Abstract P5-11-06: Understanding predictive values of short-term morphologic assays of cancer chemoprevention for efficacy in animal mammary gland tumor assays

Abstract

Abstract Background: The predictive value of chemopreventive agent efficacy in morphologic (in vitro/in vivo) assays for efficacy in animal (mouse and rat) in vivo tumor assays is not well characterized. Over a 25-year period, the Chemopreventive Agent Development Research Group in the U.S. NCI’s Division of Cancer Prevention has tested approximately 800 agents for potential chemopreventive activity. The current project focuses on a subset of 146 that were tested in both morphologic and mammary gland tumor assays in order to gain a deeper understanding of the relevant predictive value. Materials and Methods: The early stages of the testing pathway involve two critical steps: (1) in vitro/in vivo morphologic assays and, for agents successful in these, (2) testing for tumor prevention (measured in terms of tumor incidence and multiplicity reduction) in animal tumor assays. The ultimate goal is to test agents that successfully decrease tumor incidence and multiplicity in animal tumor assays in humans. In the current project we evaluated the predictive values of the earlier-stage (morphologic) assays for efficacy in the later-stage (animal tumor, specifically mammary tumor) assays. Statistical modeling to determine how well the six most commonly used morphologic assays predicted efficacy of the 146 tested agents in mouse and rat mammary gland tumor assays was carried out by multimodel inference applied to ordinal logistic regression. Results: The ability of these six morphologic assays to predict tumor outcomes was evaluated in the mouse and rat mammary gland cancer assays. Based on this statistical modeling, each morphologic assay was assigned a value describing how strongly it predicted outcomes in the mammary gland tumor assays. Selected morphologic assays (the mouse mammary organ culture (MMOC) and human foreskin epithelial cell (HFE) morphologic assays) in combination give a predictive value that meaningfully forecasts results for chemopreventive efficacy in the mouse and rat mammary gland tumor assays. Conclusions: These predictive models can be used to guide our future decision-making with respect to agent selection as well as morphologic and animal tumor assay use. Our future work is focused on deepening our understanding of our Predictive Value approach by: (1) identifying the mammary gland tumor assays that best reflect anti-tumor efficacy in animals; (2) teasing apart those classes of agents that exhibit the highest predictive values overall; and (3) examining which agent classes show the highest efficacy in specific mammary gland tumor assays. Citation Format: Barbara K Dunn, Vernon E Steele, Carol F Topp, Richard M Fagerstrom, Barnett S Kramer. Understanding predictive values of short-term morphologic assays of cancer chemoprevention for efficacy in animal mammary gland tumor assays [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-11-06.