title: Refining prognosis and identifying targetable pathways for high-risk endometrial cancer; a TransPORTEC initiative.
abstract: 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.
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Ellen
authors.initials: E
authors.lastname: Stelloo
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Tjalling
authors.initials: T
authors.lastname: Bosse
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Remi A
authors.initials: RA
authors.lastname: Nout
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Princess Margaret Hospital/University Health Network, University of Toronto, Toronto, ON, Canada.
authors.forename: Helen J
authors.initials: HJ
authors.lastname: MacKay
authors.affiliation: Molecular and Population Genetics Laboratory, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: David N
authors.initials: DN
authors.lastname: Church
authors.affiliation: Department of Gynecology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Hans W
authors.initials: HW
authors.lastname: Nijman
authors.affiliation: Department of Medicine, Gynecology Unit, Gustave Roussy, Villejuif, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Leary
authors.affiliation: Institute of Cancer Sciences, University of Manchester, St Marys Hospital, Manchester, UK.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Edmondson
authors.affiliation: Department of Clinical Oncology, Barts Health NHS Trust, London, UK.
authors.forename: Melanie E
authors.initials: ME
authors.lastname: Powell
authors.affiliation: Institute of Cancer Sciences, University of Manchester, St Marys Hospital, Manchester, UK.
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Crosbie
authors.affiliation: Institute of Cancer Sciences, University of Manchester, St Marys Hospital, Manchester, UK.
authors.forename: Henry C
authors.initials: HC
authors.lastname: Kitchener
authors.affiliation: Division of Cancer Medicine, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia.
authors.forename: Linda
authors.initials: L
authors.lastname: Mileshkin
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia.
authors.forename: Pamela M
authors.initials: PM
authors.lastname: Pollock
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Vincent T
authors.initials: VT
authors.lastname: Smit
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Carien L
authors.initials: CL
authors.lastname: Creutzberg
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D004252:DNA Mutational Analysis; D016889:Endometrial Neoplasms / Q000145:classification* / Q000235:genetics* / Q000473:pathology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011379:Prognosis; D012307:Risk Factors; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor