Abstract 2813: Chemoprevention of mammary cancer: Modeling predictive values of short-term morphologic assays for efficacy in animal tumor assays
Authors: Dunn Barbara K. , Steele Vernon E. , Fagerstrom Richard M. , Topp Carol F. , Kramer Barnett S. 
Published: August 2015

Background: Understanding the ability of chemopreventive agent efficacy in morphologic (in vitro/in vivo) assays to predict efficacy in animal (mouse and rat) in vivo tumor assays has not been well studied. The Chemopreventive Agent Development Research Group (CADRG) in the U.S. NCI's Division of Cancer Prevention has, over 25 years, tested approximately 800 agents for potential chemopreventive activity. Of these agents, a subset of 146 that were tested in both morphologic and mammary gland tumor assays constitutes the focus of our current project. Our goal is to gain deeper insight into the relevant predictive values.

Materials and Methods: Two critical steps are involved in the early stages of the CADRG testing pathway: (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. Ultimately, our goal is to test agents that successfully decrease tumor incidence and multiplicity in animal tumor assays in humans. In the project presented here, we evaluated the predictive values of earlier-stage (morphologic) assays for efficacy in later-stage (animal tumor, specifically mammary tumor) assays. We used 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. For this purpose multimodel inference was applied to ordinal logistic regression.

Results: We evaluated the ability of the six morphologic assays to predict tumor outcomes in the mouse and rat mammary gland cancer assays. In our statistical modeling approach, each morphologic assay was assigned a value describing how strongly it predicted outcomes in the mammary gland tumor assays. Specific morphologic assays (mouse mammary organ culture/MMOC and human foreskin epithelial cell/HFE morphologic assays) in combination yielded predictive values that are reasonably suggestive of the efficacy demonstrated by chemopreventive agents in the mouse and rat mammary gland tumor assays.

Conclusions: Predictive models such as these should prove useful in guiding future decision-making regarding agent selection and morphologic and animal tumor assay use. Our current strategy is to gain insight into the 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 those classes of agents that exhibit the highest efficacy in specific mammary gland tumor assays.

Citation Format: Barbara K. Dunn, Vernon E. Steele, Richard M. Fagerstrom, Carol F. Topp, Barnett S. Kramer. Chemoprevention of mammary cancer: Modeling predictive values of short-term morphologic assays for efficacy in animal tumor assays. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2813. doi:10.1158/1538-7445.AM2015-2813