Evidence that SOM230 can prevent experimental mammary hyperplasia by blocking IGF-I and thus estrogen action in the mammary gland: preliminary evidence for an effect in humans.

Abstract

Abstract Abstract #5084 Background: Antiestrogens or aromatase inhibitors are used for breast cancer chemoprevention, however, they are poorly tolerated. We have shown that IGF-I is required to permit estrogen and progesterone action in the mammary gland. A novel somatostatin analog, SOM230, which binds to several somatostatin subtype receptors (SSTR), prevents estrogen action by reducing pituitary growth hormone, and also by a direct IGF-I action inhibitory effect on the mammary gland. Menopausal symptoms have not been observed in acromegalic patients receiving SOM230. Material and Methods: Several approaches have been undertaken. 1) We developed a model of hyperplasia in hypophysectomized and oophorectomized female rats. Hyperplasia was induced by treatment with 600 mcg hGH and follicular phase concentrations of estradiol. 2) To assess translatability to humans we cell proliferation (Ki67) and apoptosis (TUNEL) were measured in normal human breast from reduction mammoplasty and in samples of proliferative fibrocystic change (FCC). 3) We also measured expression of SSTR in atypical ductal hyperplasia and DCIS, and 4) A proof of principal trial with SOM230 has begun accrual to determine whether SOM230 acts in human breast as in rats. Results: 1) hGH and E2 caused florid hyperplasia in rat mammary glands within a week. Twenty-six percent of gland structures exhibited hyperplasia with 50% of those showing florid hyperplasia. SOM230 reduced the number of areas of florid hyperplasia to 7.5 ±0.5 from 18.9±1.3 (p<0.001). This was accomplished by a reduction in cell proliferation and an increase in apoptosis. Interestingly, co-administration with tamoxifen provided no additional benefit over that of SOM230. 2) Proliferative lesions from human breast had 8.09 % of cells stain for Ki67. 3) All 5 somatostatin subtype receptor (SSTR) were present in pathology samples of atypical hyperplasias and DCIS, but SSTR3 and 5 were present in highest concentrations. SSTR 3 is the receptor most likely to mediate the effect of SOM230 with SSTR5 being the next most likely. 4) In the first patient tested we found that SOM230 increased apoptosis and reduced cell proliferation (1000 cells counted).
 
 Discussion: Our data show that SSTR are present in ADH and DCIS and normal breast tissue. Our data also show that SOM230 can prevent cell proliferation and increase apoptosis both in rats and humans. Thus, further clinical trials will be important as SOM230 may have a role in breast cancer chemoprevention. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5084.