Breast Cancer Chemoprevention in Pre-Neoplastic Lesions with a Somatostatin Analog in Nine Women: A Proof of Principle Trial.

Background: Atypical duct and lobular hyperplasia and lobular neoplasia of the mammary gland increases breast cancer risk. Tamoxifen and Raloxifene in post menopausal women are considered standard chemopreventive agents in these high risk women. We have previously shown insulin-like growth factor-I (IGF-I) is required to permit estrogen (E2) and progesterone action in the mammary gland, and that a novel somatostatin analog, SOM230, can prevent E2 action by reducing pituitary growth hormone (hGH), and by directly inhibiting IGF-I action in the mammary gland. It inhibits hGH and E2 induced cell proliferation and increases apoptosis in rat mammary gland. This study was designed to determine whether women at high risk for breast cancer respond to SOM230 in the same way that rats do.Methods: Women carrying a diagnosis of atypical hyperplasia and Lobular carcinoma in-situ (lesions that increase relative risk of breast cancer) were included. After the diagnosis was made on corebiopsies, women were treated for 9.5 days with SOM230 (600mcg BID). Surgical excision was performed on day 10. Sections were examined before and after SOM230 treatment for cell proliferation (Ki67) and apoptosis (TUNEL). Serum IGF-I, fasting glucose, insulin, and HbA1C were measured in anticipation of changes.Results: Of the nine patients who have so far completed the trial, three had LCIS. When comparing the core to surgical excision, SOM230 caused decreased proliferation and increased apoptosis. There was no atypical ductal hyperplasia tissue remaining in surgical specimens. However, all nine had typical ductal hyperplasia before and after treatment. SOM230 caused decreased cell proliferation and increased apoptosis in each case.All nine patients evaluated had elevations in fasting fingerstick glucose from a mean of 97.7 mg/dL (range 84 - 117) to a mean of 113.4 mg/dL (range 100 - 134) at three days into SOM230 treatment. This was accompanied by a reduction in fasting insulin, which occurred in all. The reductions in insulin and increase in capillary glucose resolved with discontinuation of the study medication in all patients and HbA1c levels measured at three months were unchanged from baseline.Discussion: The preliminary short-term data show that SOM230 can inhibit cell proliferation and increase apoptosis in preneoplastic human breast lesions, supporting in principle that SOM230 prevents IGF-I action in women, and therefore E2 action, as it does in rats. Further results from this and other clinical trials will be important in determining whether SOM230 will offer an alternative to replace antiestrogens in breast cancer chemoprevention, and/or reverse premalignant lesions of the breast without causing symptoms of estrogen deficiency.SOM230 causes reduced serum IGF-I and fasting hypoinsulinemia, which may explain the fasting hyperglycemia. It is not yet clear whether SOM230 will be effective as long term chemoprevention, or if its usefulness will be limited by the adverse effects on glucose and IGF-I. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1044.