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10 slides generated from the cancer page, with a quiz from the open benchmark and speaker notes that cite the sources. Arrow keys move between slides; Print gives one slide per page.
Mismatch repair deficient pancreatic cancer is the rare pancreatic cancer whose cells cannot fix spelling errors in DNA and so carry thousands of mutations. That makes it one of the few pancreatic cancers that immunotherapy works against, and pembrolizumab is approved for it, though fewer of these tumours respond than in bowel cancer; testing every pancreatic cancer for the defect is the point.
Mismatch repair deficiency (loss of MLH1, MSH2, MSH6 or PMS2) produces microsatellite instability and a very high mutation burden with many frameshift neoantigens, which is why these tumours respond to PD-1 blockade despite the immunosuppressive stroma that defeats immunotherapy in the rest of pancreatic cancer. In the pancreas the defect is found in about 1 percent of ductal adenocarcinomas, more often in Lynch syndrome carriers, in KRAS wild-type tumours and in tumours with medullary or mucinous colloid histology, including some arising in intraductal papillary mucinous neoplasms. Testing is by immunohistochemistry for the four proteins or by sequencing-based microsatellite analysis, and a positive result should prompt germline testing for Lynch syndrome.
The tumour-agnostic approval of pembrolizumab in May 2017, based on KEYNOTE-016 and related studies, covered pancreatic cancer; the pancreatic cohort of KEYNOTE-158 showed responses in a minority of patients, lower than in colorectal or endometrial cancer, but some responses were durable. Dostarlimab received a tumour-agnostic approval in 2021 for mismatch repair deficient solid tumours after chemotherapy. Reasons for the lower response rate include misclassification by immunohistochemistry, the pancreatic stroma and lower neoantigen burden in some tumours, and chemotherapy remains the first-line standard with a checkpoint inhibitor used after progression or first line in patients unfit for chemotherapy.
| Setting | Approach | Guideline |
|---|---|---|
| Testing | Mismatch repair immunohistochemistry or microsatellite instability testing for every pancreatic adenocarcinoma at diagnosis, with germline testing for Lynch syndrome when deficient. | not mapped |
| Advanced, first line | Chemotherapy as for other pancreatic adenocarcinoma; pembrolizumab first line for patients unfit for chemotherapy or in trials. | not mapped |
| Advanced, after chemotherapy | Pembrolizumab (tumour-agnostic approval, KEYNOTE-158 pancreatic cohort) or dostarlimab (tumour-agnostic approval for mismatch repair deficient solid tumours). | not mapped |
| Resectable | Surgery and adjuvant chemotherapy as for other pancreatic adenocarcinoma; neoadjuvant immunotherapy only in trials. | not mapped |