Abstract A30: Dynamics of ctDNA may serve as an early predictor of response to nontargeted chemotherapy of advanced lung cancer patients
Authors: Minarik Marek , Ptackova Renata , Belsanova Barbora , Svaton Martin , Halkova Tereza , Semyakina Anastasiya , Fiala Ondrej , Pesek Milos , Benesova Lucie 
Published: June 2020

Abstract
Introduction: Liquid biopsy methodology has long been utilized in management of patients with advanced lung cancer. The approach found its use in testing for a presence of somatic mutations of EGFR gene in circulating tumor DNA (ctDNA) to predict antiEGFR therapy response or resistance. More recently, ctDNA is being used as a biomarker for monitoring of the residual disease and early detection of progression or recurrence. The key factor in this case is in quantitative determination of the circulating mutant levels. In our project we have focused on non-small cell (NSCLC) patients receiving chemotherapy. We have first determined a presence of a nontargetable mutation in tumor tissue. Then we have searched for that specific mutation in plasma samples acquired prior and during the chemotherapy. The purpose of the study was to determine utility of ctDNA for evaluation of the disease course.
Methods: The group included 52 EGFR wild-type patients receiving nontargeted chemotherapy. All patients were subsequently monitored over the course of at least 3 cycles. Plasma was acquired at start of each cycle along with conventional imaging to evaluate therapy response (RECIST). Mutations in ctDNA were tested by Denaturing Capillary Electrophoresis (DCE) exhibiting a sensitivity of 0.1% to 0.05% MAF.
Results: Of the 52 patients, 28 had a presence of “trackable” TP53 or KRAS mutation in tumor tissue. 15 patients (15/28, 53.6%) were ctDNA positive prior to therapy start. At the end of the first cycle, ctDNA has been completely eliminated from circulation of 6 patients (6/15, 40.0%), while it was significantly reduced yet still detectable in 2 (2/15, 13.3%) or remained at a comparable level in 4 (4/15, 26.6%). In 2 patients (2/15, 13.3%) ctDNA levels have further increased. From the remaining 13 patients (13/28, 46,4%), ctDNA emerged in only 2 (2/13, 15.4%), while the rest maintained ctDNA negativity. The clinical outcome of the therapy could be closely related to the dynamics of the changing ctDNA levels. In the group of 12 monitored patients showing elimination, reduction, or unchanged ctDNA levels during the first therapy cycle were 6 patients with regression of the disease (6/12, 50%), 5 with stabilization (5/12, 41,7%), and only 1 patient with disease progression (1/12, 8.3%). At the same time progression was detected in all 4 patients whose ctDNA emerged or increased during the chemotherapy cycle. A Kaplan-Meier survival analysis revealed a significantly shorter time to progression in patients showing steady or increasing levels of ctDNA during the first cycle compared to those without any presence or significantly reduced ctDNA (median of 70 vs. 205 days, P=0.0017, long-rank test).
Conclusion: Our data indicate utility of ctDNA in prediction of therapy outcome in NSCLC patients receiving nontargeted chemotherapy. When independently validated, ctDNA could be used to assess efficiency even during the first chemotherapy cycle.
Supported by Czech Ministry of Health AZV 17-30748A project.
Citation Format: Marek Minarik, Renata Ptackova, Barbora Belsanova, Martin Svaton, Tereza Halkova, Anastasiya Semyakina, Ondrej Fiala, Milos Pesek, Lucie Benesova. Dynamics of ctDNA may serve as an early predictor of response to nontargeted chemotherapy of advanced lung cancer patients [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A30.