# Microsatellite-unstable (MSI-high) gastric cancer

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

## TL;DR

Microsatellite-unstable gastric cancer has lost its DNA mismatch repair machinery, carries thousands of mutations and is unusually visible to the immune system. It responds strongly to checkpoint antibodies, may gain little from chemotherapy, and in early-stage disease immunotherapy before surgery is making many tumours disappear entirely.

## Summary

Mismatch repair deficiency in stomach cancer usually comes from methylation of the MLH1 promoter in older patients rather than from Lynch syndrome, though germline testing is offered when the family history suggests it. The tumours are intestinal type, distal, less likely to involve nodes and carry a better prognosis stage for stage; they are one of the four TCGA molecular groups and overlap with high PD-L1 expression. Testing by immunohistochemistry for the four repair proteins or by polymerase chain reaction or sequencing is now recommended for every gastric cancer at diagnosis.

In advanced disease the microsatellite-unstable subgroups of KEYNOTE-062, CheckMate 649 and KEYNOTE-859 showed the largest benefit of any group from PD-1 blockade, with response rates and survival far above those of chemotherapy alone, and pembrolizumab has had a tumour-agnostic approval for mismatch repair-deficient cancers since 2017. Whether chemotherapy adds anything to the antibody in these patients is uncertain, and many clinicians give a PD-1 antibody alone or with a CTLA-4 antibody.

In resectable disease post hoc analyses of the MAGIC and CLASSIC trials and a 2019 meta-analysis suggested that perioperative chemotherapy gives little or no benefit in microsatellite-unstable tumours, and neoadjuvant immunotherapy trials have followed: NEONIPIGA (nivolumab and ipilimumab) produced pathological complete responses in 59 percent of patients, and INFINITY (durvalumab and tremelimumab) and DANTE reported similar findings. Organ-preserving strategies that omit surgery after a complete response are being tested, following the same path as rectal cancer.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: MSI-H gastric cancer; Mismatch repair-deficient gastric cancer; dMMR gastric cancer
- Tags: subtype-page
- Group: gastrointestinal
- Burden: Around one in five localised gastric cancers in Western series but only about one in twenty at the metastatic stage, because these tumours spread less; they occur in older patients, in the distal stomach and in intestinal-type histology.
- Subtypes: Sporadic MSI-high gastric cancer (MLH1 promoter methylation, older patients, distal stomach); Lynch syndrome-associated gastric cancer; MSI-high intestinal type; Localised MSI-high (neoadjuvant immunotherapy trials); Metastatic MSI-high (checkpoint blockade)
- Biomarkers: Mismatch repair proteins by immunohistochemistry (MLH1, MSH2, MSH6, PMS2); Microsatellite instability by polymerase chain reaction or sequencing; Tumour mutational burden (high); PD-L1 combined positive score (often high); Germline mismatch repair genes where Lynch syndrome is suspected

## 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/gastric-msi-high/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/gastric-msi-high/#overview [3 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/gastric-msi-high/#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/gastric-msi-high/#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/gastric-msi-high/#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/gastric-msi-high/#evidence [4 trials, 4 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/gastric-msi-high/#science [4 targets, 1 pathway]
- 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/gastric-msi-high/where-you-are/
- 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/gastric-msi-high/#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/gastric-msi-high/coming/ [6 medicines, 3 trials, 3 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/gastric-msi-high/data/ [35 connected records]

## Standard of care

- Advanced, first line: PD-1 antibody with or without chemotherapy (nivolumab or pembrolizumab); nivolumab with ipilimumab in selected patients; the benefit exceeds that in any other subgroup. ([Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Ipilimumab](https://onco.cc/drugs/ipilimumab/), [CheckMate 649](https://onco.cc/trials/checkmate-649/), [KEYNOTE-859](https://onco.cc/trials/keynote-859/), [Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)](https://onco.cc/terms/msi/), [Mismatch repair & microsatellite instability](https://onco.cc/pathways/mismatch-repair-msi/))
- Advanced, after chemotherapy: Pembrolizumab under its tumour-agnostic approval for mismatch repair-deficient cancers. ([Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Tumour-agnostic (tissue-agnostic) approval](https://onco.cc/terms/tumour-agnostic/), [Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)](https://onco.cc/terms/msi/))
- Resectable: Surgery with or without perioperative chemotherapy, whose benefit is doubtful here; neoadjuvant immunotherapy (nivolumab-ipilimumab, durvalumab-tremelimumab) in trials or where available. ([Gastrectomy](https://onco.cc/terms/gastrectomy/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Ipilimumab](https://onco.cc/drugs/ipilimumab/), [Durvalumab](https://onco.cc/drugs/durvalumab/), [Tremelimumab](https://onco.cc/drugs/tremelimumab/), [FLOT (5-FU, leucovorin, oxaliplatin, docetaxel)](https://onco.cc/drugs/flot/))
- Hereditary risk: Germline testing and Lynch syndrome surveillance where the pattern suggests it. ([Germline (hereditary) testing](https://onco.cc/technologies/germline-testing/), [Lynch syndrome](https://onco.cc/terms/lynch-syndrome/))

## State of the art

- Microsatellite-unstable gastric cancer is the clearest immunotherapy success story in the disease, with long remissions in metastatic patients.
- Neoadjuvant checkpoint blockade produces complete pathological responses in more than half of localised tumours.
- The evidence that chemotherapy adds little has changed how these patients are treated before surgery.

## Open problems

- Whether surgery can be omitted after a complete response to neoadjuvant immunotherapy.
- Whether chemotherapy should be dropped altogether in metastatic disease.
- A minority of MSI-high tumours do not respond, and the reasons are unclear.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Microsatellite_instability
- Pietrantonio meta-analysis (JCO 2019): https://pubmed.ncbi.nlm.nih.gov/31513484/
- NEONIPIGA (JCO 2023): https://pubmed.ncbi.nlm.nih.gov/36179271/
- Wikipedia: https://en.wikipedia.org/wiki/Microsatellite_instability

## Connected records

- cancers: [Claudin 18.2-positive gastric cancer](https://onco.cc/cancers/gastric-cldn18-2-positive/), [Early gastric cancer](https://onco.cc/cancers/early-gastric-cancer/), [Gastric & gastro-oesophageal junction cancer](https://onco.cc/cancers/gastric/), [HER2-positive gastric cancer](https://onco.cc/cancers/gastric-her2-positive/), [PD-L1-high gastric cancer](https://onco.cc/cancers/gastric-pdl1-high/)
- trials: [A Study to Evaluate the Safety and the Activity of S095029 as Part of Combination Therapy in Advanced Gastroesophageal Junction/Gastric Cancers.](https://onco.cc/trials/nct06116136/), [CheckMate 649](https://onco.cc/trials/checkmate-649/), [KEYNOTE-062](https://onco.cc/trials/keynote-062/), [KEYNOTE-859](https://onco.cc/trials/keynote-859/)
- key papers: [Comprehensive molecular characterisation of gastric adenocarcinoma (The Cancer Genome Atlas)](https://onco.cc/key-papers/paper-tcga-gastric-nature-2014/), [Individual patient data meta-analysis of microsatellite instability as a biomarker in gastric cancer (MAGIC, CLASSIC, ARTIST, ITACA-S)](https://onco.cc/key-papers/paper-pietrantonio-msi-gastric-meta-analysis-jco-2019/), [KEYNOTE-062: pembrolizumab or pembrolizumab plus chemotherapy versus chemotherapy in PD-L1-positive advanced gastric cancer](https://onco.cc/key-papers/paper-keynote-062-shitara-jama-oncol-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/)
- drugs: [Durvalumab](https://onco.cc/drugs/durvalumab/), [FLOT (5-FU, leucovorin, oxaliplatin, docetaxel)](https://onco.cc/drugs/flot/), [Ipilimumab](https://onco.cc/drugs/ipilimumab/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Tremelimumab](https://onco.cc/drugs/tremelimumab/)
- terms: [Gastrectomy](https://onco.cc/terms/gastrectomy/), [Lynch syndrome](https://onco.cc/terms/lynch-syndrome/), [Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)](https://onco.cc/terms/msi/), [MLH1 promoter methylation (sporadic versus Lynch mismatch repair loss)](https://onco.cc/terms/mlh1-promoter-methylation/), [Tumour-agnostic (tissue-agnostic) approval](https://onco.cc/terms/tumour-agnostic/)
- technologies: [Germline (hereditary) testing](https://onco.cc/technologies/germline-testing/), [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/), [MRD / molecular residual disease testing](https://onco.cc/technologies/mrd-testing/)
- pathways: [Mismatch repair & microsatellite instability](https://onco.cc/pathways/mismatch-repair-msi/)
- targets: [Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2)](https://onco.cc/targets/mmr/)
- 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/gastric-msi-high.json