The potential role of serial circulating tumor DNA (ctDNA) testing after upfront surgery to guide adjuvant chemotherapy for early stage pancreatic cancer: The AGITG DYNAMIC-Pancreas trial.
Authors: Lee Belinda , Tie Jeanne , Wang Yuxuan , Cohen Joshua D. , Shapiro Jeremy David , Wong Rachel , Aghmesheh Morteza , Kiberu Andrew Ddembe , Francesconi Alessandra , Burge Matthew E. , Roy Amitesh Chandra , Dobbyn Lisa , Ptak Janine , Silliman Natalie , Papadopoulos Nickolas , Kinzler Kenneth W. , Vogelstein Bert , Gibbs Peter 
Published: August 2024

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Background: Recurrence rates following upfront resection of pancreatic adenocarcinoma are high, with some benefit from adjuvant chemotherapy (AC). A biomarker that improves risk stratification and/or provides real time indication of AC benefit could improve routine clinical management and accelerate trial progress. Previous studies in pancreas cancer suggest that patients with detectable ctDNA post surgery are at an elevated risk of recurrence. Detectable ctDNA at the completion of AC may also be associated with an elevated recurrence risk. Methods: Patients with early stage pancreatic adenocarcinoma were enrolled following upfront resection at 26 Australian centres. Patients were ECOG 0-1 and fit for AC. A tumour-informed ctDNA assay was used to identify somatic mutations for tracking in circulating cell-free DNA. ctDNA+ patients received 6 months of AC (FOLFIRINOX or gemcitabine/capecitabine selected at the clinician's discretion), while ctDNA- patients could de-escalate to 3 months at the clinician’s discretion. ctDNA was assessed again at the end of AC. The primary study endpoint was the feasibility of ctDNA-guided therapy. Secondary endpoints included the association of ctDNA with clinicopathologic risk factors and survival outcomes. Results: A total of 102 patients were enrolled from March 2019 to Nov 2023. Median age was 68 years (range 41 – 86), with 50% male and 95% ECOG 0-1. Tumours were located in the head of pancreas in 72%. Histology revealed T1 (18%), T2 (50%), and T3 (32%) tumors, with nodal involvement in 71%, and an R0 resection in 77%. Post-operative Ca19-9 was elevated in 29%. Forty patients (40%) were ctDNA+ve post resection, 54 (53%) were ctDNA-ve, and no result was obtained in 4 (4%) due to the absence of tumor mutation, and as a result, they were considered ineligible. The presence or absence of ctDNA was not associated with known clinicopathologic risk factors. Median time to ctDNA collection was 5 weeks (range 3 – 9) and to commencing AC was 6 weeks (range 4-12). Of 54 ctDNA-ve patients, 24 (44%) were de-escalated to receive a planned 3 months of AC. With a median follow-up of 36 months (range 2-56) the median recurrence free survival (RFS) in ctDNA+ve patients was 13 months compared to 22 months for ctDNA-ve patients (HR 0.52, p = 0.003). Conclusions: A tumor informed ctDNA approach to AC selection is feasible for patients undergoing upfront resection of pancreatic adenocarcinoma, with the first blood draw to be scheduled at week 5, allowing time for ctDNA analysis to determine AC selection. A high proportion of patients had detectable ctDNA, which appears independent of known prognostic markers. ctDNA detection was associated with earlier recurrence. Analyses of the impact of changes in ctDNA over time on survival are ongoing. Clinical trial information: ACTN12618000335291.