Prognostic significance of POLE proofreading mutations in endometrial cancer

David N. Church, Ellen Stelloo, Remi A. Nout, Nadejda Valtcheva, Jeroen Depreeuw, Natalja Ter Haar, Aurelia Noske, Frederic Amant, Ian P.M. Tomlinson, Peter J. Wild, Diether Lambrechts, Ina M. Jürgenliemk-Schulz, Jan J. Jobsen, Vincent T.H.B.M. Smit, Carien L. Creutzberg, Tjalling Bosse

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252 Scopus citations

Abstract

Background: 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. Methods: 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 metaanalysis 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. Results: 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 ECrelated 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). Conclusion: 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.

Original languageEnglish
Article numberdju402
JournalJournal of the National Cancer Institute
Volume107
Issue number1
DOIs
StatePublished - 1 Jan 2015
Externally publishedYes

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