Real-world utilization of tissue-free ctDNA monitoring in patients with cholangiocarcinoma.

Abstract

515 Background: Circulating tumor DNA (ctDNA) for assessing treatment response and resistance is being explored in clinical settings. However, there is little data guiding clinical implementation. Here we describe the real-world clinical use and results of a tissue-free ctDNA monitoring assay in patients with cholangiocarcinoma. Methods: The clinical laboratory developed test, FoundationOneMonitor (F1Monitor), was available in a limited pilot. The timing and number of tests were determined by each physician as medically appropriate. Therapy abstraction was requested but not required. ctDNA was detected and quantified by ctDNA tumor fraction (TF); variants were tracked with variant allele frequency (VAF) and the short variant origin (tumor somatic, germline, or clonal hematopoiesis) predicted algorithmically. Results: F1Monitor was ordered by 11 physicians for 44 patients (113 tests) with cholangiocarcinoma. Therapies were abstracted for 32 patients: 41% on chemotherapy, 19% on targeted therapy (TT). The median follow-up was 153 days. 29 patients had ≥2 test. The median cadence of serial testing (3+ tests, 17 patients) was 35 days (IQR: 28,56) and similar between therapy types. CtDNA TF or clinically actionable alterations in NCCN guidelines were detected in 59% (26/44) of patients overall and 81% (21/26) of patients confirmed on active therapy. Actionable alterations were detected in 27% of patients including FGFR2 rearrangement (RE; n = 7), IDH1 mutation (n = 3), KRAS G12C (n = 1), and ERBB2 amplification (n = 1). The median and maximum ctDNA TF were 4.7% and 56% respectively. The lowest ctDNA TF and reportable tumor somatic VAF values quantified were 0.2% and 0.1%, respectively. Changes in ctDNA TF between tests were observed in 45% (13/29) of patients during their course of testing. In a single site cohort with confirmed pre- and post-treatment testing timepoints, 5/12 patients receiving chemotherapy and/or immunotherapy were ctDNA TF positive pre-treatment, 4/5 experienced >50% reduction in ctDNA TF by the 1 st response assessment (12 weeks). Of 7 patients with FGFR 2 RE, 6 had serial testing, and 5 were treated with FGFR TT. Decrease in RE or FGFR2 resistance variant VAF was seen following FGFR TT. An emerging FGFR2 resistance alteration was detected while on therapy, prior to progression on imaging in 1 patient. Conclusions: In real-world tissue-free ctDNA-based monitoring in cholangiocarcinoma, F1Monitor demonstrated high sensitivity in clinical practice, detecting ctDNA TF as low as 0.2% and tumor somatic VAF as low as 0.1%. In the limited follow up time, physicians chose to monitor patients approximately every 4-5 weeks. Importantly, 81% of patients had ctDNA TF or clinically actionable alterations detected while receiving therapy, and in a single site cohort with confirmed pre- and post-treatment timepoints, changes in ctDNA TF or target alterations were observed following therapy initiation.