TY - JOUR
T1 - Prognostic implications of RAS alterations in diverse malignancies and impact of targeted therapies
AU - Kato, Shumei
AU - Okamura, Ryosuke
AU - Sicklick, Jason K.
AU - Daniels, Gregory A.
AU - Hong, David S.
AU - Goodman, Aaron
AU - Weihe, Elizabeth
AU - Lee, Suzanna
AU - Khalid, Noor
AU - Collier, Rachel
AU - Mareboina, Manvita
AU - Riviere, Paul
AU - Whitchurch, Theresa J.
AU - Fanta, Paul T.
AU - Lippman, Scott M.
AU - Kurzrock, Razelle
N1 - Funding Information:
Shumei Kato serves as a consultant for Foundation Medicine. Jason K Sicklick receives research funds from Foundation Medicine Inc. and Amgen, as well as consultant fees from Grand Rounds, Deciphera and LOXO. David S Hong receives research and grant funding from AbbVie, Adaptimmune, Aldi‐Norte, Amgen, Astra‐Zeneca, Bayer, BMS, Daiichi‐Sankyo, Eisai, Fate Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa, Lilly, Loxo, Merck, MedImmune, Mirati, miRNA, Molecular Templates, Mologen, NCI‐CTEP, Novartis, Pfizer, Seattle Genetics, Takeda, Turning Point Therapeutics. Travel, accommodations, expenses from LOXO, miRNA, Genmab, AACR, ASCO and SITC. Serves as consulting or advisory role in Alpha Insights, Amgen, Axiom, Adaptimmune, Baxter, Bayer, Genentech, GLG, Group H, Guidepoint, Infinity, Janssen, Merrimack, Medscape, Numab, Pfizer, Prime Oncology, Seattle Genetics, Takeda, Trieza Therapeutics, WebMD. Other ownership interests include Molecular Match (advisor), OncoResponse (Founder) and Presagia Inc (Advisor). Paul Riviere received consulting fee from Peptide Logic. Razelle Kurzrock has Stock and Other Equity Interests in IDbyDNA, CureMatch, Inc., and Soluventis. Serves as consulting or Advisory Role for Gaido, LOXO, X‐Biotech, Actuate Therapeutics, Roche, NeoMed, Soluventis, and Pfizer. Receives speaker's fee from Roche. Research funding from Incyte, Genentech, Merck Serono, Pfizer, Sequenom, Foundation Medicine, Guardant Health, Grifols, Konica Minolta, DeBiopharm, Boerhringer Ingelheim, and OmniSeq [All institutional]) and serves as Board Member for CureMatch, Inc.
Funding Information:
This work was also supported in part by the Jon Schneider Memorial Cancer Research Fund, as well as NIH K08CA168999 and R21CA192072 (to J.K.S.). The project described was partially supported by the National Institutes of Health, Grant TL1TR001443 (to P.R.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work was supported in part by Foundation Medicine, the Joan and Irwin Jacobs Fund philanthropic fund; and by National Cancer Institute at the National Institutes of Health [grant P30 CA023100 (to R.K., rkurzrock@ucsd.edu )].
Publisher Copyright:
© 2019 UICC
PY - 2020/6/15
Y1 - 2020/6/15
N2 - 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.
AB - 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.
KW - RAS
KW - next-generation sequencing
KW - targeted therapy
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U2 - 10.1002/ijc.32813
DO - 10.1002/ijc.32813
M3 - Article
C2 - 31782524
AN - SCOPUS:85078788986
SN - 0020-7136
VL - 146
SP - 3450
EP - 3460
JO - International journal of cancer
JF - International journal of cancer
IS - 12
ER -