Broadening the therapeutic horizon of advanced biliary tract cancer through molecular characterisation

Abstract

Biliary tract cancers (BTC) comprise a group of rare and heterogeneous poor-prognosis tumours with the incidence of intrahepatic cholangiocarcinoma increasing over recent years. Combination chemotherapy with gemcitabine and cisplatin is the established first-line treatment for advanced BTC with a significant but modest survival advantage over monotherapy. There remains no accepted standard treatment in the second-line setting, although recent results from a randomised study have shown a survival benefit with 5-fluorouracil and oxaliplatin chemotherapy. Historically, clinical trials investigating targeted therapies in unselected BTC have failed to demonstrate significant clinical benefit. More recently, advancement in molecular exploration of BTC has shed light on the complex biological heterogeneity within these tumours and has also identified actionable genomic aberrations, such as fibroblast growth factor receptor 2 (FGFR2) gene fusions, isocitrate dehydrogenase (IDH) and BRAF mutations, which offer promise with the anticipation of increased responses and durable clinical benefit in selected patients. Several targeted drugs have now entered clinical development with some encouraging results being seen. Here we review the current and rapidly evolving therapeutic landscape of advanced BTC, including targeted therapies and immunotherapy. We also discuss how recent efforts and successes in BTC are overcoming the obstacles typically associated with precision medicine in rare cancers. Ultimately, the management of advanced BTC is likely to become molecularly selected in the near future with the hope of finally improving the bleak prognosis of patients with this disease.

Keywords: Biliary cancer; Cholangiocarcinoma; Molecular classification; Targeted therapies.

Figure 1.. Molecular alterations with anatomical associations in biliary tract cancers

Abbreviations: ARID1A, AT-rich interaction domain 1A; BAP1, BRCA1-associated protein 1; EGFR, epidermal growth factor receptor; FGFR1–3, fibroblast growth factor receptors 1–3; HER2, human epidermal growth factor receptor 2; IDH1/2, isocitrate dehydrogenase 1 and 2; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PKA, protein kinase A; SMAD4, SMAD family member 4; STK11, serine/threonine kinase 11; TP53, tumor protein 53.

Figure 2.. Four subtypes of cholangiocarcinoma defined by integrative clustering (adapted from Jusakul et al [52])

Abbreviations: AKT1, AKR mouse thymoma kinase 1; ARID1A, AT-rich interaction domain 1A; BAP1, BRCA1-associated protein 1; BRCA 1 or 2, breast cancer gene 1 or 2; BTLA, B- and T-lymphocyte attenuator; CNA, copy number alteration; CTNNB1, catenin beta 1; EZH2, enhancer of zeste homolog 2; FGFR, fibroblast growth factor receptor; H3K27me3, histone 3 lysine 27 trimethylation; HER2, human epidermal growth factor receptor 2; IDH, isocitrate dehydrogenase; PD-1, programmed cell death 1 receptor; PD-L1, programmed cell death receptor ligand 1; SNV, single nucleotide variant; TET1, ten-eleven translocation-1; TP53, tumor protein p53.