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

Objective: We 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). Methods: Tissue 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-cadherin ^E, N-cadherin ^E, alpha-catenin ^E, beta-catenin ^E, gamma-catenin ^E, p120-catenin ^E and Ki-67 ^E; as negative, below median or above median for p16 ^E, p27 ^E and CD44 ^S; or as negative or positive for p53 ^E, Ki-67 ^S and APC ^S (adenomatous polyposis coli). End points included response and survival. Results: E-cadherin ^E, p16 ^E, and p53 ^E varied by race (p = 0.003, p = 0.024, p = 0.002,) and N-cadherin ^E, Ki-67 ^E, p16 ^E and p27 ^E by tumor type (p = 0.015, p = 0.011, p = 0.005, p = 0.021). Correlations were observed among E-cadherin ^E with p120 ^E (r = 0.66), p53 ^E (r = - 0.32), alpha-catenin ^E (r = 0.52), beta-catenin ^E (r = 0.58), and gamma-catenin ^E (r = 0.58). High E-cadherin ^E (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 p16 ^E 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 p53 ^E was associated with worse survival in unadjusted (HR = 2.31, 95% CI = 1.16-4.60) but not adjusted models. Conclusions: E-cadherin ^E and p16 ^E 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.