The Landscape of Genomic Alterations in Receptor Tyrosine Kinase Pathways in Biliary Cancers: Implications for Targeted Therapies.

Abstract

Background: Biliary carcinomas are aggressive cancers with a high mortality rate. When metastatic, biliary cancers are associated with a short survival and low response to treatments. The first line therapy of metastatic biliary carcinomas consists of a platinum doublet chemotherapy combination with an immune checkpoint inhibitor and results in a median overall survival in the range of approximately 12-13 months, with 20% to 25% of patients surviving at 2 years. Second line chemotherapy options based on fluoropyrimidines are associated with a median survival of less than 6 months. Genomic studies in recent years have clarified molecular aspects of biliary cancers and have confirmed the molecular heterogeneity between the intrahepatic, extrahepatic and gallbladder primary sites.

Methods: Publicly available genomic cohorts of biliary cancer primary locations were interrogated for common mutations and copy number alterations with a focus on receptor tyrosine kinases and their signal transduction pathways.

Results: Specific mutations and structural alterations have different prevalence depending on the primary location. Alterations in receptor tyrosine kinases and the transduction pathways originating from them show differential prevalence in the primary locations of the biliary cancers and create diverse treatment opportunities that can be harnessed for drug development. Approximately 49% of intrahepatic, 57.6% of gallbladder, and 66% of extrahepatic carcinomas harbor RTK pathway alterations.

Conclusions: Targeted therapies for individual components of these kinase receptors and pathways, including FGFR2, HER2, BRAF and others, have already been introduced in clinical practice for the treatment of patients with biliary tumors bearing alterations in these genes. The findings underscore the need for primary site-driven genomic testing to guide therapy selection. The current analysis discusses strategies to create opportunities for clinically available targeted therapies.