The Genomic, Transcriptomic, and Immunologic Landscape of HRAS Mutations in Solid Tumors.

Tipifarnib is the only targeted therapy breakthrough for HRAS -mutant ( HRAS mt) recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). The molecular profiles of HRAS mt cancers are difficult to explore given the low frequency of HRAS mt. This study aims to understand the molecular co-alterations, immune profiles, and clinical outcomes of 524 HRAS mt solid tumors including urothelial carcinoma (UC), breast cancer (BC), non-small-cell lung cancer (NSCLC), melanoma, and HNSCC. HRAS mt was most common in UC (3.0%), followed by HNSCC (2.82%), melanoma (1.05%), BC (0.45%), and NSCLC (0.44%). HRAS mt was absent in Her2+ BC regardless of hormone receptor status. HRAS mt was more frequently associated with squamous compared to non-squamous NSCLC (60% vs. 40% in HRAS wt, p = 0.002). The tumor microenvironment (TME) of HRAS mt demonstrated increased M1 macrophages in triple-negative BC (TNBC), HNSCC, squamous NSCLC, and UC; increased M2 macrophages in TNBC; and increased CD8+ T-cells in HNSCC (all p < 0.05). Finally, HRAS mt was associated with shorter overall survival in HNSCC (HR: 1.564, CI: 1.16-2.11, p = 0.003) but not in the other cancer types examined. In conclusion, this study provides new insights into the unique molecular profiles of HRAS mt tumors that may help to identify new targets and guide future clinical trial design.