Increased paclitaxel resistance in recurrent epithelial ovarian cancer: analysis of metachronous tumors

Abstract

Whether or not ovarian cancer exhibits tumor heterogeneity before and after chemotherapy, demonstrated in an in vitro drug resistance assay, seems to remain controversial [1–4]. In the largest analysis of an unselected population with ovarian cancer, there was no significant difference in the proportion of extreme drug resistance (EDR) between primary and recurrent cases [1]. On the other hand, a taxane-free interval longer than 1 year among 34 cases of epithelial ovarian cancer receiving platinum and taxane combination chemotherapy showed significant increased risk of EDR to taxane: paclitaxel 89.7%, and docetaxel 82.8% [2]. Their results were supported by other investigators, and marked increased EDR ratio was seen for paclitaxel [3]. We previously demonstrated increased paclitaxel resistance after postoperative chemotherapy with platinum and taxane in epithelial ovarian, fallopian, and primary peritoneal cancers [4]. In our results, EDR to paclitaxel was more common in later recurrence, especially more than 5 years after the initial surgery [4]. However, most previous studies did not evaluate the factor of metachronous tumors, that is, tissues obtained from the same patient at diagnosis and at recurrence. Evaluation of metachronous tumors gives the most reliable answer to whether or not tumors exhibit heterogeneity between before and after chemotherapy exposure. The objective of the study was to compare in vitro drug resistance assays of primary and recurrent epithelial ovarian, fallopian, and primary peritoneal cancers exposed to platinum and taxane combination chemotherapy in the same patients. All patients who received postoperative chemotherapy with platinum and taxane after initial cytoreductive surgery between Jan 1995 and Jan 2009 were evaluated. Results from in vitro drug resistance assay (EDR Assay , Oncotech, Tustin, CA, USA) from the tumor tissues obtained at primary and recurrent surgery in the same patients were evaluated for extreme (EDR), intermediate (IDR), and low (LDR) drug resistance [5]. The proportion of assay results was compared between primary and recurrent tumor. Upgrade or down-grade of assay results was also compared. Up-grade of assay results included LDR to either IDR or EDR, and IDR to EDR. Down-grade of assay results included EDR to either IDR or LDR, and IDR to LDR. Fisher’s exact test was used for statistical evaluation. There were 29 cases identified for metachronous tumor; epithelial ovarian (93.1%), fallopian (0%), and primary peritoneal cancer (6.9%). Median time interval between initial diagnosis and recurrent surgery was 27.8 months (95% confidential interval, 6.6–58.4). All received platinum and taxane combination chemotherapy; however, only paclitaxel showed a statistical significance in the proportion of assay results demonstrating significant decrease in K. Matsuo (&) Department of Gynecologic Oncology, Unit 1362, M. D. Anderson Cancer Center, University of Texas, 1151 Herman Pressler Street, P.O. Box 301439, Houston, TX 77230-1439, USA e-mail: koji.matsuo@gmail.com