally advanced BC or MBC with gBRCAm, PARPi have demonstrated significant efficacy (11). The approvals of olaparib and talazoparib as monotherapies were based on the phase III OlympiAD (37) and EMBRACA (38) trials, respectively. Both randomized, multicenter trials showed significantly longer PFS with PARPi compared to physician’s choice of standard therapy, though without significant differences in OS, possibly due to subsequent therapies after progression. Neither of the studies has shown an interaction regarding hormonal receptor status, understanding that the benefit is independent of the phenotype. Even more, objective response rates (ORRs) were similar in patients according to HR status. For example, in the OlympiAD trial, ORR was 65.4% in HR⁺ and 54.7% in HR⁻ patients. An exploratory subgroup analysis of the OlympiAD trial suggested a greater OS benefit with olaparib in the first-line setting, highlighting the importance of timing in administering these agents (39,40). While no direct comparisons exist between olaparib and talazoparib, indirect analyses suggest comparable efficacy in PFS, with slightly different toxicity profiles. Additionally, the phase III BROCADE trial evaluated veliparib in combination with carboplatin-paclitaxel in HER2⁻ BC patients with gBRCAm, showing improved PFS compared to placebo, particularly in patients without prior chemotherapy for metastatic disease (41).

Another relevant strategy for patients with HR⁺/HER2⁻ MBC and gBRCAm is platinum-based chemotherapy (cisplatin or carboplatin). Results from the phase III TNT trial suggest that gBRCAm may predict greater sensitivity to carboplatin compared to docetaxel, making platinum-based therapy a preferred option, especially in unresectable recurrent or metastatic TNBC with gBRCAm (42).

Collectively, advances in targeted therapies exploiting DNA repair deficiencies have transformed the management of BC with gBRCAm, offering new options that improve disease control.

Mechanism of action of CDK4/6i and its clinical relevance

The regulation of the cell cycle is essential for tissue homeostasis, allowing controlled replacement of damaged or aging cells while preventing excessive proliferation and tumor development. In adult tissues, many cells remain in a resting state (G0), either temporarily (quiescence) or permanently (senescence). However, external signals like growth factors or hormones can reactivate their proliferative capacity. The cell cycle consists of distinct phases: G0/G1, S (DNA synthesis), G2, and M (mitosis), with critical checkpoints at G1 and G2 ensuring genomic replication fidelity.

A crucial step in the G1-to-S transition is mediated by complexes formed between D-type cyclins (D1, D2, and D3) and CDK4/6. Mitogenic signals activate genes like CCND1, CCND2, and CCND3, increasing cyclin D production. These cyclins bind CDK4/6 to form active complexes that phosphorylate the retinoblastoma protein (pRb). Normally, pRb inhibits cell cycle progression by binding and inactivating E2F transcription factors. Phosphorylation by CDK4/6 releases E2F, allowing transcription of S-phase genes, including cyclin E (CCNE1 and CCNE2) and DNA replication proteins. Beyond kinase activity, D-cyclins and CDK6 also modulate transcription through interactions with HRs like ER and androgen receptor (AR), potentially contributing to CDK4/6i resistance (43,44).

CDK4/6i (palbociclib, ribociclib, abemaciclib) block pRb phosphorylation, restoring its tumor-suppressive function and arresting the cell cycle in G1. This mechanism is particularly relevant in luminal BC, where ER activation drives cyclin D expression and CDK4/6 pathway hyperactivity. Clinically, combining CDK4/6i with endocrine therapy significantly improves PFS and, in some studies, OS in HR⁺/HER2⁻ MBC.

The gBRCAm are associated with primary resistance to endocrine therapy. While most luminal BRCA-mutated cancers involve BRCA2, emerging evidence links BRCA1 mutations to endocrine resistance as well. HR⁺ tumors with BRCA1 mutations often show luminal B features, higher proliferation rates, and increased distant metastasis compared to BRCA1 wild-type tumors (14).

BRCA1 interacts directly with ERα signaling. Its RING domain (with E3 ubiquitin ligase activity) promotes ER degradation via ubiquitination, particularly when complexed with BARD1. BRCA1 mutations disrupt this inhibition, enhancing ER activity. Similarly, BRCA1/BARD1 mediates progesterone receptor (PR) degradation, and BRCAm may increase PR expression. BRCA1 also regulates ERα acetylation by inhibiting p300 expression, and wild-type BRCA1 suppresses aromatase, reducing estrogen levels. BRCA1 mutations increase aromatase expression and plasma estrogen levels by up to 30%, amplifying estrogenic signaling (19). About 90% of BRCA1-mutated BCs are HR⁻, likely due to ERα loss from impaired BRCA1-mediated transcriptional activation and a shift toward basal-like phenotype. In HR⁺ models, BRCA1 deficiency causes resistance to selective ER degraders like fulvestrant (14).

The efficacy of CDK4/6i is intrinsically linked to the integrity of the RB1 pathway. However, the functional state of the HRR machinery, governed by BRCA1/2, significantly influences this axis through several interconnected mechanisms. BRCA1, beyond its canonical role in DNA double-strand break repair, is a critical regulator of the G1/S checkpoint. Wild-type BRCA1 facilitates G1 arrest in response to DNA damage by promoting the expression and stabilization of p21 (CDKN1A), a potent CDK inhibitor (14,19,45). This p21 induction helps maintain RB1 in its active, hypophosphorylated state, thereby enforcing cell-cycle arrest. In cells with BRCA1/2 LOF mutations, this damage-induced p21 response is attenuated, leading to compromised G1 checkpoint control and a reliance on alternative mechanisms for cell-cycle arrest, such as direct CDK4/6 inhibition. BRCA1 also interacts with AKT as a negative regulator; BRCA1 loss causes PI3K/AKT hyperactivation, promoting resistance to both endocrine therapy and CDK4/6i (14,19).

BRCAm frequently co-occur with TP53 mutations as the enrichment of TP53 alterations in germline BRCA1 carriers is robustly validated (46). Genomic instability from BRCA defects increases TP53 mutation likelihood, a common feature in CDK4/6i-resistant HR⁺/HER2⁻ BC, associated with poor outcomes (14).

A pivotal point of convergence is the frequent co-alteration of RB1 and BRCA2, which are located in close proximity on chromosome 13q. LOH events targeting the BRCA2 locus often encompass the RB1 gene. Consequently, a significant proportion of tumors with gBRCA2m exhibit concurrent RB1 LOH (46,47). In patients who underwent germline and matched tumor tissue sequencing using MSK-IMPACT, co-occurrence of BRCA2 and RB1 LOH was observed in 84% of germline BRCA2 tumors (46). Since functional RB1 is the essential target of CDK4/6i, its loss renders these agents ineffective (44,48). This molecular linkage provides a direct explanation for the observed clinical resistance to CDK4/6i in many BRCA2-mutated, HR⁺ BCs. Genomic analysis of paired pre- and post-disease progression demonstrated that acquisition of somatic RB1 LOF alteration was significantly more prevalent in germline BRCA2-associated tumors vs. germline BRCA2 wild-type tumors (31.6% vs. 4.5%) (46). The selective evolutionary pressure for RB1 LOF mutations of CDK4/6i-based combinations serves as evidence of it as a dominant mechanism of CDK4/6i resistance in these germline BRCA2 tumors.

Resistance in HR⁺ gBRCAm BC involves multiple mechanisms: altered ERα function, disrupted cell cycle/apoptosis regulation, PI3K/AKT hyperactivation, TP53 mutations, and RB1 LOH—creating an aggressive, treatment-resistant profile requiring personalized approaches (14,48-50). Possible mechanisms of resistance to CDK4/6i are summarized in Figure 3.

Figure 3 Potential mechanisms underlying reduced CDK4/6i efficacy in BRCA-mutated tumors. BRCA1m, BRCA1 mutation; BRCA2m, BRCA2 mutation; CDK4/6, cyclin-dependent kinase 4/6; CDK4/6i, cyclin-dependent kinase 4/6 inhibitor; ERα, estrogen receptor α; LOH, loss of heterozygosity; RB1, retinoblastoma 1.

However, some gBRCAm cases may respond well to CDK4/6i (45). The rationale lies in BRCA-ER-CDK interactions: functional BRCA1 inhibits ERα via estrogen-independent mechanisms, acetylation regulation, and aromatase suppression. Mutations disable these controls, potentially increasing endocrine sensitivity. BRCA1 also promotes G1 arrest via p21 and hypophosphorylated RB; mutations disrupt this, making CDK4/6 inhibition particularly relevant. Furthermore, the HRR process itself is cell-cycle phase-dependent, being most active in the S and G2 phases when a sister chromatid template is available (22,23,25). The activity of CDK4/6 itself can modulate HRR efficiency. CDK-dependent phosphorylation of key HRR proteins, including BRCA1 and BRCA2, is required for their proper localization and function at DNA damage sites. Inhibition of CDK4/6 may therefore impair the phosphorylation and activity of residual BRCA proteins in heterozygous or functionally impaired cells, creating a synthetic lethal interaction (45,51,52). CDK4/6i may also suppress HR factors like RAD51, creating synthetic lethality in BRCA-deficient cells. This supports exploring combination strategies with PARPi to exploit these vulnerabilities.

In summary, the pathways governing DNA repair fidelity and cell-cycle progression are not parallel but deeply integrated. Mutations in BRCA1/2 disrupt this integration, leading to aberrant cell-cycle progression, compromised DNA repair, and altered dependencies that ultimately influence the therapeutic efficacy of CDK4/6i (14,19,45-47).

Clinical evidence of the use CDK4/6i in BRCAm BC

A growing body of evidence from real-world clinical studies suggests that patients with gBRCAm may experience less favorable outcomes when treated with CDK4/6i (7,53). Data of all the studies is included in Table 2. For instance, an analysis of 1,097 BC patients treated with CDK4/6i at Memorial Sloan Kettering Cancer Center (including 533 in first-line therapy) revealed that germline BRCA2 pathogenic variants were significantly associated with worse PFS in both univariate and multivariate analyses [median PFS 9.0 vs. 13.7 months; multivariate hazard ratio =2.28; 95% confidence interval (CI): 1.52–3.39; P=4.9×10⁻⁵] (46). Similar results were observed across all treatment lines when accounting for endocrine therapy partner and treatment line as covariates (hazard ratio =2.02; 95% CI: 1.52–2.70; P=1.5×10⁻⁶). Data from 859 patients in the Flatiron Health database (United States) with available germline BRCA status showed that those with HR⁺/HER2⁻ MBC and gBRCAm had a shorter time to next treatment or death compared to non-carriers.

Multiple retrospective studies evaluating HR⁺/HER2⁻ MBC patients treated with CDK4/6i plus endocrine therapy consistently found that pathogenic germline variants in DNA repair genes (including BRCA1, BRCA2, either alone or in combination with other genes like PALB2) were independently associated with inferior PFS and OS (7,59). An Argentine retrospective study from Instituto Alexander Fleming involving 508 advanced HR⁺/HER2⁻ patients treated with CDK4/6i plus endocrine therapy demonstrated worse PFS and OS in carriers of germline pathogenic variants in DNA repair genes (BRCA1/2, ATM, and CHEK2), even after adjusting for age, menopausal status, and prior treatments (7). A possible selection bias was noted in the untested subgroup, which showed better PFS.

Similar findings emerged from French real-world data [Epidemiological Strategy and Medical Economics (ESME) platform] (57), which included 170 gBRCAm patients, 676 germline BRCAwt (gBRCAwt), and over 12,000 untested cases, reinforcing the hypothesis of reduced CDK4/6i benefit in gBRCAm carriers. A recent analysis restricted to first-line CDK4/6i use in patients with germline BRCA and PALB2 mutations in the same platform showed inferior PFS but no significant OS difference compared to those without alterations (58).

Circulating tumor DNA (ctDNA) analysis from the MONALEESA trials with ribociclib demonstrated that among patients receiving ≤1 prior line of endocrine therapy for metastatic disease, median PFS was 14.6 months with ribociclib vs. 8.1 months with placebo in BRCA1/2-altered patients (hazard ratio =0.38; 95% CI: 0.19–0.76), compared to 18.8 vs. 11.1 months (hazard ratio =0.58; 95% CI: 0.49–0.68) in BRCA1/2 wild-type patients (54). Ribociclib showed benefit regardless of BRCA2 status. Additionally, an exploratory analysis from the phase III PADA-1 trial reported that patients with pathogenic germline variants in BRCA1, BRCA2, or PALB2 had significantly shorter median PFS with aromatase inhibitor plus palbociclib (14.3 months) vs. gBRCAwt patients (26.7 months), suggesting reduced CDK4/6i efficacy in these subgroups (hazard ratio =0.58; P=0.056) (56).

In the early-stage setting, data on adjuvant CDK4/6i efficacy in gBRCAm patients remains limited. However, whole exome sequencing data from the monarchE trial showed that among 41 patients (3.5% of sequenced cohort) with gBRCAm (20 receiving abemaciclib + endocrine therapy, 21 endocrine therapy alone), only 1 (5%) in the abemaciclib arm experienced relapse vs. 9 (42.8%) in the endocrine therapy-only arm (62). While the small sample size precludes definitive conclusions, the relapse rate was numerically lower than in BRCAwt patients (21.8% with combination therapy).

Therapeutic considerations

Early identification of patients with gBRCAm is crucial for oncologists to select the most appropriate treatment regimen and maximize clinical outcomes. Knowledge of mutational status is not only essential for guiding surgical decisions with a risk-reduction approach but also directly impacts the choice of systemic therapy.

For early-stage HR⁺/HER2⁻ BC with BRCAm, current medical literature does not address a specific treatment sequence. However, standard management based on guidelines from the ESMO (63) and ASCO (64) recommends following established protocols for HR⁺/HER2⁻ disease, with adjuvant endocrine therapy as the mainstay and chemotherapy considered based on tumor biology along with clinical and genomic risk factors (65). The addition of CDK4/6i to adjuvant endocrine therapy is now an option per the latest guidelines for selected high-risk patients, as supported by the monarchE trial (5) and NATALEE trial (6). MonarchE trial (5) which included stage II–III HR⁺/HER2⁻ patients with ≥4 positive nodes or 1–3 positive nodes plus additional high-risk features, showed a 7.6% absolute improvement in 5-year invasive DFS (IDFS) with abemaciclib vs. endocrine therapy alone (hazard ratio =0.68; 95% CI: 0.60–0.77) and NATALEE trial (6) demonstrated a 3.3% absolute 3-year IDFS benefit with adjuvant ribociclib (hazard ratio =0.75; 95% CI: 0.62–0.91) in a broader stage II–III population, expanding treatment eligibility.

For very high-risk HR⁺/HER2⁻ patients with gBRCAm {≥4 positive nodes or insufficient neoadjuvant chemotherapy response [clinical and pathological stage (CPS) + estrogen receptor status and histologic grade (EG) score ≥3]}, the OlympiA trial established adjuvant olaparib as the preferred option over CDK4/6i due to demonstrated survival benefit, though shared decision-making is recommended for high-risk patients outside these criteria (66). Current ASCO guidelines prioritize adjuvant olaparib over CDK4/6i in this population, given OlympiA results and uncertainty about CDK4/6i efficacy in BRCA-mutated cases (64). Sequential therapy (CDK4/6i after olaparib) remains investigational, though monarchE and NATALEE allow late initiation (up to 16 and 12 months post-surgery, respectively), suggesting this may be an option for very high-risk patients (64).

In advanced/metastatic HR⁺/HER2⁻ disease with BRCAm, both ASCO (67) and ESMO (15) guidelines recommend first-line endocrine therapy plus CDK4/6i for most patients. While PFS with CDK4/6i appears shorter in gBRCAm vs. wild-type BRCA, the combination still outperforms endocrine therapy alone in both adjuvant and metastatic settings.

Following progression or endocrine resistance, gBRCAm patients may benefit from PARPi (olaparib or talazoparib), which have shown favorable efficacy and toxicity profiles compared to chemotherapy (15,68). If this strategy should be used before CDK4/6i is not supported by clinical evidence at the moment.

Beyond endocrine-based strategies, chemotherapy combined with PARP inhibition has also been evaluated in gBRCAm disease. In the phase III BROCADE3 trial, veliparib added to carboplatin and paclitaxel, and continued as monotherapy after chemotherapy discontinuation, significantly improved PFS in patients with HER2⁻ advanced BC/MBC and gBRCAm (69). A preplanned subgroup analysis focusing on patients without prior cytotoxic therapy for metastatic disease (81% of the study population) demonstrated a 30% reduction in the risk of progression, with median PFS increasing from 13.1 to 16.6 months and a more than twofold improvement in 3-year PFS rates (27.9% vs. 13%). OS exceeded 2 years in both arms and was numerically longer with veliparib (36.0 vs. 29.9 months). With response rates approaching 80% and a manageable toxicity profile, this induction-plus-maintenance strategy suggests that combining platinum chemotherapy with iPARP may provide durable disease control when used in earlier therapeutic lines for patients with advanced/metastatic gBRCAm BC when chemotherapy is indicated.

Antibody-drug conjugates like trastuzumab-deruxtecan (T-DXd) and sacituzumab-govitecan (SG) are emerging options for pretreated metastatic HR⁺/HER2⁻ disease, though their specific role in BRCA-mutated cancer remains undefined (70). Recent data presented in ASCO Annual meeting 2025 of an exploratory biomarker analysis of T-DXd vs. physician’s choice of chemotherapy in HER2-low/ultralow, HR⁺ mBC in DESTINY-Breast06 showed an increased benefit of this strategy with PFS of 21.4 vs. 5.6 months in BRCA1/2 patients (71). This information still needs to be analyzed cautiously to acquire proper understanding. In Tropics-02 trial, biomarker analysis evidence that patients who had tumors with deficiency in the DNA damage repair (DDR) pathway, their magnitude of benefit was higher with sacituzumab govitecan as compared to those patients who didn’t have tumors with damage in this pathway (hazard ratio =0.61 in patients with DDR mutated genes vs. hazard ratio =0.76), suggesting possible synergy between DDR pathway and SG anti-tumor effect (72).

Treatment selection should be continuously individualized based on prior therapies, comorbidities, patient preferences, and ongoing molecular profiling. In metastatic settings, gBRCAm status guides choices between CDK4/6i, platinum- or taxane-based chemotherapy, and timely PARPi use when appropriate, while also enabling risk-stratified family screening (11).

Beyond BRCAm, other biomarkers may influence treatment response. The efficacy of PARPi and platinum chemotherapy in HRD-positive patients without gBRCAm or with sBRCAm is under investigation. The TBCRC 048 trial (73) showed high ORR and PFS with olaparib in PALB2 mutation carriers and sBRCAm patients, while the RUBY trial (74) suggests PARPi benefit in some HRD-positive, non-BRCA-mutated cases.

Future challenges

The development of resistance to CDK4/6i represents one of the main challenges in treating HR⁺/HER2⁻ MBC, particularly in patients with gBRCAm. To overcome this resistance and enhance the efficacy of PARPi, various studies are exploring combination therapies with other agents.

Early-phase clinical trials have reported promising results when combining olaparib or niraparib with immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) in MBC patients with gBRCAm. For example, the MEDIOLA study demonstrated that olaparib plus durvalumab achieved an 80% disease control rate at 12 weeks in gBRCAm MBC, though the trial lacked an olaparib-only control arm (75).

In early-stage disease, ongoing trials evaluating PARPi-immunotherapy combinations also show encouraging data. The OlympiaN trial, for instance, tailors neoadjuvant therapy based on risk in ER-negative or ER-low cases, offering olaparib monotherapy to patients with lower tumor burden, while higher-risk patients receive olaparib plus durvalumab. Other studies are assessing olaparib plus pembrolizumab in different neoadjuvant and adjuvant settings, as well as niraparib combined with dostarlimab (76).

Another area of investigation focuses on combining CDK and PARPi. Early benefits have been observed with dinaciclib (which inhibits multiple CDKs, including 1, 2, 5, 9, and 12) plus veliparib in BC models (77). Inhibition of CDK12, CDK1, or CDK2 in BRCAwt cells induces functional HRD, increasing susceptibility to PARPi (45,51,52). Several ongoing trials aim to improve treatment efficacy in HR⁺/HER2⁻ MBC with gBRCAm. The HOPE study, which assessed olaparib, palbociclib, and fulvestrant, was discontinued due to significant myelosuppressive toxicity (78). In contrast, the EvoPAR-BR01 trial is comparing the selective PARP1 inhibitor saruparib (AZD5305) plus camizestrant (an oral selective ER degrader) vs. physician’s choice of CDK4/6i plus endocrine therapy or camizestrant alone. The goal is to determine which strategy provides superior PFS as first-line treatment in this specific patient population.

Conclusions

Analysis of current literature and clinical studies demonstrates that early identification of gBRCAm is crucial for optimizing the therapeutic management of BC, particularly in subgroups with metastatic HR⁺/HER2⁻ disease. Molecular characterization enables personalized surgical and pharmacological strategies, facilitating the appropriate selection of platinum-based chemotherapy and the timely use of PARPi, which positively impacts patient survival and quality of life.

Additionally, the recognition of other biomarkers, such as PD-L1 expression and HRD, expands the pool of patients eligible for combined targeted therapies. However, prospective studies are still needed to clearly define their predictive value and role in clinical practice. Future challenges include gaining a deeper understanding of the molecular mechanisms of resistance to CDK4/6i and PARPi, driving the development of combination regimens with immunomodulatory agents, selective PARP1 inhibitors, and next-generation endocrine therapies. Determining the optimal sequencing and combination of these therapies, as well as implementing new biomarker-driven monitoring strategies, are key research priorities.

It is recommended to strengthen the integration of advanced genomic testing into routine clinical practice for better treatment selection, promote clinical trials evaluating innovative combinations, and conduct quality-of-life studies to guide the most appropriate treatment choice for each patient. Future research should focus on identifying robust biomarkers that predict response and resistance, as well as designing personalized protocols that maximize clinical benefit while minimizing toxicity.

In summary, a multidisciplinary approach incorporating genomics and targeted therapies represents the path towards sustained improvements in outcomes for BRCA-mutated BC patients, with a special emphasis on continuously adapting strategies in response to emerging therapeutic resistance.

Acknowledgments

None.

Footnote

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Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-46/coif). The authors have no conflicts of interest to declare.

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