Abstract
Cholangiocarcinoma (CCA) is a relatively rare malignancy that arises from the epithelial cells of the intrahepatic, perihilar and distal biliary tree. Intrahepatic CCA (ICC) represents the second most common primary liver cancer, after hepatocellular cancer. Two-thirds of the patients with ICC present with locally advanced or metastatic disease. Despite standard treatment with gemcitabine and cisplatin, prognosis remains dismal with a median survival of less than one year. Several biological plausibilities can account for its poor clinical outcomes. First, despite the advent of next generation and whole exome sequencing, no oncogenic addiction loops have been validated as clinically actionable targets. Second, the anatomical, pathological and molecular heterogeneity, and rarity of CCA confer an ongoing challenge of instituting adequately powered clinical trials. Last, most of the studies were not biomarker-driven, which may undermine the potential benefit of targeted therapy in distinct subpopulations carrying the unique molecular signature. Recent whole genome sequencing efforts have identified known mutations in genes such as epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), v-raf murine sarcoma viral oncogene homolog (BRAF) and tumor protein p53 (TP53), novel mutations in isocitrate dehydrogenase (IDH), BRCA1-Associated Protein 1 (BAP1) and AT-rich interactive domain-containing protein 1A (ARID1A), and novel fusions such as fibroblast growth factor receptor 2 (FGFR2) and ROS proto-oncogene 1 (ROS1). In this review, we will discuss the evolving genetic landscape of CCA, with an in depth focus on novel fusions (e.g. FGFR2 and ROS1) and somatic mutations (e.g. IDH1/2), which are promising actionable molecular targets.
Highlights
Cholangiocarcinoma (CCA) comprises of malignancy arising from the intrahepatic, perihilar and distal biliary tree
Advanced CCA portends a dismal prognosis despite standard treatment with gemcitabine and cisplatin
Given the modest benefits with chemotherapy alone and the anatomical, pathological and molecular heterogeneity, there is an unmet and imperative need for comprehensive genomic profiling to improve the understanding of the pathogenesis of CCA, with the aim of personalized treatment
Summary
Cholangiocarcinoma (CCA) comprises of malignancy arising from the intrahepatic, perihilar and distal biliary tree. In a systemic review of 761 patients, treatment with second-line chemotherapy attained a mean OS of 7.2 months (95% CI 6.2-8.2), PFS of 3.2 months (95% CI 2.7-3.7), response rate (RR) of 7.7% (95% CI 6.5-8.9) and disease control rate (DCR) of 49.5% (95% CI 41.4-57.7) [12]. Despite the strong rationale of targeting EGFR in BTCs and early interesting results with single arm phase II trials suggesting the benefits of EGFR inhibitors either as single agents or in combination with chemotherapy (Table 2), four completed randomized studies have failed to confirm the benefits of targeting EGFR in advanced BTCs. The only phase III trial of 133 patients with BTCs demonstrated that the addition of erlotinib to gemcitabineoxaliplatin (GEMOX) significantly improved RR, but did not demonstrate any benefit in survival, with a median OS of 9.5 months in both arms [35]. The median PFS was 6.1 months for the GEMOX and cetuximab www.impactjournals.com/oncotarget
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