Mismatch-repair-deficient endometrial cancer
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.
Overview
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.
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.
Red cards
From the labels and guidelines behind the standard of care. Your team's thresholds win.- Emergency services nowHypophysitis or adrenal crisis
Persistent headache with extreme tiredness, nausea, dizziness on standing or low blood pressure. Vomiting, severe weakness or collapse is adrenal crisis.
- Emergency services nowBleeding or bruising
Bleeding that will not stop, black or bloody stools, or unexplained bruising when platelets are expected to be low.
- Check before combiningFood and drink: Pembrolizumab
No pharmacokinetic interactions expected (antibody). See the irAE guide for toxicity management.
- Check before combiningKidneys: Carboplatin
Dose by Calvert formula using GFR (see the calculators).
- Good to knowImmune-related endocrinopathies (thyroiditis, hypophysitis)
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.
- Good to knowInfusion reactions, hypersensitivity and extravasation
Reactions around the moment a drug is given: chills, fever or breathlessness from antibodies (infusion reactions), true allergy (hypersensitivity, rarely anaphylaxis), and leakage of a damaging drug into tissue around the vein (extravasation).
See all on the product pages:CarboplatinDostarlimabDurvalumabPaclitaxel / nab-paclitaxelPembrolizumab·Printable cards in the navigator
Anatomy and lymph node drainage
- Fallopian tube fimbria (origin of high-grade serous)
- Ovary (other histologies, germ cell)
- Endometrium
- Myometrium (uterine sarcoma)
- Placental site (gestational trophoblastic)
- Cervix, transformation zone
- Vulva
- Nodes: obturator and external iliac
- Nodes: internal iliac
- Nodes: para-aortic (ovary, high uterus)
- Nodes: inguinal (vulva)
Most high-grade ovarian cancers begin at the tip of the fallopian tube; endometrial cancer lines the uterus, cervical cancer starts at the transformation zone; each drains to a different node group.
- Fallopian tube fimbria (origin of high-grade serous)
- Ovary (other histologies, germ cell)
- EndometriumMSH6-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)
- Myometrium (uterine sarcoma)
- Placental site (gestational trophoblastic)
- Cervix, transformation zone
- Vulva
- obturator and external iliac
- internal iliac
- para-aortic (ovary, high uterus)
- inguinal (vulva)
Same organ: High-grade serous ovarian cancer, Low-grade serous ovarian cancer, Clear cell ovarian cancer, Mucinous ovarian cancer, Adult granulosa cell tumour of the ovary, Ovarian cancer, Endometrial cancer, Cervical cancer, Vulvar cancer, Gestational trophoblastic neoplasia, Uterine sarcoma, Vaginal cancer, POLE-ultramutated endometrial cancer, p53-abnormal endometrial cancer, including uterine serous carcinoma, Endometrial cancer with no specific molecular profile, Advanced or recurrent endometrial cancer, Uterine carcinosarcoma, Early cervical cancer and fertility-sparing surgery, Locally advanced cervical cancer, Recurrent or metastatic cervical cancer, Platinum-sensitive ovarian cancer, Platinum-resistant ovarian cancer
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.
Cases by country
No country-level case numbers. This cancer is not mapped to a GLOBOCAN site.
One section per setting: the options named, what each is for, the trials behind them, the recorded trade-offs and the questions to ask.
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.
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).
Carboplatin-paclitaxel with dostarlimab (RUBY) or pembrolizumab (NRG-GY018), continued as maintenance; durvalumab (DUO-E) is an alternative.
Single-agent dostarlimab or pembrolizumab, with durable responses in a large minority.
Annual surveillance from the mid-thirties where offered, aspirin, and risk-reducing hysterectomy with salpingo-oophorectomy after childbearing.
Subtypes & biomarkers
top- 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)
- 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)
How often this target appears
- 2013TCGA describes the hypermutated MSI class of endometrial cancer
- 2017Pembrolizumab: first tumour-agnostic approval, for mismatch-repair-deficient tumours
- 2021Dostarlimab approved for recurrent dMMR endometrial cancer after GARNET
- 2023RUBY and NRG-GY018: chemo-immunotherapy first line, PFS hazard ratios 0.28 and 0.30 in dMMR tumours
- 2023DUO-E: durvalumab with chemotherapy, PFS hazard ratio 0.42 in dMMR tumours
- 2024KEYNOTE-B21: adjuvant pembrolizumab misses its primary endpoint overall; dMMR subgroup appears to benefit
Dated changes read from the records linked to this cancer: approvals, regulatory steps, reported trials, guideline versions and milestones. Newest first; no date is inferred.
All 11 changes by month →- 2026-09-17This recordMismatch-repair-deficient endometrial cancerFacts on this page last checked
When this page itself was last checked or edited.
- 2024MilestoneStudy 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)KEYNOTE-B21: adjuvant pembrolizumab misses its primary endpoint overall; dMMR subgroup appears to benefit
A milestone in how this cancer is treated.
- 2023Trial resultDUO-E / GOG-3041 / ENGOT-EN10DUO-E / GOG-3041 / ENGOT-EN10 reported
PFS HR 0.
- 2023Trial resultNRG-GY018 / KEYNOTE-868NRG-GY018 / KEYNOTE-868 reported
PFS HR 0.
- 2023Trial resultRUBY / ENGOT-EN6 / GOG-3031RUBY / ENGOT-EN6 / GOG-3031 reported
OS 44.
- 2023MilestoneDUO-E / GOG-3041 / ENGOT-EN10DUO-E: durvalumab with chemotherapy, PFS hazard ratio 0.42 in dMMR tumours
A milestone in how this cancer is treated.
What is in development for Mismatch-repair-deficient endometrial cancer, drawn from the whole corpus: 8 items. Drugs are grouped by the most advanced trial phase they have reached anywhere; approved treatments sit under standard of care. Technologies are the methods being tested for this cancer, trials are the studies recorded here, and ideas are proposals not yet in a trial.
Trials under way · 2
- 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) · phase 3 · Merck Sharp & Dohme LLC
- 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) · phase 3 · Merck Sharp & Dohme LLC
Trials reported · 3
- DUO-E / GOG-3041 / ENGOT-EN10 · phase 3 · 2023 · positive
- NRG-GY018 / KEYNOTE-868 · phase 3 · 2023 · positive
- RUBY / ENGOT-EN6 / GOG-3031 · phase 3 · 2023 · positive
Combinations being explored · 1
Ideas not yet in a trial · 2
Open problems and what is being done
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.
Trials
topTrials recruiting now
Country and place are remembered in this browser only. A postcode is sent to OpenStreetMap's Nominatim service to find coordinates when you press the button; nothing else leaves your device.
Landmark trials
Expert centres
topExpert centres
New York · cancer center | United States | 0 | 5,100 | 94,456 | #1 | ||
Baltimore · cancer center | United States | 0 | 2,955 | 41,449 | #10 | ||
Amsterdam · cancer center | Netherlands | none recorded | 0 | 1,451 | 25,873 | #45 | |
Philadelphia, PA · consortium | United States | none recorded | 2 | 165 | 1,237 | - | |
Chicago, IL · consortium | United States | none recorded | 2 | not matched | - | - | |
Philadelphia, PA · consortium | United States | none recorded | 1 | 87 | 2,130 | none recorded | - |
Newcastle, NSW · consortium | Australia | none recorded | 1 | 34 | 760 | - | |
Wuhan · hospital | China | none recorded | 0 | 2,478 | 31,527 | - | |
Beijing · hospital | China | none recorded | 0 | 1,784 | 18,230 | - | |
Utrecht · cancer center | Netherlands | none recorded | 0 | 1,422 | 20,323 | - | |
Beijing · cancer center | China | none recorded | 0 | 1,344 | 18,195 | - | |
Leiden · university | Netherlands | none recorded | 0 | 1,245 | 16,125 | - | |
Tianjin · cancer center | China | none recorded | 0 | 1,219 | 11,455 | - | |
Hangzhou · cancer center | China | none recorded | 0 | 1,219 | 17,635 | - | |
Lyon · cancer center | France | none recorded | 0 | 1,071 | 14,301 | - |
These are the things we can measure; they are not a ranking of quality. Each column is a field on the institution record or a count over what OnCo has linked; a centre that treats many patients with Mismatch-repair-deficient endometrial cancer but is thinly recorded here will look small.
Not known: OnCo holds no case-volume or outcome figures for centres, so none are shown. Where a national audit or registry publishes them, the centre's page links to it. Default order: Newsweek rank, then trials for this cancer, then research output.
Questions to ask
topQuestions to ask your oncologist about Mismatch-repair-deficient endometrial cancer
Newly diagnosed
- What is my exact diagnosis, stage, and grade, and which tests established them?Why: Everything else follows from an accurate stage and subtype.
- Which biomarkers have been tested on my tumour (for example MMR immunohistochemistry, Microsatellite instability by PCR or sequencing, MLH1 promoter methylation, Germline mismatch-repair gene testing, Tumour mutational burden), and what were the results?Why: These results decide eligibility for targeted therapy, immunotherapy, and trials.
- Which subtype is my cancer, and does that change the recommended treatment?Why: Recognised subtypes for this cancer include Sporadic MLH1 promoter hypermethylation, Lynch syndrome germline MLH1, MSH2, MSH6 or PMS2 mutation, MSH6-deficient tumours.
- Is germline (inherited) genetic testing recommended for me or my family?Why: Inherited variants can change treatment and matter for relatives.
Diagnosis and hereditary risk
- For my situation (diagnosis and hereditary risk), which of the standard options do you recommend and why?Why: Guideline options include: 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.
Early stage after surgery
- For my situation (early stage after surgery), which of the standard options do you recommend and why?Why: Guideline options include: 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).
- How do the results of PORTEC-3 apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Advanced or recurrent, first line
- For my situation (advanced or recurrent, first line), which of the standard options do you recommend and why?Why: Guideline options include: Carboplatin-paclitaxel with dostarlimab (RUBY) or pembrolizumab (NRG-GY018), continued as maintenance; durvalumab (DUO-E) is an alternative.
- Am I a candidate for Dostarlimab, Pembrolizumab, Durvalumab or related drugs, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of RUBY / ENGOT-EN6 / GOG-3031 and NRG-GY018 / KEYNOTE-868 apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Recurrent after chemotherapy without prior immunotherapy
- For my situation (recurrent after chemotherapy without prior immunotherapy), which of the standard options do you recommend and why?Why: Guideline options include: Single-agent dostarlimab or pembrolizumab, with durable responses in a large minority.
- Am I a candidate for Dostarlimab, Pembrolizumab, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
Lynch carriers
- For my situation (lynch carriers), which of the standard options do you recommend and why?Why: Guideline options include: Annual surveillance from the mid-thirties where offered, aspirin, and risk-reducing hysterectomy with salpingo-oophorectomy after childbearing.
Any stage
- Are there clinical trials I could join, for example of 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), 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), A frameshift neoantigen vaccine for Lynch syndrome carriers as the first preventive cancer vaccine approval, WRN inhibitors: a second synthetic-lethal win for mismatch-repair cancers?Why: Trials are how the next standard of care is set; asking early keeps options open.
- Would a second opinion at a high-volume centre change anything, and can you help arrange it?Why: Rare or high-stakes decisions benefit from a centre that treats many similar patients.
- What supportive care (symptom control, nutrition, exercise, mental health, financial help) is available from the start?Why: Supportive care improves quality of life and helps patients complete treatment.
- I read that “Whether chemotherapy can be dropped in favour of immunotherapy alone”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
- I read that “Why a third of deficient tumours do not respond to checkpoint blockade”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
Newly diagnosed? Read the first 60 days with Mismatch-repair-deficient endometrial cancer, then print the one-page appointment sheet with room for the answers.
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Direct links plus the targets, companies, and technologies of this cancer's products.
technologies
7targets
2drugs
5companies
4terms
4trials
6pairings
1ideas
2Latest papers
topQuery for this cancer: (TITLE:"Mismatch-repair-deficient endometrial cancer" OR ABSTRACT:"Mismatch-repair-deficient endometrial cancer" OR TITLE:"dMMR endometrial cancer" OR ABSTRACT:"dMMR endometrial cancer" OR TITLE:"MSI-high endometrial cancer" OR ABSTRACT:"MSI-high endometrial cancer" OR TITLE:"MMRd endometrial cancer" OR ABSTRACT:"MMRd endometrial cancer" OR TITLE:"Lynch-associated endometrial cancer" OR ABSTRACT:"Lynch-associated endometrial cancer") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about Mismatch-repair-deficient endometrial cancer, not a curated reading list.
Similar pages
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Shares Hysterectomy, Endometrial cancer molecular classes (POLEmut, MMRd, p53abn, NSMP), PORTEC-3, Dostarlimab and the tag subtype-page.
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