Cadherins, catenins and cell cycle regulators: Impact on survival in a Gynecologic Oncology Group phase II endometrial cancer trial

Abstract

ObjectiveWe evaluated the clinical relevance of catenins, cadherins and cell cycle regulators in stage IV or recurrent endometrial carcinoma in a multi-center phase II trial (GOG protocol #119). MethodsTissue microarrays of metastatic or recurrent (n=42) tumor were developed and immunohistochemistry was performed. Average expression (percent staining x intensity) was assessed in tumor epithelium (E) and stroma (S) and categorized into tertiles (T1, T2, T3) for E-cadherinE, N-cadherinE, alpha-cateninE, beta-cateninE, gamma-cateninE, p120-cateninE and Ki-67E; as negative, below median or above median for p16E, p27E and CD44S; or as negative or positive for p53E, Ki-67S and APCS (adenomatous polyposis coli). End points included response and survival. ResultsE-cadherinE, p16E, and p53E varied by race (p=0.003, p=0.024, p=0.002,) and N-cadherinE, Ki-67E, p16E and p27E by tumor type (p=0.015, p=0.011, p=0.005, p=0.021). Correlations were observed among E-cadherinE with p120E (r=0.66), p53E (r=−0.32), alpha-cateninE (r=0.52), beta-cateninE (r=0.58), and gamma-cateninE (r=0.58). High E-cadherinE (T2 or T3) versus low (T1) expression was associated with better survival in unadjusted (hazard ratio [HR]=0.14, 95% confidence interval [CI]=0.06–0.37 or HR=0.17, 95% CI=0.07–0.42) and adjusted models (HR=0.18, 95% CI=0.05–0.59 or HR=0.22, 95% CI=0.07–0.70). High p16E versus negative expression was associated with worse survival in unadjusted (HR=3.87, 95% CI=1.74-8.61) and adjusted (HR=4.18, 95% CI=1.28–13.6) models. Positive versus negative expression of p53E was associated with worse survival in unadjusted (HR=2.31, 95% CI=1.16–4.60) but not adjusted models. ConclusionsE-cadherinE and p16E appear to be clinically relevant, independent prognostic factors in stage IV or recurrent endometrial cancers treated with Tamoxifen and Medroxyprogesterone acetate, and merit further study.