Abstract B004: Adaptive therapy in preclinical models of hormone-refractory breast cancer

Abstract

Abstract The goal of this study was to test whether adaptive therapy works in preclinical mouse models with hormone-refractory breast cancer and compare adaptive therapy with standard therapy. Specifically, we tested whether the drugs gemcitabine and/or capecitabine can control the MCF7 cancer cell line which is resistant to palbociclib and fulvestrant. We treated MCF7 resistant breast cancers growing orthotopically in the mammary fat pads of NSG immunodeficient mice with gemcitabine, capecitabine, or both drugs together. In the combined drug treatment, we switched drugs in every application (every 3 days) (“ping-pong”) or applied the drugs together (in tandem). In both single and multi-drug therapy, we applied drugs by either adjusting their doses or applying intermittently. We measured tumor size by bioluminescence imaging and caliper. We saw a reduction in the tumor burden of most mice treated with adaptive therapy along with prolonging overall survival. We found that the combination of gemcitabine and capecitabine in both intermittent and dose adjustment protocols significantly increased the survival of mice in comparison to standard therapy when we applied the drugs in a ping-pong strategy. The combination therapy in tandem was less successful compared to dose adjustment, but better than standard therapy in increasing overall survival. Moreover, we had several weeks off-treatment in most of the mice when the tumor was under the threshold, therefore lower drug doses were used. Among single drug therapies, capecitabine dose adjustment protocol was better than using both intermittent and the maximum tolerated dose in terms of increasing overall survival of mice and accumulating less dose of the drug. However, the capecitabine intermittent treatment was better compared to the capecitabine maximum tolerated dose. In contrast, there were no significant differences between adaptive protocols and standard therapy. However, in both intermittent and dose adjustment protocols we had several weeks off-treatment in most of the mice, so lower drug doses were used. In conclusion, we found that lower drug doses can be used under adaptive therapy, once the tumor is controlled. We had several weeks off- treatment for some cases and we saw a continued decline in tumor size. Overall, adaptive therapy strategies could prolong progression-free survival besides reduction in the tumor burden. Citation Format: Sareh Seyedi, Carlo Maley. Adaptive therapy in preclinical models of hormone-refractory breast cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr B004.