Abstract
Simple SummaryBiliary tract cancers (BTCs) are rare tumors with devastating prognosis. Gallbladder cancer (GBC) is the most common BTC, and even though recent advances have been carried out in the field of clinical management, research for molecular targets for precision medicine is proceeding at slow steps. This review discuss the molecular targets highlighted to date, focusing on clinical trials exploring the efficacy of precision medicine and immunotherapeutic compounds for the treatment of advanced GBC. Points of strength and weakness of each molecular biomarker are discussed, designing new landscapes for new therapeutic approaches for this malignancy, and suggesting new roles for cytotoxic agents, to date considered the gold standard for patients’ clinical management.Biliary tract cancers (BTCs), for their low incidence, have been often considered together. Gallbladder cancer (GBC) is the most common biliary tract malignancy, characterized by late diagnosis and poor prognosis, and although it is considered a rare tumor in western countries, other areas of the world show considerable incidence rates. In 2010, results from the large phase III ABC-02 clinical trial on GBC identified the gemcitabine and cisplatin combination as the most effective first-line regimen for both GBC and other BTCs. Since then, various systemic therapies have proven active in BTCs in both first- and second-line settings. Molecular profiling has highlighted important genetic differences between GBC and other BTCs, opening new ways for targeted therapy in advanced disease where standard chemotherapies show marginal benefit. Genome-wide data analysis have shown that GBC molecular landscape offer possible strategies for precision medicine approaches, and a better molecular understanding of the GBC is needed to better stratify patients for treatment. In this review, we discuss the molecular targetable agents for GBC, including the results that emerged by clinical trials exploring new treatment strategies.
Highlights
Biliary tract cancers (BTCs) comprise a heterogeneous group of malignancies that include gallbladder cancer (GBC), ampulla of Vater cancer (AVC) and cholangiocarcinoma (CCA); the latter is further classified into intrahepatic, perihilar and distal, while pCCa and dCCA are referred to extrahepatic cholangiocarcinoma
While for BTC molecular alterations have been mainly found to affect FGF, IDH and PI3KCA pathways, GBC is mainly characterized for HER2 alteration; on the other hand, TP53 and KRAS mutations are common in all these malignancies [7,8]
Another large study including 353 GBC found that BRCA1 and -2 were mutated in 0.3% and 4%, respectively; a correlation between BRCA mutants and high microsatellite instability (MSI)/deficient MMR was highlighted in the whole BTC case series, suggesting that a subset of BTC patients could benefit from checkpoint targeting [60]
Summary
Biliary tract cancers (BTCs) comprise a heterogeneous group of malignancies that include gallbladder cancer (GBC), ampulla of Vater cancer (AVC) and cholangiocarcinoma (CCA); the latter is further classified into intrahepatic (iCCA), perihilar (pCCA) and distal (dCCA), while pCCa and dCCA are referred to extrahepatic cholangiocarcinoma (eCCA). Chemotherapy is the actual standard of care for advanced disease, as emerged from the results of ABC-02 trial, a large multicenter phase III study that showed a significant survival advantage for cisplatin plus gemcitabine versus gemcitabine alone: overall survival (OS) 11.7 vs 8.1 months (hazard ratio [HR] 0.64; 95% confidence interval (CI) 0.52–0.80; p < 0.001) [9] This trial included 410 patients with heterogeneous BTCs (25% locally advanced, 75% metastatic), with 36.3% GBC. A Japanese phase III trial (KHBO1401-MITSUBA) showed a slight albeit significant superiority of the gemcitabine/cisplatin/S-1 combination over the standard treatment (cisplatin plus gemcitabine) in advanced BTC, including GBC [11] Another phase III study designed for unresectable GBC (17.7% stage III, 82.3% stage IV) failed to show the equivalence of a modified gemcitabine + oxaliplatin schedule (mGemOx) compared with the standard gemcitabine + cisplatin (GemCis) regimen, reporting a numerically better OS with mGemOx [12]. The study did not meet the primary endpoint of the phase 2 stage (PFS rate at 6 months) [15]
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