Prevalence of Homologous Recombination Pathway Gene Mutations in Melanoma: Rationale for a New Targeted Therapeutic Approach.

Abstract Homologous recombination DNA-damage repair (HR-DDR) deficiency has been used to treat patients with various solid tumors with poly(ADP-ribose) polymerase inhibitors (PARPi). However, the clinical characteristics of melanoma patients with HR-DDR gene mutations, and the consequences of PARP inhibition, are poorly understood. We compared commercially-available next-generation sequencing data from 84 melanomas from our institution with a dataset of 1,986 patients, as well as 1,088 patients profiled in cBioportal. 21.4% of patients had ≥1 functional HR-DDR mutation, most commonly involving BRCA1, ARID1A, ATM, ATR, and FANCA. Concurrent NF1, BRAF, and NRAS mutations were found in 39%, 39% and 22% of cases, respectively. HR-DDR gene mutation was associated with high tumor mutational burden (TMB) and clinical response to checkpoint blockade. A higher prevalence of HR-DDR mutations was observed in datasets from Foundation Medicine and TCGA. Treatment of HR-DDR-mutated patient-derived xenograft models of melanoma with PARPi produced significant anti-tumor activity in vivo, and was associated with increased apoptotic activity. RNA sequencing analysis of PARPi-treated tumors indicated alterations in pathways involving extracellular matrix remodeling, cell adhesion and cell cycle progression. Melanomas with HR-DDR mutations represent a unique subset, which are more likely to benefit from checkpoint blockade, and may be targeted with PARPi.