The Homologous Recombination Deficiency Scar in Advanced Cancer: Agnostic Targeting of Damaged DNA Repair

SIMPLE SUMMARY: Tumor-suppressor genes are involved in DNA break repair through the homologous recombination system and are widely known for their role in hereditary cancer. Beyond breast and ovarian cancer, prostate and pancreatic cancer also have targetable homologous recombination deficiency (HRD) beyond the well-known BRCA1 and BRCA2 with relevance that exceeds diagnostic purposes. In this review, we aim to summarize the roles of HRD across tumor types and the treatment landscape to guide the targeting of damaged DNA repair based on the cancer’s genetic features. ABSTRACT: BRCA1 and BRCA2 are the most recognized tumor-suppressor genes involved in double-strand DNA break repair through the homologous recombination (HR) system. Widely known for its role in hereditary cancer, HR deficiency (HRD) has turned out to be critical beyond breast and ovarian cancer: for prostate and pancreatic cancer also. The relevance for the identification of these patients exceeds diagnostic purposes, since results published from clinical trials with poly-ADP ribose polymerase (PARP) inhibitors (PARPi) have shown how this type of targeted therapy can modify the long-term evolution of patients with HRD. Somatic aberrations in other HRD pathway genes, but also indirect genomic instability as a sign of this DNA repair impairment (known as HRD scar), have been reported to be relevant events that lead to more frequently than expected HR loss of function in several tumor types, and should therefore be included in the current diagnostic and therapeutic algorithm. However, the optimal strategy to identify HRD and potential PARPi responders in cancer remains undefined. In this review, we summarize the role and prevalence of HRD across tumor types and the current treatment landscape to guide the agnostic targeting of damaged DNA repair. We also discuss the challenge of testing patients and provide a special insight for new strategies to select patients who benefit from PARPi due to HRD scarring.