Assessment of DNA Ploidy in the ProMisE molecular subgroups of endometrial cancer.

OBJECTIVE: We sought to determine whether DNA ploidy correlates with the four molecular subgroups of endometrial carcinoma (EC) as determined using ProMisE (Proactive Molecular Risk Classifier for Endometrial Cancer). METHODS: 90 cases of EC previously characterized by clinicopathological parameters, outcomes, and ProMisE molecular subgroup (POLE EDM, MMR-D, p53 wt or p53 abn) were assessed for DNA ploidy using image cytometry. Associations of ploidy with traditional clinicopathological parameters were also tested. RESULTS: Abnormal DNA ploidy status differed amongst the ProMisE groups (p<0.001) and was found in 80.9% (17/21) of p53 abn, 37.0% (10/27) of p53 wt, 28.6% (4/14) of POLE EDM and 14.3% (4/28) of MMR-D. Abnormal DNA content was significantly associated with lower BMI (p=0.034) and grade 3 tumors (p=0.001). In the entire cohort, abnormal DNA content was significantly associated with worse progression free survival (p=0.0094) but not disease specific survival (p=0.249) or overall survival (p=0.187). When examining ploidy within each of the ProMisE groups, abnormal DNA content correlated with worse overall survival (p=0.041) and progression free survival (p=0.011) in the MMR-D group. No statistically significant relationship was seen in the remaining 3 groups. CONCLUSION: Abnormal DNA ploidy status did correlate with the molecular subgroups of EC; abnormal DNA content was seen in the large majority of p53 abn cases. Abnormal ploidy however was also seen in smaller numbers in the p53 wt, POLE EDM and MMR-D groups; therefore abnormal DNA content was not a specific marker for any one molecular group. The addition of ploidy to the ProMisE molecular categories conferred additional prognostic value within the MMR-D group, which merits further study.

Low-risk endometrial carcinoma: assessment of a treatment policy based on tumor ploidy and identification of additional prognostic indicators.

OBJECTIVES: The aims of this study were (1) to assess a treatment policy for patients with low-risk endometrioid endometrial carcinoma where adjuvant treatment decisions have been based on ploidy status of the tumor, and (2) to screen diploid, low-risk tumors for additional features of prognostic significance. METHODS: Between 01/1992 and 08/1996, 406 patients were referred to the B.C. Cancer Agency-Vancouver Clinic with typical endometrial adenocarcinomas limited to <50% myometrial invasion and no vascular space invasion or grade 3 disease on pathology review ("low-risk stage I endometrial carcinoma"). Patients were prospectively assigned to treatment groups based on tumor ploidy. Those patients with aneuploid tumors (n = 91) were treated with adjuvant vaginal vault radiotherapy while those with diploid tumors (n = 315) were followed and treated only at relapse. The hysterectomy specimens from all 14 patients in the untreated, diploid group who relapsed, as well as 28 stage- and grade-matched diploid controls who did not fail, were analyzed by immunohistochemical staining for estrogen receptor (ER), Bcl-2, and p53 proteins. RESULTS: There were no significant differences in the stage (Ia vs Ib) and grade (G1 vs G2) distribution for the diploid and aneuploid groups. Overall median age was 64 years (range 27-90 years) and was also not significantly different for the two groups. The median follow-up for the entire cohort is 45 months (range 1-76 months). There have been 14 failures in the diploid group and 4 failures in the aneuploid group with actuarial 5-year disease-free survival rates of 95.0 and 95.2%, respectively (P = NS). Eight of the failures in the diploid group occurred at the vaginal vault and were all subsequently salvaged with radiotherapy. All but 1 of the failures in the aneuploid group were considered incurable. Of the 14 diploid tumors from patients who failed, 7 stained positively for p53, compared to 4 of 28 diploid controls (P = 0.02). No significant differences were seen in the diploid tumors that recurred, compared to controls, with respect to Bcl-2 or ER expression. CONCLUSIONS: Patients with diploid, low-risk stage I endometrial cancers have excellent prospects for relapse-free and overall survival. Patients with aneuploid tumors treated with adjuvant radiotherapy have the same risk of relapse as untreated patients with diploid tumors; however, their ultimate survival may be lower as a smaller proportion of aneuploid failures are salvageable. While p53 expression in diploid tumors is associated with increased risk of relapse, Bcl-2 and ER are not useful prognostic indicators in this setting.