Therapeutic implications of germline vulnerabilities in DNA repair for precision oncology. (March 2022) - Shah, Shreya M.
Highlights: Growing appreciation that germline variation in DNA repair predicts response to multiple therapeutic strategies. Germline testing has identified clinically actionable variants in multiple DNA repair genes. Increasing evidence that genetic testing can benefit patients who do not meet current guidelines for testing, implications for population testing and benefit for treatment decision. Multiple preclinical and clinical studies are evaluating the therapeutic implications of germline variants in additional DNA repair genes or genes that regulate DNA repair pathways. Abstract: DNA repair vulnerabilities are present in a significant proportion of cancers. Specifically, germline alterations in DNA repair not only increase cancer risk but are associated with treatment response and clinical outcomes. The therapeutic landscape of cancer has rapidly evolved with the FDA approval of therapies that specifically target DNA repair vulnerabilities. The clinical success of synthetic lethality between BRCA deficiency and poly(ADP-ribose) polymerase (PARP) inhibition has been truly revolutionary. Defective mismatch repair has been validated as a predictor of response to immune checkpoint blockade associated with durable responses and long-term benefit in many cancer patients. Advances in next generation sequencing technologies and their decreasing cost have supported increased genetic profiling of tumors coupled with germline testing of cancer risk genes in patients. The clinical adoption of panel testing for germline assessment in high-risk individuals has generated a plethora of genetic data, particularly on DNA repair genes. Here, we highlight the therapeutic relevance of germline aberrations in DNA repair to identify patients eligible for precision treatments such as PARP inhibitors (PARPis), immune checkpoint blockade, chemotherapy, radiation therapy and combined treatment. We also discuss emerging mechanisms that regulate DNA repair.