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Breast Cancer Res. 2014 Nov 11;16(6):463. doi: 10.1186/s13058-014-0463-1.

Insulin-like growth factor-I inhibition with pasireotide decreases cell proliferation and increases apoptosis in pre-malignant lesions of the breast: a phase 1 proof of principle trial.

Author information

1
Department of Pathology, New York University School of Medicine, New York, NY, 10016, USA. baljit.singh@nyumc.org.
2
Department of Medicine, Division of Oncology, New York University School of Medicine, New York, NY, 10016, USA. julia.smith@nyumc.org.
3
Department of Surgery, New York University School of Medicine, New York, NY, 10016, USA. deborah.axelrod@nyumc.org.
4
Department of Medicine, Division of Endocrinology and Bunnie Joan Sachs Laboratory, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA. pietro.ameri@nyumc.org.
5
Department of Veterans Affairs Medical Center, New York, NY, 10016, USA. pietro.ameri@nyumc.org.
6
Department of Internal Medicine, University of Genoa, Genoa, 16132, Italy. pietro.ameri@nyumc.org.
7
Department of Medicine, Division of Endocrinology and Bunnie Joan Sachs Laboratory, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA. heather.levitt@nyumc.org.
8
Department of Medicine, Division of Endocrinology and Bunnie Joan Sachs Laboratory, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA. ann.danoff@nyumc.org.
9
Feinstein Institute for Medical Research, North Shore - LIJ Health System, Manhasset, NY, 11030, USA. marty@nshs.edu.
10
Department of Medicine, Division of Endocrinology and Bunnie Joan Sachs Laboratory, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA. cristinadeangelis83@hotmail.it.
11
Department of Veterans Affairs Medical Center, New York, NY, 10016, USA. cristinadeangelis83@hotmail.it.
12
Department of Medicine, Division of Endocrinology and Bunnie Joan Sachs Laboratory, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA. Irineu.bochaca@nyumc.org.
13
Department of Veterans Affairs Medical Center, New York, NY, 10016, USA. Irineu.bochaca@nyumc.org.
14
Department of Medicine, Division of Endocrinology and Bunnie Joan Sachs Laboratory, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA. drlubitz@gmail.com.
15
Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, 08901, USA. drlubitz@gmail.com.
16
Department of Medicine, Division of Endocrinology and Bunnie Joan Sachs Laboratory, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA. daniel.huberman@gmail.com.
17
Department of Veterans Affairs Medical Center, New York, NY, 10016, USA. daniel.huberman@gmail.com.
18
Department of Pathology, New York University School of Medicine, New York, NY, 10016, USA. farbod.darvishian@nyumc.org.
19
Department of Medicine, Division of Endocrinology and Bunnie Joan Sachs Laboratory, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA. david.kleinberg@nyumc.org.
20
Department of Veterans Affairs Medical Center, New York, NY, 10016, USA. david.kleinberg@nyumc.org.

Abstract

INTRODUCTION:

Estrogen inhibition is effective in preventing breast cancer in only up to 50% of women with precancerous lesions and many experience side effects that are poorly tolerated. As insulin-like growth factor I (IGF-I) underlies both estrogen and progesterone actions and has other direct effects on mammary development and carcinogenesis, we hypothesized that IGF-I inhibition might provide a novel approach for breast cancer chemoprevention.

METHODS:

In total, 13 women with core breast biopsies diagnostic of atypical hyperplasia (AH) were treated for 10 days with pasireotide, a somatostatin analog which uniquely inhibits IGF-I action in the mammary gland. They then had excision biopsies. 12 patients also had proliferative lesions and one a ductal carcinoma in situ (DCIS). Primary outcomes were changes in cell proliferation and apoptosis after treatment. Expression of estrogen receptor (ER), progesterone receptor (PR), and phosphorylated Insulin-like growth factor I receptor (IGF-1R), protein kinase B (AKT) and extracellular signal-regulated kinases 1/2 (ERK1/2) were also assessed. Core and excision biopsies from 14 untreated patients served as non-blinded controls. Hyperglycemia and other side effects were carefully monitored.

RESULTS:

Pasireotide decreased proliferation and increased apoptosis in all AH (from 3.6 ± 2.6% to 1.3 ± 1.2% and from 0.3 ± 0.2% to 1.5 ± 1.6%, respectively) and 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 IGF-1R, ERK1/2 and AKT phosphorylation decreased significantly. In contrast, tissue from untreated controls showed no change in cell proliferation or phosphorylation of IGF-1R, AKT or ERK 1/2. Mild to moderate hyperglycemia associated with reduced insulin levels was found. Glucose fell into the normal range after discontinuing treatment. Pasireotide was well tolerated and did not cause symptoms of estrogen deprivation.

CONCLUSIONS:

IGF-I inhibition by pasireotide, acting through the IGF-1R, was associated with decreased proliferation and increased apoptosis in pre-malignant breast lesions and one DCIS. Assuming hyperglycemia can be controlled, these data suggest that inhibiting the IGF-I pathway may prove an effective alternative for breast cancer chemoprevention.

TRIAL REGISTRATION:

NCT01372644 Trial date: July 1, 2007.

PMID:
25385439
PMCID:
PMC4303192
DOI:
10.1186/s13058-014-0463-1
[Indexed for MEDLINE]
Free PMC Article

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