Cyclin-dependent kinase (CDK) activity as a prognostic marker in primary epithelial ovarian cancer

Abstract

5575 Background: The unpredictable nature of primary epithelial ovarian cancer (EOC) response to treatment necessitates the identification of factors that predict long-term outcome. CDK activity is the core regulator of the cell-cycle checkpoint for cancer cells. We previously found that cell death induced by taxanes requires increased activity of CDK1 and CDK2- fundamental kinases in cell proliferation. Thus, we hypothesized that CDK1/2 activities can determine the prognosis of patients with primary EOC. Methods: We retrospectively analyzed frozen ovarian cancer specimens from 72 women treated with cytoreductive surgery and adjuvant chemotherapy for newly diagnosed EOC. Median patient age was 61 years (range, 38–80), 91% had FIGO stage III/IV disease, and 86% were treated with platinum- or taxane-based regimens. Median follow-up was 32 months; median time to treatment failure (TTF), defined as time from surgery to first relapse for patients who had achieved complete response or time to disease progression for those who had persistent disease, was 15 months. Enzymatic activity of CDK1/2 in the tumor tissues was determined by a modified in vitro kinase activity assay using a C2P device (Sysmex Inc.). Recursive partitioning and regression trees algorithm (RPART) was used to identify the cohorts based on CDK1/2 activities. Results: In the univariate analysis, disease stage (p=0.021), type of surgery (optimal vs. suboptimal) (p=0.004), presence of ascites (p=0.043), and CA125 after the adjuvant therapy (p=0.005) were significant predictors of TTF. The cohort with CDK2 activity = 87.3 had a significantly shorter TTF (p=0.014) and the cohort with CDK1 activity = 226.35 showed a trend toward longer TTF (p=0.094). Multivariate Cox proportional hazards regression analysis revealed CDK2 activity (<87.3 vs. = 87.3) (p=0.012) and CA125 level at completion of the adjuvant chemotherapy regimen (p=0.02) to be independent predictors of TTF. Conclusion: Our data supports kinase activity of cell cycle as a clinically significant prognostic factor. To extend these findings, we plan to conduct a large prospective study to determine whether CDK1/2 profiling can predict long-term outcome in primary EOC. [Table: see text]