Genomic Features of Homologous Recombination Deficiency in Breast Cancer: Impact on Testing and Immunotherapy

Simple Summary Cancer is the second most common cause of death in the USA. Genomic instability is one of the well-established hallmarks of cancer. The homologous recombination repair (HRR) pathway plays a critical role in correcting the double-stranded breaks due to DNA damage. Conventionally, BRCA1/2 genes, which are part of the HRR pathway, have been utilized for testing in breast cancer patients. Nonetheless, other genes in the HRR pathway, such as the RAD51c, PALB2, BRIP1, and BARD1 gene defects, have also been shown to impact breast cancer progression and outcomes. In this communication, we review the impact of the HRR pathway in breast cancer and examine various clinical trials that study the role of HRR genetic testing on treatment outcomes.Abstract Genomic instability is one of the well-established hallmarks of cancer. The homologous recombination repair (HRR) pathway plays a critical role in correcting the double-stranded breaks (DSB) due to DNA damage in human cells. Traditionally, the BRCA1/2 genes in the HRR pathway have been tested for their association with breast cancer. However, defects in the HRR pathway (HRD, also termed 'BRCAness'), which has up to 50 genes, have been shown to be involved in tumorigenesis and treatment susceptibility to poly-ADP ribose polymerase inhibitors (PARPis), platinum-based chemotherapy, and immune checkpoint inhibitors (ICIs). A reliable consensus on HRD scores is yet to be established. Emerging evidence suggests that only a subset of breast cancer patients benefit from ICI-based immunotherapy. Currently, albeit with limitations, the expression of programmed death-ligand 1 (PDL1) and tumor mutational burden (TMB) are utilized as biomarkers to predict the favorable outcomes of ICI therapy in breast cancer patients. Preclinical studies demonstrate an interplay between the HRR pathway and PDL1 expression. In this review, we outline the current understanding of the role of HRD in genomic instability leading to breast tumorigenesis and delineate outcomes from various clinical trials. Furthermore, we discuss potential strategies for combining HRD-targeted therapy with immunotherapy to achieve the best healthcare outcomes in breast cancer patients.