Analysis of pancreatobiliary adenocarcinoma (PBC) treatment response and resistance utilizing circulating tumor DNA (ctDNA).

Abstract

758 Background: Accurate disease monitoring in PBC is instrumental for optimal therapeutic decision-making. CA 19-9 is the most utilized biomarker, though it has limited sensitivity/specificity and cannot be used in CA 19-9 non-secretors (n-S). ctDNA is a potentially helpful monitoring aid and surrogate for PBC n-S. Serial ctDNA could identify emerging resistant driver mutations. Our study prospectively examined ctDNA in PBC patients receiving treatment and retrospectively correlated it with clinical response. Methods: We performed genomic testing of ctDNA from metastatic PBC patients’ plasma from 11/2016 to 08/2019. This included 77 patients, of those, 18 had >1 ctDNA measurement with 49 correlative data points in total. Demographics, serial CA 19-9 levels and imaging results were collected. ctDNA analysis by parallel sequencing of amplified target genes (74) using Guardant360 was obtained. We correlated imaging and CA 19-9 responses with molecular alterations in patients receiving systemic chemotherapy. Descriptive statistics and logistic regression of the data was performed. Results: Of those included, median age was 66 yo, 50% male, and 92% pancreatic ductal adenocarcinoma. Baseline ctDNA showed 103 mutations including TP53 12.6%, KRAS 9.7%, MET 6.8%, APC, ARID1A and NF1 4.8% each, and others < 3%. 44% of patients were n-S with 75% having both TP53 and KRAS mutations. APC, ARID1A, and NF1 were only present in n-S. 91% vs 90% KRAS and 84% vs 78% TP53 of n-S and secretors (S), respectively, had correlation between ctDNA levels and imaging response. S TP53 and KRAS mutations correlated to CA19-9 levels and scans in 78% and 70% responses. New TP53 subclonal variant mutations were the most common resistance mutations for all progressions (75%). A logistic regression model of imaging progression on change in CA19-9 secretion and TP53 or KRAS expression was not statistically significant. Conclusions: Baseline ctDNA level changes ( TP53 and KRAS) can potentially act as a biomarker of response in PBC, specifically in n-S. TP53 subclonal mutations were the most common resistant alterations at progression and can be explored as future targets. This is being explored in larger prospective trials.