Background: The genetic background of cholangiocarcinoma (CCA) commonly involves alterations in kinase signaling, tumor suppression, oxidative stress modulation, and proto-oncogenic coupling pathways. Novel agents targeting such pathways have shown promise in systemic treatment; however, studies examining differences in the mutational landscapes between primary and recurrent, metastatic, or progressive disease after systemic therapy are lacking. The present study aimed to determine if recurrent, metastatic, or progressive disease genetically parallels the primary or not. Methods: Patients with biopsy proven CCA (primary tumor and paired recurrent/metastatic or progressive disease) from two institutions (MSKCC and Duke) were identified. Targeted next-generation sequencing (Integrated Mutation Profiling of Actionable Cancer Targets (IMPACT)) capturing single nucleotide variants, copy number alterations, and structural variants was used to compare driver alteration concordance across the paired samples. Subgroup analyses were performed based on exposure to systemic therapy in patients with disease progression and tumor type (intrahepatic versus extrahepatic). Results: Sample pairs from 65 patients with intrahepatic (ICCA, n=54) and extrahepatic CCA (ECCA, n=11) were analyzed. Median time between samples was 19.6 months (range 2.7 - 122.9). Some de novo alterations were identified in recurrent/metastatic samples, but overall concordance (70%) was demonstrated between patient pairs for common oncogenic driver genes (Table). Subgroup analyses of summative ICCA and ECCA mutations revealed concordance of 65% and 88%, respectively. Concordance was also demonstrated between pairs exposed to systemic therapy between sample collections (n=50, 71%). Conclusions: In this dataset of CCA patients, a concordance rate of 70% was identified in the genomic alterations between primary and recurrent/metastatic pairs, and this did not appear to be altered by prior treatment with systemic chemotherapy. While limited by sample size, concordance in ICCA pairs was lower than that seen in ECCA.

Oncogenic Mutations Identified in Paired Samples from Patients with CCA, stratified by exclusive to primary samples or recurrent/metastatic samples and those concordant between samples. For each gene, the number and percentage of mutations identified are listed. Stratification is reported as number and percentage of that mutation. *1 patient had mutations at different loci of ARID1A.