Germline Mutations as Cancer Drug Targets

Hereditary cancer syndromes are associated with causative pathogenic variants and clinical pathologies. Therapeutic advances have provided proof-of-concept for the actionability of the germline, whereas epidemiologic studies have identified pathogenic germline variants across tumor types regardless of hereditary syndromes. Drug development advances in synthetic lethal approaches, immunotherapeutics, cancer vaccines, and other strategies have led to regulatory approval of multiple agents, supporting the incorporation of universal germline testing. We review the current landscape of germline mutations as cancer drug targets, compare available clinical diagnostics, discuss the development of promising antitumor agents, and envision the future of universal germline testing in cancer medicine.

Recent studies have led to the development of novel therapeutic strategies that are redefining germline BRCA1/2, MSH2, VHL, and other alterations as therapeutically actionable. The current cost-effectiveness of high-throughput germline testing has now made it feasible to consider universal germline testing for all patients with cancer, which will ease access to an increasingly large and effective therapeutic portfolio.