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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.
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.
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.
Squamous cancers sit in the upper and middle oesophagus, adenocarcinomas at the junction and in the stomach; the stomach wall also gives rise to GIST from its pacemaker cells.
Same organ: Gastric & gastro-oesophageal junction cancer, HER2-positive gastric cancer, Claudin 18.2-positive gastric cancer, PD-L1-high gastric cancer, Early gastric cancer, Oesophageal squamous cell carcinoma, Oesophageal and junctional adenocarcinoma, Oesophageal cancer, Gastrointestinal stromal tumour (GIST), KIT exon 11-mutant GIST, PDGFRA D842V-mutant GIST, Imatinib-resistant GIST
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Also on OnCo: Symptoms and red flags · Early detection roadmap.
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 under its tumour-agnostic approval for mismatch repair-deficient cancers.
Surgery with or without perioperative chemotherapy, whose benefit is doubtful here; neoadjuvant immunotherapy (nivolumab-ipilimumab, durvalumab-tremelimumab) in trials or where available.
Germline testing and Lynch syndrome surveillance where the pattern suggests it.
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Single-agent pembrolizumab is an option for microsatellite-unstable gastric cancer first line, whereas for the broader PD-L1-positive population chemo-immunotherapy from CheckMate 649 and KEYNOTE-859 became standard.
Microsatellite instability testing is recommended before perioperative chemotherapy for gastric cancer, and immunotherapy-based trials are the preferred approach for unstable tumours.
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.
The immunotherapy sensitivity of microsatellite-unstable and Epstein-Barr virus-positive gastric cancer and the claudin 18.2 and HER2 targets map onto these subtypes.
Query for this cancer: (TITLE:"Microsatellite-unstable MSI-high gastric cancer" OR ABSTRACT:"Microsatellite-unstable MSI-high gastric cancer" OR TITLE:"MSI-H gastric cancer" OR ABSTRACT:"MSI-H gastric cancer" OR TITLE:"Mismatch repair-deficient gastric cancer" OR ABSTRACT:"Mismatch repair-deficient gastric cancer" OR TITLE:"dMMR gastric cancer" OR ABSTRACT:"dMMR gastric cancer") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about Microsatellite-unstable (MSI-high) gastric cancer, 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.
Persistent headache with extreme tiredness, nausea, dizziness on standing or low blood pressure. Vomiting, severe weakness or collapse is adrenal crisis.
Bleeding that does not stop by itself, bleeding from more than one site, or new bruising in several places or one large area.
No pharmacokinetic interactions expected (antibody). See the irAE guide for toxicity management.
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.
Inflammation of the bowel caused by immunotherapy releasing the immune system against the gut lining, producing diarrhoea that can be severe. It is the commonest serious side effect of CTLA-4 antibodies and is treated with steroids and, if needed, infliximab.
See all on the product pages:DurvalumabFLOT (5-FU, leucovorin, oxaliplatin, docetaxel)IpilimumabNivolumabPembrolizumabTremelimumab·Printable cards in the navigator
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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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