Jan Stenvang
Posters-Accepted Abstracts: Chemotherapy
Studies in taxane and/or anthracycline refractory metastatic breast cancer patients have shown approximately 30% response rates to irinotecan. Hence, a significant number of patients will experience irinotecan-induced side effects without obtaining any benefit. The aim of this study was to lay the groundwork for development of predictive biomarkers for irinotecan treatment in breast cancer. We established breast cancer cell lines with acquired or de novo resistance to SN-38 by exposing human breast cancer cell lines (MCF-7 and MDA-MB-231) to either stepwise increasing concentrations over six months or an initial high dose of SN-38 (the active metabolite of irinotecan). The resistant cell lines were analyzed for cross-resistance to other anti-cancer drugs, global gene expression, growth rates, TOP1 and TOP2A gene copy numbers, Top1 and Top2a protein expression, and inhibition of the ABCG2 encoded breast cancer resistance protein (BCRP) drug efflux pump. The resistant cell lines showed 7-100 fold increased resistance to SN-38 but remained sensitive to docetaxel and the non-camptothecin Top1 inhibitor LMP400. The resistant cell lines were characterized by Top1 down-regulation, changed isoelectric points of Top1 and reduced growth rates. The gene and protein expression of ABCG2/ BCRP was up-regulated in the resistant sub-lines and functional assays revealed BCRP as a key mediator of SN-38 resistance. Based on our preclinical results, we suggest analyzing the predictive value of the BCRP in breast cancer patients scheduled for irinotecan treatment. Moreover, LMP400 should be tested in a clinical setting in breast cancer patients with resistance to irinotecan.
