Refining prognosis and identifying targetable pathways for high-risk endometrial cancer: a TransPORTEC initiative.
Open accessAbstract
This study aimed to investigate whether molecular analysis can be used to refine risk assessment, direct adjuvant therapy, and identify actionable alterations in high-risk endometrial cancer. TransPORTEC, an international consortium related to the PORTEC3 trial, was established for translational research in high-risk endometrial cancer. In this explorative study, routine molecular analyses were used to detect prognostic subgroups: p53 immunohistochemistry, microsatellite instability and POLE proofreading mutation. Furthermore, DNA was analyzed for hotspot mutations in 13 additional genes (BRAF, CDKNA2, CTNNB1, FBXW7, FGFR2, FGFR3, FOXL2, HRAS, KRAS, NRAS, PIK3CA, PPP2R1A, and PTEN) and protein expression of ER, PR, PTEN, and ARID1a was analyzed. Rates of distant metastasis, recurrence-free, and overall survival were calculated using the Kaplan-Meier method and log-rank test. In total, samples of 116 high-risk endometrial cancer patients were included: 86 endometrioid; 12 serous; and 18 clear cell. For endometrioid, serous, and clear cell cancers, 5-year recurrence-free survival rates were 68%, 27%, and 50% (P=0.014) and distant metastasis rates 23%, 64%, and 50% (P=0.001), respectively. Four prognostic subgroups were identified: (1) a group of p53-mutant tumors; (2) microsatellite instable tumors; (3) POLE proofreading-mutant tumors; and (4) a group with no specific molecular profile (NSMP). In group 3 (POLE-mutant; n=14) and group 2 (microsatellite instable; n=19) patients, no distant metastasis occurred, compared with 50% distant metastasis rate in group 1 (p53-mutant; n=36) and 39% in group 4 (NSMP; P<0.001). Five-year recurrence-free survival was 93% and 95% for group 3 (POLE-mutant) and group 2 (microsatellite instable) vs 42% (group 1, p53-mutant) and 52% (group 4, NSMP; P<0.001). Targetable FBXW7 and FGFR2 mutations (6%), alterations in the PI3K-AKT pathway (60%) and hormone receptor positivity (45%) were frequently found. In conclusion, molecular analysis of high-risk endometrial cancer identifies four distinct prognostic subgroups, with potential therapeutic implications. High frequencies of targetable alterations were identified and may serve as targets for individualized treatment.
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Interest has grown in using biomarkers such as DNA methylation to improve early detection of endometrial cancer.
“Interest has increased in the use of biomarkers, such as DNA methylation, to i mprove early detection of endometrial cancer. 31,32,170,171”
From Association of Endometrial Cancer Risk With Postmenopausal Bleeding in Women (2018) · cites this paper as [32]
The Methylation Specific PCR section (page not provided) describes testing MLH1 methylation in tumor samples, and the Abstract discusses molecular markers for classifying high-risk endometrial cancers. The paper addresses prognosis and treatment decisions, not growing interest in DNA methylation biomarkers for early detection. (LLM, conf=0.82)
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- Authors
- Stelloo, E., Bosse, T., Nout, R. A., MacKay, H. J., Church, D. N., Nijman, H. W., Leary, A., Edmondson, R. J., Powell, M. E., Crosbie, E. J., Kitchener, H. C., Mileshkin, L., Pollock, P. M., Smit, V. T., & Creutzberg, C. L.
- Affiliations
- Leiden University Medical Center (NL)
- University Health Network (CA)
- Centre for Human Genetics (GB)
- University Medical Center Groningen (NL)
- Institut Gustave Roussy (FR)
- University of Manchester (GB)
- Barts Health NHS Trust (GB)
- Peter MacCallum Cancer Centre (AU)
- Queensland University of Technology (AU)
- Corresponding author
- Bosse, Tjalling
- ORCID
- Venue
- Modern Pathology
- Publisher
- Elsevier BV
- Published
- 2015-06
- Volume
- 28
- Issue
- 6
- Pages
- 836-844
- ISSN
- 0893-3952 (ISSN-L)
- OpenAlex
- W2081748041
- Cited by
- 486
- References
- 35
- Citations by year
- 2026: 34 · 2025: 49 · 2024: 51 · 2023: 51 · 2022: 66 · 2021: 57 · 2020: 46 · 2019: 43 · 2018: 32 · 2017: 22 · 2016: 24 · 2015: 11
- FWCI
- 33.66
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Modern Pathology (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Funders
- KWF Kankerbestrijding (KWF-UL2012-5719)
- Topics
- Health Sciences › Medicine › Obstetrics and Gynecology › Endometrial and Cervical Cancer Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Health Sciences › Medicine › Reproductive Medicine › Ovarian cancer diagnosis and treatment
- Keywords
- high-risk endometrial cancer, prognostic subgroups, TP53 mutation, microsatellite instability, targeted therapy, FGFR2 mutations, FGFR3 mutation, PTEN, ARID1A, endometrioid endometrial cancer, serous endometrial carcinoma, distant metastasis, recurrence-free survival
- MeSH terms
- Adult, Aged, DNA Mutational Analysis, Female, Humans, Immunohistochemistry, Middle Aged, Prognosis, Risk Factors, Biomarkers, Tumor, Polymerase Chain Reaction, Endometrial Neoplasms, Tissue Array Analysis, Kaplan-Meier Estimate
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