Tumor heterogeneity in ovarian cancer as demonstrated by in vitro chemoresistance assays.
OBJECTIVE
Tumor heterogeneity has been demonstrated in solid tumors. In vitro assays were developed in an effort to predict in vivo tumor response to therapy. We compare the in vitro assay results from multiple synchronous tumor samples in primary and recurrent ovarian cancers.


METHODS
38 patients underwent surgery for primary (18) or recurrent (20) ovarian cancer. Two (22) or three (16) samples were obtained per patient and tested using the EDR assay (Oncotech, Inc.). The percentage of Extreme (E), Intermediate (I) and Low (L) drug resistance for each chemotherapy was compared between synchronous specimens.


RESULTS
A total of 92 samples were collected and 787 drug assays were performed. Tumor heterogeneity was seen in 22.4% of all cases, including 18.6% primary and 26.1% recurrent diseases (p=0.01). Two category differences (L vs. E) were seen in 4.1% primary and 11.3% recurrent cases (7.8% of all cases). Overall, an increased frequency in EDR was seen in recurrent disease as compared to primary for all agents tested (22.9% primary vs. 31.6% recurrent, p=0.006). Marked heterogeneity of the drug resistance profiles was seen with paclitaxel as compared with cisplatin/gemcitabine (p=0.03), taxotere (p=0.04) or topotecan (p=0.04). No association was demonstrated between assay results and clinicopathologic parameters collected in this cohort.


CONCLUSIONS
Treatment failure is often attributed to the development of chemoresistance. These results suggest that tumor heterogeneity may play an equally important role in treatment failure. Recurrent lesions exhibit greater heterogeneity and more frequent EDR. These data can influence therapeutic strategy i.e., multiple samples, sequential, or consolidation therapy.
McAlpine
J N
JN
Department of Gynecology and Obstetrics, Division of Gynecologic Oncology, University of British Columbia, Vancouver, BC, Canada. jessica.mcalpine@vch.ca
Eisenkop
S M
SM
Spirtos
N M
NM
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002945:Cisplatin / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology* / Q000601:surgery; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology* / Q000601:surgery; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology; D011446:Prospective Studies; D043823:Taxoids / Q000494:pharmacology; D019772:Topotecan / Q000494:pharmacology; D000093542:Gemcitabine
D043823:Taxoids; D003841:Deoxycytidine; D000077143:Docetaxel; D019772:Topotecan; D017239:Paclitaxel; D002945:Cisplatin; D000093542:Gemcitabine