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.

The current state of molecular profiling in gastrointestinal malignancies

“…PDAC is highly KRAS -mutated and harbors rarer targetable mutations. Many studies have evaluated KRAS and TP53 ctDNA detection and kinetics as prognostic and predictive biomarkers in PDAC cases [ 145 , 147 , 149 , 150 ].…”