RAD51 as a functional biomarker for homologous recombination deficiency in cancer: a promising addition to the HRD toolbox?

Introduction: Carcinomas with defects in the homologous recombination (HR) pathway are sensitive to PARP inhibitors (PARPi). A robust method to identify HR-deficient (HRD) carcinomas is therefore of utmost clinical importance. Currently, available DNA-based HRD tests either scan HR-related genes such as and for the presence of pathogenic variants or identify HRD-related genomic scars or mutational signatures by using whole-exome or whole-genome sequencing data. As an alternative to DNA-based HRD tests, functional HRD tests have been developed that assess the actual ability of tumors to accumulate RAD51 protein at DNA double-strand breaks as a proxy for HR proficiency.

Areas Covered: This review presents an overview of currently available HRD tests and discusses the pros and cons of the different methodologies including their sensitivity for the identification of HRD tumors, their concordance with other HRD tests, and their capacity to predict therapy response.

Expert Opinion: With the increasing use of PARPi in the treatment of several cancers, there is an urgent need to implement HRD testing in routine clinical practice. To this end, calibration of HRD thresholds and clinical validation of both DNA-based and RAD51-based HRD tests should have top-priority in the coming years.