<i>HRAS</i> Mutations Define a Distinct Subgroup in Head and Neck Squamous Cell Carcinoma.

Abstract

In head and neck squamous cell carcinoma (HNSCC), <i>HRAS</i> mutation is a new actionable oncogene driver. We aimed to evaluate <i>HRAS</i> mutational variants, comutation profile, and survival outcomes of this molecularly defined population. We leveraged four deidentified patient data sets with <i>HRAS</i>-mutant HNSCC, MD Anderson Cancer Center, Kura Oncology, Inc trial, Foundation Medicine, and American Association for Cancer Research GENIE v.12. Patient demographic information and clinical courses were extracted, when available, in addition to <i>HRAS</i> mutation type and co-occurring mutations. Survival outcomes were analyzed (Kaplan-Meier method). Two hundred forty-nine patients with <i>HRAS</i>-mutant HNSCC were identified from the four data sets. Median age ranged from 55 to 65 years, with a higher frequency in male patients (64%); the majority of <i>HRAS</i>-mutant HNSCC occurred in human papillomavirus-negative HNSCC. <i>HRAS</i> mutation patterns were similar across data sets; G12S was the most common (29%). Treatment responses to tipifarnib were not codon-specific. Compared with wild-type, significantly co-occurring mutations with <i>HRAS</i> were <i>Casp8</i> (Fisher's exact test, <i>P</i> < .00013), <i>TERT</i> (<i>P</i> < .0085), and <i>NOTCH1</i> (<i>P</i> < .00013). Analysis of clinical courses from the MD Anderson Cancer Center and Kura Oncology, Inc data sets demonstrated poor clinical outcomes with a high rate of recurrence following primary definitive treatment (50%-67% relapse < 6 months) and short disease-free survival (4.0 months; 95% CI, 1.0 to 36.0) and overall survival (OS; 15.0 months; 95% CI, 6.0 to 52.0). Use of tipifarnib in this data set demonstrated improved OS (25.5 months; 95% CI, 18.0 to 48.0). Oncogenic mutations in <i>HRAS</i> occur in 3%-4% of HNSCC, with G12S being the most frequent. Without targeted therapy, patients with <i>HRAS</i>-mutant HNSCC had poor clinic outcomes; observable trend toward improvement in OS has been noted in cohorts receiving treatments such as tipifarnib. The comutation pattern of <i>HRAS</i>-mutant in HNSCC is distinct, which may provide insight to future therapeutic combination strategies.