title: Next-generation sequencing survey of biliary tract cancer reveals the association between tumor somatic variants and chemotherapy resistance.
abstract: 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.
  
  
  
  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).
  
  
  
  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.
  
  
  
  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.
authors: Division of Medical Oncology, The Ohio State University Medical Center, Columbus, OH, USA.|Mayo Clinic, 5777 E. Mayo Blvd, Phoenix, AZ, USA.
authors: Daniel H
authors: DH
authors: Ahn
authors: Division of Cancer Medicine, MD Anderson Cancer Center, Houston, Texas, USA.
authors: Milind
authors: M
authors: Javle
authors: Department of Clinical Sciences, UT Southwestern Medical Center, Dallas, Texas, USA.
authors: Chul W
authors: CW
authors: Ahn
authors: Division of Cancer Medicine, MD Anderson Cancer Center, Houston, Texas, USA.
authors: Apurva
authors: A
authors: Jain
authors: Division of Medical Oncology, The Ohio State University Medical Center, Columbus, OH, USA.
authors: Sameh
authors: S
authors: Mikhail
authors: Division of Medical Oncology, The Ohio State University Medical Center, Columbus, OH, USA.
authors: Anne M
authors: AM
authors: Noonan
authors: Kristen
authors: K
authors: Ciombor
authors: Division of Medical Oncology, The Ohio State University Medical Center, Columbus, OH, USA.
authors: Christina
authors: C
authors: Wu
authors: Division of Cancer Medicine, MD Anderson Cancer Center, Houston, Texas, USA.
authors: Rachna T
authors: RT
authors: Shroff
authors: Division of Medical Oncology, The Ohio State University Medical Center, Columbus, OH, USA.|Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA.
authors: James L
authors: JL
authors: Chen
authors: Mayo Clinic, 5777 E. Mayo Blvd, Phoenix, AZ, USA.
authors: Tanios
authors: T
authors: Bekaii-Saab
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001661:Biliary Tract Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D011379:Prognosis; D011795:Surveys and Questionnaires; D016896:Treatment Outcome; D055815:Young Adult; D000093542:Gemcitabine
chemical_list: D009944:Organoplatinum Compounds; D003841:Deoxycytidine; D018844:Cyclin-Dependent Kinases; D000093542:Gemcitabine
keywords: biliary tract cancer; gemcitabine and platinum-based therapy response; next-generation sequencing; tumor somatic variants