Prognostic significance of POLE proofreading mutations in endometrial cancer

• Published in: JNCI : Journal of the National Cancer Institute Vol. 107; no. 1; p. 402
• Main Authors: Church, David N, Stelloo, Ellen, Nout, Remi A, Valtcheva, Nadejda, Depreeuw, Jeroen, ter Haar, Natalja, Noske, Aurelia, Amant, Frederic, Tomlinson, Ian P M, Wild, Peter J, Lambrechts, Diether, Jürgenliemk-Schulz, Ina M, Jobsen, Jan J, Smit, Vincent T H B M, Creutzberg, Carien L, Bosse, Tjalling
• Format: Journal Article
• Language: English
• Published: United States Oxford Publishing Limited (England) 01.01.2015; Oxford University Press
• Subjects: Adult; Biomarkers; Biomarkers, Tumor - genetics; Cancer; Disease-Free Survival; DNA Polymerase II - genetics; Endometrial Neoplasms - genetics; Endometrial Neoplasms - mortality; Endometrial Neoplasms - pathology; Female; Humans; Kaplan-Meier Estimate; Medical treatment; Mutation; Neoplasm Grading; Odds Ratio; Poly-ADP-Ribose Binding Proteins; Predictive Value of Tests; Prognosis; Risk assessment; Tumors
• ISSN: 0027-8874; 1460-2105
• DOI: 10.1093/jnci/dju402

Current risk stratification in endometrial cancer (EC) results in frequent over- and underuse of adjuvant therapy, and may be improved by novel biomarkers. We examined whether POLE proofreading mutations, recently reported in about 7% of ECs, predict prognosis. We performed targeted POLE sequencing in ECs from the PORTEC-1 and -2 trials (n = 788), and analyzed clinical outcome according to POLE status. We combined these results with those from three additional series (n = 628) by meta-analysis to generate multivariable-adjusted, pooled hazard ratios (HRs) for recurrence-free survival (RFS) and cancer-specific survival (CSS) of POLE-mutant ECs. All statistical tests were two-sided. POLE mutations were detected in 48 of 788 (6.1%) ECs from PORTEC-1 and-2 and were associated with high tumor grade (P < .001). Women with POLE-mutant ECs had fewer recurrences (6.2% vs 14.1%) and EC deaths (2.3% vs 9.7%), though, in the total PORTEC cohort, differences in RFS and CSS were not statistically significant (multivariable-adjusted HR = 0.43, 95% CI = 0.13 to 1.37, P = .15; HR = 0.19, 95% CI = 0.03 to 1.44, P = .11 respectively). However, of 109 grade 3 tumors, 0 of 15 POLE-mutant ECs recurred, compared with 29 of 94 (30.9%) POLE wild-type cancers; reflected in statistically significantly greater RFS (multivariable-adjusted HR = 0.11, 95% CI = 0.001 to 0.84, P = .03). In the additional series, there were no EC-related events in any of 33 POLE-mutant ECs, resulting in a multivariable-adjusted, pooled HR of 0.33 for RFS (95% CI = 0.12 to 0.91, P = .03) and 0.26 for CSS (95% CI = 0.06 to 1.08, P = .06). POLE proofreading mutations predict favorable EC prognosis, independently of other clinicopathological variables, with the greatest effect seen in high-grade tumors. This novel biomarker may help to reduce overtreatment in EC.