Abstract CT306: Breast cancer chemoprevention by IGF-I inhibition in women with atypical hyperplasia of the breast: A phase 1/2 proof of principle trial

Abstract

Abstract SERMs are effective in breast cancer prevention in women at high risk, but they are not without side effects. We assessed a potential alternative approach, based on the knowledge that IGF-I is essential for E2 action in the mammary gland. Inhibitors of IGF-I block both IGF-I and E2 actions. We employed a somatostatin receptor ligand (SRL), pasireotide, which targets the mammary gland to stimulate local IGFBP5, and, as a result, blocks IGF-I binding to IGF-1R. Unlike octreotide that mainly targets SSTR2 receptors, pasireotide targets 4 of the 5 somatostatin receptors, which accounts for its unique action in potently preventing IGF-I from activating IGF-IR. Like other SRLs, pasireotide also inhibits GH secretion from the pituitary, lowering serum IGF-I. We enrolled 15 women with atypical hyperplasia (AH) diagnosed on core biopsy. They were treated with pasireotide for 10 days. 13 patients completed the trial. They had wire placement prior to surgical excision to identify the exact location of the core lesion, before surgical excision. Core and excision biopsies were stained for H&E, Ki67, TUNEL, ER and PR. Phosphorylated AKT and ERK 1/2 were assessed in a subset. Twelve of thirteen patients also had proliferative lesions (PL) on both core and excision specimens, and one had DCIS. Pasireotide decreased proliferation and increased apoptosis in all 6 AH lesions (from a mean of 3.6±2.6% to 1.3±1.2% and from 0.3±0.2% to 1.5±1.6%, respectively) and 12 proliferative lesions (from 3.8±2.5% to 1.8±1.8% and from 0.3±0.2% to 1.3±0.6%, respectively). The DCIS responded similarly. ER and PR were not affected by pasireotide, while phosphorylated ERK 1/2 and AKT decreased significantly. We also examined core and excision biopsies from untreated patients and found no change in cell proliferation or phosphorylation of AKT or ERK 1/2. In depth assessment of side effects including mild to moderate hyperglycemia associated with reduced insulin levels were studied. Glucose fell into the normal range after discontinuing treatment. Pasireotide was generally well tolerated and did not cause symptoms of estrogen deprivation. In conclusion, IGF-I inhibition was found to significantly reduce cell proliferation and increase apoptosis via effects on the downstream IGF-IR pathway in women with AH and PL. ER and PR were not affected by pasireotide. Proliferation was also decreased and apoptosis increased in one patient with DCIS. That IGF-I is known to affect DNA damage, genomic stability and stem or progenitor cells, raises the possibility that inhibition of IGF-I could have effects on other aspects of breast cancer chemoprevention, in addition to inhibiting proliferation and increasing apoptosis. Citation Format: David L. Kleinberg, Deborah Axelrod, Julia Smith, Baljit Singh, Martin Lesser, Pietro Ameri, Ann Danoff, Irineu Illa Bochaca, Cristina de Angelis. Breast cancer chemoprevention by IGF-I inhibition in women with atypical hyperplasia of the breast: A phase 1/2 proof of principle trial. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT306. doi:10.1158/1538-7445.AM2014-CT306