Pancreatic Cancer Progression in a Patient With Lynch Syndrome Receiving Immunotherapy: A Cautionary Tale
Bibliographic record
Abstract
Pancreatic ductal adenocarcinomas (PDACs) with DNA mismatch repair deficiency (MMRd) respond preferentially to immune checkpoint inhibitors (ICIs). However, a subset of MMRd PDACs does not respond to these agents. This report describes a patient with PDAC who experienced rapid disease progression suggestive of hyperprogressive disease. The case involved a 63-year-old man carrying a pathogenic germline PMS2 mutation who developed metastatic PDAC. His tumor showed isolated loss of PMS2 expression by immunohistochemistry (IHC). He was treated with pembrolizumab, but his disease rapidly progressed. Whole-genome and transcriptome sequencing of a liver metastasis biopsy, acquired at disease progression, showed a retained wild-type PMS2 allele and hallmarks of microsatellite stability, including low tumor mutational burden and low MSIsensor score. PCR-based microsatellite instability (MSI) testing of the treatment-naïve tumor showed microsatellite stability. The ICI-treated tumor had a lower density of CD8+ T-cell infiltration than the treatment-naïve tumor, which is contrary to the expected evolution with ICI responsiveness. Through this case and a review of the literature, we highlight the low penetrance of PMS2 germline mutations in PDAC and discuss pitfalls in ascertaining MMRd and MSI based on IHC testing alone. An orthogonal confirmatory assay is warranted in the presence of uncommon immunophenotypes, such as isolated PMS2 loss, to optimize selection of patients with PDAC for immunotherapy.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.005 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.002 | 0.001 |
| Scholarly communication | 0.002 | 0.002 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.005 | 0.003 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".