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; Po 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; Po 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. Modern Pathology (2015) 28, 836-844; doi:10.1038/modpathol.2015 published online 27 February 2015 Risk classification of endometrial carcinomas is based upon a combination of clinical and histopathological factors and is used in guiding adjuvant therapy. High-risk factors are (combinations of) advanced age, high-grade, non-endometrioid histology, extensive lymphovascular space invasion, and

Endometrial Carcinomas with POLE Exonuclease Domain Mutations Have a Favorable Prognosis

“…The survival advantage of POLE-mutated high-grade endometrioid carcinomas has been observed in multiple studies (10)(11)(12)29) but not all (24). We did not show a significant association between grade, histology, and POLE status; however, we did confirm that POLE-mutated grade 3 endometrial carcinomas have an excellent prognosis.…”

“…Previous studies have demonstrated that POLE-mutated cases are mostly grade 3 endometrial carcinomas (11,12,29). To compare with these studies, we also assessed the outcome of all POLE-mutated grade 3 tumor histologies.…”

Improved Risk Assessment by Integrating Molecular and Clinicopathological Factors in Early-stage Endometrial Cancer—Combined Analysis of the PORTEC Cohorts

“…Evaluations were done independently with discrepancies resolved at simultaneous viewing. For DNA analyses, tumor DNA was isolated as reported previously (11).…”

“…Integrated genomic characterization by The Cancer Genome Atlas (TCGA) defined four distinct endometrial carcinoma subgroups with possible prognostic value (10). Using methods broadly available in clinical practice, these four subgroups can be easily determined by their surrogate markers: p53, microsatellite instability (MSI), and POLE resulting in a practically and clinically useful molecular classification tool (11,12). In relatively small series of unselected endometrial carcinomas, the combination of both the clinicopathologic and molecular classification improved the clinicopathologic risk assessment (12).…”

Practical issues in the diagnosis of serous carcinoma of the endometrium

“…The TCGA prognostic classification has been recently validated in 152 endometrial carcinoma cases. 62,63 Utility of immunohistochemical and molecular tools in distinguishing SC from EEC Histological type has consistently been proved to be an important predictor of survival, but also a determinant for the extent of the initial surgical procedure and subsequent use of adjuvant therapy. There is moderate to excellent agreement (0.62-0.87) in overall histologic typing, but also significant interobserver variability among high-grade tumors.…”