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Next‐generation sequencing survey of biliary tract cancer reveals the association between tumor somatic variants and chemotherapy resistance
Author(s) -
Ahn Daniel H.,
Javle Milind,
Ahn Chul W.,
Jain Apurva,
Mikhail Sameh,
Noonan Anne M.,
Wu Christina,
Shroff Rachna T.,
Chen James L.,
BekaiiSaab Tanios
Publication year - 2016
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.30247
Subject(s) - medicine , cdkn2a , gemcitabine , oncology , arid1a , cancer , chemotherapy , proportional hazards model , mutation , cohort , cancer research , gene , genetics , biology
BACKGROUND Biliary tract cancers (BTCs) are uncommon and are associated with a dismal prognosis. Combinations of gemcitabine and platinum chemotherapy (gemcitabine and platinum–based therapy [GP]) form the standard approach for treating advanced BTC. To characterize the spectrum of mutations and to identify potential biomarkers for a GP response in BTC, this study evaluated the genomic landscape and assessed whether mutations affecting DNA repair were associated with GP resistance. METHODS Pretreatment, formalin‐fixed, paraffin‐embedded samples from 183 BTC patients treated with GP were analyzed. Cox regression models were used to determine the association between mutations, progression‐free survival (PFS), and overall survival (OS). RESULTS When genes with an incidence > 10% were considered, no individual gene was independently predictive of a GP response. In patients with unresectable BTC who received GP as their first‐line therapy, the joint status of cyclin‐dependent kinase inhibitor 2A ( CDKN2A ), tumor protein 53 ( TP53 ), and AT‐rich interaction domain 1A ( ARID1A ) was associated with PFS ( P = .0004) and OS ( P ≤ .0001). Patients with mutations in CDKN2A and TP53 were identified as a poor‐prognosis cohort with a median PFS of 2.63 months and a median OS of 5.22 months. Patients with mutant ARID1A , regardless of the single‐mutation status of TP53 or CDKN2A , had similar outcomes. A patient who exhibited mutations in all 3 genes had a median PFS of 20.37 months, and OS was not reached. CONCLUSIONS In the largest exploratory analysis of this kind for BTC, 3 prevalent, mutually exclusive mutations represent distinct patient cohorts. These mutations are prognostic and may represent a predictive biomarker for a GP response. Prospective studies to validate these findings are needed, and they should include the incorporation of therapies that exploit the genomic instability observed with these mutations in BTC. Cancer 2016;122:3657‐66. © 2016 American Cancer Society .