pasireotide and Precancerous-Conditions

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.. 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.. 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.. 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.. NCT01372644 Trial date: July 1, 2007.

Topics: Apoptosis; Breast; Breast Neoplasms; Carcinoma in Situ; Carcinoma, Intraductal, Noninfiltrating; Cell Proliferation; Female; Humans; Hyperplasia; Insulin-Like Growth Factor I; Middle Aged; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Phosphorylation; Precancerous Conditions; Proto-Oncogene Proteins c-akt; Receptor, IGF Type 1; Receptors, Estrogen; Receptors, Progesterone; Receptors, Somatomedin; Somatostatin

Pasireotide was shown in a randomized trial to decrease the rate of postoperative pancreatic fistula (POPF). However, retrospective series from other centers have failed to confirm these results.. Patients who underwent pancreatoduodenectomy or distal pancreatectomy between January 2014 and February 2019 were included. Patients treated after November 2016 routinely received pasireotide and were compared to a retrospective cohort. Multivariate analysis was performed for the outcome of clinically relevant POPF (CR-POPF), with stratification by fistula risk score (FRS).. Ninety-nine of 300 patients received pasireotide. The distribution of high, intermediate, low, and negligible risk patients by FRS was comparable (P = .487). There were similar rates of CR-POPF (19.2% pasireotide vs 14.9% control, P = .347) and percutaneous drainage (12.1% vs 10.0%, P = .567), with greater median number of drain days in the pasireotide group (6 vs 4 days, P < .001). Multivariate modeling for CR-POPF showed no correlation with operation or pasireotide use. Adjustment with propensity weighted models for high (OR, 1.02, 95% CI, 0.45-2.29) and intermediate (OR, 1.02, CI, 0.57-1.81) risk groups showed no correlation of pasireotide with reduction in CR-POPF.. Pasireotide administration after pancreatectomy was not associated with a decrease in CR-POPF, even when patients were stratified by FRS.

Topics: Aged; Female; Humans; Male; Middle Aged; Multivariate Analysis; Pancreatectomy; Pancreatic Fistula; Pancreatic Neoplasms; Pancreaticoduodenectomy; Postoperative Complications; Precancerous Conditions; Randomized Controlled Trials as Topic; Retrospective Studies; Risk; Somatostatin