Genome-wide analyses of cell-free DNA for therapeutic monitoring of patients with pancreatic cancer
Carolyn Hruban, Daniel C. Bruhm, Inna M. Chen, Shashikant Koul, Akshaya V. Annapragada, Nicholas A. Vulpescu, Sarah Short, Susann Theile, Kavya Boyapati, Bahar Alipanahi, Zachary L. Skidmore, Alessandro Leal, Stephen Cristiano, Vilmos Adleff, Julia S. Johansen, Robert B. Scharpf, Zachariah H. Foda, Jillian Phallen, Victor E. Velculescu
Abstract
Determining response to therapy for patients with pancreatic cancer can be challenging. We evaluated methods for assessing therapeutic response using cell-free DNA (cfDNA) in plasma from patients with metastatic pancreatic cancer in the CheckPAC trial (NCT02866383). Patients were evaluated before and after initiation of therapy using tumor-informed plasma whole-genome sequencing (WGMAF) and tumor-independent genome-wide cfDNA fragmentation profiles and repeat landscapes (ARTEMIS-DELFI). Using WGMAF, molecular responders had a median overall survival (OS) of 319 days compared to 126 days for nonresponders [hazard ratio (HR) = 0.29, 95% confidence interval (CI) = 0.11–0.79, P = 0.011]. For ARTEMIS-DELFI, patients with low scores after therapy initiation had longer median OS than patients with high scores (233 versus 172 days, HR = 0.12, 95% CI = 0.046–0.31, P < 0.0001). We validated ARTEMIS-DELFI in patients with pancreatic cancer in the PACTO trial (NCT02767557). These analyses suggest that noninvasive mutation and fragmentation-based cfDNA approaches can identify therapeutic response of individuals with pancreatic cancer.