Utility of circulating tumor DNA (ctDNA) for the detection of minimal residual disease (MRD) after curative-intent therapy for patients with localized pancreatic adenocarcinoma (PDAC): A single institution series and meta-analysis.
Authors: Yanala Ujwal R. , Martos Mary P. , Dickey Erin M. , Corona Andres M , Ezenwajiaku Nkiruka , Pizzolato Joseph F. , Terrero Gretel , Hester Caitlin A. , Merchant Nipun B. , Datta Jashodeep , Hosein Peter Joel 
Published: January 2024

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Background: PDAC is associated with a high recurrence rate even after curative-intent surgical resection and perioperative chemotherapy. Detection of MRD in this setting can inform prognosis and may be actionable for innovative targeted therapies or additional chemotherapy to improve outcomes. While CA19-9 may detect disease before it is clinically apparent, it lacks specificity and up to 20% of patients (pts) are non-producers. ctDNA has been shown to be useful for MRD detection in other cancers but its utility in PDAC is not established. Methods: Pts with PDAC who had a commercial ctDNA assay (Natera) after completion of all curative-intent therapy (surgery and chemotherapy) in the MRD setting were included. Recurrence and survival data were correlated with the end-of-treatment (EOT) ctDNA result. Published literature and abstracts for studies examining ctDNA for MRD detection in PDAC using the same testing platform were identified. Available data were pooled to determine EOT ctDNA positivity rate, positive and negative predictive values (PPV, NPV), and lead time from a positive ctDNA to documented recurrence. Results: A total of 33 pts had EOT ctDNA samples collected at our institution. At EOT, ctDNA was + in 30.3% (n = 10). At a median follow-up time of 14.3 months, median recurrence free survival (RFS) for + vs negative ctDNA was 3.6 vs 25.1 months (HR = 15.8 [4.7-53.4], p < 0.001). Correlation of +ctDNA with recurrence showed a sensitivity of 52% (10/19), specificity of 100% (14/14), PPV of 100% (10/10) and NPV of 61% (14/23). Our institutional data were then combined with 138 pts reported in 3 prior publications/abstracts, for a total of 171 pts. Median follow-up ranged from 11.9-14.3 months and the overall EOT+ rate was 39% in the pooled cohort. The pooled sensitivity was 67% (49/73), specificity was 83% (81/98), PPV was 74% (49/66) and NPV was 77% (81/105). In each study as well as the pooled analysis, an EOT+ ctDNA was associated with significantly shorter RFS (HR = 8.1-120.5). Among 10 pts at our institution with recurrence, a + ctDNA test was detected after the recurrence 90% of the time, with a median lag-time of 4.70 months after recurrence (range -2.2 to 16.67 months). In the pooled cohort, among the 73 pts with recurrences, the ctDNA test was + before, at the time of, or after the recurrence in 23 (32%), 9 (12%) and 17 (23%) pts respectively; the ctDNA was negative despite recurrence in the remaining 24 (33%) pts. Conclusions: A tumor-informed positive ctDNA test after EOT shows high specificity and PPV for recurrence and is associated with significantly worse RFS in the MRD setting, while sensitivity of the test remains low. When positive, ctDNA assessment provides an opportunity for innovative therapies in the adjuvant setting to improve outcomes for localized PDAC.