Molecular Mechanisms of Platinum Resistance in Ovarian Cancer

In 2012, approximately 22,280 women will be diagnosed with ovarian carcinoma in the United States and roughly 15,500 will die from this disease, ranked the most common cause of death among gynecologic malignancies in developed countries [1]. Most women with epithelial ovarian cancer (EOC) present with advanced disease (stage III or IV) at the time of diagnosis. This phenomenon is mainly due to the lack of specific symptoms until disease has spread beyond the ovaries, at which time the chance of cure is dramatically reduced [2]. Current standard treatment of ovarian cancer, in both early and advanced stages, consists of complete cytoreductive surgery followed by chemotherapy, usually based on a platinum and a taxane doublet [3,4,5]. Initial response rate (RR) is high (70%-80%); but the majority of patients with advanced disease relapse within two years. Recurrent ovarian cancer is not curable, due to the development of chemoresistance [6,7]. The Gynecologic Oncology Group (GOG) adopted the definition of sensitivity to chemotherapy (or sensitivity to platinum) in EOC based on clinical criteria from retrospective case series [8]. When patients were re-challenged with a platinum compound the longer the interval from the last dose of platinum patients had received the better the response (and outcome) was. This clinical observation set the base for the current classification of platinum resistance in relapsed EOC (Figure 1), and allowed the commonly used stratification criteria in clinical trials of recurrent EOC. Platinum-resistant disease is also characterized by resistance to other cytotoxic agents, and not necessarily only resistant to platinum. However, current treatment for platinum-resistant EOC consists of chemotherapy agents whose mechanism of action is somewhat different from that of platinum compounds [9].