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Meta-Analysis
. 2014 Dec 12;107(1):402.
doi: 10.1093/jnci/dju402. Print 2015 Jan.

Prognostic significance of POLE proofreading mutations in endometrial cancer

David N Church  1 , Ellen Stelloo  1 , Remi A Nout  1 , Nadejda Valtcheva  1 , Jeroen Depreeuw  1 , Natalja ter Haar  1 , Aurelia Noske  1 , Frederic Amant  1 , Ian P M Tomlinson  2 , Peter J Wild  1 , Diether Lambrechts  1 , Ina M Jürgenliemk-Schulz  1 , Jan J Jobsen  1 , Vincent T H B M Smit  1 , Carien L Creutzberg  1 , Tjalling Bosse  1
Affiliations
Meta-Analysis

Prognostic significance of POLE proofreading mutations in endometrial cancer

David N Church et al. J Natl Cancer Inst. .

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 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.

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 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).

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.

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Figures

Figure 1.
Figure 1.
Cumulative probability of recurrence (A) and cancer-specific survival (B) according to POLE proofreading mutation in the combined PORTEC studies. P values are obtained by two-sided log-rank test.
Figure 2.
Figure 2.
Cumulative probability of recurrence (A) and cancer-specific survival (B) according to POLE proofreading mutation in patients with grade 3 tumors in the combined PORTEC studies. P values are obtained by two-sided log-rank test.
Figure 3.
Figure 3.
Pooled HRs for recurrence-free survival (A) and cancer-specific survival (B) of POLE proofreading-mutant endometrial cancer derived from the PORTEC studies and additional series. Results from multivariable analyses were combined by meta-analysis using Mantel-Haenszel weights to generate pooled, adjusted HRs and 95% confidence intervals. All statistical tests were two-sided. CI = confidence interval; HR = hazard ratio; TCGA = The Cancer Genome Atlas.
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