Ductal carcinoma in situ (DCIS) accounts for 1 in 5 cases of all new breast cancers in the United States; approximately 60,000 cases annually are DCIS. DCIS starts in the milk ducts of the breast, and left untreated these and other similar lesions spread beyond milk ducts (invasive cancer). Women diagnosed with DCIS have a 30% chance of developing more serious types of breast cancers. Currently treatment recommendations for DCIS include surgery together with radiation therapy, followed by antiestrogens, if the tumors are estrogen sensitive (ER-positive). In this situation, tamoxifen has been shown to prevent development of invasive breast cancer. Unfortunately, tamoxifen has some undesirable side effects, such as early menopause, blood clots, stroke, and endometrial cancers, and is also not effective as a stand-alone treatment for DCIS.

Our work in animals has revealed that neither estrogen (E2) nor progesterone (P) can stimulate normal or abnormal breast development in the absence of another hormone, called IGF-I. Not only is IGF-I essential for normal breast development, but it appears to be essential for any actions of E2 and P on the breast. We therefore reasoned that inhibition of IGF-I would not only prevent actions of E2 and P on the breast, but also would prevent the actions of IGF-I not related to E2 or P.

We discovered that a medication, SOM230, used to treat pituitary and endocrine pancreatic tumors, can work directly on the mammary gland of rats by preventing IGF-I action. So far we have found that SOM230 can prevent normal breast development and mammary hyperplasia (a piling up of cells) by preventing proliferation of cells and increasing programmed death of cells in experimental animals. The reduction in new cells and increased death of existing cells provide the benefit. Hyperplasia is a disorder that puts women and animals at increased risk for breast cancer. Based on our findings, we applied for and received a Synergistic Idea Award, and are in the last stages of testing whether SOM230 will in principle prevent cell proliferation and increase cell death in women with abnormal hyperplasia as it does in animals. Indeed, we found that SOM230 inhibited IGFI action by significantly inhibiting cell proliferation (p=0.003) and increasing programmed cell death (p=0.003) in all 11 women at high risk for breast cancer. Parenthetically, SOM230 did not cause menopausal symptoms. While tamoxifen also acts by inhibiting cell proliferation and increasing cell death, our research suggests that not only can SOM230 fully substitute for tamoxifen, but that inhibition of IGF-I action in the breast may be more powerful than the effect of antiestrogens and therefore could theoretically become a stand-alone treatment.

We now wish to expand this work to measure more closely the effectiveness of SOM230 in reducing tumor volume and recurrence and the extent of side effects, if any, over a longer trial period and with a population-based test group. In fact, we inadvertently treated one patient who turned out to have DCIS with SOM230 and there was a significant reduction in cell proliferation and increase in cell death. We now plan on treating 24 women, presenting low-grade (8), intermediate grade (8), and high-grade (8) estrogen-receptive DCIS tumors, with SOM230 for 19.5 days. Tissue from initial diagnostic biopsies will be compared to the remaining tissue excised after treatment. Measurements of cell proliferation, cell death, new vessel formation, and other endpoints will detect the effect of the medication. In addition, we plan to do mammography and dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) before and after treatment, which may permit us to determine if SOM230 will inhibit new vessel formation (angiogenesis) and whether this will be accompanied by a decrease in tumor volume.

In our previous Department of Defense trial, we found that women had moderately increased blood sugar early after starting SOM230. In other studies in normal individuals this effect disappeared by a week or two. We found some evidence of improvement during administration. However, extending the treatment period from 9.5 to 19.5 days will enable us to make certain that the early elevated sugar associated with SOM230 is only temporary. Another side effect was reduction in circulating levels of IGF-I. Theoretically, this could lead to body changes associated with growth hormone deficiency (GHD). Interestingly, tamoxifen and raloxifene, also lower serum IGF-I, and women taking it do not regularly complain of symptoms of GHD. However, this will eventually require further study if SOM230 is found to be very effective in patients with DCIS. If SOM230 can treat DCIS, the benefits of treatment would probably outweigh the risks.