Abstract 320: Frequency and patient characteristics of homologous recombination deficiency in metastatic cutaneous melanoma

Abstract

Abstract Purpose: In various cancer types, cells with a homologous recombination (HR) deficiency have been shown to be sensitive to PARP inhibitors. We investigated the frequency of HR pathway gene mutations in melanoma.Experimental Design: Next-generation sequencing analysis that included the entire coding sequence of 315 cancer-related genes was performed on formalin-fixed, paraffin-embedded melanoma samples. Clinical and pathologic characteristics of 62 patients with advanced melanoma were reviewed, and compared with a dataset of 1,986 melanoma patients with available molecular profiling data.Results: Nineteen (30.6%) patients had ≥1 functional HR mutation. The characteristics of patients with HR-deficient melanoma were: median age 69, male predominance (79%) and primary head and neck melanoma (53%). TMB was high in 12 (67%) patients and low in 1 (6%) patient. The most commonly mutated HR-associated gene was ARID2 (13%), followed by ARID1A, ATM, BRCA1, and FANCA (3% each). Among the 19 patients with HR mutation(s), concurrent NF1, NRAS, V600 BRAF, and KIT mutations were found in 7 (37%), 6 (32%), 5 (26%) and 1 (5%) patients, respectively. Presence of HR pathway mutation was associated with absence of ulceration at the primary site, high TMB and clinical response to checkpoint immunotherapy. A larger dataset analyzed by Foundation Medicine, Inc. (n=1,986) showed a similar frequency and pattern of HR mutations. Conclusions: HR pathway gene mutations are frequently observed in advanced melanoma. Melanomas with these alterations may represent a unique subset of patients who are more likely to benefit from checkpoint blockade, and also may be targeted with PARP inhibitors. Clinical and pathologic characteristics of patients with genetic HR mutationsHR mutation (n=19)Non HR mutation (n=43)p-valueUlceration statusn=16*n=33*0.0050Present2 (12.5%)18 (54.5%)0.0114Absent14 (87.5%)15 (45.5%)0.0479Tumor mutation burdenn=18*n=38*0.0114Low1 (5.6%)17 (44.7%)Intermediate5 (27.8%)8 (21.1%)High12 (66.7%)13 (34.2%)Response to anti-PD-1 antibody inhibitors (+/- ipilimumab)n=12*n=23*0.0479Response10 (83.3%)10 (43.5%)Early Progression1 (8.3%)10 (43.5%)Stable disease1 (8.3%)3 (13.0%) Citation Format: Kevin B. Kim, Sherri Z. Millis, Jeffrey Ross, Laurie M. Gay, Elham Vosoughi, John Moretto, Stanley P. Leong, Mark I. Singer, Brian M. Parrett, David R. Minor, Mohammed Kashani-Sabet. Frequency and patient characteristics of homologous recombination deficiency in metastatic cutaneous melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 320.