title: Genomics of gallbladder cancer: the case for biomarker-driven clinical trial design.
abstract: Gallbladder carcinoma is a rare, aggressive malignancy of the biliary tract associated with a poor prognosis. Despite the deployment of targeted therapies that have demonstrated marked survival benefits in many tumor types, traditional cytotoxic chemotherapy has remained the mainstay of treatment for unresectable and metastatic gallbladder cancer.
  
  
  
  Systematic review of ongoing and prior clinical studies shows a paucity of biomarker-driven therapeutic trials using targeted agents in gallbladder cancer. In fact, over the past 6 years, of the 38 therapeutic biliary tract protocols listed on clinicaltrials.gov, only 6 (21 %) utilized targeted therapies based upon tumor biomarkers or genomics. Now that we have entered the era of next-generation sequencing and precision medicine, we are beginning to identify common and specific genetic alterations in gallbladder carcinomas.
  
  
  
  A review of the literature reveals alterations in ARID1A, BRAF, CDKN2A/B, EGFR, ERBB2-4, HKN-RAS, PIK3CA, PBRM1, and TP53. Given the widespread use of tumor genomic profiling and the fact that most of the aforementioned alterations are pharmacologically tractable, these observations suggest the potential for new therapeutic strategies in this aggressive malignancy.
  
  
  
  Taken together, further understanding of the genomic landscape of gallbladder cancer coupled with biomarker-driven clinical trials that match therapies to targets are urgently needed.
authors: Center for Personalized Cancer Therapy, San Diego, CA, USA. jsicklick@ucsd.edu.|Division of Surgical Oncology, Department of Surgery, University of California, San Diego Moores Cancer Center, 3855 Health Sciences Drive, MC 0987, La Jolla, CA, 92093-0987, USA. jsicklick@ucsd.edu.
authors: Jason K
authors: JK
authors: Sicklick
authors: Center for Personalized Cancer Therapy, San Diego, CA, USA.|Division of Hematology and Oncology, University of California, San Diego Moores Cancer Center, 3855 Health Sciences Drive, MC 0987, La Jolla, 92093-0987, CA, USA.
authors: Paul T
authors: PT
authors: Fanta
authors: Center for Personalized Cancer Therapy, San Diego, CA, USA.|Division of Hematology and Oncology, University of California, San Diego Moores Cancer Center, 3855 Health Sciences Drive, MC 0987, La Jolla, 92093-0987, CA, USA.
authors: Kelly
authors: K
authors: Shimabukuro
authors: Center for Personalized Cancer Therapy, San Diego, CA, USA.|Division of Hematology and Oncology, University of California, San Diego Moores Cancer Center, 3855 Health Sciences Drive, MC 0987, La Jolla, 92093-0987, CA, USA.
authors: Razelle
authors: R
authors: Kurzrock
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001661:Biliary Tract Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000628:therapy; D014408:Biomarkers, Tumor; D002277:Carcinoma / Q000175:diagnosis / Q000235:genetics / Q000628:therapy; D002986:Clinical Trials as Topic; D019468:Disease Management; D005706:Gallbladder Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D023281:Genomics / Q000379:methods; D006801:Humans; D058990:Molecular Targeted Therapy; D057285:Precision Medicine; D011379:Prognosis; D012107:Research Design; D015398:Signal Transduction / Q000187:drug effects; D059039:Standard of Care; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor
keywords: Biliary tract cancers; Cholangiocarcinoma; Gallbladder cancer; Targeted therapy