Molecular Subtype Not Immune Response Drives Outcomes in Endometrial Carcinoma

Talhouk, Aline; Derocher, Heather; Schmidt, Pascal; Leung, Samuel; Milne, Katy; Gilks, C Blake; Anglesio, Michael S.; Nelson, Brad H.; McAlpine, Jessica N.

doi:10.1158/1078-0432.ccr-18-3241

Cited by 109 publications

(112 citation statements)

References 68 publications

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“…While previous studies have shown the strong prognostic value of the molecular EC classification [11,16], and of the density of tumor-infiltrating lymphocytes in EC [19,20], to our knowledge our study is one of only two to examine the combination of these factors. The other study, by Talhouk and colleagues [23], reported no prognostic effect of intraepithelial CD3 + CD8 + cells in multivariable analysis which included the molecular EC classification, although a tendency to improved survival was observed. The discordance with our results is currently unexplained, but may relate to the methodology used for immune cell localization, statistical analysis, or the smaller, non-trial population of mixed histotypes and stages used in their study.…”

Section: Discussionmentioning

confidence: 91%

“…While the potential clinical utility of both the molecular EC classification and quantification of the antitumor immune response appear considerable, the variable prognosis of molecular EC subgroups may be explained by a marked variation in intratumoral T-cell infiltrate between them [21,22], and it is unclear whether these genomic and immune biomarkers confer independent prognostic value. An analysis of an EC cohort of mixed stages and histotypes demonstrated that while application of the molecular classification improves upon the prognostic value provided by clinicopathological variables, the additional analysis of Tcell infiltrate conferred no further benefit [23]. Here, we examined this in a more homogenous population of stage I endometrioid ECs from two large randomized clinical trials.…”

Section: Introductionmentioning

confidence: 99%

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Prognostic Integrated Image-Based Immune and Molecular Profiling in Early-Stage Endometrial Cancer

Horeweg

Bruyn

Nout

et al. 2020

Cancer Immunology Research

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Optimum risk stratification in early-stage endometrial cancer (EC) combines clinicopathological factors and the molecular EC classification defined by The Cancer Genome Atlas (TCGA). It is unclear whether analysis of intratumoral immune infiltrate improves this. We developed a machine-learning image-based algorithm to quantify density of CD8 + and CD103 + immune cells in tumor epithelium and stroma in 695 stage I endometrioid ECs from the PORTEC-1&-2 trials. The relationship between immune cell density and clinicopathological/molecular factors was analyzed by hierarchical clustering and multiple regression. The prognostic value of immune infiltrate by cell type and location was analyzed by univariable and multivariable Cox regression, incorporating the molecular EC classification. Tumor-infiltrating immune cell density varied substantially between cases, and more modestly by immune cell type and location. Clustering revealed three groups with high, intermediate and low densities, with highly significant variation in the proportion of molecular EC subgroups between them. Univariable analysis revealed intraepithelial CD8 + cell density as the strongest predictor of EC recurrence; multivariable analysis confirmed this was independent of pathological factors and molecular subgroup. Exploratory analysis suggested this association was not uniform across molecular subgroups, but greatest in tumors with mutant p53 and absent in DNA mismatch repair deficient cancers. Thus, this work identified that quantification of intraepithelial CD8 + cells improved upon the prognostic utility of the molecular EC classification in early-stage EC.

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Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Prognostic Integrated Image-Based Immune and Molecular Profiling in Early-Stage Endometrial Cancer

Horeweg

Bruyn

Nout

et al. 2020

Cancer Immunology Research

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“…POLE EDMs in ECs not described previously in the TCGA classification. The presence of a pathogenic POLE EDM is causal for ultramutated EC, a subtype associated with enhanced immune response [2,42] and excellent clinical outcome [6,7,13]. De-escalating adjuvant treatment in these patients is currently under investigation in the randomised PORTEC4a trial.…”

Section: Estimation Of Pathogenicity Of Somatic Pole Mutations In Thementioning

confidence: 99%

Interpretation of somatic POLE mutations in endometrial carcinoma

León‐Castillo

Britton

McConechy³

et al. 2020

The Journal of Pathology

273

207

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Pathogenic somatic missense mutations within the DNA polymerase epsilon (POLE) exonuclease domain define the important subtype of ultramutated tumours (‘POLE‐ultramutated’) within the novel molecular classification of endometrial carcinoma (EC). However, clinical implementation of this classifier requires systematic evaluation of the pathogenicity of POLE mutations. To address this, we examined base changes, tumour mutational burden (TMB), DNA microsatellite instability (MSI) status, POLE variant frequency, and the results from six in silico tools on 82 ECs with whole‐exome sequencing from The Cancer Genome Atlas (TCGA). Of these, 41 had one of five known pathogenic POLE exonuclease domain mutations (EDM) and showed characteristic genomic alterations: C>A substitution > 20%, T>G substitutions > 4%, C>G substitutions < 0.6%, indels < 5%, TMB > 100 mut/Mb. A scoring system to assess these alterations (POLE‐score) was developed; based on their scores, 7/18 (39%) additional tumours with EDM were classified as POLE‐ultramutated ECs, and the six POLE mutations present in these tumours were considered pathogenic. Only 1/23 (4%) tumours with non‐EDM showed these genomic alterations, indicating that a large majority of mutations outside the exonuclease domain are not pathogenic. The infrequent combination of MSI‐H with POLE EDM led us to investigate the clinical significance of this association. Tumours with pathogenic POLE EDM co‐existent with MSI‐H showed genomic alterations characteristic of POLE‐ultramutated ECs. In a pooled analysis of 3361 ECs, 13 ECs with DNA mismatch repair deficiency (MMRd)/MSI‐H and a pathogenic POLE EDM had a 5‐year recurrence‐free survival (RFS) of 92.3%, comparable to previously reported POLE‐ultramutated ECs. Additionally, 14 cases with non‐pathogenic POLE EDM and MMRd/MSI‐H had a 5‐year RFS of 76.2%, similar to MMRd/MSI‐H, POLE wild‐type ECs, suggesting that these should be categorised as MMRd, rather than POLE‐ultramutated ECs for prognostication. This work provides guidance on classification of ECs with POLE mutations, facilitating implementation of POLE testing in routine clinical care. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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“…Despite treatment, such as surgical resection, chemotherapy, and/or radiotherapy, the survival rate of EC is low due to its propensity to proliferate and metastasize. Immunotherapy is effective for EC, and immune cells, which infiltrate in the tumour microenvironment, play important roles in tumour progression and metastasis [2].…”

Section: Introductionmentioning

confidence: 99%

Tissue Infiltrating Immune Cells as Prognostic Biomarkers in Endometrial Cancer: A Meta-Analysis

et al. 2020

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Background. The association between tumour-infiltrating immune cells and the prognosis of endometrial cancer (EC) is controversial due to the smaller sample sizes and limited statistical power of the extant studies. We carried out a meta-analysis of the relationship between tumour-infiltrating immune cells and EC survival outcomes. Methods. A literature search in multiple databases was carried out up to December 2019. Pooled hazard ratio (HRs) and 95% confidence intervals (CIs) were calculated by the Z-test to assess the association between infiltrating immune cells and overall survival (OS), progression-free survival (PFS), relapse-free survival (RFS), disease-specific survival (DSS), and disease-free survival (DFS). A subgroup analysis was performed based on the localisation of immune cells in tumour parenchyma or stroma, immune markers, and the International Federation of Gynecology and Obstetrics stage. Heterogeneity and publication bias between studies were evaluated by Cochran’s Q-test and Egger regression test, respectively. Results. Seventeen studies were included in the analysis. The pooled HR of OS, PFS, DSS, and DFS indicated that a high CD8+ T cell density was associated with a favorable prognosis in EC patients. A significant relationship was found between a high density of CD45RO+ T cells and a favorable OS in EC patients, but the FoxP3+ T cell density was not associated with either OS or RFS. A high TAM density was associated with a worse PFS. However, a sensitivity analysis indicated that the findings of PFS and DSS in CD8+ T cell and PFS in TAM were not robust results. Conclusion. This is the first meta-analysis of the relationship between tumour-infiltrating immune cells and the prognosis of EC. High CD8+ and CD45RO+ T cell densities in tumours were associated with favorable outcomes in EC patients.

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Molecular Subtype Not Immune Response Drives Outcomes in Endometrial Carcinoma

Cited by 109 publications

References 68 publications

Prognostic Integrated Image-Based Immune and Molecular Profiling in Early-Stage Endometrial Cancer

Prognostic Integrated Image-Based Immune and Molecular Profiling in Early-Stage Endometrial Cancer

Interpretation of somatic POLE mutations in endometrial carcinoma

Tissue Infiltrating Immune Cells as Prognostic Biomarkers in Endometrial Cancer: A Meta-Analysis

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