{"entity":{"id":"gastric-msi-high","kind":"cancer","name":"Microsatellite-unstable (MSI-high) gastric cancer","aka":["MSI-H gastric cancer","Mismatch repair-deficient gastric cancer","dMMR gastric cancer"],"tldr":"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.\n\nIn 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.\n\nIn 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.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Microsatellite_instability","links":[{"label":"Pietrantonio meta-analysis (JCO 2019)","url":"https://pubmed.ncbi.nlm.nih.gov/31513484/"},{"label":"NEONIPIGA (JCO 2023)","url":"https://pubmed.ncbi.nlm.nih.gov/36179271/"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Microsatellite_instability"}],"tags":["subtype-page"],"related":[],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"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"],"standardOfCare":[{"setting":"Advanced, first line","approach":"PD-1 antibody with or without chemotherapy (nivolumab or pembrolizumab); nivolumab with ipilimumab in selected patients; the benefit exceeds that in any other subgroup.","refs":["pembrolizumab","nivolumab","ipilimumab","checkmate-649","keynote-859","msi","mismatch-repair-msi"]},{"setting":"Advanced, after chemotherapy","approach":"Pembrolizumab under its tumour-agnostic approval for mismatch repair-deficient cancers.","refs":["pembrolizumab","tumour-agnostic","msi"]},{"setting":"Resectable","approach":"Surgery with or without perioperative chemotherapy, whose benefit is doubtful here; neoadjuvant immunotherapy (nivolumab-ipilimumab, durvalumab-tremelimumab) in trials or where available.","refs":["gastrectomy","nivolumab","ipilimumab","durvalumab","tremelimumab","flot"]},{"setting":"Hereditary risk","approach":"Germline testing and Lynch syndrome surveillance where the pattern suggests it.","refs":["germline-testing","lynch-syndrome"]}],"stateOfArt":["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."],"history":[{"year":2014,"title":"TCGA classifies gastric cancer into four molecular groups including MSI-high","refs":[]},{"year":2017,"title":"Pembrolizumab receives tumour-agnostic approval for mismatch repair-deficient cancers","refs":["pembrolizumab","tumour-agnostic"]},{"year":2019,"title":"Meta-analysis of MAGIC, CLASSIC, ARTIST and ITACA-S: no chemotherapy benefit in MSI-high tumours","refs":[]},{"year":2021,"title":"CheckMate 649 and KEYNOTE-062 subgroups: large gains from PD-1 blockade in MSI-high disease","refs":["checkmate-649","nivolumab"]},{"year":2023,"title":"NEONIPIGA: neoadjuvant nivolumab and ipilimumab give pathological complete response in 59 percent","refs":["nivolumab","ipilimumab"]}],"pipeline":["nivolumab","ipilimumab","durvalumab","tremelimumab","mrd-testing","liquid-biopsy"],"openProblems":["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."],"parent":"gastric"},"route":"/cancers/gastric-msi-high/","neighbours":{"drug":[{"id":"durvalumab","kind":"drug","name":"Durvalumab","route":"/drugs/durvalumab/"},{"id":"flot","kind":"drug","name":"FLOT (5-FU, leucovorin, oxaliplatin, docetaxel)","route":"/drugs/flot/"},{"id":"ipilimumab","kind":"drug","name":"Ipilimumab","route":"/drugs/ipilimumab/"},{"id":"nivolumab","kind":"drug","name":"Nivolumab","route":"/drugs/nivolumab/"},{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/"},{"id":"tremelimumab","kind":"drug","name":"Tremelimumab","route":"/drugs/tremelimumab/"}],"term":[{"id":"gastrectomy","kind":"term","name":"Gastrectomy","route":"/terms/gastrectomy/"},{"id":"lynch-syndrome","kind":"term","name":"Lynch syndrome","route":"/terms/lynch-syndrome/"},{"id":"msi","kind":"term","name":"Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)","route":"/terms/msi/"},{"id":"tumour-agnostic","kind":"term","name":"Tumour-agnostic (tissue-agnostic) approval","route":"/terms/tumour-agnostic/"}],"trial":[{"id":"checkmate-649","kind":"trial","name":"CheckMate 649","route":"/trials/checkmate-649/"},{"id":"keynote-859","kind":"trial","name":"KEYNOTE-859","route":"/trials/keynote-859/"}],"technology":[{"id":"germline-testing","kind":"technology","name":"Germline (hereditary) testing","route":"/technologies/germline-testing/"},{"id":"liquid-biopsy","kind":"technology","name":"Liquid biopsy (ctDNA)","route":"/technologies/liquid-biopsy/"},{"id":"mrd-testing","kind":"technology","name":"MRD / molecular residual disease testing","route":"/technologies/mrd-testing/"}],"pathway":[{"id":"mismatch-repair-msi","kind":"pathway","name":"Mismatch repair & microsatellite instability","route":"/pathways/mismatch-repair-msi/"}],"cancer":[{"id":"gastric","kind":"cancer","name":"Gastric & gastro-oesophageal junction cancer","route":"/cancers/gastric/"}]}}