Gallbladder Cancer: Current Insights in Genetic Alterations and their Possible Therapeutic Implications

Abstract

Introduction: Due to the fast progression of molecular technologies such as next-generation sequencing, knowledge of genetic alterations in gallbladder cancer (GBC) is increasing. This systematic review aims to provide an overview of genetic alterations in GBC and their possible therapeutic implications. Method: This systematic review was prospectively registered in the PROSPERO registry (CRD42021265246). The study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A literature search was performed utilizing Pubmed, EMBASE, Cochrane Library and Web of Science. Only studies identifying genetic alterations in human GBC were included. Results: In total, data was extracted from 62 articles, describing a total of 3,893 GBC samples. Of all frequently (>5% across all studies) detected gene alterations in GBC, mutations in ATM, ERBB2, and PIK3CA, and amplifications in ERBB2 are potentially targetable. High tumor mutational burden (TMB) and microsatellite instability (MSI) were infrequently observed in GBC (1.7% and 3.5%, respectively). For tumors with high TMB or MSI, the highly active immune checkpoint inhibitor Pembrolizumab is approved by the United States Food and Drug Administration (FDA), with promising objective response rates in solid tumors including biliary tract cancer (50% and 41%, respectively). Only nine clinical trials which target frequently detected genetic alterations were identified. Conclusions: In conclusion, ATM mutations, ERBB2 amplifications and mutations, and PIK3CA mutations are potentially targetable alterations which were frequently detected in GBC. Few clinical trials targeting the frequently altered genes in GBC are performed, emphasizing the need for future, multi-center, clinical basket trials.