# Mismatch-repair-deficient endometrial cancer

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

## TL;DR

Mismatch-repair-deficient endometrial cancer has lost the machinery that corrects copying errors in DNA, so it accumulates thousands of mutations that make it visible to the immune system. Adding dostarlimab or pembrolizumab to chemotherapy in advanced disease cut the risk of progression by about seventy percent, and many patients remain in remission years later.

## Summary

Loss of MLH1, PMS2, MSH2 or MSH6 on immunohistochemistry, or microsatellite instability on a molecular test, defines this class. In most tumours the cause is methylation of the MLH1 promoter; in a minority it is a germline mutation in a mismatch-repair gene, which is Lynch syndrome, so every deficient tumour without MLH1 methylation should prompt germline testing and family cascade testing. Mismatch-repair-deficient tumours are usually endometrioid, often high grade, with abundant tumour-infiltrating lymphocytes, and they carry an intermediate prognosis at early stage. The class has the same recurrence risk as no specific molecular profile after adjuvant radiotherapy, and PORTEC-3 found no benefit from adding chemotherapy in this group.

The mutational load makes these tumours the most immunotherapy-responsive solid cancers outside melanoma. Pembrolizumab's tumour-agnostic approval for mismatch-repair-deficient tumours in 2017 and dostarlimab's approval after the GARNET trial in 2021 established single-agent checkpoint inhibition after chemotherapy. RUBY then moved immunotherapy to the first line: dostarlimab with carboplatin-paclitaxel raised progression-free survival at two years from 15.7 to 61.4 percent in the deficient population, with a hazard ratio of 0.28. NRG-GY018 found the same with pembrolizumab, a hazard ratio of 0.30 for progression in deficient tumours, and DUO-E with durvalumab a hazard ratio of 0.42. Both dostarlimab and pembrolizumab gained approvals with chemotherapy in 2023 and 2024.

The next question is whether chemotherapy is needed at all. KEYNOTE-C93 compares pembrolizumab alone with platinum doublet chemotherapy as first-line treatment of deficient advanced disease. In the adjuvant setting KEYNOTE-B21 did not improve disease-free survival overall when pembrolizumab was added to chemotherapy after surgery, but the mismatch-repair-deficient subgroup appeared to benefit, and RAINBO's MMRd-GREEN trial randomises deficient stage II to III tumours to radiotherapy with or without durvalumab. Prevention in Lynch carriers rests on surveillance, aspirin and risk-reducing hysterectomy once childbearing is complete, and frameshift neoantigen vaccines are in early trials.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: dMMR endometrial cancer; MSI-high endometrial cancer; MMRd endometrial cancer; Lynch-associated endometrial cancer
- Tags: subtype-page
- Group: gynaecologic
- Burden: About a quarter to three in ten endometrial cancers, the largest molecular class after no specific molecular profile; most are sporadic and caused by MLH1 promoter methylation, and about three percent of all endometrial cancers arise in Lynch syndrome carriers.
- Subtypes: Sporadic MLH1 promoter hypermethylation (most cases); Lynch syndrome germline MLH1, MSH2, MSH6 or PMS2 mutation; MSH6-deficient tumours (older age, lower MSI signal); Dedifferentiated and undifferentiated carcinoma (often MMRd with SWI/SNF loss); Stage II to III MMRd (RAINBO MMRd-GREEN, radiotherapy with or without durvalumab); Advanced or recurrent MMRd (chemo-immunotherapy first line)
- Biomarkers: MMR immunohistochemistry (MLH1, PMS2, MSH2, MSH6); Microsatellite instability by PCR or sequencing; MLH1 promoter methylation (separates sporadic from Lynch); Germline mismatch-repair gene testing; Tumour mutational burden; PD-L1 (not required for treatment)

## 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/endometrial-mmr-deficient/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/endometrial-mmr-deficient/#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/endometrial-mmr-deficient/#what-it-is [6 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/endometrial-mmr-deficient/#finding-it [6 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/endometrial-mmr-deficient/#treating-it [5 settings, 4 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/endometrial-mmr-deficient/#evidence [11 trials, 5 key papers, 6 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/endometrial-mmr-deficient/#science [3 targets]
- 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/endometrial-mmr-deficient/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/endometrial-mmr-deficient/#living-with-it [18 questions, 6 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/endometrial-mmr-deficient/coming/ [5 medicines, 9 trials, 2 ideas, 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/endometrial-mmr-deficient/data/ [47 connected records]

## Standard of care

- Diagnosis and hereditary risk: Universal MMR immunohistochemistry on every endometrial cancer; MLH1 methylation testing on MLH1-deficient tumours; germline testing and cascade testing of relatives when methylation is absent. ([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/), [Histopathology & immunohistochemistry](https://onco.cc/technologies/histopathology-ihc/), [Endometrial cancer molecular classes (POLEmut, MMRd, p53abn, NSMP)](https://onco.cc/terms/endometrial-molecular-classes/))
- Early stage after surgery: Adjuvant therapy by stage and risk factors as for no specific molecular profile: vaginal brachytherapy for intermediate risk, pelvic radiotherapy for high-intermediate risk; chemotherapy adds little (PORTEC-3). ([Brachytherapy](https://onco.cc/technologies/brachytherapy/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/), [PORTEC-3](https://onco.cc/trials/portec-3/))
- Advanced or recurrent, first line: Carboplatin-paclitaxel with dostarlimab (RUBY) or pembrolizumab (NRG-GY018), continued as maintenance; durvalumab (DUO-E) is an alternative. ([Dostarlimab](https://onco.cc/drugs/dostarlimab/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Durvalumab](https://onco.cc/drugs/durvalumab/), [Carboplatin](https://onco.cc/drugs/carboplatin/), [Paclitaxel / nab-paclitaxel](https://onco.cc/drugs/paclitaxel/), [RUBY / ENGOT-EN6 / GOG-3031](https://onco.cc/trials/ruby/), [NRG-GY018 / KEYNOTE-868](https://onco.cc/trials/nrg-gy018-keynote-868/), [DUO-E / GOG-3041 / ENGOT-EN10](https://onco.cc/trials/duo-e/), [Chemotherapy + PD-1/PD-L1 blockade, first-line advanced endometrial cancer](https://onco.cc/pairings/chemo-io-first-line-endometrial/))
- Recurrent after chemotherapy without prior immunotherapy: Single-agent dostarlimab or pembrolizumab, with durable responses in a large minority. ([Dostarlimab](https://onco.cc/drugs/dostarlimab/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/), [Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)](https://onco.cc/terms/msi/))
- Lynch carriers: Annual surveillance from the mid-thirties where offered, aspirin, and risk-reducing hysterectomy with salpingo-oophorectomy after childbearing. ([Lynch syndrome](https://onco.cc/terms/lynch-syndrome/), [Germline (hereditary) testing](https://onco.cc/technologies/germline-testing/), [Hysterectomy](https://onco.cc/terms/hysterectomy/))

## State of the art

- RUBY and NRG-GY018 made chemo-immunotherapy the first-line standard, with about seventy percent fewer progressions in deficient tumours.
- Universal MMR testing doubles as a Lynch syndrome screen.
- KEYNOTE-C93 asks whether immunotherapy alone can replace chemotherapy.

## Open problems

- Whether chemotherapy can be dropped in favour of immunotherapy alone.
- Why a third of deficient tumours do not respond to checkpoint blockade.
- Getting germline testing to every woman with an unmethylated deficient tumour.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Endometrial_cancer
- Wikipedia: https://en.wikipedia.org/wiki/Endometrial_cancer

## Connected records

- cancers: [Advanced or recurrent endometrial cancer](https://onco.cc/cancers/advanced-recurrent-endometrial-cancer/), [Endometrial cancer](https://onco.cc/cancers/endometrial/), [Endometrial cancer with no specific molecular profile](https://onco.cc/cancers/endometrial-nsmp/), [p53-abnormal endometrial cancer, including uterine serous carcinoma](https://onco.cc/cancers/endometrial-p53-abnormal/), [POLE-ultramutated endometrial cancer](https://onco.cc/cancers/endometrial-pole-ultramutated/), [Uterine carcinosarcoma](https://onco.cc/cancers/uterine-carcinosarcoma/)
- trials: [A Study of Dostarlimab in Combination With Carboplatin-paclitaxel in Chinese Participants With Primary Advanced or Recurrent Endometrial Cancer (EC)](https://onco.cc/trials/nct07108270/), [A Study to Investigate the Safety, Pharmacokinetics, and Preliminary Effectiveness of GSK4418959 Alone or in Combination With Other Anti-cancer Agents in Participants With Solid Tumors](https://onco.cc/trials/nct06710847/), [DUO-E / GOG-3041 / ENGOT-EN10](https://onco.cc/trials/duo-e/), [EIK1005-002: A Clinical Research Study Evaluating EIK1005, a Werner Helicase Inhibitor, as Monotherapy and in Combination With Pembrolizumab in Partic](https://onco.cc/trials/nct07262619/), [GARNET](https://onco.cc/trials/garnet/), [NRG-GY018 / KEYNOTE-868](https://onco.cc/trials/nrg-gy018-keynote-868/), [PORTEC-3](https://onco.cc/trials/portec-3/), [RAINBO](https://onco.cc/trials/rainbo/), [RUBY / ENGOT-EN6 / GOG-3031](https://onco.cc/trials/ruby/), [Study of Pembrolizumab (MK-3475) in Combination With Adjuvant Chemotherapy With or Without Radiotherapy in Participants With Newly Diagnosed Endometrial Cancer After Surgery With Curative Intent (MK-3475-B21 / KEYNOTE-B21 / ENGOT-en11 / GOG-3053)](https://onco.cc/trials/nct04634877/), [Study of Pembrolizumab (MK-3475) Versus Chemotherapy in Mismatch Repair Deficient (dMMR) Advanced or Recurrent Endometrial Carcinoma (MK-3475-C93/KEYNOTE-C93/GOG-3064/ENGOT-en15)](https://onco.cc/trials/nct05173987/)
- key papers: [Confirmation of ProMisE: a genomics-based clinical classifier for endometrial cancer](https://onco.cc/key-papers/paper-promise-talhouk-cancer-2017/), [GARNET: dostarlimab in mismatch repair-deficient recurrent or advanced endometrial cancer](https://onco.cc/key-papers/paper-garnet-dostarlimab-oaknin-jama-oncol-2020/), [Molecular classification of the PORTEC-3 trial: prognosis and benefit from adjuvant chemotherapy by molecular group](https://onco.cc/key-papers/paper-portec-3-molecular-leon-castillo-jco-2020/), [NRG-GY018: pembrolizumab plus chemotherapy in advanced or recurrent endometrial cancer](https://onco.cc/key-papers/paper-nrg-gy018-nejm-2023/), [RUBY: dostarlimab with chemotherapy for advanced or recurrent endometrial cancer](https://onco.cc/key-papers/paper-ruby-nejm-2023/)
- terms: [Endometrial cancer molecular classes (POLEmut, MMRd, p53abn, NSMP)](https://onco.cc/terms/endometrial-molecular-classes/), [Hysterectomy](https://onco.cc/terms/hysterectomy/), [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/)
- drugs: [Carboplatin](https://onco.cc/drugs/carboplatin/), [Dostarlimab](https://onco.cc/drugs/dostarlimab/), [Durvalumab](https://onco.cc/drugs/durvalumab/), [Paclitaxel / nab-paclitaxel](https://onco.cc/drugs/paclitaxel/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/)
- ideas: [A frameshift neoantigen vaccine for Lynch syndrome carriers as the first preventive cancer vaccine approval](https://onco.cc/ideas/idea-moon-lynch-vaccine-phase3/), [WRN inhibitors: a second synthetic-lethal win for mismatch-repair cancers](https://onco.cc/ideas/idea-bio1-wrn-msi-programme/)
- technologies: [Brachytherapy](https://onco.cc/technologies/brachytherapy/), [Germline (hereditary) testing](https://onco.cc/technologies/germline-testing/), [Histopathology & immunohistochemistry](https://onco.cc/technologies/histopathology-ihc/), [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/)
- pairings: [Chemotherapy + PD-1/PD-L1 blockade, first-line advanced endometrial cancer](https://onco.cc/pairings/chemo-io-first-line-endometrial/)
- people: [Ana Oaknin](https://onco.cc/people/ana-oaknin/)
- 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/endometrial-mmr-deficient.json