The prognostic impact of early ctDNA kinetics in metastatic pancreatic cancer using the ctDNA Response Evaluation Criteria in Solid Tumors (ctDNA-RECIST).

Abstract

INTRODUCTION Changes in ctDNA levels during systemic treatment may predict treatment efficacy in patients with metastatic pancreatic ductal adenocarcinoma (PDAC), but quantitative response criteria are not yet established. This study evaluates our recently proposed ctDNA Response Evaluation Criteria in Solid Tumors (ctDNA-RECIST). MATERIAL AND METHOD Blood samples were collected pre-treatment, before the second treatment cycle, and at time of the first CT-evaluation from 220 patients with metastatic PDAC receiving first line palliative chemotherapy. Plasma ctDNA levels were measured using digital droplet PCR (ddPCR) with HOXA9 methylation assays. ctDNA response was determined according to ctDNA-RECIST and correlated with overall survival (OS). RESULTS ctDNA was positive pre-treatment in 71% of the patients, and was related with OS (HR=1.61, 95% CI 1.19-2.19, p=0.002). Among ctDNA-positive patients, ctDNA Maximal Response (MR) (n=41) and ctDNA Disease Control (DC) (n=107) before the second treatment cycle had longer OS compared with ctDNA Progressive Disease (PD) (n=5) (median OS: MR 11.9 months, DC 7.2 months, PD 3.6 months; p=0.002). In Cox regression ctDNA DC (HR=1.55, 95% CI 1.07-2.26, p=0.021) and ctDNA PD (HR=4.50, 1.74-11.6, p=0.002) showed shorter OS compared to ctDNA MR. The same applied to ctDNA response from the second treatment cycle (p<0.001) and at time of the first CT-evaluation assessed from treatment start (p<0.001) Conclusion: ctDNA-RECIST applied to liquid biopsies holds potential for early evaluation of treatment benefit in patients with metastatic PDAC, offering a novel, minimally invasive method to guide early clinical decision making. Future studies should validate ctDNA-RECIST prospectively, preferably in randomised controlled trials.