Epithelial ovarian cancer is the leading cause of death from gynecologic cancers with 22,280 new cases anticipated in 2016 and 14,240 deaths. Most patients are diagnosed at late stages and have a poor prognosis. Radical surgery and chemotherapy are the primary treatment. When relapse occurs there are few treatment options. The overall survival rate of women with ovarian cancer is unchanged in 50 years. Approximately 70% of epithelial ovarian cancers are serous including low grade serous tumors, some of which may evolve from serous borderline tumors, and high grade serous carcinomas. The latter are thought to originate in the fallopian tube. There are eight other subtypes of invasive ovarian cancer. All invasive ovarian cancers have recently been classified into two subtypes, Type 1 (indolent) and Type 2 (aggressive). The Wilms’ Tumor 1 (WT1) protein is expressed in some normal tissues including the fallopian tube and ovary as well as in tumors such as ovarian and breast cancers and in leukemia. WT1 is a highly immunogenic tumor associated antigen. Mutated p53 is found in many high grade ovarian cancers. Recent reports indicate that WT1 and p53 may interact physically and functionally. Both WT1 and mutated p53 have been suggested as prognostic markers in ovarian cancer. We sought to determine the role of co-expression of mutated p53 and WT1 in overall survival of patients with ovarian cancer. Histologic sections were prepared from archived FFPE surgical specimens donated by St. Elizabeth Healthcare (Northern KY) and fully annotated by hospital records. H&E stained sections were diagnosed and graded by a board certified pathologist (LED) and included histologic sections from 41 borderline tumors and 98 Type 1 and Type 2 cancers. Adjacent sections were stained immunohistochemically using monoclonal antibodies (DAKO) to WT1 and p53. For survival analysis p53 was considered mutated if 75-100% of the tumor nuclei were stained (missense mutations) or if all nuclei were negative (truncated protein) and WT1 was considered either non-expressed (no stain) or expressed (some or all nuclei stained). While either mutated p53 or WT1 were prognostic alone of patient survival with Type 1 and Type 2 tumors, WT1 was a better predictor as seen by log-rank Chi-square. The 20 year survival probability of patients with tumors negative for both mutated p53 and WT1 was 70% and was significantly better than other patients (p < 0.0001). The 20 year survival probability for tumors negative for WT1 but expressing mutated p53 was 41%, and was 9% for tumors expressing WT1 and non-mutated p53. Patients with tumors expressing both WT1 and mutated p53 had a 20 year survival probability of 6%. Given these data and the immunogenicity of the WT1 tumor associated antigen we conclude that IHC detection of mutated p53 and WT1 in invasive ovarian cancers would be useful in stratifying patients eligible for immunologic approaches targeting WT1 for therapy of lethal ovarian cancers.
Citation Format: Julia H. Carter, James A. Deddens, Gretchen Mueller, Thomas G. Lewis, Mariah K. Dooley, Jackson O. Pemberton, Larry E. Douglass. Evidence for WT1 as a potential target for immunotherapy of lethal ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2793. doi:10.1158/1538-7445.AM2017-2793