Genetic diagnosis for chemosensitivity with drug-resistance genes in epithelial ovarian cancer

Proc Amer Assoc Cancer Res, Volume 46, 2005 5947 Background/Purpose: Most of patients with advanced ovarian cancer relapse and develop chemoresistance. Although topoisomerase inhibitors, etoposide and CPT-11, have been commonly used as a second-line chemotherapy, no useful predictor of sensitivity to chemotherapy is known. We previously found that MDR-1 gene expression was related to sensitivity of combined chemotherapy with paclitaxel and CBDCA (TJ) and that topoisomerase activity was also associated with sensitivity to topoisomerase inhibitors. Genetic diagnosis is more convenient compared with previous test with using cell culture. We conducted the present study to know whether and how chemosensitivity could be determined by genetic diagnosis with drug-resistance genes including topoisomerase (topo)-I and topo-IIα gene, in epithelial ovarian cancer. Method: To obtain the cut-off values of the gene expression, a total of 62 patients with epithelial ovarian cancer, who had measurable lesions, were examined. Thirty-three patients received TJ therapy as the first line chemotherapy. As the second or third line chemotherapy, 12 patients received EP, consisting of etoposide and CDDP, and 17 received CPT-11 and CDDP. The tumor samples were obtained before chemotherapy. mRNA expressions of multidrug resistance gene-1(MDR-1), multidrug resistance-associated protein-1(MRP-1), topo-I, and topo-IIα were measured by real-time RT-PCR. Responder was defined as a greater than 50% reduction in all measurable lesions without the appearance of new lesions during over 4 weeks. The cut-off value of each gene was determined by ROC curve according to chemoresponse. In order to determine the accuracy of genetic diagnosis, a total of 28 patients (14 TJ, 9 EP, and 5 CPT-11/CDDP ) were newly added. Results: Of 33 patients, 21 patients (63.6%) responded to TJ therapy. MDR-1 expression was significantly higher in non-responders (129.6 ± 61.7 vs 30.6 ± 10.4). Whereas, MRP-1 expression level did not differ between responders and non-responders. EP therapy was effective in 3 of 12 patients. The expression level of topo-IIα was significantly higher in responders (186.1 ± 7.9 vs 61.0 ± 21.9). CPT-11/CDDP therapy was effective in 3 of 17 patients. The expression level of topo-I was higher in responders. MRP-1 mRNA expression did not differ between responders and non-responders in EP and CPT-11/CDDP therapy. The cut-off value was 80 for MDR-1, 90 for topo-IIα, and 200 for topo-I. The accuracy of current genetic diagnosis for chemosensitivity was 85.7 % for TJ, 77.8% for EP and 100.0% for CPT-11/CDDP therapy, respectively. Conclusion: Genetic diagnosis for chemosensitivity may be a useful procedure in epithelial ovarian cancer.