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. 2024 Jul 15;30(14):2986-2995.
doi: 10.1158/1078-0432.CCR-23-2819.

Clinical and Genomic Landscape of RAS Mutations in Gynecologic Cancers

Ji Son  1 , Yingao Zhang  1 , Heather Lin  2 , Oriol Mirallas  3 , Pablo Alvarez Ballesteros  3 , Mirella Nardo  3 , Natalie Clark  1 , R Tyler Hillman  1 , Erick Campbell  3 , Vijaykumar Holla  4 , Amber M Johnson  4 , Amadeo B Biter  3 , Ying Yuan  2 , Lauren P Cobb  1 , David M Gershenson  1 , Amir A Jazaeri  1 , Karen H Lu  1 , Pamela T Soliman  1 , Shannon N Westin  1 , Elizabeth D Euscher  5 , Barrett C Lawson  5 , Richard K Yang  5 , Funda Meric-Bernstam  3 , David S Hong  3
Affiliations

Clinical and Genomic Landscape of RAS Mutations in Gynecologic Cancers

Ji Son et al. Clin Cancer Res. .

Abstract

Purpose: We aimed to describe RAS mutations in gynecologic cancers as they relate to clinicopathologic and genomic features, survival, and therapeutic implications.

Experimental design: Gynecologic cancers with available somatic molecular profiling data at our institution between February 2010 and August 2022 were included and grouped by RAS mutation status. Overall survival was estimated by the Kaplan-Meier method, and multivariable analysis was performed using the Cox proportional hazard model.

Results: Of 3,328 gynecologic cancers, 523 (15.7%) showed any RAS mutation. Patients with RAS-mutated tumors were younger (57 vs. 60 years nonmutated), had a higher prevalence of endometriosis (27.3% vs. 16.9%), and lower grades (grade 1/2, 43.2% vs. 8.1%, all P < 0.0001). The highest prevalence of KRAS mutation was in mesonephric-like endometrial (100%, n = 9/9), mesonephric-like ovarian (83.3%, n = 5/6), mucinous ovarian (60.4%), and low-grade serous ovarian (44.4%) cancers. After adjustment for age, cancer type, and grade, RAS mutation was associated with worse overall survival [hazard ratio (HR) = 1.3; P = 0.001]. Specific mutations were in KRAS (13.5%), NRAS (2.0%), and HRAS (0.51%), most commonly KRAS G12D (28.4%) and G12V (26.1%). Common co-mutations were PIK3CA (30.9%), PTEN (28.8%), ARID1A (28.0%), and TP53 (27.9%), of which 64.7% were actionable. RAS + MAPK pathway-targeted therapies were administered to 62 patients with RAS-mutated cancers. While overall survival was significantly higher with therapy [8.4 years [(95% confidence interval (CI), 5.5-12.0) vs. 5.5 years (95% CI, 4.6-6.6); HR = 0.67; P = 0.031], this effect did not persist in multivariable analysis.

Conclusions: RAS mutations in gynecologic cancers have a distinct histopathologic distribution and may impact overall survival. PIK3CA, PTEN, and ARID1A are potentially actionable co-alterations. RAS pathway-targeted therapy should be considered.

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Conflict of interest statement

Conflict of Interest

The authors declare no conflict of interest directly relating to this study. Outside of the submitted work, the authors report the following:

J.S. reports institutional research funding from NIH/NCI P30CA016672 and the T32 training grant CA101642.

O.M. reports research funding from the Spanish Society of Medical Oncology; speaker invitation from ROVI; and travel expenses by Kyowa Kirin, Sanofi, and Almirall.

Y.Y. reports consulting fees from AbbVie, Affinixttx, Amgen, Ascendis, Bexion, Boehringer Ingelheim, Boren Hospital, Bristol Myers Squibb, Century, Frontier Medicine, GT Medical, NeoImmueTech, Merck, NextCure, Repare, Servier, Starpax, Xinthera, and Vertex.

D.M.G. reports clinical trial support to the institution from the National Cancer Institute (NRG Oncology), Novartis, and the GOG Foundation; royalties or licenses from Elsevier and UpToDate outside the submitted work; consulting fees from Genentech; advisory fees from Springworks, Verastem, Aadi, and Onconova; equity interest from Johnson & Johnson, Bristol Myers Squibb, and Procter and Gamble; and membership on the Board of the International Consortium for Low-Grade Serous Ovarian Cancer.

A.A.J. reports clinical trial support to the institution from Iovance, Macrogenics, AstraZeneca, BMS, Merck, Eli Lilly, Pfizer, Immatics, Imunon, Break Through Cancer, and Aravive; and advisory fees from Guidepoint, Gerson Lehrman Group, Macrogenics, Theolytics, and Adicet Bio.

P.T.S. reports clinical trial support or research grants to the institution from Merck, Novartis, Incyte, GSK; consulting fees from Aadi, GSK, Essau.

S.N.W. reports clinical trial support or research grants to the institution from Astra Zeneca, AvengeBio, Bayer, Bio-Path, Clovis Oncology, GSK, Jazz Pharmaceuticals, Mereo, Novartis, Nuvectis, Roche/Genentech, Zentalis; consulting fees from AstraZeneca, Caris, Clovis Oncology, Eisai, EQRX, Gilead, GSK, Immunocore, ImmunoGen, Lilly, Merck, Mereo, Mersana, NGM Bio, Nuvectis, Roche/Genentech, SeaGen, Verastem, Vincerx, Zentalis, ZielBio.

F.M.B. reports clinical trial support to the Institution from Aileron Therapeutics, Inc. AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc., Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., Klus Pharma, Takeda Pharmaceutical, Novartis, Puma Biotechnology Inc., Taiho Pharmaceutical Co.; consulting fees from AbbVie, Aduro BioTech Inc., Alkermes, AstraZeneca, Daiichi Sankyo Co. Ltd., Calibr (a division of Scripps Research), DebioPharm, Ecor1 Capital, eFFECTOR Therapeutics, F. Hoffman-La Roche Ltd., GT Apeiron, Genentech Inc., Harbinger Health, IBM Watson, Infinity Pharmaceuticals, Jackson Laboratory, Kolon Life Science, LegoChem Bio, Lengo Therapeutics, Menarini Group, OrigiMed, PACT Pharma, Parexel International, Pfizer Inc., Protai Bio Ltd, Samsung Bioepis, Seattle Genetics Inc., Tallac Therapeutics, Tyra Biosciences, Xencor, Zymeworks; advisory fees from Black Diamond, Biovica, Eisai, FogPharma, Immunomedics, Inflection Biosciences, Karyopharm Therapeutics, Loxo Oncology, Mersana Therapeutics, OnCusp Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Sanofi, Silverback Therapeutics, Spectrum Pharmaceuticals, Theratechnologies, Zentalis; and travel fees from European Organisation for Research and Treatment of Cancer (EORTC), European Society for Medical Oncology (ESMO), Cholangiocarcinoma Foundation.

D.S.H. reports clinical trial support to the institution from AbbVie, Adaptimmune, Adlai-Nortye, Amgen, Astra-Zeneca, Bayer, Biomea, Bristol-Myers Squibb, Daiichi-Sankyo, Deciphera, Eisai, Eli Lilly, Endeavor, Erasca, F. Hoffmann-LaRoche, Fate Therapeutics, Genentech, Genmab, Immunogenesis, Infinity, Kyowa Kirin, Merck, Mirati, Navier, NCI-CTEP, Novartis, Numab, Pfizer, Pyramid Bio, Revolution Medicine, SeaGen, STCube, Takeda, TCR2, Turning Point Therapeutics, VM Oncology; consulting fees from 28Bio, Abbvie, Acuta, Adaptimmune, Alkermes, Alpha Insights, Amgen, Affini-T, Astellas, Aumbiosciences, Axiom, Baxter, Bayer, Boxer Capital, BridgeBio, CARSgen, CLCC, COG, COR2ed, Cowen, Ecor1, EDDC, Erasca, Exelixis, Fate Therapeutics, F.Hoffmann-La Roche, Genentech, Gennao Bio, Gilead, GLG, Group H, Guidepoint, HCW Precision Oncology, Immunogenesis, Incyte Inc, Inhibrix Inc, InduPro, Janssen, Jounce Therapeutics Inc, Liberium, MedaCorp, Medscape, Novartis, Numab, Oncologia Brasil, ORI Capital, Pfizer, Pharma Intelligence, POET Congress, Prime Oncology, Projects in Knowledge, Quanta, RAIN, Ridgeline, SeaGen, Stanford, STCube, Takeda, Tavistock, Trieza Therapeutics, Turning Point Therapeutics, WebMD, YingLing Pharma, Ziopharm; travel fees from AACR, ASCO, CLCC, Bayer, Genmab, SITC, Telperian; and other ownership interests from Molecular Match (Advisor), OncoResponse (Founder, Advisor), Telperian (Founder, Advisor).

Y.Z., H.L., P.A.B., M.N., N.C., R.T.H., E.C., V.H, A.M.J., A.A.B., L.P.C., K.H.L, E.D.E., B.C.L, K.R.Y. report no potential conflict of interest.

MD Anderson Cancer Center receives licensing fees for Precision Oncology Decision Support database from Philips Healthcare which support continued development of the system. We acknowledge the Cancer Prevention Research Institute of Texas (CPRIT) Precision Oncology Decision Support Core (RP150535), and Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy.

Figures

Figure 1.
Figure 1.
Prevalence of KRAS mutations in gynecologic cancers by histology. In parentheses, KRASmut (n) / histology (n). See Supplemental Table 2 for tabulated data, Supplemental Figure 2 for NRAS and HRAS mutations.
See this image and copyright information in PMC

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