Biliary cancer: Utility of next-generation sequencing for clinical management.
BACKGROUND
Biliary tract cancers (BTCs) typically present at an advanced stage, and systemic chemotherapy is often of limited benefit.


METHODS
Hybrid capture-based comprehensive genomic profiling (CGP) was performed for 412 intrahepatic cholangiocarcinomas (IHCCAs), 57 extrahepatic cholangiocarcinomas (EHCCAs), and 85 gallbladder carcinomas (GBCAs). The mutational profile was correlated with the clinical outcome of standard and experimental therapies for 321 patients. Clinical variables, detected mutations, and administered therapies were correlated with overall survival (OS) in a Cox regression model.


RESULTS
The most frequent genetic aberrations (GAs) observed were tumor protein 53 (TP53; 27%), cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B; 27%), KRAS (22%), AT-rich interactive domain-containing protein 1A (ARID1A; 18%), and isocitrate dehydrogenase 1 (IDH1; 16%) in IHCCA; KRAS (42%), TP53 (40%), CDKN2A/B (17%), and SMAD4 (21%) in EHCCA; and TP53 (59%), CDKN2A/B (19%), ARID1A (13%), and ERBB2 (16%) in GBCA. Fibroblast growth factor receptor (FGFR; 11%) and IDH mutations (20%) were mostly limited to IHCCA but appeared to be mutually exclusive. In the IHCCA group, TP53 and KRAS mutations were associated significantly with poor OS, whereas FGFR2 mutations were associated with improved OS (P = .001), a younger age at onset, and female sex. IDH1/2 mutations were not prognostic. In a multivariate model, the effects of TP53 and FGFR GAs remained significant (P < .05). Patients with FGFR GAs had superior OS with FGFR-targeted therapy versus standard regimens (P = .006). Targeted therapy in IHCCA was associated with a numerical OS improvement (P = .07).


CONCLUSIONS
This is the largest clinically annotated data set of BTC cases with CGP and indicates the potential of CGP for improving outcomes. CGP should be strongly considered in the management of BTC patients. Cancer 2016;122:3838-3847. © 2016 American Cancer Society.
Department of Gastrointestinal (GI) Medical Oncology, UT-MD Anderson Cancer Center, Houston, Texas.
Milind
M
Javle
Division of Medical Oncology, Ohio State University Medical Center, Columbus, Ohio.
Tanios
T
Bekaii-Saab
Department of Gastrointestinal (GI) Medical Oncology, UT-MD Anderson Cancer Center, Houston, Texas.
Apurva
A
Jain
Department of Bioinformatics & Computational Biology, UT-MD Anderson Cancer Center, Houston, Texas.
Ying
Y
Wang
Department of Medicine (Hematology/Oncology), UCSF, San Francisco, California.
Robin Katie
RK
Kelley
Foundation Medicine, Inc., Cambridge, Massachusetts.
Kai
K
Wang
Department of Diagnostic Radiology, UT-MD Anderson Cancer Center, Houston, Texas.
Hyunseon C
HC
Kang
Department of Medicine, Section of Hematology/Oncology, University of Chicago Medical Center, Chicago, Illinois.
Daniel
D
Catenacci
Foundation Medicine, Inc., Cambridge, Massachusetts.
Siraj
S
Ali
Department of Radiation Oncology, UT-MD Anderson Cancer Center, Houston, Texas.
Sunil
S
Krishnan
Division of Medical Oncology, Ohio State University Medical Center, Columbus, Ohio.
Daniel
D
Ahn
Department of Medicine (Hematology/Oncology), UCSF, San Francisco, California.
Andrea Grace
AG
Bocobo
Department of Gastrointestinal (GI) Medical Oncology, UT-MD Anderson Cancer Center, Houston, Texas.
Mingxin
M
Zuo
Department of Gastrointestinal (GI) Medical Oncology, UT-MD Anderson Cancer Center, Houston, Texas.
Ahmed
A
Kaseb
Foundation Medicine, Inc., Cambridge, Massachusetts.
Vincent
V
Miller
Foundation Medicine, Inc., Cambridge, Massachusetts.
Philip J
PJ
Stephens
Department of Investigational Cancer Therapeutics, UT-MD Anderson Cancer Center, Houston, Texas.
Funda
F
Meric-Bernstam
Department of Gastrointestinal (GI) Medical Oncology, UT-MD Anderson Cancer Center, Houston, Texas.
Rachna
R
Shroff
Department of Pathology, Albany Medical College Albany, New York.
Jeffrey
J
Ross
D001650:Bile Duct Neoplasms / Q000235:genetics* / Q000628:therapy*; D018281:Cholangiocarcinoma / Q000235:genetics; D018844:Cyclin-Dependent Kinases / Q000235:genetics; D005260:Female; D005706:Gallbladder Neoplasms / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods; D009154:Mutation / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
D009363:Neoplasm Proteins; D018844:Cyclin-Dependent Kinases
AT-rich interactive domain-containing protein 1A (ARID1A); biliary tract cancers; comprehensive genomic profiling; fibroblast growth factor receptor 2 (FGFR2); isocitrate dehydrogenase 1/2 (IDH1/2); prognosis; targeted therapy