MSI-High Endometrial Cancer

MONDO:0011962 Pathograph 3 endometrial cancer

MSI-high endometrial cancer is a molecularly-defined subset of endometrial carcinoma characterized by deficient mismatch repair (dMMR) and high microsatellite instability (MSI-H). This phenotype occurs in approximately 25-30% of endometrial cancers and may arise from germline MMR gene mutations (Lynch syndrome) or somatic MLH1 promoter hypermethylation. MSI-H tumors have hypermutated genomes generating neoantigens that make them highly responsive to immune checkpoint inhibition. The combination of pembrolizumab plus lenvatinib has transformed treatment of advanced MSI-H endometrial cancer.

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0
Mappings
0
Definitions
0
Inheritance
3
Pathophysiology
1
Histopathology
3
Phenotypes
3
Pathograph
4
Genes
4
Treatments
2
Subtypes
0
Differentials
0
Datasets
0
Trials
0
Models
14
References
1
Deep Research
🏷

Classifications

Harrison's Chapter
cancer solid tumor
ICD-O Morphology
Adenocarcinoma
◆

Subtypes

2
Lynch Syndrome-Associated Endometrial Cancer
Germline mutations in MMR genes (MLH1, MSH2, MSH6, PMS2) cause Lynch syndrome with substantially increased lifetime risk of endometrial cancer. Regular surveillance and risk-reducing surgery may be considered.
Show evidence (1 reference)
PMID:15340260 NO_EVIDENCE
"Colorectal cancers resulting from defective DNA mismatch repair can occur in both hereditary non-polyposis colon cancer (HNPCC) and in the sporadic setting."
This study establishes that MMR-deficient cancers can arise from hereditary (Lynch syndrome) or sporadic causes, applicable to endometrial cancer as well.
Sporadic MSI-H Endometrial Cancer
Most common subtype caused by somatic MLH1 promoter hypermethylation leading to loss of MLH1/PMS2 expression. Not associated with germline mutations or increased cancer risk in family members.
Show evidence (1 reference)
PMID:15340260 NO_EVIDENCE
"significant differences can be demonstrated at the molecular level including widespread promoter hypermethylation and BRAF -activating mutations which occur significantly less often in HNPCC"
Study demonstrates that sporadic MSI-H tumors are characterized by promoter hypermethylation, distinguishing them from Lynch syndrome cases.
⚙

Pathophysiology

3
Mismatch Repair Deficiency
Loss of functional mismatch repair (MMR) proteins impairs the ability to correct base-base mismatches and insertion-deletion loops during DNA replication. This leads to accumulation of mutations, particularly at microsatellite regions.
endometrial epithelial cell link
mismatch repair link ↓ DECREASED
endometrium link
Downstream
Microsatellite Instability dMMR leads to expansion/contraction of microsatellite repeat sequences
Hypermutation and Neoantigen Generation Accumulated mutations generate tumor-specific neoantigens
Show evidence (1 reference)
PMID:39860407 PARTIAL
"Cancer immunotherapy through the use of PD-1/PD-L1 inhibitors have shown significant promise in endometrial carcinoma (EC), particularly in tumors with microsatellite instability (MSI) or mismatch repair deficiency (dMMR), present in approximately 30% of cases."
Supports the frequency of MSI/dMMR in endometrial carcinoma.
Microsatellite Instability
Deficient mismatch repair leads to instability at microsatellite loci, short tandem repeat sequences throughout the genome. MSI-H status is defined by instability at multiple markers and serves as a biomarker for dMMR.
DNA repair link ↓ DECREASED
Show evidence (1 reference)
PMID:19620942 PARTIAL
"Microsatellite instability (MSI) is the hallmark of a molecular pathway to carcinogenesis due to sporadic or inherited abnormalities of DNA mismatch repair genes."
Abstract links MSI to mismatch repair abnormalities, supporting this mechanism.
Hypermutation and Neoantigen Generation
MMR deficiency causes a hypermutated tumor phenotype with high tumor mutational burden (TMB). Frameshift mutations at coding microsatellites generate neoantigens recognized by the immune system, explaining the high response rates to immune checkpoint inhibition.
immune response link ↑ INCREASED
✶

Histopathology

1
Endometrioid Adenocarcinoma VERY_FREQUENT
Endometrioid adenocarcinoma is the most frequent histological subtype.
Show evidence (1 reference)
PMID:26354523 PARTIAL
"histological subtype is endometrioid adenocarcinoma."
Abstract notes endometrioid adenocarcinoma as the most frequent histological subtype.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for MSI-High Endometrial Cancer Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

3
Constitutional 2
Fatigue FREQUENT Fatigue (HP:0012378)
Pelvic Pain OCCASIONAL Pelvic pain (HP:0034267)
Other 1
Postmenopausal Bleeding VERY_FREQUENT Postmenopausal bleeding (HP:0033840)
🧬

Genetic Associations

4
MLH1 (Germline or Promoter Hypermethylation)
Autosomal Dominant
MSH2 (Germline Loss-of-Function Mutations)
Autosomal Dominant
MSH6 (Germline Loss-of-Function Mutations)
Autosomal Dominant
PMS2 (Germline Loss-of-Function Mutations)
Autosomal Dominant
💊

Treatments

4
Pembrolizumab Plus Lenvatinib
Action: immunotherapy Ontology label: Immunotherapy NCIT:C15262
Agent: lenvatinib ↗
Combination of PD-1 inhibitor pembrolizumab with multi-kinase inhibitor lenvatinib is approved for advanced endometrial cancer including MSI-H tumors. Shows remarkable efficacy in dMMR/MSI-H patients with durable responses.
Show evidence (1 reference)
PMID:35045221 PARTIAL
"Lenvatinib plus pembrolizumab led to significantly longer progression-free survival and overall survival than chemotherapy among patients with advanced endometrial cancer."
KEYNOTE-775 demonstrated significant PFS and OS benefit with lenvatinib plus pembrolizumab versus chemotherapy in advanced endometrial cancer.
Pembrolizumab Monotherapy
Action: immunotherapy Ontology label: Immunotherapy NCIT:C15262
Agent: pembrolizumab ↗
PD-1 inhibitor pembrolizumab has tumor-agnostic approval for MSI-H/dMMR cancers. Highly effective in MSI-H endometrial cancer with significant response rates and durable remissions.
Show evidence (1 reference)
PMID:34990208 SUPPORT
"The objective response rate was 48% (95% CI, 37 to 60)"
KEYNOTE-158 abstract reports response rate for pembrolizumab in MSI-H/dMMR endometrial cancer.
Dostarlimab
Action: immunotherapy Ontology label: Immunotherapy NCIT:C15262
Agent: dostarlimab ↗
PD-1 inhibitor approved for dMMR recurrent or advanced endometrial cancer. Another effective immunotherapy option for MSI-H tumors.
Show evidence (1 reference)
PMID:35064011 SUPPORT
"In cohort A1, ORR was 43.5% (95% CI 34.0% to 53.4%) with 11 complete responses and 36 partial responses."
GARNET trial demonstrated 43.5% objective response rate with dostarlimab in dMMR/MSI-H endometrial cancer.
Hysterectomy
Action: surgical procedure MAXO:0000004
Total hysterectomy with bilateral salpingo-oophorectomy is standard surgical treatment for localized endometrial cancer regardless of MSI status.
Show evidence (1 reference)
PMID:35045221 NO_EVIDENCE
"Standard therapy for advanced endometrial cancer after failure of platinum-based chemotherapy remains unclear."
While the study focuses on advanced disease after chemotherapy failure, it implies surgery (hysterectomy) and platinum chemotherapy are standard initial therapies.
🔬

Biochemical Markers

2
MMR Protein Expression by IHC
MSI Testing
{ }

Source YAML

click to show 
name: MSI-High Endometrial Cancer
creation_date: '2026-01-26T02:55:13Z'
updated_date: '2026-04-22T20:13:21Z'
description: >-
  MSI-high endometrial cancer is a molecularly-defined subset of endometrial carcinoma
  characterized by deficient mismatch repair (dMMR) and high microsatellite instability
  (MSI-H). This phenotype occurs in approximately 25-30% of endometrial cancers and
  may arise from germline MMR gene mutations (Lynch syndrome) or somatic MLH1 promoter
  hypermethylation. MSI-H tumors have hypermutated genomes generating neoantigens
  that
  make them highly responsive to immune checkpoint inhibition. The combination of
  pembrolizumab plus lenvatinib has transformed treatment of advanced MSI-H endometrial
  cancer.
categories:
- Gynecologic Cancer
- Molecularly-Defined Cancer
- DNA Repair Deficiency Syndrome
parents:
- endometrial cancer
has_subtypes:
- name: Lynch Syndrome-Associated Endometrial Cancer
  description: >-
    Germline mutations in MMR genes (MLH1, MSH2, MSH6, PMS2) cause Lynch syndrome
    with substantially increased lifetime risk of endometrial cancer. Regular
    surveillance and risk-reducing surgery may be considered.
  evidence:
  - reference: PMID:15340260
    reference_title: "Promoter hypermethylation frequency and BRAF mutations distinguish hereditary non-polyposis colon cancer from sporadic MSI-H colon cancer."
    supports: NO_EVIDENCE
    snippet: >-
      Colorectal cancers resulting from defective DNA mismatch repair can occur
      in both hereditary non-polyposis colon cancer (HNPCC) and in the sporadic
      setting.
    explanation: >-
      This study establishes that MMR-deficient cancers can arise from hereditary
      (Lynch syndrome) or sporadic causes, applicable to endometrial cancer as well.
- name: Sporadic MSI-H Endometrial Cancer
  description: >-
    Most common subtype caused by somatic MLH1 promoter hypermethylation leading
    to loss of MLH1/PMS2 expression. Not associated with germline mutations or
    increased cancer risk in family members.
  evidence:
  - reference: PMID:15340260
    reference_title: "Promoter hypermethylation frequency and BRAF mutations distinguish hereditary non-polyposis colon cancer from sporadic MSI-H colon cancer."
    supports: NO_EVIDENCE
    snippet: >-
      significant differences can be demonstrated at the molecular level including
      widespread promoter hypermethylation and BRAF -activating mutations which
      occur significantly less often in HNPCC
    explanation: >-
      Study demonstrates that sporadic MSI-H tumors are characterized by promoter
      hypermethylation, distinguishing them from Lynch syndrome cases.
pathophysiology:
- name: Mismatch Repair Deficiency
  description: >-
    Loss of functional mismatch repair (MMR) proteins impairs the ability to
    correct base-base mismatches and insertion-deletion loops during DNA replication.
    This leads to accumulation of mutations, particularly at microsatellite regions.
  evidence:
  - reference: PMID:39860407
    reference_title: "PD-1 and PD-L1 Expression in Endometrial Cancer: A Systematic Review of the Literature."
    supports: PARTIAL
    snippet: "Cancer immunotherapy through the use of PD-1/PD-L1 inhibitors have shown significant promise in endometrial carcinoma (EC), particularly in tumors with microsatellite instability (MSI) or mismatch repair deficiency (dMMR), present in approximately 30% of cases."
    explanation: "Supports the frequency of MSI/dMMR in endometrial carcinoma."
  cell_types:
  - preferred_term: endometrial epithelial cell
    term:
      id: CL:0002149
      label: epithelial cell of uterus
  biological_processes:
  - preferred_term: mismatch repair
    modifier: DECREASED
    term:
      id: GO:0006298
      label: mismatch repair
  locations:
  - preferred_term: endometrium
    term:
      id: UBERON:0001295
      label: endometrium
  downstream:
  - target: Microsatellite Instability
    description: dMMR leads to expansion/contraction of microsatellite repeat sequences
  - target: Hypermutation and Neoantigen Generation
    description: Accumulated mutations generate tumor-specific neoantigens
- name: Microsatellite Instability
  description: >-
    Deficient mismatch repair leads to instability at microsatellite loci, short
    tandem repeat sequences throughout the genome. MSI-H status is defined by
    instability at multiple markers and serves as a biomarker for dMMR.
  evidence:
  - reference: PMID:19620942
    reference_title: "DNA mismatch repair deficiency in endometrial carcinoma."
    supports: PARTIAL
    snippet: "Microsatellite instability (MSI) is the hallmark of a molecular pathway to carcinogenesis due to sporadic or inherited abnormalities of DNA mismatch repair genes."
    explanation: "Abstract links MSI to mismatch repair abnormalities, supporting this mechanism."
  biological_processes:
  - preferred_term: DNA repair
    modifier: DECREASED
    term:
      id: GO:0006281
      label: DNA repair
- name: Hypermutation and Neoantigen Generation
  description: >-
    MMR deficiency causes a hypermutated tumor phenotype with high tumor
    mutational burden (TMB). Frameshift mutations at coding microsatellites
    generate neoantigens recognized by the immune system, explaining the
    high response rates to immune checkpoint inhibition.
  biological_processes:
  - preferred_term: immune response
    modifier: INCREASED
    term:
      id: GO:0006955
      label: immune response
histopathology:
- name: Endometrioid Adenocarcinoma
  finding_term:
    preferred_term: Endometrioid Adenocarcinoma
    term:
      id: NCIT:C3769
      label: Endometrioid Adenocarcinoma
  frequency: VERY_FREQUENT
  description: Endometrioid adenocarcinoma is the most frequent histological subtype.
  evidence:
  - reference: PMID:26354523
    reference_title: "Endometrial cancer."
    supports: PARTIAL
    snippet: "histological subtype is endometrioid adenocarcinoma."
    explanation: Abstract notes endometrioid adenocarcinoma as the most frequent histological subtype.

phenotypes:
- category: Gynecologic
  name: Postmenopausal Bleeding
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Postmenopausal bleeding or abnormal premenopausal bleeding is the most
    common presenting symptom of endometrial cancer regardless of MSI status.
  phenotype_term:
    preferred_term: postmenopausal bleeding
    term:
      id: HP:0033840
      label: Postmenopausal bleeding
- category: Constitutional
  name: Fatigue
  frequency: FREQUENT
  description: >-
    Constitutional symptoms may occur in advanced disease or secondary to
    anemia from chronic blood loss.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
- category: Abdominal
  name: Pelvic Pain
  frequency: OCCASIONAL
  description: >-
    Pelvic pain or pressure may indicate locally advanced disease with
    extension beyond the uterus.
  phenotype_term:
    preferred_term: Pelvic pain
    term:
      id: HP:0034267
      label: Pelvic pain
biochemical:
- name: MMR Protein Expression by IHC
  notes: >-
    Immunohistochemistry for MLH1, MSH2, MSH6, and PMS2 is standard for detecting
    dMMR. Loss of MLH1/PMS2 suggests sporadic hypermethylation; loss of MSH2/MSH6
    suggests germline mutation.
- name: MSI Testing
  notes: >-
    PCR-based microsatellite instability testing using Bethesda markers or
    next-generation sequencing confirms MSI-H status.
genetic:
- name: MLH1
  association: Germline or Promoter Hypermethylation
  inheritance:
  - name: Autosomal Dominant
  notes: >-
    MLH1 loss is most common in endometrial cancer, usually due to somatic
    promoter hypermethylation. Germline MLH1 mutations cause Lynch syndrome.
- name: MSH2
  association: Germline Loss-of-Function Mutations
  inheritance:
  - name: Autosomal Dominant
  notes: >-
    MSH2 germline mutations cause Lynch syndrome with high endometrial cancer
    risk. Loss of MSH2 causes concurrent loss of MSH6.
- name: MSH6
  association: Germline Loss-of-Function Mutations
  inheritance:
  - name: Autosomal Dominant
  notes: >-
    MSH6 mutations are particularly associated with endometrial cancer risk
    in Lynch syndrome.
- name: PMS2
  association: Germline Loss-of-Function Mutations
  inheritance:
  - name: Autosomal Dominant
  notes: >-
    PMS2 germline mutations cause Lynch syndrome with lower penetrance than
    MLH1 or MSH2 mutations.
treatments:
- name: Pembrolizumab Plus Lenvatinib
  description: >-
    Combination of PD-1 inhibitor pembrolizumab with multi-kinase inhibitor
    lenvatinib is approved for advanced endometrial cancer including MSI-H tumors.
    Shows remarkable efficacy in dMMR/MSI-H patients with durable responses.
  evidence:
  - reference: PMID:35045221
    reference_title: "Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer."
    supports: PARTIAL
    snippet: >-
      Lenvatinib plus pembrolizumab led to significantly longer progression-free
      survival and overall survival than chemotherapy among patients with advanced
      endometrial cancer.
    explanation: >-
      KEYNOTE-775 demonstrated significant PFS and OS benefit with lenvatinib plus
      pembrolizumab versus chemotherapy in advanced endometrial cancer.
  treatment_term:
    preferred_term: immunotherapy
    term:
      id: NCIT:C15262
      label: Immunotherapy
    therapeutic_agent:
    - preferred_term: lenvatinib
      term:
        id: CHEBI:85994
        label: lenvatinib
- name: Pembrolizumab Monotherapy
  description: >-
    PD-1 inhibitor pembrolizumab has tumor-agnostic approval for MSI-H/dMMR
    cancers. Highly effective in MSI-H endometrial cancer with significant
    response rates and durable remissions.
  evidence:
  - reference: PMID:34990208
    reference_title: "Pembrolizumab in Patients With Microsatellite Instability-High Advanced Endometrial Cancer: Results From the KEYNOTE-158 Study."
    supports: SUPPORT
    snippet: "The objective response rate was 48% (95% CI, 37 to 60)"
    explanation: "KEYNOTE-158 abstract reports response rate for pembrolizumab in MSI-H/dMMR endometrial cancer."
  treatment_term:
    preferred_term: immunotherapy
    term:
      id: NCIT:C15262
      label: Immunotherapy
    therapeutic_agent:
    - preferred_term: pembrolizumab
      term:
        id: NCIT:C106432
        label: Pembrolizumab
- name: Dostarlimab
  description: >-
    PD-1 inhibitor approved for dMMR recurrent or advanced endometrial cancer.
    Another effective immunotherapy option for MSI-H tumors.
  evidence:
  - reference: PMID:35064011
    reference_title: "Safety and antitumor activity of dostarlimab in patients with advanced or recurrent DNA mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) or proficient/stable (MMRp/MSS) endometrial cancer: interim results from GARNET-a phase I, single-arm study."
    supports: SUPPORT
    snippet: >-
      In cohort A1, ORR was 43.5% (95% CI 34.0% to 53.4%) with 11 complete responses
      and 36 partial responses.
    explanation: >-
      GARNET trial demonstrated 43.5% objective response rate with dostarlimab in
      dMMR/MSI-H endometrial cancer.
  treatment_term:
    preferred_term: immunotherapy
    term:
      id: NCIT:C15262
      label: Immunotherapy
    therapeutic_agent:
    - preferred_term: dostarlimab
      term:
        id: NCIT:C126799
        label: Dostarlimab
- name: Hysterectomy
  description: >-
    Total hysterectomy with bilateral salpingo-oophorectomy is standard
    surgical treatment for localized endometrial cancer regardless of MSI status.
  evidence:
  - reference: PMID:35045221
    reference_title: "Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer."
    supports: NO_EVIDENCE
    snippet: >-
      Standard therapy for advanced endometrial cancer after failure of platinum-based
      chemotherapy remains unclear.
    explanation: >-
      While the study focuses on advanced disease after chemotherapy failure, it implies
      surgery (hysterectomy) and platinum chemotherapy are standard initial therapies.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
disease_term:
  preferred_term: endometrial cancer
  term:
    id: MONDO:0011962
    label: endometrial cancer

classifications:
  icdo_morphology:
    classification_value: Adenocarcinoma
  harrisons_chapter:
  - classification_value: cancer
  - classification_value: solid tumor
references:
- reference: DOI:10.1002/cncr.35267
  title: 'A tale of two pathways: Review of immune checkpoint inhibitors in DNA mismatch repair‐deficient and microsatellite instability‐high endometrial cancers'
  found_in:
  - MSI_High_Endometrial_Cancer-deep-research-falcon.md
  findings:
  - statement: The DNA mismatch repair (MMR) pathway is critical for correcting DNA mismatches generated during DNA replication.
    supporting_text: The DNA mismatch repair (MMR) pathway is critical for correcting DNA mismatches generated during DNA replication.
    evidence:
    - reference: DOI:10.1002/cncr.35267
      reference_title: 'A tale of two pathways: Review of immune checkpoint inhibitors in DNA mismatch repair‐deficient and microsatellite instability‐high endometrial cancers'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The DNA mismatch repair (MMR) pathway is critical for correcting DNA mismatches generated during DNA replication.
      explanation: Deep research cited this publication as relevant literature for MSI High Endometrial Cancer.
- reference: DOI:10.1002/ijgo.14923
  title: '<scp>FIGO</scp> staging of endometrial cancer: 2023'
  found_in:
  - MSI_High_Endometrial_Cancer-deep-research-falcon.md
  findings:
  - statement: Many advances in the understanding of the pathologic and molecular features of endometrial cancer have occurred since the FIGO staging was last updated in 2009.
    supporting_text: Many advances in the understanding of the pathologic and molecular features of endometrial cancer have occurred since the FIGO staging was last updated in 2009.
    evidence:
    - reference: DOI:10.1002/ijgo.14923
      reference_title: '<scp>FIGO</scp> staging of endometrial cancer: 2023'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Many advances in the understanding of the pathologic and molecular features of endometrial cancer have occurred since the FIGO staging was last updated in 2009.
      explanation: Deep research cited this publication as relevant literature for MSI High Endometrial Cancer.
- reference: DOI:10.1007/s00404-024-07504-3
  title: Real-world prevalence of microsatellite instability testing and related status in women with advanced endometrial cancer in Europe
  found_in:
  - MSI_High_Endometrial_Cancer-deep-research-falcon.md
  findings:
  - statement: To assess the real-world prevalence of microsatellite instability (MSI)/mismatch repair (MMR) testing and related tumor status in recurrent/advanced endometrial cancer patients in Europe.
    supporting_text: To assess the real-world prevalence of microsatellite instability (MSI)/mismatch repair (MMR) testing and related tumor status in recurrent/advanced endometrial cancer patients in Europe.
    evidence:
    - reference: DOI:10.1007/s00404-024-07504-3
      reference_title: Real-world prevalence of microsatellite instability testing and related status in women with advanced endometrial cancer in Europe
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: To assess the real-world prevalence of microsatellite instability (MSI)/mismatch repair (MMR) testing and related tumor status in recurrent/advanced endometrial cancer patients in Europe.
      explanation: Deep research cited this publication as relevant literature for MSI High Endometrial Cancer.
- reference: DOI:10.1038/s41588-023-01499-4
  title: Mismatch repair deficiency is not sufficient to elicit tumor immunogenicity
  found_in:
  - MSI_High_Endometrial_Cancer-deep-research-falcon.md
  findings:
  - statement: DNA mismatch repair deficiency (MMRd) is associated with a high tumor mutational burden (TMB) and sensitivity to immune checkpoint blockade (ICB) therapy.
    supporting_text: DNA mismatch repair deficiency (MMRd) is associated with a high tumor mutational burden (TMB) and sensitivity to immune checkpoint blockade (ICB) therapy.
    evidence:
    - reference: DOI:10.1038/s41588-023-01499-4
      reference_title: Mismatch repair deficiency is not sufficient to elicit tumor immunogenicity
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: DNA mismatch repair deficiency (MMRd) is associated with a high tumor mutational burden (TMB) and sensitivity to immune checkpoint blockade (ICB) therapy.
      explanation: Deep research cited this publication as relevant literature for MSI High Endometrial Cancer.
- reference: DOI:10.1056/nejmoa2216334
  title: Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer
  found_in:
  - MSI_High_Endometrial_Cancer-deep-research-falcon.md
  findings:
  - statement: Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer
    supporting_text: Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer
- reference: DOI:10.1056/nejmoa2302312
  title: Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer
  found_in:
  - MSI_High_Endometrial_Cancer-deep-research-falcon.md
  findings:
  - statement: Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer
    supporting_text: Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer
- reference: DOI:10.1097/ogx.0000000000000623
  title: 'Association of Endometrial Cancer Risk With Postmenopausal Bleeding in Women: A Systematic Review and Meta-analysis'
  found_in:
  - MSI_High_Endometrial_Cancer-deep-research-falcon.md
  findings:
  - statement: (Abstracted from JAMA Intern Med 2018;178:1210–1222) The incidence of endometrial cancer and deaths from this cancer has increased in recent years and is projected to rise over the next decade.
    supporting_text: (Abstracted from JAMA Intern Med 2018;178:1210–1222) The incidence of endometrial cancer and deaths from this cancer has increased in recent years and is projected to rise over the next decade.
    evidence:
    - reference: DOI:10.1097/ogx.0000000000000623
      reference_title: 'Association of Endometrial Cancer Risk With Postmenopausal Bleeding in Women: A Systematic Review and Meta-analysis'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: (Abstracted from JAMA Intern Med 2018;178:1210–1222) The incidence of endometrial cancer and deaths from this cancer has increased in recent years and is projected to rise over the next decade.
      explanation: Deep research cited this publication as relevant literature for MSI High Endometrial Cancer.
- reference: DOI:10.1158/1078-0432.ccr-22-3915
  title: 'Safety, Efficacy, and Biomarker Analyses of Dostarlimab in Patients with Endometrial Cancer: Interim Results of the Phase I GARNET Study'
  found_in:
  - MSI_High_Endometrial_Cancer-deep-research-falcon.md
  findings:
  - statement: 'This interim report of the GARNET phase I trial presents efficacy and safety of dostarlimab in patients with advanced or recurrent endometrial cancer (EC), with an analysis of tumor biomarkers as prognostic indicators.'
    supporting_text: 'This interim report of the GARNET phase I trial presents efficacy and safety of dostarlimab in patients with advanced or recurrent endometrial cancer (EC), with an analysis of tumor biomarkers as prognostic indicators.'
    evidence:
    - reference: DOI:10.1158/1078-0432.ccr-22-3915
      reference_title: 'Safety, Efficacy, and Biomarker Analyses of Dostarlimab in Patients with Endometrial Cancer: Interim Results of the Phase I GARNET Study'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'This interim report of the GARNET phase I trial presents efficacy and safety of dostarlimab in patients with advanced or recurrent endometrial cancer (EC), with an analysis of tumor biomarkers as prognostic indicators.'
      explanation: Deep research cited this publication as relevant literature for MSI High Endometrial Cancer.
- reference: DOI:10.14288/1.0422939
  title: Investigation into the early pathogenesis of lynch syndrome associated endometrial cancer
  found_in:
  - MSI_High_Endometrial_Cancer-deep-research-falcon.md
  findings:
  - statement: Endometrial cancer is the most common gynecologic malignancy in Canada with increasing rates of both incidence and mortality.
    supporting_text: Endometrial cancer is the most common gynecologic malignancy in Canada with increasing rates of both incidence and mortality.
    evidence:
    - reference: DOI:10.14288/1.0422939
      reference_title: Investigation into the early pathogenesis of lynch syndrome associated endometrial cancer
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Endometrial cancer is the most common gynecologic malignancy in Canada with increasing rates of both incidence and mortality.
      explanation: Deep research cited this publication as relevant literature for MSI High Endometrial Cancer.
- reference: DOI:10.3389/fonc.2023.1147657
  title: Epigenetic MMR defect identifies a risk group not accounted for through traditional risk stratification algorithms in endometrial cancer
  found_in:
  - MSI_High_Endometrial_Cancer-deep-research-falcon.md
  findings:
  - statement: Epigenetic MMR defect identifies a risk group not accounted for through traditional risk stratification algorithms in endometrial cancer
    supporting_text: We sought to evaluate the contribution of mismatch repair (MMR) status to traditional risk stratification algorithms used to predict nodal involvement and recurrence in a large single-institution cohort.MethodsEndometrioid endometrial cancer (EC) cases from 2014-2020 were evaluated.
    evidence:
    - reference: DOI:10.3389/fonc.2023.1147657
      reference_title: Epigenetic MMR defect identifies a risk group not accounted for through traditional risk stratification algorithms in endometrial cancer
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: We sought to evaluate the contribution of mismatch repair (MMR) status to traditional risk stratification algorithms used to predict nodal involvement and recurrence in a large single-institution cohort.MethodsEndometrioid endometrial cancer (EC) cases from 2014-2020 were evaluated.
      explanation: Deep research cited this publication as relevant literature for MSI High Endometrial Cancer.
- reference: DOI:10.3390/cancers16203452
  title: 'Unraveling the Heterogeneity of Deficiency of Mismatch Repair Proteins in Endometrial Cancer: Predictive Biomarkers and Assessment Challenges'
  found_in:
  - MSI_High_Endometrial_Cancer-deep-research-falcon.md
  findings:
  - statement: Endometrial cancer (EC) poses a significant global health challenge, with increasing prevalence in 26 of 43 countries and over 13,000 deaths projected in the United States by 2024.
    supporting_text: Endometrial cancer (EC) poses a significant global health challenge, with increasing prevalence in 26 of 43 countries and over 13,000 deaths projected in the United States by 2024.
    evidence:
    - reference: DOI:10.3390/cancers16203452
      reference_title: 'Unraveling the Heterogeneity of Deficiency of Mismatch Repair Proteins in Endometrial Cancer: Predictive Biomarkers and Assessment Challenges'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Endometrial cancer (EC) poses a significant global health challenge, with increasing prevalence in 26 of 43 countries and over 13,000 deaths projected in the United States by 2024.
      explanation: Deep research cited this publication as relevant literature for MSI High Endometrial Cancer.
- reference: DOI:10.3390/cancers16233970
  title: 'Detection of Mismatch Repair Deficiency in Endometrial Cancer: Assessment of IHC, Fragment Length Analysis, and Amplicon Sequencing Based MSI Testing'
  found_in:
  - MSI_High_Endometrial_Cancer-deep-research-falcon.md
  findings:
  - statement: Mismatch repair (MMR) deficiency can be indicative of Lynch syndrome (LS) and guide treatment with immune checkpoint inhibitors.
    supporting_text: Mismatch repair (MMR) deficiency can be indicative of Lynch syndrome (LS) and guide treatment with immune checkpoint inhibitors.
    evidence:
    - reference: DOI:10.3390/cancers16233970
      reference_title: 'Detection of Mismatch Repair Deficiency in Endometrial Cancer: Assessment of IHC, Fragment Length Analysis, and Amplicon Sequencing Based MSI Testing'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Mismatch repair (MMR) deficiency can be indicative of Lynch syndrome (LS) and guide treatment with immune checkpoint inhibitors.
      explanation: Deep research cited this publication as relevant literature for MSI High Endometrial Cancer.
- reference: DOI:10.6004/jnccn.2024.0061
  title: 'Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric, Version 3.2024, NCCN Clinical Practice Guidelines In Oncology'
  found_in:
  - MSI_High_Endometrial_Cancer-deep-research-falcon.md
  findings:
  - statement: Multigene panel testing has allowed for the detection of a growing number of inherited pathogenic/likely pathogenic variants in people at high risk of cancer, including endometrial cancer (EC).
    supporting_text: Multigene panel testing has allowed for the detection of a growing number of inherited pathogenic/likely pathogenic variants in people at high risk of cancer, including endometrial cancer (EC).
    evidence:
    - reference: DOI:10.6004/jnccn.2024.0061
      reference_title: 'Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric, Version 3.2024, NCCN Clinical Practice Guidelines In Oncology'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Multigene panel testing has allowed for the detection of a growing number of inherited pathogenic/likely pathogenic variants in people at high risk of cancer, including endometrial cancer (EC).
      explanation: Deep research cited this publication as relevant literature for MSI High Endometrial Cancer.
- reference: DOI:10.7717/peerj.15920
  title: A retrospective study of consistency between immunohistochemistry and polymerase chain reaction of microsatellite instability in endometrial cancer
  found_in:
  - MSI_High_Endometrial_Cancer-deep-research-falcon.md
  findings:
  - statement: Identification of endometrial cancers (EC) with mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H) is essential for Lynch syndrome screening and treatment stratification.
    supporting_text: Identification of endometrial cancers (EC) with mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H) is essential for Lynch syndrome screening and treatment stratification.
    evidence:
    - reference: DOI:10.7717/peerj.15920
      reference_title: A retrospective study of consistency between immunohistochemistry and polymerase chain reaction of microsatellite instability in endometrial cancer
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Identification of endometrial cancers (EC) with mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H) is essential for Lynch syndrome screening and treatment stratification.
      explanation: Deep research cited this publication as relevant literature for MSI High Endometrial Cancer.
📚

References & Deep Research

References

14
DOI:10.1002/cncr.35267
A tale of two pathways: Review of immune checkpoint inhibitors in DNA mismatch repair‐deficient and microsatellite instability‐high endometrial cancers
1 finding
The DNA mismatch repair (MMR) pathway is critical for correcting DNA mismatches generated during DNA replication.
"The DNA mismatch repair (MMR) pathway is critical for correcting DNA mismatches generated during DNA replication."
Show evidence (1 reference)
DOI:10.1002/cncr.35267 SUPPORT Human Clinical
"The DNA mismatch repair (MMR) pathway is critical for correcting DNA mismatches generated during DNA replication."
Deep research cited this publication as relevant literature for MSI High Endometrial Cancer.
DOI:10.1002/ijgo.14923
<scp>FIGO</scp> staging of endometrial cancer: 2023
1 finding
Many advances in the understanding of the pathologic and molecular features of endometrial cancer have occurred since the FIGO staging was last updated in 2009.
"Many advances in the understanding of the pathologic and molecular features of endometrial cancer have occurred since the FIGO staging was last updated in 2009."
Show evidence (1 reference)
DOI:10.1002/ijgo.14923 SUPPORT Human Clinical
"Many advances in the understanding of the pathologic and molecular features of endometrial cancer have occurred since the FIGO staging was last updated in 2009."
Deep research cited this publication as relevant literature for MSI High Endometrial Cancer.
DOI:10.1007/s00404-024-07504-3
Real-world prevalence of microsatellite instability testing and related status in women with advanced endometrial cancer in Europe
1 finding
To assess the real-world prevalence of microsatellite instability (MSI)/mismatch repair (MMR) testing and related tumor status in recurrent/advanced endometrial cancer patients in Europe.
"To assess the real-world prevalence of microsatellite instability (MSI)/mismatch repair (MMR) testing and related tumor status in recurrent/advanced endometrial cancer patients in Europe."
Show evidence (1 reference)
DOI:10.1007/s00404-024-07504-3 SUPPORT Human Clinical
"To assess the real-world prevalence of microsatellite instability (MSI)/mismatch repair (MMR) testing and related tumor status in recurrent/advanced endometrial cancer patients in Europe."
Deep research cited this publication as relevant literature for MSI High Endometrial Cancer.
DOI:10.1038/s41588-023-01499-4
Mismatch repair deficiency is not sufficient to elicit tumor immunogenicity
1 finding
DNA mismatch repair deficiency (MMRd) is associated with a high tumor mutational burden (TMB) and sensitivity to immune checkpoint blockade (ICB) therapy.
"DNA mismatch repair deficiency (MMRd) is associated with a high tumor mutational burden (TMB) and sensitivity to immune checkpoint blockade (ICB) therapy."
Show evidence (1 reference)
DOI:10.1038/s41588-023-01499-4 SUPPORT Model Organism
"DNA mismatch repair deficiency (MMRd) is associated with a high tumor mutational burden (TMB) and sensitivity to immune checkpoint blockade (ICB) therapy."
Deep research cited this publication as relevant literature for MSI High Endometrial Cancer.
DOI:10.1056/nejmoa2216334
Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer
1 finding
Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer
"Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer"
DOI:10.1056/nejmoa2302312
Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer
1 finding
Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer
"Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer"
DOI:10.1097/ogx.0000000000000623
Association of Endometrial Cancer Risk With Postmenopausal Bleeding in Women: A Systematic Review and Meta-analysis
1 finding
(Abstracted from JAMA Intern Med 2018;178:1210–1222) The incidence of endometrial cancer and deaths from this cancer has increased in recent years and is projected to rise over the next decade.
"(Abstracted from JAMA Intern Med 2018;178:1210–1222) The incidence of endometrial cancer and deaths from this cancer has increased in recent years and is projected to rise over the next decade."
Show evidence (1 reference)
DOI:10.1097/ogx.0000000000000623 SUPPORT Other
"(Abstracted from JAMA Intern Med 2018;178:1210–1222) The incidence of endometrial cancer and deaths from this cancer has increased in recent years and is projected to rise over the next decade."
Deep research cited this publication as relevant literature for MSI High Endometrial Cancer.
DOI:10.1158/1078-0432.ccr-22-3915
Safety, Efficacy, and Biomarker Analyses of Dostarlimab in Patients with Endometrial Cancer: Interim Results of the Phase I GARNET Study
1 finding
This interim report of the GARNET phase I trial presents efficacy and safety of dostarlimab in patients with advanced or recurrent endometrial cancer (EC), with an analysis of tumor biomarkers as prognostic indicators.
"This interim report of the GARNET phase I trial presents efficacy and safety of dostarlimab in patients with advanced or recurrent endometrial cancer (EC), with an analysis of tumor biomarkers as prognostic indicators."
Show evidence (1 reference)
DOI:10.1158/1078-0432.ccr-22-3915 SUPPORT Human Clinical
"This interim report of the GARNET phase I trial presents efficacy and safety of dostarlimab in patients with advanced or recurrent endometrial cancer (EC), with an analysis of tumor biomarkers as prognostic indicators."
Deep research cited this publication as relevant literature for MSI High Endometrial Cancer.
DOI:10.14288/1.0422939
Investigation into the early pathogenesis of lynch syndrome associated endometrial cancer
1 finding
Endometrial cancer is the most common gynecologic malignancy in Canada with increasing rates of both incidence and mortality.
"Endometrial cancer is the most common gynecologic malignancy in Canada with increasing rates of both incidence and mortality."
Show evidence (1 reference)
DOI:10.14288/1.0422939 SUPPORT Human Clinical
"Endometrial cancer is the most common gynecologic malignancy in Canada with increasing rates of both incidence and mortality."
Deep research cited this publication as relevant literature for MSI High Endometrial Cancer.
DOI:10.3389/fonc.2023.1147657
Epigenetic MMR defect identifies a risk group not accounted for through traditional risk stratification algorithms in endometrial cancer
1 finding
Epigenetic MMR defect identifies a risk group not accounted for through traditional risk stratification algorithms in endometrial cancer
"We sought to evaluate the contribution of mismatch repair (MMR) status to traditional risk stratification algorithms used to predict nodal involvement and recurrence in a large single-institution cohort.MethodsEndometrioid endometrial cancer (EC) cases from 2014-2020 were evaluated."
Show evidence (1 reference)
DOI:10.3389/fonc.2023.1147657 SUPPORT Human Clinical
"We sought to evaluate the contribution of mismatch repair (MMR) status to traditional risk stratification algorithms used to predict nodal involvement and recurrence in a large single-institution cohort.MethodsEndometrioid endometrial cancer (EC) cases from 2014-2020 were evaluated."
Deep research cited this publication as relevant literature for MSI High Endometrial Cancer.
DOI:10.3390/cancers16203452
Unraveling the Heterogeneity of Deficiency of Mismatch Repair Proteins in Endometrial Cancer: Predictive Biomarkers and Assessment Challenges
1 finding
Endometrial cancer (EC) poses a significant global health challenge, with increasing prevalence in 26 of 43 countries and over 13,000 deaths projected in the United States by 2024.
"Endometrial cancer (EC) poses a significant global health challenge, with increasing prevalence in 26 of 43 countries and over 13,000 deaths projected in the United States by 2024."
Show evidence (1 reference)
DOI:10.3390/cancers16203452 SUPPORT Human Clinical
"Endometrial cancer (EC) poses a significant global health challenge, with increasing prevalence in 26 of 43 countries and over 13,000 deaths projected in the United States by 2024."
Deep research cited this publication as relevant literature for MSI High Endometrial Cancer.
DOI:10.3390/cancers16233970
Detection of Mismatch Repair Deficiency in Endometrial Cancer: Assessment of IHC, Fragment Length Analysis, and Amplicon Sequencing Based MSI Testing
1 finding
Mismatch repair (MMR) deficiency can be indicative of Lynch syndrome (LS) and guide treatment with immune checkpoint inhibitors.
"Mismatch repair (MMR) deficiency can be indicative of Lynch syndrome (LS) and guide treatment with immune checkpoint inhibitors."
Show evidence (1 reference)
DOI:10.3390/cancers16233970 SUPPORT Human Clinical
"Mismatch repair (MMR) deficiency can be indicative of Lynch syndrome (LS) and guide treatment with immune checkpoint inhibitors."
Deep research cited this publication as relevant literature for MSI High Endometrial Cancer.
DOI:10.6004/jnccn.2024.0061
Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric, Version 3.2024, NCCN Clinical Practice Guidelines In Oncology
1 finding
Multigene panel testing has allowed for the detection of a growing number of inherited pathogenic/likely pathogenic variants in people at high risk of cancer, including endometrial cancer (EC).
"Multigene panel testing has allowed for the detection of a growing number of inherited pathogenic/likely pathogenic variants in people at high risk of cancer, including endometrial cancer (EC)."
Show evidence (1 reference)
DOI:10.6004/jnccn.2024.0061 SUPPORT Human Clinical
"Multigene panel testing has allowed for the detection of a growing number of inherited pathogenic/likely pathogenic variants in people at high risk of cancer, including endometrial cancer (EC)."
Deep research cited this publication as relevant literature for MSI High Endometrial Cancer.
DOI:10.7717/peerj.15920
A retrospective study of consistency between immunohistochemistry and polymerase chain reaction of microsatellite instability in endometrial cancer
1 finding
Identification of endometrial cancers (EC) with mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H) is essential for Lynch syndrome screening and treatment stratification.
"Identification of endometrial cancers (EC) with mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H) is essential for Lynch syndrome screening and treatment stratification."
Show evidence (1 reference)
DOI:10.7717/peerj.15920 SUPPORT Human Clinical
"Identification of endometrial cancers (EC) with mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H) is essential for Lynch syndrome screening and treatment stratification."
Deep research cited this publication as relevant literature for MSI High Endometrial Cancer.

Deep Research

1
Falcon ▸
1. Disease Information
Edison Scientific Literature 40 citations 2026-04-05T19:52:27.908322

1. Disease Information

1.1 Overview / definition

MSI-H endometrial cancer refers to endometrial tumors with microsatellite instability caused by defects in the DNA mismatch repair pathway (dMMR). MSI-H/dMMR tumors accumulate replication errors leading to a hypermutated state and increased neoantigen burden, which underlies heightened sensitivity to immune checkpoint blockade in many patients (omalley2022pembrolizumabinpatients pages 1-2, oaknin2023safetyefficacyand pages 1-2).

Key definitional quote (abstract-level): KEYNOTE-158 notes that dMMR may arise from Lynch syndrome germline variants in MMR genes or sporadic MLH1 promoter methylation, leading to MSI and high mutation/neoantigen burden (omalley2022pembrolizumabinpatients pages 1-2).

1.2 Synonyms / alternative names

  • MMR-deficient endometrial cancer (MMRd EC)
  • MSI-high endometrial carcinoma
  • TCGA MSI/hypermutated endometrial cancer subtype (berek2023figostagingof pages 8-9, berek2023figostagingof pages 11-12)

1.3 Key identifiers (available from retrieved sources)

  • Disease ontology: Endometrial cancer MONDO_0011962 (kelkar2024realworldprevalenceof pages 1-2)
  • FIGO (2023): FIGO 2023 recommends molecular subtype annotation (including MMRd) appended to stage (e.g., “m” with a subscript) (berek2023figostagingof pages 1-4, berek2023figostagingof pages 4-5)

Note: ICD, MeSH, and Orphanet codes specific to “MSI-H endometrial cancer” were not directly retrievable from the provided corpus; MSI-H is typically represented as a biomarker-defined subtype rather than a separate coding entity in clinical classifications.

1.4 Evidence sources (patient-level vs aggregated)

Evidence in this report comes from: - Aggregated clinical trials and reviews (KEYNOTE-158; GARNET; RUBY; NRG-GY018) (omalley2022pembrolizumabinpatients pages 1-2, oaknin2023safetyefficacyand pages 1-2, mirza2023dostarlimabforprimary pages 1-3, liu2024ataleof pages 19-21) - Retrospective cohorts and real-world chart reviews (Europe ECHO-EU; single-institution molecular cohorts) (kelkar2024realworldprevalenceof pages 1-2, riedinger2023epigeneticmmrdefect pages 1-2, wang2023aretrospectivestudy pages 1-2)

2. Etiology

2.1 Disease causal factors (molecular causes)

MSI-H/dMMR in endometrial cancer arises primarily through: 1) Inherited (germline) pathogenic variants in MMR genes (Lynch syndrome) (omalley2022pembrolizumabinpatients pages 1-2) 2) Sporadic epigenetic silencing, most commonly MLH1 promoter hypermethylation, leading to MLH1/PMS2 protein loss and MSI (omalley2022pembrolizumabinpatients pages 1-2, riedinger2023epigeneticmmrdefect pages 1-2)

Quantitative mechanism distribution: In a cohort of 1,514 endometrioid EC, 25.9% were MMR-deficient and 80.4% of MMR defects were attributed to epigenetic MLH1 silencing (MLH1 promoter hypermethylation) (riedinger2023epigeneticmmrdefect pages 1-2).

2.2 Risk factors (general EC risk factors; not MSI-H specific)

A systematic review/meta-analysis on postmenopausal bleeding contextualizes major endometrial cancer risk factors such as obesity, anovulation/irregular menses, diabetes, and tamoxifen exposure (clarke2018associationofendometrial pages 1-2). These are general endometrial cancer risks and are not specific to MSI-H biology.

2.3 Protective factors / gene–environment interactions

Protective factors and formal gene–environment interaction evidence specific to MSI-H endometrial cancer were not directly available in the retrieved evidence set.

3. Phenotypes

3.1 Common presenting symptoms and clinical features

  • Postmenopausal bleeding (PMB): pooled prevalence among women with endometrial cancer 91% (95% CI 87–93%) (clarke2018associationofendometrial pages 1-2). (This statistic is not MSI-H-specific but is the dominant clinical presentation of endometrial cancer.)
  • MSI/dMMR status may correlate with tumor grade/histology: in a 333-patient cohort, MMR/MSI status correlated with high-grade endometrioid or non-endometrioid components (wang2023aretrospectivestudy pages 1-2).

3.2 Age distribution

In a 333-case cohort, the dMMR subgroup was significantly younger than pMMR, especially for patients <60 years (wang2023aretrospectivestudy pages 1-2).

In European recurrent/advanced endometrial cancer chart review cohorts, median age at recurrent/advanced diagnosis was 69 years (not MSI-H-specific) (kelkar2024realworldprevalenceof pages 1-2).

3.3 HPO term suggestions (symptom-oriented)

(ontology suggestions; frequencies are not always available per MSI-H subtype) - Abnormal uterine bleeding / postmenopausal bleeding: HP:0000858 (Abnormal uterine bleeding) and/or HP:0000141 (Postmenopausal bleeding; term availability may vary by HPO release) - Anemia from chronic bleeding: HP:0001903 - Pelvic pain: HP:0000233

3.4 Quality-of-life impact

Direct QoL instruments (e.g., EQ-5D, PROMIS) specific to MSI-H endometrial cancer were not extracted from the available texts.

4. Genetic / Molecular Information

4.1 Causal genes and pathways

Core mismatch repair genes implicated in MSI-H/dMMR endometrial cancer include MLH1, PMS2, MSH2, MSH6, with heterodimer pairing (MLH1–PMS2; MSH2–MSH6) and loss patterns detectable by IHC (oaknin2023safetyefficacyand pages 1-2, carvalho2024unravelingtheheterogeneity pages 5-7).

4.2 Somatic vs germline contributions

KEYNOTE-158 explicitly frames dMMR etiology as either inherited mutations (Lynch syndrome) or sporadic MLH1 promoter methylation (omalley2022pembrolizumabinpatients pages 1-2).

4.3 Frequent MMR IHC loss patterns (tumor phenotype)

In a 333-case study: - Overall dMMR: 25.2% - Overall MSI-H: 24.0% - Among dMMR: MLH1/PMS2 loss 59.5%, MSH2/MSH6 loss 22.6%, isolated PMS2 loss 8.3%, isolated MSH6 loss 9.5% (wang2023aretrospectivestudy pages 1-2).

4.4 Epigenetics

MLH1 promoter hypermethylation is repeatedly supported as a major driver of sporadic dMMR/MSI-H EC (riedinger2023epigeneticmmrdefect pages 1-2, omalley2022pembrolizumabinpatients pages 1-2).

5. Environmental Information

No specific environmental toxicant, occupational, or infectious cause unique to MSI-H endometrial cancer was identified in the retrieved evidence. General endometrial cancer risk factors are summarized in Section 2.2 (clarke2018associationofendometrial pages 1-2).

6. Mechanism / Pathophysiology

6.1 Causal chain (from molecular defect to phenotype and treatment sensitivity)

1) MMR deficiency → replication mismatches not corrected → genome-wide mutation accumulation, including at microsatellites (MSI) (oaknin2023safetyefficacyand pages 1-2) 2) Hypermutated state → increased neoantigens and immune infiltration/immune checkpoint engagement → potential susceptibility to PD-1 blockade (omalley2022pembrolizumabinpatients pages 1-2, mirza2023dostarlimabforprimary pages 1-3) 3) Clinical phenotype: MSI-H/dMMR subset constitutes ~25–31% of EC and is clinically actionable for immunotherapy selection (omalley2022pembrolizumabinpatients pages 1-2, mirza2023dostarlimabforprimary pages 1-3)

6.2 Mechanistic heterogeneity: epigenetic vs mutational MMRd

A major contemporary concept is that mechanism of MMR loss (e.g., MLH1 hypermethylation vs MMR gene mutations) may shape immune microenvironment and response heterogeneity, motivating more nuanced biomarker strategies (liu2024ataleof pages 19-21, riedinger2023epigeneticmmrdefect pages 1-2).

6.3 GO / CL / UBERON term suggestions

  • UBERON: Endometrium UBERON:0001295; Uterus UBERON:0000995 (anatomy suggestions)
  • GO biological processes: DNA mismatch repair GO:0006298; DNA replication GO:0006260; somatic hypermutation-like mutation accumulation (conceptual)
  • CL cell types: Endometrial epithelial cell CL:0000066 (epithelial cell; more specific endometrial epithelial subtypes may be available depending on CL version); CD8-positive T cell CL:0000625 (immune infiltration relevance from MSI biology)

7. Anatomical Structures Affected

7.1 Primary site

  • Endometrium (uterine lining) and uterine corpus are primary tissues affected (UBERON suggestions above).

7.2 Metastatic/advanced disease patterns

In advanced settings, a European recurrent/advanced cohort had >75% Stage IIIB–IV at initial diagnosis, reflecting frequent extrauterine spread in the real-world advanced population (kelkar2024realworldprevalenceof pages 1-2).

8. Temporal Development

8.1 Onset and course

Endometrial cancer typically presents in mid-to-late adulthood; dMMR cases may be younger than pMMR (wang2023aretrospectivestudy pages 1-2). MSI-H endometrial cancer can be diagnosed at early stages but also occurs in advanced/recurrent settings where systemic therapy selection is biomarker-driven (kelkar2024realworldprevalenceof pages 1-2, mirza2023dostarlimabforprimary pages 1-3).

8.2 Staging system updates (FIGO 2023)

FIGO 2023 explicitly promotes integrating molecular subtype (including MMRd) into reporting by appending molecular information to FIGO stage (“m” with subscript) and notes that molecular testing can change stage assignment for some tumors (especially POLEmut/p53abn examples) (berek2023figostagingof pages 1-4, berek2023figostagingof pages 4-5).

9. Inheritance and Population

9.1 MSI-H/dMMR prevalence within endometrial cancer

Multiple sources converge on MSI-H/dMMR comprising roughly ~25–31% of endometrial cancers: - KEYNOTE-158 cites ~25–31% MSI-H in endometrial cancers (omalley2022pembrolizumabinpatients pages 1-2) - RUBY notes dMMR/MSI-H tumors account for ~25–30% of endometrial cancers; trial population had 23.9% dMMR/MSI-H (118/494) (mirza2023dostarlimabforprimary pages 1-3) - A 333-case cohort found 25.2% dMMR and 24.0% MSI-H (wang2023aretrospectivestudy pages 1-2)

9.2 Real-world testing patterns (implementation statistic)

Before biomarker-directed therapy became widely available in Europe, MSI/MMR testing rates in recurrent/advanced endometrial cancer were ~one-third: - 36.4% tested in 1L and 34.9% tested in 2L cohorts; among those tested, ~15% were MSI-H/dMMR (kelkar2024realworldprevalenceof pages 1-2).

10. Diagnostics

10.1 Clinical tumor testing (core diagnostic definition)

MMR immunohistochemistry (IHC) is commonly used to define dMMR status based on loss of MMR protein expression. - Presence of all four proteins (MLH1, MSH2, MSH6, PMS2) indicates MMR proficiency; loss of one or more indicates dMMR (oaknin2023safetyefficacyand pages 1-2).

PCR-based MSI testing classifies MSI-H and can be defined by instability in ≥2 loci using standard panels (carvalho2024unravelingtheheterogeneity pages 5-7).

10.2 Test concordance / discordance (statistics)

  • In 333 EC cases tested by IHC and PCR-CE: overall concordance 98.8% (κ=0.98); dMMR 25.2%; MSI-H 24.0% (wang2023aretrospectivestudy pages 6-8, wang2023aretrospectivestudy pages 1-2).
  • Discrepancies are clinically meaningful: isolated MSH6 loss may be MSS by MSI assays; in a 2024 multi-assay evaluation, 7/8 Lynch tumors classified as MSS by MSI assays had isolated MSH6 loss (sowter2024detectionofmismatch pages 1-2).

10.3 MLH1 promoter methylation testing (reflex testing)

MLH1 promoter hypermethylation is a key discriminator of sporadic vs hereditary pathways, and methylation was used as an independent measure (“truth set”) in discordance resolution; an amplicon-sequencing MSI assay achieved 90% concordance with MLH1 methylation among discordant samples (62/69) (sowter2024detectionofmismatch pages 1-2).

10.4 Germline testing and Lynch syndrome screening workflow

A practical workflow described in a 2024 review includes parallel assessment of MMR IHC and MSI with MLH1 promoter methylation testing as appropriate, and triage to genetic referral based on results and family history (liu2024ataleof pages 19-21).

Guideline-level source retrieved: NCCN Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric Version 3.2024 is available as a peer-reviewed guideline summary article (JNCCN, Dec 2024; DOI: https://doi.org/10.6004/jnccn.2024.0061) but detailed surveillance schedules were not extracted from full text in the present evidence set.

11. Outcome / Prognosis

11.1 Response and survival outcomes with immunotherapy (biomarker-selected)

MSI-H/dMMR endometrial cancer has high response rates to PD-1 blockade, with durable responses in a substantial subset.

KEYNOTE-158 (pembrolizumab; previously treated advanced MSI-H/dMMR EC): - ORR 48% (95% CI 37–60) - Median PFS 13.1 months - Median OS not reached (omalley2022pembrolizumabinpatients pages 1-2)

GARNET (dostarlimab; recurrent/advanced dMMR/MSI-H EC): - ORR 45.5% in dMMR/MSI-H - Median DOR not reached at ~27.6 months follow-up (oaknin2023safetyefficacyand pages 1-2)

RUBY (first-line dostarlimab + carboplatin/paclitaxel): - dMMR/MSI-H subgroup: 24-month PFS 61.4% vs 15.7% with placebo-chemo; HR 0.28 (mirza2023dostarlimabforprimary pages 1-3)

NRG-GY018 (first-line pembrolizumab + carboplatin/paclitaxel): - dMMR cohort: 12-month PFS 74% vs 38%; HR 0.30 (liu2024ataleof pages 19-21)

11.2 Prognostic implications of epigenetic MMR defects

In a large endometrioid EC cohort, epigenetic MLH1-associated MMR defects were associated with higher LN metastasis risk and worse DFS compared with MMR-proficient tumors, supporting the idea that not all MMRd mechanisms are equivalent in clinical behavior (riedinger2023epigeneticmmrdefect pages 1-2).

12. Treatment

12.1 Current applications / real-world implementations

In 2023–2024, MSI-H/dMMR status is routinely used as a predictive biomarker to select PD-1–based therapies in advanced/recurrent disease and increasingly in first-line advanced/recurrent disease (mirza2023dostarlimabforprimary pages 1-3, liu2024ataleof pages 19-21).

A key implementation gap is testing uptake: in pre-approval European cohorts, only ~35–36% of recurrent/advanced patients were tested for MSI/MMR (kelkar2024realworldprevalenceof pages 1-2).

12.2 Key therapies (with MAXO suggestions)

  • Pembrolizumab (anti–PD-1) monotherapy in previously treated MSI-H/dMMR advanced EC (KEYNOTE-158 outcomes above) (omalley2022pembrolizumabinpatients pages 1-2)
  • MAXO suggestions: immune checkpoint inhibitor therapy; anti–PD-1 therapy
  • Dostarlimab (anti–PD-1) monotherapy for recurrent/advanced dMMR/MSI-H EC (GARNET outcomes above) (oaknin2023safetyefficacyand pages 1-2)
  • MAXO suggestions: immune checkpoint inhibitor therapy; anti–PD-1 therapy
  • Chemo-immunotherapy (frontline advanced/recurrent):
  • Dostarlimab + carboplatin/paclitaxel (RUBY) (mirza2023dostarlimabforprimary pages 1-3)
  • Pembrolizumab + carboplatin/paclitaxel (NRG-GY018) (liu2024ataleof pages 19-21)
  • MAXO suggestions: combination antineoplastic therapy; platinum-based chemotherapy; taxane therapy; immune checkpoint inhibitor therapy

13. Prevention

13.1 Secondary prevention: universal tumor screening to identify Lynch syndrome

Universal MMR testing (IHC ± MSI) is used for Lynch syndrome screening and also informs immunotherapy eligibility (wang2023aretrospectivestudy pages 1-2, liu2024ataleof pages 19-21).

13.2 Cascade testing impact

A Lancet review reports that cascade testing can identify “an average three family members with Lynch syndrome per index case” (crosbie2022endometrialcancer pages 5-6).

Note: Specific chemoprevention and gynecologic surveillance intervals for Lynch syndrome (e.g., aspirin; endometrial biopsy schedules) were not extracted from full guideline text in the current evidence set.

14. Other Species / Natural Disease

No naturally occurring veterinary MSI-H endometrial cancer evidence was retrieved.

15. Model Organisms

15.1 Endometrial-specific organoid models (Lynch syndrome–related)

A 2023 thesis reports CRISPR-Cas9 generation of MLH1- and PMS2-deficient endometrial organoids from benign hysterectomy tissues of Lynch syndrome patients and single-cell RNA-seq, concluding that MMR deficiency alone may not immediately alter transcriptomic state or differentiation of benign endometrial glands (degrood2023investigationintothe pages 1-7).

15.2 Mouse genetic models relevant to gynecologic malignancies

The same thesis reviews murine models with constitutive/conditional loss of Mlh1, Msh2, Msh6, Pms2 and highlights models with increased gynecologic relevance (e.g., Msh6−/− showing higher gynecologic rates among knockouts; Mlh1−/−/Pten+/− increasing endometrial cancer incidence) (degrood2023investigationintothe pages 25-28).

15.3 Cross-cancer MMRd models informing immunogenicity constraints

A Nature Genetics study developed autochthonous mouse models with engineered MMR deficiency (targeting Msh2/Mlh1/Msh3/Msh6) and found that despite hypermutation, tumors “did not display increased T cell infiltration or ICB response,” emphasizing the importance of clonal architecture and intratumor heterogeneity for immunogenicity (westcott2023mismatchrepairdeficiency pages 1-2).

Expert opinions / analysis (authoritative sources, 2023–2024 emphasis)

  • A 2024 Cancer review emphasizes that endometrial cancers require comprehensive assessment using IHC and sequencing-based techniques and that heterogeneity (e.g., MLH1 hypermethylation vs germline/somatic MMR mutation) may affect response to immune checkpoint inhibitors (liu2024ataleof pages 19-21).
  • A 2024 Cancers review highlights that dMMR status alone is not always sufficient to predict immunotherapy response and that better predictive biomarkers are needed (carvalho2024unravelingtheheterogeneity pages 4-5).

Key recent statistics (quick reference)

  • MSI-H/dMMR fraction of EC: ~25–31% across multiple sources (omalley2022pembrolizumabinpatients pages 1-2, mirza2023dostarlimabforprimary pages 1-3)
  • Large endometrioid cohort: 25.9% MMRd, with 80.4% of MMR defects epigenetic MLH1 silencing (riedinger2023epigeneticmmrdefect pages 1-2)
  • Real-world Europe (advanced/recurrent, pre-approval era): only 34.9–36.4% tested; among tested, ~15% MSI-H/dMMR (kelkar2024realworldprevalenceof pages 1-2)

Evidence Table: Practice-changing trials and implementation data

Setting Study/Trial Agent(s) Biomarker population Key outcomes (ORR, PFS/OS with timepoints/HR) Publication (journal, month year) URL/DOI
Previously treated advanced/recurrent KEYNOTE-158 Pembrolizumab monotherapy Advanced MSI-H/dMMR endometrial cancer ORR 48% (95% CI 37–60); median DOR not reached; median PFS 13.1 months (95% CI 4.3–34.4); median OS not reached; treatment-related AEs in 76%, grade 3–4 in 12% (omalley2022pembrolizumabinpatients pages 1-2) J Clin Oncol, Mar 2022 https://doi.org/10.1200/JCO.21.01874
Previously treated advanced/recurrent GARNET Dostarlimab monotherapy Recurrent/advanced dMMR/MSI-H endometrial cancer ORR 45.5% (65/143); median DOR not reached at median follow-up 27.6 months; ORR 54.9% in CPS≥1 subgroup; high TMB subgroup ORR 47.8% (oaknin2023safetyefficacyand pages 1-2) Clin Cancer Res, Jun 2023 https://doi.org/10.1158/1078-0432.CCR-22-3915
First-line primary advanced or first recurrent RUBY Dostarlimab + carboplatin/paclitaxel, then dostarlimab maintenance dMMR/MSI-H subgroup within stage III/IV or first recurrent EC dMMR/MSI-H tumors in 118/494 (23.9%); 24-month PFS 61.4% vs 15.7% with placebo-chemo; HR for progression/death 0.28 (95% CI 0.16–0.50; P<0.001). Overall population: 24-month PFS 36.1% vs 18.1%; HR 0.64; 24-month OS 71.3% vs 56.0%; HR for death 0.64 (95% CI 0.46–0.87) (mirza2023dostarlimabforprimary pages 1-3) N Engl J Med, Jun 2023 https://doi.org/10.1056/NEJMoa2216334
First-line advanced/recurrent NRG-GY018 Pembrolizumab + carboplatin/paclitaxel dMMR cohort and pMMR cohort in measurable stage III/IVA, stage IVB, or recurrent EC In dMMR cohort, 12-month PFS 74% with pembrolizumab-chemo vs 38% with placebo-chemo; HR for progression/death 0.30 (95% CI 0.19–0.48; P<0.001). In pMMR cohort, median PFS 13.1 vs 8.7 months; HR 0.54 (95% CI 0.41–0.71) (liu2024ataleof pages 19-21) N Engl J Med, Jun 2023 https://doi.org/10.1056/NEJMoa2302312
Real-world implementation in advanced/recurrent care ECHO-EU-1L / ECHO-EU-2L MSI/MMR testing in practice (not therapeutic trial) Recurrent/advanced EC in UK, Germany, Italy, France, Spain Testing prevalence: 36.4% in first-line cohort and 34.9% in second-line cohort. Among tested patients, ~15% had MSI-H/MMRd in both cohorts; most were non-MSI-high/MMR-proficient (80.7% first-line; 74.7% second-line); discordant results in 3.4% and 10.8%, respectively (kelkar2024realworldprevalenceof pages 1-2) Arch Gynecol Obstet, Apr 2024 https://doi.org/10.1007/s00404-024-07504-3

Table: This table summarizes pivotal therapeutic trial results and real-world biomarker testing implementation for MSI-H/dMMR endometrial cancer. It is useful for quickly comparing response and survival outcomes across approved PD-1–based strategies and understanding how often MSI/MMR testing was being performed in practice.

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