Abstract A42: Doses of selective estrogen receptor modulations (SERMS) required for prevention and therapy of chemically induced mammary cancers

Selective estrogen receptor modulators (SERMs) interfere with the activation of the estrogen receptor. SERMs have been shown to be effective for both treatment and prevention of breast cancer. Here we examine the ability of tamoxifen and arzoxifene, a more easily absorbed form of raloxifene, to prevent mammary tumors at a significantly lower dosage than those used for treatment. For prevention studies, female Sprague-Dawley rats (50 days of age) were injected with a single i.v. dose of MNU resulting in the development of multiple ER-positive mammary tumors beginning 7 weeks after carcinogen treatment. Rats were administered the preventive agent beginning five days after carcinogen administration. When the agents were tested at does varying between 0.15-3.3 ppm in the diet, both agents caused a dose dependent increase in preventive activity. The highest doses of tamoxifen (3.3 ppm) and arzoxifene (3.0 ppm) both decreased tumor multiplicity greater than 90%. Both of these doses are less than one-fifth the human equivalent dose (HED) based on standard FDA scaling factors. Both doses also resulted in substantial decreases in mammary gland development. These dosages were then used in a therapy setting to compare the efficacy. For these studies, MNU treated rats were allowed to develop their first palpable mammary tumor (70-150 mm2) before initiating treatment. Tumor growth or regression was followed by caliper measurements. Neither of the preventive doses of these SERMs exhibited therapeutic activity although substantially higher doses of tamoxifen (33 or 100 ppm) were relatively effective. These results are in contrast to our prior findings with other classes of agents (RXR agonists, EGFR inhibitors, and aromatase inhibitors) in which highly effective preventive doses were as effective as therapeutic doses in this model. These results demonstrate the unique dose differential regarding prevention and therapy with SERMs. Microarray analysis of tumors treated for 5 days with tamoxifen at doses of 3.3ppm or 100ppm reveals overlapping significant gene changes of similar magnitude in comparison to control treated tumors although there were significant gene changes seen at the therapeutic dose which were not observed at the lower dose. These studies raise two questions: 1) whether this class of agents might be used at significantly lower doses in a pure prevention setting as contrasted with a therapeutic setting where they were initially defined; 2) are there gene expression changes which might be used to help identify this differential dosing for prevention vs. therapy. Citation Information: Cancer Prev Res 2010;3(12 Suppl):A42.