The study group included 248 patients with endometrioid endometrial carcinoma. The median follow-up time was 68.1 months (range, 0.1 to 167.2 months). The demographics and clinicopathologic characteristics of the study group are presented in .
Patient Demographics and Clinicopathologic Characteristics
Mutations in the A10 mononucleotide repeat in exon 10 of the ATR gene were identified in 12 cases (4.8%). Three tumors had insertion of a single A, and nine tumors had deletion of an A. All mutations occurred in MSI-positive tumors (P = .02). illustrates the chromatographic appearance of the wild-type sequence as well as the mutated genotypes. ATR mutations were not associated with age, race, surgical stage, FIGO grade, MLH1 methylation status, or use of adjuvant treatment.
Fig 1. Representative examples of ATR genotypes. Mutation in A10 mononucleotide repeat in ATR exon 10. T1231: microsatellite instability (MSI)–positive tumor, A9 mononucleotide illustrates deletion (arrow). T1138: Microsatellite stable tumor, A10 mononucleotide (more ...)
Univariate analysis () revealed that mutations in the region of interest of ATR were indeed associated with shorter OS (hazard ratio [HR], 2.35; 95% CI, 1.08 to 5.11; P = .03). Advanced stage (HR, 3.82; 95% CI, 1.76 to 8.32; P = .0007), higher FIGO grade (HR, 2.66; 95% CI, 1.43 to 4.94; P = .002), use of adjuvant treatment (HR, 1.82; 95% CI, 1.16 to 2.84; P = .009), and, to a lesser degree, age (HR, 1.05; 95% CI, 1.03 to 1.07; P < .0001) were also associated with worse OS. MSI status and race were not associated with OS. Variables that approached significance (P < .2) were incorporated in the multivariate model (). After controlling for confounding factors, the effects of ATR mutations (HR, 3.88; 95% CI, 1.64 to 9.18; P = .002), surgical stage (HR, 1.75; 95% CI, 1.32 to 2.31; P = .0001), higher FIGO grade (HR, 1.40; 95% CI, 1.02 to 1.91; P = .04), and age (HR, 1.06; 95% CI, 1.04 to 1.08; P < .0001) on OS remained statistically significant.
We also evaluated the impact of ATR mutations and other clinicopathologic variables on DFS. Univariate analysis () suggested that DFS was associated with advanced surgical stage (HR, 17.49; 95% CI, 2.33 to 131.11; P = .005), ATR mutations (HR, 3.72; 95% CI, 1.45 to 9.54; P = .006), use of adjuvant treatment (HR, 3.20; 95% CI, 1.69 to 6.07; P = .0004), and higher FIGO grade (HR, 3.15; 95% CI, 1.27 to 7.83; P = .01). MSI status, age, and race were not associated with DFS. Variables that approached significance (P < .2) were again incorporated in the multivariate model (), which indicated that both ATR mutations (HR, 4.29; 95% CI, 1.48 to 12.45; P = .007) and surgical stage (HR, 2.12; 95% CI, 1.44 to 3.13; P = .0002) were significantly associated with DFS.
Kaplan-Meier survival plots for OS and DFS according to ATR mutation status for the entire cohort are presented in and Appendix Figure A3 (online only). ATR mutations were significantly associated with reduced OS (log-rank test, P = .027) and DFS (log-rank test, P = .003) in this cohort of patients with endometrioid endometrial cancer.
Kaplan-Meier curves for (A) overall survival and (B) disease-free survival by ATR mutation status. Vertical bars represent censored cases.
Given ATR mutations were seen only in MSI-positive tumors, we performed survival analyses including MSI-positive cases alone (). This subgroup analyses confirmed the effects of ATR mutations on OS (HR, 3.52; 95% CI, 1.45 to 8.57; P = .005; log-rank test, P = .043) and DFS (HR, 3.01; 95% CI, 1.28 to 7.08; P = 0.01; log-rank test, P = .001).
Kaplan-Meier curves for (A) overall survival and (B) disease-free survival by ATR mutation status among patients with microsatellite instability–positive (MSI+) tumors. Vertical bars represent censored cases.