Abstract
Simple SummaryOver the last decade, immune checkpoint inhibitors (ICIs) targeting programmed death 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte antigen 4 (CTLA-4) have dramatically changed the therapeutic algorithm of several hematological and solid tumors. Of note, these agents have been also investigated in biliary tract cancer (BTC), reporting controversial results so far; in this setting, the role of ICIs is still to be established, and available data on immunotherapy in BTC patients are mainly limited to sub-analyses of basket trials and small single-arm studies. A crucial challenge is represented by the lack of validated predictive biomarkers, that could help identify responders to immunotherapy, a high unmet need in these immunologically “cold” malignancies where ICIs are still looking for their niche.Biliary tract cancer (BTC) represents the second most frequently diagnosed primary liver cancer worldwide following hepatocellular carcinoma, and the overall survival of patients with unresectable disease remains poor. In recent years, the advent of immune checkpoint inhibitors (ICIs) has revolutionized the therapeutic landscape of several malignancies with these agents, which have also been explored in advanced BTC, as monotherapy or in combination with other anticancer agents. However, clinical trials evaluating ICIs in BTC have shown conflicting results, and the clinical benefit provided by immunotherapy seems limited to a small subgroup of BTC patients. Thus, the identification of reliable predictors of the response to immunotherapy represents a significant challenge in this setting. This review provides an overview of the available evidence on the biomarkers predictive of the response to ICIs in patients with advanced BTC, especially focusing on programmed death-ligand 1 (PD-L1), tumor mutational burden (TMB), microsatellite instability (MSI), and other emerging biomarkers.
Highlights
Biliary tract cancers (BTCs) encompass a group of aggressive, rare, and heterogeneous tumors arising in the bile duct system, comprising gallbladder cancer (GBC), ampulla of Vater cancer (AVC), and cholangiocarcinoma (CCA) [1,2]
Breast Related Cancer Antigens (BRCA) mutations were observed in 3.6% of tumor samples, without showing significant differences according to tumor site [66]; in addition, an important finding of this report is the association between BRCA mutations, microsatellite instability (MSI)/dMMR, and tumor mutational burden (TMB)-H, something that supports the evaluation of immune checkpoint inhibitors (ICIs) in a specific subgroup of BTC patients, with DNA damage repair (DDR) gene mutations potentially representing biomarkers predictive of the response to immunotherapy [66,67]
The immune “cold” subgroup—which seems to represent the majority of these malignancies on the basis of the response rate observed in clinical trials assessing ICIs—presents a prevalence of immunosuppressive cells and a non-T cell-infiltrated tumor microenvironment (TME) [75]
Summary
Biliary tract cancers (BTCs) encompass a group of aggressive, rare, and heterogeneous tumors arising in the bile duct system, comprising gallbladder cancer (GBC), ampulla of Vater cancer (AVC), and cholangiocarcinoma (CCA) [1,2]. Most BTC patients receiving ICIs as a monotherapy or in combination with other anticancer agents do not achieve response, and the mechanisms behind the variations in the response to immunotherapy in this setting have been poorly studied [26] Based on these premises, the identification of biomarkers able to predict responses to ICIs and the understanding of resistance mechanisms in non-responders represent high unmet needs. 5-FU: 5-fluorouracil; AEs, adverse events; ATM, ataxia-telangiectasia mutation; AVC, ampulla of Vater cancer; BTC, biliary tract cancer; CisGem, cisplatin plus gemcitabine combination; CTLA-4, cytotoxic T-lymphocyte antigen 4; DCR: disease control rate; DLTs, dose-limiting toxicities; eCCA: extrahepatic cholangiocarcinoma; FGFR, fibroblast growth factor receptor; GBC, gallbladder cancer; GEMOX, gemcitabine plus oxaliplatin; iCCA, intrahepatic cholangiocarcinoma; ORR, overall response rate; OS, overall survival; PARP, poly ADP ribose polymerase; PDGFR, platelet-derived growth factor receptor; PD-1, programmed death 1, PFS, progression-free survival; RP2D, recommended phase II dose; S-1: tegafur/gimeracil/oteracil; TILs: tumor infiltrating lymphocytes; TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor This table includes ongoing clinical trials assessing immunotherapy as first-, second-, or later-line treatment. 5-FU: 5-fluorouracil; AEs, adverse events; ATM, ataxia-telangiectasia mutation; AVC, ampulla of Vater cancer; BTC, biliary tract cancer; CisGem, cisplatin plus gemcitabine combination; CTLA-4, cytotoxic T-lymphocyte antigen 4; DCR: disease control rate; DLTs, dose-limiting toxicities; eCCA: extrahepatic cholangiocarcinoma; FGFR, fibroblast growth factor receptor; GBC, gallbladder cancer; GEMOX, gemcitabine plus oxaliplatin; iCCA, intrahepatic cholangiocarcinoma; ORR, overall response rate; OS, overall survival; PARP, poly ADP ribose polymerase; PDGFR, platelet-derived growth factor receptor; PD-1, programmed death 1, PFS, progression-free survival; RP2D, recommended phase II dose; S-1: tegafur/gimeracil/oteracil; TILs: tumor infiltrating lymphocytes; TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor
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