Faculty Collaboration Database

Prognostic implications of RAS alterations in diverse malignancies and impact of targeted therapies. Int J Cancer 2020 Jun 15;146(12):3450-3460

Date

11/30/2019

Pubmed ID

31782524

Pubmed Central ID

PMC10200262

DOI

10.1002/ijc.32813

Scopus ID

2-s2.0-85078788986 (requires institutional sign-in at Scopus site)   10 Citations

Abstract

RAS alterations are often found in difficult-to-treat malignancies and are considered "undruggable." To better understand the clinical correlates and coaltered genes of RAS alterations, we used targeted next-generation sequencing (NGS) to analyze 1,937 patients with diverse cancers. Overall, 20.9% of cancers (405/1,937) harbored RAS alterations. Most RAS-altered cases had genomic coalterations (95.3%, median: 3, range: 0-51), often involving genes implicated in oncogenic signals: PI3K pathway (31.4% of 405 cases), cell cycle (31.1%), tyrosine kinase families (21.5%) and MAPK signaling (18.3%). Patients with RAS-altered versus wild-type RAS malignancies had significantly worse overall survival (OS; p = 0.02 [multivariate]), with KRAS alterations, in particular, showing shorter survival. Moreover, coalterations in both RAS and PI3K signaling or cell-cycle-associated genes correlated with worse OS (p = 0.004 and p < 0.0001, respectively [multivariate]). Among RAS-altered patients, MEK inhibitors alone did not impact progression-free survival (PFS), while matched targeted therapy against non-MAPK pathway coalterations alone showed a trend toward longer PFS (vs. patients who received unmatched therapy) (HR: 0.79, 95% CI: 0.61-1.03, p = 0.07). Three of nine patients (33%) given tailored combination therapies targeting both MAPK and non-MAPK pathways achieved objective responses. In conclusion, RAS alterations correlated with poor survival across cancers. The majority of RAS alterations were accompanied by coalterations impacting other oncogenic pathways. MEK inhibitors alone were ineffective against RAS-altered cancers while matched targeted therapy against coalterations alone correlated with a trend toward improved PFS. A subset of the small number of patients given MEK inhibitors plus tailored non-MAPK-targeting agents showed responses, suggesting that customized combinations warrant further investigation.

Author List

Kato S, Okamura R, Sicklick JK, Daniels GA, Hong DS, Goodman A, Weihe E, Lee S, Khalid N, Collier R, Mareboina M, Riviere P, Whitchurch TJ, Fanta PT, Lippman SM, Kurzrock R

Author

Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols
California
Female
Humans
MAP Kinase Signaling System
Male
Middle Aged
Mitogen-Activated Protein Kinase Kinases
Molecular Targeted Therapy
Mutation
Neoplasms
Observational Studies as Topic
Precision Medicine
Prognosis
Protein Kinase Inhibitors
ras Proteins