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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.
Open questions are whether checkpoint inhibitors should be used first line, whether dual checkpoint blockade (as in colorectal cancer) or combination with chemotherapy improves responses, and whether frameshift neoantigen vaccines being tested in Lynch syndrome could prevent pancreatic cancer in carriers. Because the group is so small, evidence comes from baskets and case series rather than pancreatic-specific trials.
About 1 percent of pancreatic ductal adenocarcinomas are mismatch repair deficient, a smaller share than in bowel or womb cancer; many arise in people with Lynch syndrome, and medullary and mucinous histology are clues.
Most pancreatic cancers arise in the head next to the bile duct, which is why jaundice is the presenting sign; bile duct cancers are named by where along the tree they sit.
Same organ: Glucagonoma, VIPoma, Somatostatinoma, Pancreatic ductal adenocarcinoma, Biliary tract cancer (cholangiocarcinoma), Intrahepatic cholangiocarcinoma, Extrahepatic cholangiocarcinoma (perihilar and distal), Biliary tract cancer (all types), Neuroendocrine tumours, Pancreatic neuroendocrine tumours, Grade 3 well-differentiated neuroendocrine tumour, Extrapulmonary neuroendocrine carcinoma, Gallbladder cancer, Gallbladder adenocarcinoma, Papillary carcinoma of the gallbladder, Mucinous carcinoma of the gallbladder, Adenosquamous and squamous carcinoma of the gallbladder, Neuroendocrine carcinoma of the gallbladder, Incidental gallbladder cancer (found after cholecystectomy), Carcinoma in situ and dysplasia of the gallbladder, Cystic duct carcinoma, Ampullary cancer (ampulla of Vater), Resectable pancreatic ductal adenocarcinoma, Borderline resectable pancreatic ductal adenocarcinoma, Locally advanced unresectable pancreatic ductal adenocarcinoma, Metastatic pancreatic ductal adenocarcinoma, KRAS G12C-mutant pancreatic ductal adenocarcinoma, KRAS wild-type pancreatic ductal adenocarcinoma, BRCA or PALB2-mutant pancreatic ductal adenocarcinoma, Pancreatic acinar cell carcinoma, Intraductal papillary mucinous neoplasm and other pancreatic cystic precursors, Pancreatoblastoma, Adenosquamous carcinoma of the pancreas, Colloid (mucinous non-cystic) carcinoma of the pancreas, Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells, Invasive carcinoma arising in an intraductal papillary mucinous neoplasm (IPMN-associated carcinoma), Mucinous cystic neoplasm of the pancreas with associated invasive carcinoma (MCN-associated carcinoma), Solid pseudopapillary neoplasm of the pancreas
Mismatch repair immunohistochemistry or microsatellite instability testing for every pancreatic adenocarcinoma at diagnosis, with germline testing for Lynch syndrome when deficient.
Chemotherapy as for other pancreatic adenocarcinoma; pembrolizumab first line for patients unfit for chemotherapy or in trials.
Pembrolizumab (tumour-agnostic approval, KEYNOTE-158 pancreatic cohort) or dostarlimab (tumour-agnostic approval for mismatch repair deficient solid tumours).
Surgery and adjuvant chemotherapy as for other pancreatic adenocarcinoma; neoadjuvant immunotherapy only in trials.
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This is the fusion and immune-marker table for the wild-type minority, the group in which RNA sequencing pays for itself.
It tells the pathologist which pancreatic cancers to test for the one immunotherapy-responsive subgroup and how.
Every pancreatic cancer should be tested for mismatch repair deficiency because the 1 percent who have it can receive pembrolizumab, but responses in pancreatic cancer are less frequent and less durable than in other MSI-high cancers.
Because Lynch syndrome tumours make the same abnormal proteins in almost every patient, a single vaccine could in principle be given to carriers before cancer develops. This small trial showed the concept is safe and immunogenic; whether it prevents cancer requires the randomised trials now being planned.
It fixed the working numbers for a comprehensive panel in pancreatic cancer: a hit worth acting on in about one patient in six, most of it in repair genes and the KRAS wild-type minority.
Guidelines recommending universal mismatch repair testing in pancreatic cancer, by immunohistochemistry or sequencing rather than PCR alone, rest on this and similar series.
This paper established a new regulatory paradigm: a drug approved for a molecular feature regardless of organ. It made MSI/MMR testing standard across advanced cancers and remains the clearest example of a biomarker that works across histologies. It also anchored the idea that mutation load, via neoantigens, is what makes tumours visible to T cells.
Query for this cancer: (TITLE:"Mismatch repair deficient MSI-high pancreatic ductal adenocarcinoma" OR ABSTRACT:"Mismatch repair deficient MSI-high pancreatic ductal adenocarcinoma" OR TITLE:"MSI-high pancreatic cancer" OR ABSTRACT:"MSI-high pancreatic cancer" OR TITLE:"dMMR pancreatic cancer" OR ABSTRACT:"dMMR pancreatic cancer" OR TITLE:"Mismatch repair deficient PDAC" OR ABSTRACT:"Mismatch repair deficient PDAC" OR TITLE:"Lynch syndrome-associated pancreatic cancer" OR ABSTRACT:"Lynch syndrome-associated pancreatic cancer") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about Mismatch repair deficient (MSI-high) pancreatic ductal adenocarcinoma, not a curated reading list.
The targets of this cancer's medicines and the ones linked to it directly.
Cases by country, the UK and NHS pathway and other country lenses, the expert centres with trials on record, and the centres named on this cancer's subtypes.
One section per setting: the options named, what each is for, the trials behind them, the recorded trade-offs and the questions to ask.
Bleeding that does not stop by itself, bleeding from more than one site, or new bruising in several places or one large area.
Persistent headache with extreme tiredness, nausea, dizziness on standing or low blood pressure. Vomiting, severe weakness or collapse is adrenal crisis.
No pharmacokinetic interactions expected (antibody). See the irAE guide for toxicity management.
The three main regimens share low blood counts, tiredness, sickness and sore mouth; FOLFIRINOX and NALIRIFOX add irinotecan diarrhoea and oxaliplatin's cold-triggered tingling and rare throat spasm, gemcitabine with nab-paclitaxel adds hair loss and neuropathy, and every regimen comes with the same temperature rule for ringing the 24-hour line.
Immunotherapy can attack hormone-producing glands: most often the thyroid (usually ending in an under-active thyroid needing lifelong tablets), and less often the pituitary (hypophysitis) or adrenal glands, which can be life-threatening if missed.
See all on the product pages:DostarlimabFOLFIRINOX / mFOLFIRINOXGemcitabine + nab-paclitaxelPembrolizumab·Printable cards in the navigator
Newly diagnosed? Read the first 60 days with Mismatch repair deficient (MSI-high) pancreatic ductal adenocarcinoma, then print the one-page appointment sheet with room for the answers.
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Everything in development, the medicines held by this cancer's subtypes, the open problems and what is being done about them, the roadmaps, and what changed on this record.
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