Abstract 1575: Circulating tumor DNA as a tool for predicting response to targeted therapy in gastrointestinal malignancies
Authors: Schneider Jaime L. , Parikh Aparna , Rethinam Mehlika , Nadres Brandon , Seventer Emily Van , Shahzade Heather , Corcoran Ryan B. 
Published: August 2018

Abstract
Background: Patients with gastrointestinal (GI) malignancies undergoing treatment are surveyed for disease relapse with radiographic imaging and measurement of standard tumor markers. However, there is a need for more sensitive techniques to detect early cancer progression. Measurement of circulating tumor DNA (ctDNA) is emerging as an important diagnostic tool that can provide real-time information about disease response during treatment. In this study, we evaluated whether dynamic monitoring of ctDNA may predict cancer progression earlier than standard methods in patients with GI malignancies undergoing targeted therapy. Methods: Tumor and blood specimens were obtained from patients treated at the Massachusetts General Hospital (MGH) under IRB-approved studies. Tumor biopsies were performed at the time of diagnosis and were subjected to the MGH standard molecular diagnostics panel for 104 known cancer genes. Blood samples for ctDNA analysis were collected at baseline at the start of targeted therapy, and one more more driver mutations were followed longitudinaly at two week intervals starting one month after treatment. ctDNA was extracted from plasma using QIAGEN-based protocols and amplified by digital droplet PCR (ddPCR) using primers for tumor-specific point mutations. Tumor markers and CT scans were part of routine clinical care and procured using standard procedures at MGH. RECIST measurements, if available, were obtained in a blinded fashion using the Tumor Imaging Metrics Core. Results: We studied 44 patients with GI malignancies undergoing treatment with targeted therapies. Represented cancer types included colorectal (53%), gastroesophageal (21%), biliary (20%), and pancreatic cancers (6%). We correlated the % change in ctDNA mutant allele fraction (MAF) or standard tumor markers 4 weeks after treatment initiation with radiographic response by RECIST. Tumor-specific MAF decreased by 88% in patients who went on to show partial response (PR) or stable disease (SD), compared to an increase by 51% in patients shown to have progressive disease (PD) (p=1.8x10-5). All patients who achieved PR, except one, had a reduction in ctDNA levels by at least 93% or more. In contrast, standard tumor markers did not predict response as there was no significant difference in the % change at 4 weeks in the PR/SD group compared to PD (p=0.64). Conclusions: Real-time monitoring of patient-specific tumor mutations by ctDNA analysis has the potential to predict response to targeted therapy earlier than standard surveillance mechanisms. Integration of liquid biopsies into medical decision-making may allow for earlier identification of cancer progression and consequent modification of therapeutic approach. However, more studies are needed to determine whether incorporation of ctDNA analysis into clinical practice would impact patient outcomes.
Citation Format: Jaime L. Schneider, Aparna Parikh, Mehlika Rethinam, Brandon Nadres, Emily Van Seventer, Heather Shahzade, Ryan B. Corcoran. Circulating tumor DNA as a tool for predicting response to targeted therapy in gastrointestinal malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1575.