Abstract A58: Application of evolutionary principles to control ER+ breast tumors

Abstract

Abstract Introduction: Estrogen receptor-positive (ER+) breast cancers are initially treated with estrogen deprivation, usually using estrogen receptor modulator drugs (SERM) that are administered at near maximal dose until progression. However, in many of ER+ tumors, preexisting resistant populations that do not express ER on immunohistochemistry are observed. Furthermore, a number of other resistance mechanisms to SERM drugs have been observed including overexpression of MDR1 cell-membrane systems, which consume energy to extrude the drug from the cell. While the vast majority of ER+ tumors respond to SERM drugs, resistant populations can rapidly emerge due to preexisting or acquired phenotypic strategies. Herein, we examine nonconventional treatment strategies, based on the Darwinian evolutionary dynamics that govern tumor evolution, designed to maintain tumor control while delaying evolution of resistance. Materials and Methods: Different cohorts (20, 24, 4, and 41) of Nu/nu mice were injected in the mammary fat pad with 5*106 MCF7 cells. Prior to the cell injections, an estrogen pellet was subcutaneously implanted in mice. When tumors reached 300 mm3, mice were randomly distributed in treatment groups using different algorithm that combined tamoxifen, paclitaxel, and periods of no treatment. Tumor volumes were monitored by MRI, using T2-weighted images. At the end of the experimental time, tumors were collected and stained for IHC studies with H&E, CD31, SMA, MDR1, and ER. Results: Treatments in which tamoxifen therapy was interrupted by none-drug periods permitted tumor control equal to that of high-dose standard treatment while maintaining a large population of ER+ cells. Algorithms in which tamoxifen and paclitaxel were combined achieved tumor control equal to standard therapy and decreased MDR1 expressions. Conclusions: Treatment algorithms designed to exploit evolutionary principles to delay or prevent emergence of resistant populations maintained tumor control using lower cumulative drug doses than the standard-of-care therapy while maintaining populations of cells that are sensitive to the therapy. Note: This abstract was not presented at the conference. Citation Format: Pedro M. Enriquez-Navas, Libia Garcia, Robert J. Gillies, Robert A. Gatenby. Application of evolutionary principles to control ER+ breast tumors [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A58.