Abstract PR008: Genome-wide analyses of cfDNA fragmentomes for therapeutic monitoring of patients with pancreatic cancer
Authors: Hruban Carolyn A , Bruhm Daniel C. , Chen Inna M , Koul Shashikant , Annapragada Akshaya V , Vulpescu Nicholas A , Short Sarah , Theile Susann , Boyapati Kavya , Cristiano Stephen , Adleff Vilmos , Johannsen Julia S , Scharpf Robert B , Foda Zachariah H , Phallen Jillian A , Velculescu Victor E 
Published: November 2024

Abstract
Determining response to therapy for patients with pancreatic cancer can be challenging using imaging alone, and there is an unmet need for noninvasive assessment of tumor burden. We developed a method for assessing response to therapy using circulating cell-free DNA (cfDNA) and tested it using 217 plasma samples from 40 patients with metastatic pancreatic cancer treated with immune checkpoint inhibition and radiation as part of the CheckPAC trial (NCT02866383). Samples were evaluated before and after initiation of therapy using a mutation-independent and tumor-independent approach (ARTEMIS-DELFI), combining genome-wide cfDNA fragmentation profiles and repeat landscapes. Patients with below median scores (n=16) at the time of the first follow up CT scan at 8 weeks had a longer median progression free survival (PFS) and longer median overall survival (OS) than patients with above median scores (n=17) (PFS: 153 days versus 50 days; HR=0.26, 95% CI=0.11-0.64, p=0.0013) (OS: 375 days versus 121 days; HR=0.12, 95% CI=0.045-0.30, p&lt;0.0001). Additionally, a “fast fail” analysis of patients with scores above the 75th percentile evaluated at 2 weeks after initiation of therapy (n=9) resulted in shorter median PFS and shorter median OS than patients with lower scores (n=27) (PFS: 46 days versus 110 days; HR=0.29 95% CI=0.13-0.66, p=0.0027), (OS: 88 days versus 230 days; HR=0.35 95% CI=0.16-0.78, p=0.00011). We validated the approach in a separate cohort of 205 samples from 40 patients with pancreatic cancer treated with first line chemotherapy, with and without IL-6 inhibition, as part of the PACTO trial (NCT02767557). Patients with below median scores at the 8-week first follow up CT scan (n=16) had a longer median OS than patients with above median scores (n=16) (OS: 288 days vs 199 days, HR=0.488, 95% CI=0.24–1.01, p=0.048). Similar results were observed at 2 weeks after initiation of therapy when considering patients with scores above the 75th percentile (n=9) compared to patients with lower scores (n=27) (OS: 196 days versus 280 days) (HR=0.17, 95% CI=0.06-0.46, p=0.0074). These analyses suggest that non-invasive fragmentation-based cfDNA approaches can identify individuals with pancreatic cancer who are not responding to therapy as early as two weeks after treatment initiation. Incorporation of these molecular methods to evaluate tumor burden may provide timely information for patient-physician decision making to improve patient care.
Citation Format: Carolyn A Hruban, Daniel C. Bruhm, Inna M Chen, Shashikant Koul, Akshaya V Annapragada, Nicholas A Vulpescu, Sarah Short, Susann Theile, Kavya Boyapati, Stephen Cristiano, Vilmos Adleff, Julia S Johannsen, Robert B Scharpf, Zachariah H Foda, Jillian A Phallen, Victor E Velculescu. Genome-wide analyses of cfDNA fragmentomes for therapeutic monitoring of patients with pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr PR008.