Abstract P5-11-01: Correlation of the effects of potential and known chemopreventive agents on proliferation rates in normal mammary glands and mammary cancers with their chemopreventive efficacy
Authors: Heckman-Stoddard Brandy M , Grubbs Clinton J , Moeinpour Fariba , Steele Vernon E , Lubet Ronald A 
Published: May 2015

Core needle biopsy, fine needle aspiration, or imaging (e.g., mammography) are currently used to examine chemopreventive agent efficacy in Phase II breast cancer trials. However, biomarker endpoints, such as proliferation rates using Ki67 in normal or "at risk" breast tissue, have not been formally validated relative to cancer outcome. The aim of this study was to validate Ki-67 in "normal" mammary tissue from the methylnitrosourea (MNU) rat mammary tumor model with mammary cancer multiplicity within the same animal as surrogate biomarker for agent efficacy. Multiple studies were performed in female Sprague-Dawley rats to correlate this proliferation biomarker in mammary tissue after two weeks of chemoprevention agent treatment with mammary cancer incidence and multiplicity at the end of the study. In brief, MNU was given at 50 days of age, one week later administration of the agent was started, and after two weeks a biopsy of the mammary gland was taken. Treatment with the agents continued for approximately 150 days, at which time the study was terminated and mammary tumor multiplicity was measured. Changes in proliferation and mammary tumor multiplicity were compared to a control group of untreated group of animals within the same experiment using a two-sided Student t-test.

[table1]AgentNormal Mammary Gland Proliferation IndexFinal Mammary Cancer MultiplicityVorozole (1.25 mg/kg BW/day)88%↓90%↓Lipitor (125 mg/kg diet)38%↓16%↓Targretin (150 mg/kg diet)90%↓92%↓Naproxen (200 mg/kg diet)6%↑45%↑Iressa (10 mg/kg BW/day)52%↓93%↓Tamoxifen (3.3 mg/kg diet)77%↓100%↓Metformin (150 mg/kg BW/day)25%↓71%↑

In general, highly effective agents to preventing cancers (e.g., tamoxifen) also prevented normal mammary gland proliferation after only two weeks of treatment, while inactive agents (e.g., naproxen) had minimal effects on normal gland proliferation. The effects of the agents on established mammary cancers (in which the agents were given for 7 days to rats bearing small MNU-induced mammary cancers) showed similar correlations. Additional biomarkers, as well as the proliferation change and efficacy of these agents in rats fed a high-fat (Western) diet, will also be presented. In conclusion, determining the effect of a potential chemopreventive agent on cell proliferation following short-term treatment appears to be an effective method for predicting its efficacy in preventing mammary cancers. These data further confirm that Ki67 measurements are useful in Phase II prevention trials as a biomarker of agent efficacy.

Citation Format: Brandy M Heckman-Stoddard, Clinton J Grubbs, Fariba Moeinpour, Vernon E Steele, Ronald A Lubet. Correlation of the effects of potential and known chemopreventive agents on proliferation rates in normal mammary glands and mammary cancers with their chemopreventive efficacy [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 P5-11-01.