In vitro drug responses in primary and metastatic colorectal cancers

Objective. Treatment of primary and metastatic colorectal carcinoma (CRC) based on 5-fluorouracil and folinic acid (5FU + FA), combined with irinotecan (FOLFIRI) or oxaliplatin (FOLFOX), provides response rates approaching 50% and a 20-month overall survival. Approximately 50% of CRC patients fail to respond to one or more drugs in either regimen, in many cases due to inherent or acquired drug resistance. We therefore characterized in vitro drug response and cross-resistance in primary and metastatic CRC lesions. Materials and methods. The in vitro Extreme Drug Resistance Assay (EDRA) identifies extreme drug resistance (EDR) in solid tumors with over 99% accuracy and appears to mimic the clinical experience. We analyzed EDRA results from 4854 freshly resected CRC biopsies, including 1740 primary and 847 liver metastases. Results. Primary and metastatic CRCs responded similarly to single agents 5FU + FA, irinotecan, and oxaliplatin. Primary and metastatic tumors expressing EDR to 5FU + FA demonstrated up to 58% cross-resistance to a variety of chemotherapy agents, with the lowest percentages for oxaliplatin (11% and 8%, respectively) and irinotecan (16% and 14%). Importantly, approximately 20% of tumors showed EDR to either FULFOX or FOLFIRI. Conclusion. Overall data analyses indicated that EDRA results obtained at initial diagnosis may be useful in guiding therapy selection for metastatic disease. Pre-testing of tumors before treatment may provide essential drug cross-resistance information for better chemotherapy selection. Prospective clinical trials employing the EDRA are needed to substantiate these data.