Abstract
Background
Pancreatic adenocarcinoma (PDAC) is highly lethal with up to 80% of resected patients experiencing disease recurrence within 2 years (Watanabe, Nakamura, Kimura et al in Int J Mol Sci 23(19):11521, 2022). Cross-sectional imaging and serum tumor markers are used for monitoring post-operative recurrence; however, both have significant limitations (Edland, Tjensvoll, Oltedal et al in Mol Oncol 17:1857–1870, 2023). Circulating tumor DNA (ctDNA) has emerged as a valuable prognostic tool to measure molecular residual disease (MRD) and predict recurrence in solid tumors (Watanabe, Nakamura, Kimura et al in Int J Mol Sci 23(19):11521, 2022). In this study, we evaluated the feasibility of a personalized, tumor-informed ctDNA assay to detect recurrence prior to standard surveillance tools in patients with PDAC.
Patients and Methods
After Institutional Review Board (IRB) approval (Pro00106870), we assessed serial ctDNA measurements (n = 177) from 35 patients with resectable PDAC treated by either upfront resection or neoadjuvant chemotherapy. Plasma samples (median 4 ml, interquartile range 0.6–5.9 ml) were isolated from blood collected in EDTA tubes and banked at diagnosis, during neoadjuvant therapy if applicable, on the day of surgery, and every 2–3 months postoperatively. A tumor-informed assay (Signatera™, Natera, Inc.) that tracks up to 16 individual-specific, somatic single nucleotide variants in the corresponding patient’s plasma samples were used for ctDNA detection. Survival was calculated using Kaplan–Meier curves, and significance was determined with the log-rank test.
Results
Personalized ctDNA assays were successfully designed for all patients (with 32/35 patients having 16-plex assays). Median follow-up from initial treatment was 13 months (range 1–26 months; Table 1). ctDNA-positivity at any time point was observed in 40% (14/35) of patients. During the follow-up period, 18 patients (51%) developed radiographic evidence of recurrence after a median of 9 months of follow-up (range 1–26 months). At the time of radiographic recurrence, 50% (9/18) of patients were ctDNA-positive. During the immediate postoperative period (up to 9 weeks post-surgery), RFS and OS were significantly inferior in patients who were ctDNA-positive versus ctDNA-negative (RFS 97 versus 297 days, p < 0.001; OS 110 versus 381 days, p < 0.001; Fig. 1).
a Overview plot showing longitudinal ctDNA status, treatment regimen, and clinical outcomes for each patient (N = 35); median follow-up from the start of the neoadjuvant therapy/surgery was 13 months (range 1–26 months); ctDNA at any time point was 40% (14/35); out of the 35 patients, 18 (51%) developed radiographic evidence of recurrence (median RFS: 9 months), and of these 18 patients with clinical recurrence, 9 (50%) were ctDNA-positive and the remaining ctDNA-negative; notably, all ctDNA-negative patients with recurrence had suboptimal plasma volume available for ctDNA analysis; b, c Kaplan–Meier estimates representing the association of ctDNA status with (b) RFS and (c) OS, at MRD time point (9 weeks post-surgery)
Discussion
Our study demonstrates the feasibility of tumor-informed ctDNA-based MRD testing in resectable PDAC and shows that MRD detected by ctDNA within the immediate postoperative period portends a dismal prognosis. This information is valuable for both patients and clinicians in setting prognostic expectations.
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References
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Funding
Austin Eckhoff acknowledges support from a NIH T-32 Grant (T32-CA093245) for translational research in surgical oncology and from the Duke Cancer Institute as part of the P30 Cancer Center Support Grant (Grant ID: P30 CA014236). Signatera granted $15,000 to cover supplies, histology review, and mailing for the study.
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Eckhoff, A.M., Kanu, E., Fletcher, A. et al. Initial Report: Personalized Circulating Tumor DNA and Survival in Patients with Resectable Pancreatic Cancer. Ann Surg Oncol 31, 1444–1446 (2024). https://doi.org/10.1245/s10434-023-14751-2
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DOI: https://doi.org/10.1245/s10434-023-14751-2