Title : Beyond BRCA: Challenges in defining clinically actionable homologous recombination deficiency in breast cancer

Background: Homologous recombination deficiency (HRD) is an established predictive biomarker for sensitivity to DNA damage response-targeted therapies, particularly PARP inhibitors. While germline BRCA1/2 alterations represent the best-characterised HRD-associated events, increasing evidence suggests that clinically relevant HRD extends beyond BRCA mutations. However, the identification of patients with actionable non-BRCA HRD remains challenging, limiting the broader implementation of precision oncology strategies.

Methods: A narrative review of recent translational and clinical literature was conducted to evaluate emerging approaches to HRD assessment beyond BRCA alterations in breast cancer. Key themes included genomic scar assays, functional HRD testing, homologous recombination repair gene alterations, and implications for therapeutic decision-making.

Results: HRD represents a biologically heterogeneous phenotype involving multiple homologous recombination repair pathway genes, including PALB2, RAD51C, RAD51D, ATM, and others. Current genomic scar-based assays demonstrate predictive potential but may incompletely reflect dynamic tumour biology and acquired resistance mechanisms. Functional approaches, including RAD51-based assays, have emerged as promising complementary strategies for assessing real-time homologous recombination competency. Despite advances in molecular characterisation, significant challenges remain regarding assay standardisation, biomarker concordance, tumour heterogeneity, and the translation of HRD status into consistent therapeutic benefit.

Conclusions: The expanding landscape of HRD beyond BRCA offers important opportunities to refine patient selection for targeted therapies in breast cancer. Future precision oncology strategies will likely require integration of genomic, functional, and longitudinal biomarker approaches to improve identification of clinically actionable HRD and optimise therapeutic decision-making.

Dr Abu Saleh Md Taher is a Medical Oncology Specialist Registrar at The Royal Marsden NHS Foundation Trust and an MD(Res) candidate at The Institute of Cancer Research. His research focuses on breast cancer, precision oncology, and treatment optimisation, with particular interests in biomarker development, real-world evidence, and clinical trial methodology. He is passionate about translating scientific discoveries into improved patient care.