title: Intrahepatic cholangiocarcinoma and gallbladder cancer: distinguishing molecular profiles to guide potential therapy.
abstract: BACKGROUND
  Chemotherapy regimens for intrahepatic cholangiocarcinoma (ICC) and gallbladder adenocarcinoma (GC) remain interchangeable; however, response rates are frequently suboptimal. Biomarkers from ICC and GC patients were interrogated to identify actionable differences with potential therapeutic implications.
  
  
  METHODS
  From 2009 to 2012, pathological specimens from 217 ICC and 28 GC patients referred to Caris Life Sciences were evaluated. Specific testing by immunohistochemical analysis for 17 different biomarkers was performed.
  
  
  RESULTS
  In the collective cohort (n = 245), actionable targets included: 95% low thymidylate synthase (TS), 82% low ribonucleotide reductase subunit M (RMM) 1 and 74% low excision repair cross complementation group (ERCC) 1, indicating potential susceptibility to fluoropyrimidines/capecitabine, gemcitabine and platinum agents, respectively. Additional targets included TOPO1 (53.3% high, Irinotecan), MGMT (50.3% low, temozolomide), TOP2A (33% high, anthracyclines) and PGP (30.1% low, taxanes). Subgroup analysis by tumour origin demonstrated a differential biomarker expression pattern with a higher frequency of ICC tumours showing low levels of TS (99% versus 72%, P < 0.01), and RRM1 (85% versus 64%, P = 0.02) when compared with GC. Conversely a greater frequency of GC demonstrated high levels of TOPO1 (76% versus 50%, P = 0.02) versus ICC, indicating a potential increased benefit from irinotecan.
  
  
  CONCLUSIONS
  Differences in the molecular profiles between ICC and GC provide evidence that the two are distinct diseases, requiring different treatment strategies to optimize a response.
authors.affiliation: Division of Surgical Oncology, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Potkonjak
authors.affiliation: Division of Surgical Oncology, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Miura
authors.affiliation: Division of Surgical Oncology, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Kiran K
authors.initials: KK
authors.lastname: Turaga
authors.affiliation: Division of Surgical Oncology, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Fabian M
authors.initials: FM
authors.lastname: Johnston
authors.affiliation: Division of Surgical Oncology, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Tsai
authors.affiliation: Division of Surgical Oncology, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Kathleen K
authors.initials: KK
authors.lastname: Christians
authors.affiliation: Division of Surgical Oncology, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: T Clark
authors.initials: TC
authors.lastname: Gamblin
mesh_terms: D000230:Adenocarcinoma / Q000737:chemistry* / Q000188:drug therapy / Q000473:pathology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001650:Bile Duct Neoplasms / Q000737:chemistry* / Q000188:drug therapy / Q000473:pathology; D014408:Biomarkers, Tumor / Q000032:analysis*; D018281:Cholangiocarcinoma / Q000737:chemistry* / Q000188:drug therapy / Q000473:pathology; D003937:Diagnosis, Differential; D005260:Female; D005706:Gallbladder Neoplasms / Q000737:chemistry* / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D025202:Molecular Diagnostic Techniques; D058990:Molecular Targeted Therapy; D018579:Patient Selection; D011237:Predictive Value of Tests; D012189:Retrospective Studies
chemical_list: D014408:Biomarkers, Tumor