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

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