Utility of an amplicon-based ctDNA platform for advanced cholangiocarcinomas (CCA) in Asia.

Abstract

e16206 Background: Cholangiocarcinoma represents a major cause of cancer mortality in Asia. While clinical outcomes have improved with the addition of anti-PD1/PDL1 agents to standard-of-care chemotherapy for advanced disease, recent data suggests that novel agents against IDH1 mutations, FGFR2 and NTRK rearrangements, BRAF V600E mutations, and microsatellite instability (MSI) are effective. Tumor-based next generation sequencing (NGS) is routinely recommended by guidelines but is limited by tissue availability and quality in patients with unresectable disease. A comprehensive circulating tumor DNA-based (ctDNA) NGS platform offers an acceptable alternative, but its clinical utility and pickup rate for oncogenic drivers remain unknown. Methods: In our multi-national cohort of advanced CCA across 5 countries, we explored the utility of Lucence LiquidHALLMARK (LHM), a Medicare-reimbursed, amplicon-based NGS ctDNA platform targeting 80 cancer related genes, 10 fusions, and MSI. Performance of LHM has been previously reported. Data was retrieved in-house by a de-identified centralized database and pooled for analysis. Here, we report the demographic and genomic findings of our cohort and highlight the impact of testing on actionable molecular alteration discovery. Results: Between Jan 2020 and Dec 2023, 60 samples from 56 patients (62.5% male) with advanced CCA in Hong Kong SAR (50.0%), Singapore (41.1%), Thailand (3.6%), Philippines (3.6%), and Malaysia (1.8%) underwent LHM testing. Metastatic disease accounted for 83.9% and 8.9% had locally advanced disease. Median age was 67 years (range 33-88), with 34% and 30% of tests obtained during first-line therapy and at diagnosis respectively. Only 6 cases had available tissue NGS results. Analysis on 56 baseline samples showed an 80.4% discovery rate (45/56 patients) for ≥1 molecular alterations. A median of 2 variants (mean 3.27) was detected per sample, with variant allele fraction ranging from 0.05% to 66.5%. Importantly, 8.9% (5/56) of patients harbored ≥1 actionable variants, including 3 with FGFR2 rearrangements ( FGFR2- WAC, FGFR2- ACTR1A, FGFR2- CAMK2D) and 2 with BRAF V600E drivers. A further 3 patients had potentially druggable variants in IDH2 and FGFR3 and 12 harbored BRCA1/2 variants, of which 4 were deleterious. None of the samples had MSI. Top 10 mutated genes were TP53 (48%), KRAS (21%), BRCA2 (18%), PIK3CA (11%), TERT (9%), CDKN2A (9%), SMAD4 (9%), FGFR2 (7%), BRAF (7%), and CDK6 (5%). Limited histopathological and treatment outcomes are available in the current dataset. Conclusions: Our advanced cholangiocarcinoma cohort of 56 patients from 5 Asian countries showed that an amplicon based ctDNA liquid biopsy platform overcomes the tissue-related challenges of genomic profiling specific to unresectable biliary tumors. We showed an 80.4% discovery rate for any molecular alterations and a 8.9% pickup rate for variants with strong actionability.