TY - JOUR
T1 - Gallbladder Cancer
T2 - Current Insights in Genetic Alterations and Their Possible Therapeutic Implications
AU - Kuipers, Hendrien
AU - de Bitter, Tessa J J
AU - de Boer, Marieke T
AU - van der Post, Rachel S
AU - Nijkamp, Maarten W
AU - de Reuver, Philip R
AU - Fehrmann, Rudolf S N
AU - Hoogwater, Frederik J H
PY - 2021/10/20
Y1 - 2021/10/20
N2 - Due to the fast progression in molecular technologies such as next-generation sequencing, knowledge of genetic alterations in gallbladder cancer (GBC) increases. This systematic review provides an overview of frequently occurring genetic alterations occurring in GBC and their possible therapeutic implications. A literature search was performed utilizing PubMed, EMBASE, Cochrane Library, and Web of Science. Only studies reporting genetic alterations in human GBC were included. In total, data were extracted from 62 articles, describing a total of 3893 GBC samples. Frequently detected genetic alterations (>5% in >5 samples across all studies) in GBC for which targeted therapies are available in other cancer types included mutations in ATM, ERBB2, and PIK3CA, and ERBB2 amplifications. High tumor mutational burden (TMB-H) and microsatellite instability (MSI-H) were infrequently observed in GBC (1.7% and 3.5%, respectively). For solid cancers with TMB-H or MSI-H pembrolizumab is FDA-approved and shows an objective response rates of 50% for TMB-H GBC and 41% for MSI-H biliary tract cancer. Only nine clinical trials evaluated targeted therapies in GBC directed at frequently altered genes (ERBB2, ARID1A, ATM, and KRAS). This underlines the challenges to perform such clinical trials in this rare, heterogeneous cancer type and emphasizes the need for multicenter clinical trials.
AB - Due to the fast progression in molecular technologies such as next-generation sequencing, knowledge of genetic alterations in gallbladder cancer (GBC) increases. This systematic review provides an overview of frequently occurring genetic alterations occurring in GBC and their possible therapeutic implications. A literature search was performed utilizing PubMed, EMBASE, Cochrane Library, and Web of Science. Only studies reporting genetic alterations in human GBC were included. In total, data were extracted from 62 articles, describing a total of 3893 GBC samples. Frequently detected genetic alterations (>5% in >5 samples across all studies) in GBC for which targeted therapies are available in other cancer types included mutations in ATM, ERBB2, and PIK3CA, and ERBB2 amplifications. High tumor mutational burden (TMB-H) and microsatellite instability (MSI-H) were infrequently observed in GBC (1.7% and 3.5%, respectively). For solid cancers with TMB-H or MSI-H pembrolizumab is FDA-approved and shows an objective response rates of 50% for TMB-H GBC and 41% for MSI-H biliary tract cancer. Only nine clinical trials evaluated targeted therapies in GBC directed at frequently altered genes (ERBB2, ARID1A, ATM, and KRAS). This underlines the challenges to perform such clinical trials in this rare, heterogeneous cancer type and emphasizes the need for multicenter clinical trials.
KW - gallbladder cancer
KW - gene mutations
KW - genetic alterations
KW - tumor mutational burden
KW - microsatellite instability
KW - targeted therapy
KW - TUMOR MUTATIONAL BURDEN
KW - LAPATINIB PLUS CAPECITABINE
KW - BILIARY-TRACT CARCINOMAS
KW - GROWTH-FACTOR RECEPTOR
KW - K-RAS ONCOGENE
KW - MICROSATELLITE INSTABILITY
KW - OPEN-LABEL
KW - GENOMIC ALTERATIONS
KW - SOMATIC MUTATIONS
KW - TRASTUZUMAB
U2 - 10.3390/cancers13215257
DO - 10.3390/cancers13215257
M3 - Review article
C2 - 34771420
VL - 13
JO - Cancers
JF - Cancers
SN - 2072-6694
IS - 21
M1 - 5257
ER -