Pancreatic ductal adenocarcinoma (PDAC) remains one of the digestive cancers with the poorest prognosis, and therapeutic options are still limited. The advent of immunotherapies based on immune checkpoint inhibitors has nonetheless opened an avenue for a particular subgroup of tumors: those exhibiting deficient DNA mismatch repair (dMMR) and the resulting microsatellite instability (MSI). This phenotype, already associated with clinical responses to immunotherapies across several metastatic cancers, is detected in only a small proportion of PDAC. Its true frequency remained to be clarified and, above all, the tumor subtypes likely to be enriched for it remained to be identified.
To address this question, the authors analyzed 445 PDAC samples from consecutive patients recruited across several centers, relying primarily on immunohistochemistry to detect loss of expression of the four repair proteins MLH1, MSH2, MSH6, and PMS2. This methodological choice is justified by the fact that PDAC are highly inflammatory tumors contaminated by stromal cells, a setting in which PCR-based detection of instability loses sensitivity; immunohistochemistry therefore served as a first filter, with pentaplex PCR and the HSP110 T17 marker being used only to confirm suspected cases or those of uncertain status. The study drew on several cohorts, including a multicenter retrospective cohort, a single-center cohort of PDAC associated with intraductal papillary mucinous neoplasms (IPMN), as well as a series of patient-derived xenografts free of contaminating human inflammatory cells.
The dMMR phenotype was found in only 1.6% of all tumors. The most striking finding, however, lies in its uneven distribution: IPMN-related PDAC exhibited repair deficiency in 6.9% of cases (4 of 58), compared with only 1.3% for PDAC not associated with IPMN (5 of 385), a statistically significant difference (P = 0.02). The dMMR or MSI tumors carried potentially immunogenic mutations within coding repeat sequences. They also displayed a higher density of CD8+ T lymphocytes at the invasive front (P = 0.08) and more frequently expressed the PD-L1 molecule (CD274): 8 of 9 cases, versus 4 of 10 among tumors without deficiency (P = 0.05).
In contrast, no significant difference in recurrence-free survival or overall survival was demonstrated between patients harboring dMMR or MSI tumors and the others. The authors conclude that further studies are needed to determine whether these features may constitute prognostic factors.