PD-10 Comprehensive circulating tumor (ct) DNA NGS for molecular profiling in advanced cholangiocarcinoma

Abstract

Cholangiocarcinoma (CCA) is a rare and heterogeneous cancer with dismal prognosis. At the molecular level, CCA is highly heterogeneous, with multiple druggable alterations some of them with already targeted therapies approved. Accordingly, ESMO has recently recommended NGS tissue testing in routine clinical practice for patients with advanced CCA. However, access to tumor biopsy for CCA is technically difficult in a subset of patients. Sequencing of circulating tumor (ct) DNA (liquid biopsy) is a potential alternative to tissue molecular testing, that overcomes intratumoral heterogeneity with a minimal invasive approach and easy access. We aimed at assessing the feasibility and clinical utility of ctDNA genotyping for patients with advanced CCA in a group of referral Oncology centers across Spain. We genotyped ctDNA from blood samples from patients with advanced CCA, treated between 2019 and 2021 at 9 Spanish University Hospitals. ctDNA sequencing was performed by an NGS-based comprehensive approach using Guardant360™ (G360). ctDNA sequencing data were available for 112 patients. The main clinical characteristics were as follow: median age was 62.5 years (range: 28-86), 62 patients (55.3%) were men, 65 patients (58%) had intrahepatic cholangiocarcinoma, 70 patients (62.5%) had stage IV disease at diagnosis and 98 patients (87.5%) had received cisplatin plus gemcitabine as first-line treatment for advanced disease. Determination of ctDNA was performed at baseline in 36.6% of patients and at the time of progression to first-line treatment in 48 patients (42.8%). 96% of patients had ≥ 1genomic alteration detected. Median number of alterations per patient was 2 and median VAF was 0.5%. 245 genomic alterations (GAs) have been identified among 35 different genes. 89% of GAs identified were SNVs, being the most frequent TP53 (33.9%), KRAS (9.8%), IDH1 (6.5%), ATM (6.5%), PIK3CA (4.9%) and ARID1A (4.5%). CNVs accounted for 7.7% of GA and consisted in amplifications of: EGFR (1.6%), MYC (1.6%), BRAF (1.2%) and ERBB2 (0.8%). FGFR2 and FGFR3 fusions were identified in 1.2% and 0.4% patients, respectively. High-microsatellite instability was identified in 1.2% of patients. These findings are similar to previously reported data on tissue molecular profiling in CCA. Importantly, sixty-seven patients (53%) had GA considered as actionable, including three patients with FGFR2 fusions, for which Pemigatinib is approved. ctDNA genotyping for molecular profiling of advanced cholangiocarcinoma patients is feasible and a non-invasive procedure, especially relevant for CCA patients in which increase in actionable biomarkers and insufficient tissue availability is becoming a challenge.