Certain structural abnormalities in breast tissue put women at risk for developing breast cancer. The objective of this proposal is to develop a treatment that does not have antiestrogenic side effects like tamoxifen (e.g., endometrial cancer, blood clots, hot flashes), but will, nevertheless, prevent breast cancer in high risk women. While antiestrogens reduce breast cancer occurrence by up to 50% in post-menopausal women, theoretically substances that inhibit IGF-I action will be as or more efficacious without causing the above side effects. We base this assertion on studies from our laboratory that prove that neither estrogen nor progesterone can act on the breast in the absence of insulin-like growth factor-I (IGF-I). Thus, IGF-I inhibition would prevent not only E2 action but also progesterone action, both of which have been implicated in causing breast cancer. Furthermore, we believe that a new somatostatin analog medication will be effective in preventing changes in the breast that put women at high risk for cancer. This medication, SOM230, has recently been shown to inhibit the effects of IGF-I and estrogen in the mammary gland and prevent mammary development in rats despite the presence of estrogen. The abnormal piling up of cells that predisposes these women to breast cancer (hyperplasia) can likely be prevented, according to our data.

We believe that the findings in animals discussed above are ready to be translated into human studies. This proposal envisions a proof of principle trial to assess whether short-term administration of SOM230 will inhibit IGF-I action in human breast as it does in rats, i.e., increase cell death and decrease cell division, the first steps in preventing cancer. Assuming this process starts by blocking the effect of IGF-I at the IGF-I receptor, the cascade of events leading to decreased cell division and increased cell death should also be deactivated, i.e., less production of certain downstream substances that control the process. In this case there should be a reduction in activated insulin receptor substrate 1 (IRS-1) (as there was in the rats) and a reduction in activated AKT. This is the substance that mediates the process of apoptosis or programmed cell death. In addition to these critical endpoints, we will study the mechanism of action of the treatment with SOM230. Receptors for SOM230 will be measured both in normal and abnormal breast tissue taken at biopsy, and potential mediators of action such as binding proteins for IGF-I will be studied. Women will be selected in whom a needle or core biopsy indicates a high-risk lesion. They will then be given the opportunity to volunteer to take SOM230 for either 10 or 30 days to ascertain the ideal time needed to observe the histologic changes. We will compare two dose regimes of SOM230 (400 mcg three time a day vs. 600 mcg twice a day). For these trial pilots, three patients will be tested for each dose and time period. The optimum regimen will be selected from results of these trial pilots, and a group of 20 volunteers will be enrolled at that dose and schedule. If 600 mcg twice a day does not produce sufficient histologic results, 600 mcg three times daily will be piloted. These doses are similar to those being tested for acromegaly. The risk to the patients, therefore, would be a possible delay of a second biopsy by 30 days. This falls well within the time course accepted as standard of care. Known side effects of somatostatin analogs are abdominal cramps, diarrhea (usually rapidly abating), and gall bladder problems. SOM230 can also cause an elevation in serum glucose or worsening of underlying diabetes. In normal volunteers, while there may be a slight increase in glucose the first week, the glucose usually normalizes soon thereafter. Anyone with diabetes or significant insulin resistance will be excluded from these studies. The potential advantage of this study is the identification of a treatment that can prevent the development of breast cancer, or reverse premalignant lesions of the breast, while maintaining intact circulating estrogen levels.