# Mismatch repair deficient (MSI-high) pancreatic ductal adenocarcinoma

Source: https://onco.cc/cancers/msi-high-pdac/  
OnCo record `msi-high-pdac` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Summary

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.

## Fields

- Kind: Cancer
- Last checked: 2026-09-18
- Also known as: MSI-high pancreatic cancer; dMMR pancreatic cancer; Mismatch repair deficient PDAC; Lynch syndrome-associated pancreatic cancer
- Tags: subtype-page; gastrointestinal
- Group: gastrointestinal
- Burden: 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.
- Subtypes: Lynch syndrome-associated mismatch repair deficient PDAC (germline MLH1, MSH2, MSH6, PMS2 or EPCAM); Sporadic mismatch repair deficient PDAC (MLH1 promoter methylation); Medullary or mucinous colloid carcinoma of the pancreas (histology enriched for the defect); Mismatch repair deficient PDAC arising in an IPMN; Mismatch repair deficient PDAC after progression on chemotherapy (pembrolizumab or dostarlimab)
- Biomarkers: Mismatch repair protein immunohistochemistry (MLH1, MSH2, MSH6, PMS2) or sequencing-based microsatellite instability testing on every pancreatic cancer; Tumour mutational burden (high in most mismatch repair deficient tumours); Germline Lynch syndrome testing when the tumour is deficient; KRAS status (wild-type more often) and medullary or colloid histology; CA 19-9 for response monitoring

## Sections of this record

The page is a hub with ten sections in reading order; large sections have their own page. The same plan as JSON: https://onco.cc/api/v1/cancers/msi-high-pdac/sections.json

- Overview (on the hub): The TL;DR, the family this cancer belongs to, the organ, who gets it and what the state of the art is. https://onco.cc/cancers/msi-high-pdac/#overview [4 state-of-the-art points]
- Types and stages (on the hub): Anatomy, the subtypes and how they differ, how it is staged, and where advanced disease spreads. https://onco.cc/cancers/msi-high-pdac/#what-it-is [5 subtypes]
- Symptoms and diagnosis (on the hub): How this cancer shows itself, how the diagnosis is confirmed, and the biomarkers clinicians test for. https://onco.cc/cancers/msi-high-pdac/#finding-it [5 biomarkers]
- Treatment (on the hub): The standard of care by setting, the medicines, surgery and radiotherapy named in it, and the regimens behind them. https://onco.cc/cancers/msi-high-pdac/#treating-it [4 settings, 2 decisions with options]
- Trials and papers (on the hub): Trials recruiting now, the landmark trials, the trials held by this cancer's subtypes, the key papers and what they mean, the latest literature, and the milestones year by year. https://onco.cc/cancers/msi-high-pdac/#evidence [5 trials, 7 key papers, 5 milestones]
- Biology and targets (on the hub): The molecular landscape: the targets and how often each appears, the pathways, the mechanics stages and the preclinical models. https://onco.cc/cancers/msi-high-pdac/#science [4 targets, 4 pathways]
- Countries and centres (own page): 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. https://onco.cc/cancers/msi-high-pdac/where-you-are/ [32 UK centres]
- Decisions and support (on the hub): The decisions you may face, the aids that walk through them, the warnings on record, the first sixty days and the questions to ask. https://onco.cc/cancers/msi-high-pdac/#living-with-it [17 questions, 5 red cards]
- Pipeline and open problems (own page): 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. https://onco.cc/cancers/msi-high-pdac/coming/ [6 medicines, 3 trials, 1 idea, 4 open problems]
- Data (own page): Every connected record, the notes, the JSON, Markdown and RDF twins, and where the record came from and when it was checked. https://onco.cc/cancers/msi-high-pdac/data/ [51 connected records]

## Standard of care

- Testing: Mismatch repair immunohistochemistry or microsatellite instability testing for every pancreatic adenocarcinoma at diagnosis, with germline testing for Lynch syndrome when deficient. ([Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)](https://onco.cc/terms/msi/), [Lynch syndrome](https://onco.cc/terms/lynch-syndrome/), [Germline (hereditary) testing](https://onco.cc/technologies/germline-testing/), [Tumour mutational burden (TMB)](https://onco.cc/terms/tmb/))
- Advanced, first line: Chemotherapy as for other pancreatic adenocarcinoma; pembrolizumab first line for patients unfit for chemotherapy or in trials. ([FOLFIRINOX / mFOLFIRINOX](https://onco.cc/drugs/folfirinox/), [Gemcitabine + nab-paclitaxel](https://onco.cc/drugs/gemcitabine-nab-paclitaxel/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/))
- Advanced, after chemotherapy: Pembrolizumab (tumour-agnostic approval, KEYNOTE-158 pancreatic cohort) or dostarlimab (tumour-agnostic approval for mismatch repair deficient solid tumours). ([Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Dostarlimab](https://onco.cc/drugs/dostarlimab/), [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/), [PD-1](https://onco.cc/targets/pd1/))
- Resectable: Surgery and adjuvant chemotherapy as for other pancreatic adenocarcinoma; neoadjuvant immunotherapy only in trials. ([Whipple procedure (pancreaticoduodenectomy)](https://onco.cc/terms/whipple/), [FOLFIRINOX / mFOLFIRINOX](https://onco.cc/drugs/folfirinox/), [PRODIGE 24 / CCTG PA6](https://onco.cc/trials/prodige-24/))

## State of the art

- Pembrolizumab and dostarlimab are approved for mismatch repair deficient pancreatic cancer through tumour-agnostic labels.
- Universal testing is guideline standard because the defect cannot be predicted from the clinic.
- Responses are less frequent than in bowel cancer, and combinations are being tested.
- Frameshift neoantigen vaccines in Lynch syndrome carriers aim at prevention.

## Open problems

- Response rates to PD-1 blockade are lower than in colorectal cancer and the reasons are not settled.
- Whether checkpoint inhibitors should replace chemotherapy first line is untested in the pancreas.
- Immunohistochemistry misses some deficient tumours and over-calls others; confirmatory sequencing is not universal.
- Lynch syndrome carriers have no proven pancreatic surveillance strategy.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Microsatellite_instability
- Wikipedia: https://en.wikipedia.org/wiki/Microsatellite_instability
- NCCN Guidelines: Pancreatic Adenocarcinoma: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455

## Connected records

- cancers: [BRCA or PALB2-mutant pancreatic ductal adenocarcinoma](https://onco.cc/cancers/brca-palb2-pdac/), [Intraductal papillary mucinous neoplasm and other pancreatic cystic precursors](https://onco.cc/cancers/ipmn-cystic-precursors/), [KRAS G12C-mutant pancreatic ductal adenocarcinoma](https://onco.cc/cancers/kras-g12c-pdac/), [KRAS wild-type pancreatic ductal adenocarcinoma](https://onco.cc/cancers/kras-wild-type-pdac/), [Locally advanced unresectable pancreatic ductal adenocarcinoma](https://onco.cc/cancers/locally-advanced-pdac/), [Metastatic pancreatic ductal adenocarcinoma](https://onco.cc/cancers/metastatic-pdac/), [Mismatch-repair deficient (MSI-high) colorectal cancer](https://onco.cc/cancers/msi-high-colorectal/), [Pancreatic ductal adenocarcinoma](https://onco.cc/cancers/pancreatic/)
- technologies: [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/), [Cytotoxic chemotherapy](https://onco.cc/technologies/cytotoxic-chemotherapy/), [Germline (hereditary) testing](https://onco.cc/technologies/germline-testing/), [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/), [Off-the-shelf cancer vaccines](https://onco.cc/technologies/shared-antigen-vaccine/)
- targets: [CTLA-4](https://onco.cc/targets/ctla4/), [KRAS](https://onco.cc/targets/kras/), [PD-1](https://onco.cc/targets/pd1/), [PD-L1](https://onco.cc/targets/pdl1/)
- drugs: [Dostarlimab](https://onco.cc/drugs/dostarlimab/), [FOLFIRINOX / mFOLFIRINOX](https://onco.cc/drugs/folfirinox/), [Gemcitabine + nab-paclitaxel](https://onco.cc/drugs/gemcitabine-nab-paclitaxel/), [Ipilimumab](https://onco.cc/drugs/ipilimumab/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/)
- companies: [Bristol Myers Squibb](https://onco.cc/companies/bms/), [Merck & Co. (MSD)](https://onco.cc/companies/merck/)
- pathways: [Cold tumours: immune deserts and exclusion](https://onco.cc/pathways/immune-desert-exclusion/), [Mismatch repair & microsatellite instability](https://onco.cc/pathways/mismatch-repair-msi/), [PD-1 / PD-L1 immune checkpoint & T-cell activation](https://onco.cc/pathways/pd1-checkpoint/), [The cancer-immunity cycle](https://onco.cc/pathways/cancer-immunity-cycle/)
- terms: [Germline vs somatic mutations](https://onco.cc/terms/germline-vs-somatic/), [Lynch syndrome](https://onco.cc/terms/lynch-syndrome/), [Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)](https://onco.cc/terms/msi/), [Microsatellite-stable (MSS) / mismatch-repair proficient (pMMR)](https://onco.cc/terms/mss-pmmr/), [Neoantigen](https://onco.cc/terms/neoantigen/), [Pancreatic cancer drugs in England: NICE appraisals and the Cancer Drugs Fund (September 2026)](https://onco.cc/terms/pancreatic-cancer-uk-drug-access/), [Tumour mutational burden (TMB)](https://onco.cc/terms/tmb/), [Whipple procedure (pancreaticoduodenectomy)](https://onco.cc/terms/whipple/)
- trials: [Dostarlimab for Locally Advanced or Metastatic Cancer (Non-colorectal/Non-endometrial) With Tumor dMMR/MSI](https://onco.cc/trials/nct06333314/), [KEYNOTE-158](https://onco.cc/trials/keynote-158/), [KEYNOTE-177](https://onco.cc/trials/keynote-177/), [Pembrolizumab With Olaparib as Combined Therapy in Metastatic Pancreatic Cancer](https://onco.cc/trials/nct05093231/), [PRODIGE 24 / CCTG PA6](https://onco.cc/trials/prodige-24/)
- people: [Bert Vogelstein](https://onco.cc/people/bert-vogelstein/), [Dung T. Le](https://onco.cc/people/dung-le/), [Eileen M. O'Reilly](https://onco.cc/people/eileen-oreilly/), [Elizabeth M. Jaffee](https://onco.cc/people/elizabeth-jaffee/)
- key papers: [Comprehensive characterisation of pancreatic ductal adenocarcinoma with microsatellite instability: histology, molecular pathology and clinical implications](https://onco.cc/key-papers/paper-luchini-msi-dmmr-pancreatic-systematic-review-gut-2021/), [First trial of a vaccine against the shared neoantigens of mismatch-repair-deficient cancers](https://onco.cc/key-papers/paper-lynch-frameshift-vaccine-ccr-2020/), [Hu 2018: evaluating mismatch repair deficiency in pancreatic adenocarcinoma, challenges and recommendations](https://onco.cc/key-papers/paper-hu-mismatch-repair-deficiency-pancreatic-adenocarcinoma-ccr-2018/), [KEYNOTE-158: pembrolizumab in non-colorectal high microsatellite instability or mismatch repair-deficient cancer](https://onco.cc/key-papers/paper-keynote-158-pembrolizumab-msi-high-noncolorectal-jco-2020/), [Le 2017: mismatch-repair deficiency predicts response to PD-1 blockade across twelve tumour types, leading to the first tissue-agnostic drug approval](https://onco.cc/key-papers/paper-le-mmr-deficiency-science-2017/), [Molecular characterization of KRAS wild-type tumors in patients with pancreatic adenocarcinoma](https://onco.cc/key-papers/paper-philip-kras-wild-type-pancreatic-ccr-2022/), [Real-time targeted genome profile analysis of pancreatic ductal adenocarcinomas identifies genetic alterations that might be targeted with existing drugs or used as biomarkers](https://onco.cc/key-papers/paper-singhi-targeted-genome-profiling-3594-pdac-gastroenterology-2019/)
- ideas: [Automatic germline testing for every cancer type where it changes care](https://onco.cc/ideas/idea-prev-reflex-germline-testing/)
- biomarkers: [dMMR (mismatch repair deficiency by IHC)](https://onco.cc/biomarkers/dmmr-ihc/), [MSI-high (microsatellite instability by PCR or sequencing)](https://onco.cc/biomarkers/msi-high/)

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JSON: https://onco.cc/api/v1/entities/msi-high-pdac.json