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. 2025 May;32(5):3568-3577.
doi: 10.1245/s10434-024-16621-x. Epub 2024 Dec 10.

Survival of Patients with Resected Microsatellite Instability-High, Mismatch Repair Deficient, and Lynch Syndrome-Associated Pancreatic Ductal Adenocarcinomas

Ellis L Eikenboom #  1   2   3 , Naaz Nasar #  1 , Kenneth Seier  4 , Mithat Gönen  4 , Manon C W Spaander  3 , Eileen M O'Reilly  5 , William R Jarnagin  1 , Jeffrey Drebin  1 , Michael I D'Angelica  1 , T Peter Kingham  1 , Vinod P Balachandran  1   6 , Kevin C Soares  1 , Anja Wagner  2 , Alice C Wei  7
Affiliations

Survival of Patients with Resected Microsatellite Instability-High, Mismatch Repair Deficient, and Lynch Syndrome-Associated Pancreatic Ductal Adenocarcinomas

Ellis L Eikenboom et al. Ann Surg Oncol. 2025 May.

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) remains a challenging disease due to its aggressiveness, late-stage diagnosis, and limited treatment options. Microsatellite instability-high (MSI-H) cancers are susceptible to immune checkpoint inhibitors. Survival outcomes for patients with MSI-H PDAC are unknown as the disease is rare.

Methods: This study included patients with PDACs surgically resected from 1990 to 2023, and those with germline or sporadic pathogenic variants in DNA mismatch repair genes were identified. The study matched MSI-H, mismatch repair-deficient (MMRd), and Lynch syndrome (LS)-associated PDAC cases (on age, gender, and year of surgery) with microsatellite-stable (MSS), mismatch repair-proficient, or non-LS-associated PDAC cases in a 1:2 ratio. A generalized estimating equation Cox model with a robust sandwich estimator was used to compare overall survival (OS) in the matched cohorts.

Results: Of 936 cases, 18 were included. Eight cases were MSI-H/MMRd, two were MSI/IHC-indeterminate, seven were MSS, and one was not tested for MSI. Nine patients had LS (MLH1 [n = 1], MSH2 [n = 4], MSH6 [n = 1], PMS2 [n = 3]), and nine patients had sporadic pathogenic variants in DNA MMR genes (MLH1 [n = 4], MSH6 [n = 5]). After matching to 36 control patients, the MSI-H/MMRd/LS PDACs had a significantly better OS (hazard ratio [HR], 0.36 [95% confidence interval [CI], 0.18-0.73; p = 0.005]; 5-year OS: MSI-H 77% [95% CI 58-100%] vs. MSS 27% [95% CI 15-51%]).

Conclusion: Before routine use of immune checkpoint inhibitors, the patients with MSI-H, MMRd, and LS-associated PDACs displayed significantly better survival than the patients with MSS, MMR-proficient, non-LS-associated PDACs. It is expected that survival for this cohort will further improve with increased availability of immunotherapy.

Keywords: Lynch syndrome; Microsatellite instability; Mismatch repair deficient; Overall survival; Pancreatic ductal adenocarcinoma.

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Conflict of interest statement

Disclosure: Eileen M. O’Reilly reports research funding to Genentech/Roche, BioNTech, AstraZeneca, Arcus, Elicio, Parker Institute, NIH/NCI, and Digestive Care, Break Through Cancer, as well as consulting/DSMB for Arcus, Alligator, Agenus, BioNTech, Ipsen, Merck, Moma Therapeutics, Novartis, Syros, Leap Therapeutics, Astellas, BMS, Fibrogen, Revolution Medicine, Merus Agios (spouse), Genentech-Roche (spouse), Eisai (spouse), Servier (spouse). Jeffrey Drebin reports employment and leadership at American Regent (spouse) and stock and other ownership interests in Alnylam, Arrowhead Pharmaceuticals and Ions pharmaceuticals. Vinod P. Balachandran reports research funding from Genetech/Roche and was an inventor on patent applications related to antigen cross-reactivity and neoantigen quality modeling. Alice C. Wei reports consulting for Histosonics and clinical trial funding from Ipsen. The remaining authors have no conflicts of interest.

References

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