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

Author:

Kareff Samuel A.1ORCID,Trabolsi Asaad1ORCID,Krause Harris B.2ORCID,Samec Timothy2ORCID,Elliott Andrew2ORCID,Rodriguez Estelamari3ORCID,Olazagasti Coral3,Watson Dionysios C.3,Bustos Matias A.4ORCID,Hoon Dave S. B.4,Graff Stephanie L.5ORCID,Antonarakis Emmanuel S.6ORCID,Goel Sanjay7ORCID,Sledge George2,Lopes Gilberto3

Affiliation:

1. Department of Graduate Medical Education, University of Miami Sylvester Comprehensive Cancer Center/Jackson Memorial Hospital, Miami, FL 33136, USA

2. Caris Life Sciences, Phoenix, AZ 85040, USA

3. Division of Medical Oncology, Department of Medicine, University of Miami Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA

4. Division of Translational Molecular Medicine, St. Johns’ Cancer Institute at Providence Saint John’s Health Center, Santa Monica, CA 90404, USA

5. Department of Medicine, Lifespan Cancer Institute, Providence, RI 02903, USA

6. Division of Hematology, Oncology, and Transplantation, University of Minnesota Masonic Cancer Center, Minneapolis, MN 55455, USA

7. Division of Medical Oncology, Rutgers University, New Brunswick, NJ 08901, USA

Abstract

Tipifarnib is the only targeted therapy breakthrough for HRAS-mutant (HRASmt) recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). The molecular profiles of HRASmt cancers are difficult to explore given the low frequency of HRASmt. This study aims to understand the molecular co-alterations, immune profiles, and clinical outcomes of 524 HRASmt solid tumors including urothelial carcinoma (UC), breast cancer (BC), non-small-cell lung cancer (NSCLC), melanoma, and HNSCC. HRASmt was most common in UC (3.0%), followed by HNSCC (2.82%), melanoma (1.05%), BC (0.45%), and NSCLC (0.44%). HRASmt was absent in Her2+ BC regardless of hormone receptor status. HRASmt was more frequently associated with squamous compared to non-squamous NSCLC (60% vs. 40% in HRASwt, p = 0.002). The tumor microenvironment (TME) of HRASmt 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, HRASmt 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 HRASmt tumors that may help to identify new targets and guide future clinical trial design.

Funder

National Cancer Institute

NCI Cancer Center

DOD grant

Publisher

MDPI AG

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