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.

Abstract

Background and objective: Breast cancer (BC) remains the most prevalent malignancy in women globally, with hormone receptor-positive (HR⁺)/human epidermal growth factor receptor 2-negative (HER2^-) tumors representing approximately 70% of cases. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have revolutionized treatment for this subtype, significantly improving progression-free survival (PFS) and overall survival (OS). However, emerging evidence suggests that patients with germline BRCA mutations (gBRCAm) may derive less benefit from CDK4/6i due to molecular alterations such as retinoblastoma 1 (RB1) gene loss and endocrine resistance mechanisms. This review critically evaluates the efficacy of CDK4/6i in gBRCAm HR⁺/HER2^- BC, explores underlying biological mechanisms of resistance, and aims to guide clinical decision-making for this distinct subgroup.

Methods: A narrative review was conducted using PubMed, Google Scholar, and abstracts from major oncology congresses [European Society for Medical Oncology (ESMO), American Society of Clinical Oncology (ASCO), and San Antonio Breast Cancer Symposium]. The search employed terms including "CDK inhibitors", "BRCA", and "breast cancer", with no restriction on publication date. References from identified studies were screened for additional relevant literature. Two authors independently selected studies, including phase III trials, subgroup analyses, and real-world evidence, with final inclusion determined by consensus.

Key content and findings: The review synthesizes data from retrospective studies and clinical trials, revealing consistent trends of shorter PFS and OS in gBRCAm patients treated with CDK4/6i compared to wild-type counterparts. Key mechanisms implicated include co-occurring RB1 alterations, PI3K/AKT hyperactivation, and disrupted cell-cycle regulation. The review also discusses therapeutic sequencing in gBRCAm patients, new treatment alternatives with their implications in this specific population, and highlights ongoing trials exploring combination strategies to overcome resistance.

Conclusions: This review underscores the need for prospective studies to clarify the prognostic and predictive role of gBRCAm in CDK4/6i-treated HR⁺/HER2^- BC. Current evidence supports routine BRCA testing to inform therapeutic sequencing, with poly(ADP-ribose) polymerase inhibitors (PARPis) prioritized in high-risk early-stage and metastatic settings. Future research should focus on biomarker-driven strategies, including combinations to optimize outcomes. These insights may refine clinical guidelines, advocate for personalized treatment algorithms, and stimulate research into resistance mechanisms, ultimately improving care for BRCA-mutated BC patients.