Evolving therapeutic landscape of advanced biliary tract cancer: from chemotherapy to molecular targets

Abstract

Biliary tract cancer, the second most common type of liver cancer, remains a therapeutic challenge due to its late diagnosis and poor prognosis. In recent years, it has become evident that classical chemotherapy might not be the optimal treatment for patients with biliary tract cancer, especially after failure of first-line therapy. Finding new treatment options and strategies to improve the survival of these patients is therefore crucial. With the rise and increasing availability of genetic testing in patients with tumor, novel treatment approaches targeting specific genetic alterations have recently been proposed and have demonstrated their safety and efficacy in numerous clinical trials. In this review, we will first consider chemotherapy options and the new possibility of combining chemotherapy with immune checkpoint inhibitors in first-line treatment. We will then provide an overview of genomic alterations and their potential for targeted therapy especially in second-line therapy. In addition to the most common alterations such as isocitrate dehydrogenase 1 or 2 (IDH1/2) mutations, fibroblast growth factor receptor 2 (FGFR2) fusions, and alterations, we will also discuss less frequently encountered alterations such as BRAF V600E mutation and neurotrophic tyrosine kinase receptor gene (NTRK) fusion. We highlight the importance of molecular profiling in guiding therapeutic decisions and emphasize the need for continued research to optimize and expand targeted treatment strategies for this aggressive malignancy.

Keywords: FGFR2; IDH1; biliary tract cancer; precision oncology; targeted therapy.

Figure 1

The genomic landscape of BTC and the corresponding available drugs. Numbers in brackets indicate the frequency of the corresponding targetable and nontargetable genetic alterations in the different BTC subtypes (iCCA, eCCA, and GBC). The percentages are based on Lamarca et al. For the druggable genetic alterations (IDH mutations, FGFR2 alterations, NTRK fusions, BRAF mutation, and HER2 amplification/overexpression), the substances that are currently available and described in the review article are listed. Some of them have already been approved by the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) (created with BioRender). ARID 1A, AT-rich interaction domain 1A; BAP1, BRCA1 associated deubiquitinase 1; BRAF, B-Raf proto-oncogene, serine/threonine kinase; BTC, biliary tract cancer; CDKN2A, cyclin-dependent kinase inhibitor 2A/B; eCCA, extrahepatic CCA; FGFR2, fibroblast growth factor receptor 2; GBC, gallbladder carcinoma; HER2, human epidermal growth factor receptor 2; iCCA, intrahepatic cholangiocarcinoma; IDH, isocitrate dehydrogenase; KRAS, Kirsten rat sarcoma virus; NTRK, neurotrophic tyrosine kinase receptor gene; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; SMAD 4, SMAD family member 4.