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Biliary cancer: intrahepatic cholangiocarcinoma vs. extrahepatic cholangiocarcinoma vs. gallbladder cancers: classification and therapeutic implications.

ABSTRACT: Biliary cancers (BCs) are a diverse group of tumors that arise from the bile duct epithelium and are divided into cholangiocarcinomas of the intrahepatic and extrahepatic cholangiocarcinoma (EHCC) and cancer of the gallbladder. Despite improvements in treatment and diagnosis, BCs are often diagnosed at an advanced stage and associated with poor prognosis and limited treatment options. Recent discoveries have allowed us to have a better understanding of the genomic diversity in BC, and identify genes that are likely contributing to its pathogenesis, proliferation and treatment resistance. Additionally, these advances have allowed us to reason that each anatomic group within BC behave as distinct diseases, with differences in prognosis and outcomes. Based on this knowledge, recent advances have allowed us to identify actionable mutations that form rational therapeutic targets with novel agents, where their relevance will be better understood through the completion of prospective clinical trials.

SUBMITTER: Ahn DH

PROVIDER: S-EPMC5401855 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Biliary cancer: intrahepatic cholangiocarcinoma <i>vs.</i> extrahepatic cholangiocarcinoma <i>vs.</i> gallbladder cancers: classification and therapeutic implications.

Ahn Daniel H DH Bekaii-Saab Tanios T

Journal of gastrointestinal oncology 20170401 2

Biliary cancers (BCs) are a diverse group of tumors that arise from the bile duct epithelium and are divided into cholangiocarcinomas of the intrahepatic and extrahepatic cholangiocarcinoma (EHCC) and cancer of the gallbladder. Despite improvements in treatment and diagnosis, BCs are often diagnosed at an advanced stage and associated with poor prognosis and limited treatment options. Recent discoveries have allowed us to have a better understanding of the genomic diversity in BC, and identify g ...[more]

PMID: 28480068

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Project description:Background & aimsCholangiocarcinoma (CCA), a deadly malignancy of the bile ducts, can be classified based on its anatomical location into either intrahepatic (iCCA) or extrahepatic (eCCA), each with different pathogenesis and clinical management. There is limited understanding of the molecular landscape of eCCA and no targeted therapy with clinical efficacy has been approved. We aimed to provide a molecular classification of eCCA and identify potential targets for molecular therapies.MethodsAn integrative genomic analysis of an international multicenter cohort of 189 eCCA cases was conducted. Genomic analysis included whole-genome expression, targeted DNA-sequencing and immunohistochemistry. Molecular findings were validated in an external set of 181 biliary tract tumors from the ICGC.ResultsKRAS (36.7%), TP53 (34.7%), ARID1A (14%) and SMAD4 (10.7%) were the most prevalent mutations, with ∼25% of tumors having a putative actionable genomic alteration according to OncoKB. Transcriptome-based unsupervised clustering helped us define 4 molecular classes of eCCA. Tumors classified within the Metabolic class (19%) showed a hepatocyte-like phenotype with activation of the transcription factor HNF4A and enrichment in gene signatures related to bile acid metabolism. The Proliferation class (23%), more common in patients with distal CCA, was characterized by enrichment of MYC targets, ERBB2 mutations/amplifications and activation of mTOR signaling. The Mesenchymal class (47%) was defined by signatures of epithelial-mesenchymal transition, aberrant TGFβ signaling and poor overall survival. Finally, tumors in the Immune class (11%) had a higher lymphocyte infiltration, overexpression of PD-1/PD-L1 and molecular features associated with a better response to immune checkpoint inhibitors.ConclusionAn integrative molecular characterization identified distinct subclasses of eCCA. Genomic traits of each class provide the rationale for exploring patient stratification and novel therapeutic approaches.Lay summaryTargeted therapies have not been approved for the treatment of extrahepatic cholangiocarcinoma. We performed a multi-platform molecular characterization of this tumor in a cohort of 189 patients. These analyses revealed 4 novel transcriptome-based molecular classes of extrahepatic cholangiocarcinoma and identified ∼25% of tumors with actionable genomic alterations, which has potential prognostic and therapeutic implications.

Project description:IntroductionTumor-related liver failure (TRLF) is the most common cause of death in patients with intrahepatic cholangiocarcinoma (ICC). Though we previously showed that liver radiotherapy (L-RT) for locally advanced ICC is associated with less frequent TRLF and longer overall survival (OS), the role of L-RT for patients with extrahepatic metastatic disease (M1) remains undefined. We sought to compare outcomes for M1 ICC patients treated with and without L-RT.MethodsWe reviewed ICC patients that found to have M1 disease at initial diagnosis at a single institution between 2010 and 2021 who received L-RT, matching them with an institutional cohort by propensity score and a National Cancer Database (NCDB) cohort by frequency technique. The median biologically effective dose was 97.5 Gy (interquartile range 80.5-97.9 Gy) for L-RT. Patients treated with other local therapies or supportive care alone were excluded. We analyzed survival with Cox proportional hazard modeling.ResultsWe identified 61 patients who received L-RT and 220 who received chemotherapy alone. At median follow-up of 11 months after diagnosis, median OS was 9 months (95% confidence interval [CI] 8-11) and 21 months (CI: 17-26) for patients receiving chemotherapy alone and L-RT, respectively. TRLF was the cause of death more often in the patients who received chemotherapy alone compared to those who received L-RT (82% vs. 47%; p = 0.001). On multivariable propensity score-matched analysis, associations with lower risk of death included duration of upfront chemotherapy (hazard ratio [HR] 0.82; p = 0.005) and receipt of L-RT (HR: 0.40; p = 0.002). The median OS from diagnosis for NCDB chemotherapy alone cohort was shorter than that of the institutional L-RT cohort (9 vs. 22 months; p < 0.001).ConclusionFor M1 ICC, L-RT associated with a lower rate of death due to TRLF and longer OS versus those treated with chemotherapy alone. Prospective studies of L-RT in this setting are warranted.

Dataset Information

Biliary cancer: intrahepatic cholangiocarcinoma vs. extrahepatic cholangiocarcinoma vs. gallbladder cancers: classification and therapeutic implications.

Publications

Biliary cancer: intrahepatic cholangiocarcinoma <i>vs.</i> extrahepatic cholangiocarcinoma <i>vs.</i> gallbladder cancers: classification and therapeutic implications.

Similar Datasets

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