Prognostic Integrated Image-Based Immune and Molecular Profiling in Early-Stage Endometrial Cancer
Cancer Immunology Research, vol. 8, pp. 1508–1519
Abstract
Abstract Optimum risk stratification in early-stage endometrial cancer combines clinicopathologic factors and the molecular endometrial cancer 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 endometrial cancers from the PORTEC-1 and -2 trials. The relationship between immune cell density and clinicopathologic/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 endometrial cancer 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 endometrial cancer subgroups between them. Univariable analysis revealed intraepithelial CD8+ cell density as the strongest predictor of endometrial cancer recurrence; multivariable analysis confirmed this was independent of pathologic 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 endometrial cancer classification in early-stage endometrial cancer.
Authors 19
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Leiden University Medical Center
Affiliation as printed
1Department of Radiation Oncology, Leiden University Medical Center, Leiden, the Netherlands
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University Medical Center Groningen
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2Department of Gynaecologic Oncology, University Medical Center Groningen, Groningen, the Netherlands
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Leiden University Medical Center
Affiliation as printed
1Department of Radiation Oncology, Leiden University Medical Center, Leiden, the Netherlands
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Leiden University Medical Center
Affiliation as printed
3Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands
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Centre for Human Genetics · University of Oxford
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4Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, United Kingdom
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Leiden University Medical Center
Affiliation as printed
3Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands
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University Medical Center Groningen
Affiliation as printed
2Department of Gynaecologic Oncology, University Medical Center Groningen, Groningen, the Netherlands
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Affiliation as printed
5Cantonal Hospital Baselland, Institute of Pathology, Liestal, Switzerland
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Leiden University Medical Center
Affiliation as printed
3Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands
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University Medical Center Utrecht
Affiliation as printed
6Department of Radiation Oncology, University Medical Center Utrecht, Utrecht, the Netherlands
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Affiliation as printed
7Maastricht Radiation Oncology Clinic, Maastricht, the Netherlands
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Affiliation as printed
8Department of Radiotherapy, Medisch Spectrum Twente, Enschede, the Netherlands
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Affiliation as printed
9Radiotherapiegroep, Arnhem, the Netherlands
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Leiden University Medical Center
Affiliation as printed
3Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands
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Leiden University Medical Center
Affiliation as printed
1Department of Radiation Oncology, Leiden University Medical Center, Leiden, the Netherlands
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Leiden University Medical Center
Affiliation as printed
3Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands
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University Medical Center Groningen
Affiliation as printed
2Department of Gynaecologic Oncology, University Medical Center Groningen, Groningen, the Netherlands
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University of Zurich · University of Oxford
Affiliation as printed
10Department of Pathology and Molecular Pathology, University of Zurich, Zurich, Switzerland
11Department of Oncology and Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
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Leiden University Medical Center · Churchill Hospital · Oxford University Hospitals NHS Trust
Affiliation as printed
12Oxford Cancer Centre, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
13Oxford NIHR Comprehensive Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
3Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands
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