Real-world microscopic residual disease (MRD) monitoring with circulating tumor DNA (ctDNA) in pancreatic adenocarcinoma (PDAC).
Authors: Li Peter Chi-Win , Winters Harrison David , Geng Xue , Wang Hongkun , Schumann Alan , Noel Marcus Smith , He Aiwu Ruth , Weinberg Benjamin Adam , Marshall John , Tesfaye Anteneh A. , Mukherji Reetu 
Published: January 2025

696

Background:
ctDNA is a powerful tool that can detect MRD with limited but emerging data in patients (pts) with PDAC. We describe the clinical outcomes of pts with PDAC who underwent real-world MRD testing at our institutions.
Methods:
We retrospectively analyzed pts at 2 institutions with ≥1 tumor-informed ctDNA test (Natera, Inc) ordered for MRD testing post-operation (post-op) between June 2020-August 2024. Descriptive statistics were used to characterize clinicopathologic factors, ctDNA positivity (ctDNA+), and relapse rates (RR). Median relapse-free survival (mRFS) and overall survival (mOS) were calculated using Kaplan-Meier methods, comparisons between groups by log-rank test, and hazard ratios (HR) by Cox proportional hazard models. Associations between clinicopathologic factors and outcomes were assessed by Fisher’s exact and Chi-square tests.
Results:
Of the 54 pts who underwent MRD testing, 48 pts (88.9%) had successful tests. Failures were due to insufficient tissue. Patients with successful tests were staged as follows: 31.2% stage 1, 50.0% stage 2, and 18.8% stage 3, with 12.5% having R1/2 resections and 46.8% being node-positive. With a median follow-up of 21.0 months (mo), 22 (45.8%) pts had relapsed and 22 (45.8%) were anytime-ctDNA+. Sensitivity and specificity of ctDNA for relapse was 77.3% and 86.4%, respectively. Between anytime- and never-ctDNA+ pts, RR were 77.0% vs. 23.1%, mRFS 14.2 mo vs. not reached (NR) (HR 4.9, 95% CI 1.9-12.9), and mOS 31.7 mo vs. NR (HR 3.3, 95% CI 1.0-10.9), respectively. For 27 pts tested in the MRD window (2-12 weeks post-op), mRFS was 6.6 vs. 25.0 mo (HR 3.1, 95% CI 1.0-9.4) and mOS was 25.5 mo vs. NR (HR 2.5, 95% CI 0.6-10.2) in ctDNA+ vs. negative pts. ctDNA+ preceded radiographic relapse in 54.5% of patients with a median lead time of 166 days (IQR 70-332). In anytime-ctDNA+ pts, there were non-statistically significant trends for improved RFS and OS based on ctDNA decrease and clearance (table). No clinicopathologic factors predicted ctDNA+. Post-op ctDNA+ (p <0.001) and CA 19-9 (p=0.03) were the only factors that had a significant association with RFS.
Conclusions:
Post-op ctDNA is a strong prognostic marker for survival in PDAC, predicting relapse about five months before imaging. ctDNA+ status is independent of clinicopathologic factors and the strongest predictor of recurrence. These findings highlight a window where novel therapies could be tested to eradicate MRD. Longer follow up and prospective studies are needed to validate its predictive role with therapies in the MRD setting to improve outcomes in high-risk pts.

RFS events/total
mRFS (mo)
HR (95% CI)
p
OS events/total
mOS (mo)
HR (95% CI)
p

ctDNA clearance
Yes
6/9
17.0
0.61 (0.2-1.7)
0.35
2/9
NR
0.37 (0.08-1.8)
0.20

No
11/13
10.3
8/13
31.7

ctDNA MTM/mL reduction
≥50%
8/11
15.5
0.93 (0.3-2.9)
0.90
3/11
NR
0.54 (0.1-2.4)
0.42

<50%
6/8
13.6
4/8
31.7