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Prognostic implications of RAS alterations in diverse malignancies and impact of targeted therapies
Author(s) -
Kato Shumei,
Okamura Ryosuke,
Sicklick Jason K.,
Daniels Gregory A.,
Hong David S.,
Goodman Aaron,
Weihe Elizabeth,
Lee Suzanna,
Khalid Noor,
Collier Rachel,
Mareboina Manvita,
Riviere Paul,
Whitchurch Theresa J.,
Fanta Paul T.,
Lippman Scott M.,
Kurzrock Razelle
Publication year - 2020
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.32813
Subject(s) - medicine , targeted therapy , oncology , cancer
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.

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