The p16-Cyclin D1/CDK4-pRb Pathway and Clinical Outcome in Epithelial Ovarian Cancer

A significant positive association has been reported between p16 expression and clinical outcome for epithelial ovarian cancer patients. However, there is a reciprocal correlation between genetic alterations of single members of the p16-cyclin D1/CDK4-pRb pathway (G 1 pathway). Simultaneous evaluation of these four elements may produce a better prognostic factor than p16 alone. We studied the prognostic significance of the G 1 pathway in 59 epithelial ovarian cancer patients undergoing surgery and platinum-based chemotherapy by immunohistochemical technique. Abnormal expression of p16 or pRb was defined by negative nuclei staining, and that of CDK4 and cyclin D1 was defined by 50% nuclear staining. An abnormal G 1 pathway was indicated in cases that have at least one abnormality among these four elements. Abnormal expression of p16, pRb, and cyclin D1/CDK4 was observed in 33.9, 3.4, and 15.3% of studied cases, respectively. Abnormal G 1 pathway was detected in 49.2% (29 of 59) of all cases. The patients with normal G 1 pathway tended to achieve a higher complete response rate (81.0%) to chemotherapy, compared with patients with abnormal G 1 pathway (55.0%); however, there was no significant difference ( P = 0.1001) between the two groups. Univariate analyses identified advanced stage [hazards ratio (HR), 3.665; P = 0.0218], histological low grade (HR, 3.625; P = 0.0066), and abnormal G 1 pathway (HR, 2.935; P = 0.03) as prognostic factors for overall survival. The G 1 pathway might help as a prognostic factor to select high-risk patients.