Refining prognosis and identifying targetable pathways for high-risk endometrial cancer; a TransPORTEC initiative

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. Trans PORTEC, 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