Comparative Landscape of Actionable Somatic Alterations in Advanced Cholangiocarcinoma From Circulating Tumor and Tissue-Based DNA Profiling

ASCO Gastrointestinal Cancers Symposium 2021 Presentation
Authors Pashtoon Murtaza Kasi, Alexander D Le, and Alex Barrett

Background: Cholangiocarcinoma (CCA) is a target-rich disease. Despite this, treatment guidelines lack recommendations for broad molecular profiling in CCA to identify potentially actionable targets. Furthermore, comparative data assessing similarities and differences in actionable ctDNA and tissue based genomic biomarkers remain limited. As such, we sought to broadly characterize the genomic alterations that are linked to targeted therapies that may facilitate a more personalized approach to therapy.

Methods: We retrospectively analyzed NGS data obtained from 137 advanced cholangiocarcinoma patients via Tempus xT tissue biopsy assay (DNA sequencing of 648 genes in tumor and matched normal samples at 500x depth) and/or Tempus xF liquid biopsy assay (ctDNA sequencing of 105 genes in peripheral blood samples at 5,000x depth) for germline and/or somatic mutations including single nucleotide variants, specific insertion/deletions, amplifications and gene fusions.

Results: 110 patients were tested once and 27 patients had two or more tests available. Of the 174 genomic results, 113 were tissue-based NGS results, and 61 were liquid-based NGS results. The total number of unique alterations was found to be 296. Focusing on aberrations for which there are approved therapies in the same or other tumor types or inclusion in guidelines and/or active clinical trials, we found FGFR2 fusions (6.8%), IDH1/2 (8.4%), BRAF-V600E (2.5%), HER2 (3%), MET (0.7%), BRCA1/2/ATM (2%), PIK3CA (4.7%), and ERRFI1 (0.7%). This comprises ~30% (Table). Of note, within this bucket of actionable findings, if we focus on ctDNA liquid biopsy cohort, the proportion goes up to 33.1% vs. 23.2% for tissue based genomic testing. For example, comparison of liquid to tissue, FGFR2 fusion was noted in 11.3% vs. 3.4%, BRAF-V600E in 3% vs. 1% and HER2 0% vs. 3.8%, respectively. Also, no MSI-High patients but two (1.5%) had KRAS-G12C mutation. Notable differences in the prevalence of actionable somatic mutations in solid vs. liquid results were observed (Table).

Conclusions: These data provide an updated benchmark for guiding the development of targeted therapies in molecularly profiled CCA and support the use of both solid and liquid biopsy molecular profiling to guide therapy selection in patients with advanced cholangiocarcinoma. Additionally, liquid biopsy molecular profiling can fill the void where tissue may not be readily available.