Faculty Bibliography

Pasireotide has a broader somatostatin receptor binding profile than other somatostatin analogues. A 16-week, Phase II trial showed that pasireotide may be an effective treatment for acromegaly. An extension to this trial assessed the long-term efficacy and safety of pasireotide. This study was an open-label, single-arm, open-ended extension study (primary efficacy and safety evaluated at month 6). Patients could enter the extension if they achieved biochemical control (GH /=24 months in the extension; three who were biochemically controlled at month 24 had achieved control during the core study. Of 29 patients with MRI data, nine had significant (>/=20 %) tumor volume reduction during the core study; an additional eight had significant reduction during the extension. The most common adverse events were transient gastrointestinal disturbances; hyperglycemia-related events occurred in 14 patients. Twenty patients had fasting plasma glucose shifted to a higher category during the extension. However, last available glucose measurements were normal for 17 patients. Pasireotide has the potential to be an effective, long-term medical treatment for acromegaly, providing sustained biochemical control and significant reductions in tumor volume.

In March 2013, the Acromegaly Consensus Group met to revise and update guidelines for the medical treatment of acromegaly. The meeting comprised experts skilled in the medical management of acromegaly. The group considered treatment goals covering biochemical, clinical and tumour volume outcomes, and the place in guidelines of somatostatin receptor ligands, growth hormone receptor antagonists and dopamine agonists, and alternative modalities for treatment including combination therapy and novel treatments. This document represents the conclusions of the workshop consensus.

Background:Oral octreotide acetate (OOA), a novel formulation of octreotide, is biologically active, inhibiting pituitary growth hormone (GH) secretion in healthy volunteers. Accordingly, OOA was tested for acromegaly efficacy and safety in a phase III, global, multicenter, open-label, dose-titration, baseline-controlled study. Methods:After screening, 155 subjects shown to be controlled (defined as IGF-I levels <1.3 ULN, and 2hr integrated GH <2.5 ng/mL, measured centrally), while on 3 months of injectable somatostatin receptor ligand (SRL), were enrolled. Following OOA pre-treatment baseline establishment and after 4 weeks from last SRL injection, subjects were switched to OOA. All entered a dose escalation phase, initially receiving OOA 40 mg/day, titrated as required to 60 mg/day, and up to 80 mg/day (divided into two separate daily doses), to normalize IGF-I levels. This was followed by a fixed dose phase for up to a total duration of 7 months of OOA treatment (core treatment period). Controlled patients were then offered an additional 6-month extension phase. Results:Of 151 evaluable subjects that initiated OOA treatment and had at least one evaluation following first dose, 98 (65%) achieved the primary endpoint of hormonal control at their last assessment during the core treatment period, with IGF-I levels <1.3 ULN and mean 2 hr GH concentrations of <2.5 ng/mL. Following individual dose titration based on IGF-I levels, 61, 33, and 57 patients reached doses of 40, 60, and 80 mg, respectively. Of the 91 subjects who were controlled (IGF-I <1.3 ULN) at the end of dose escalation, 83 (91%) maintained this response at the end of the core treatment period. A total of 102 subjects completed the core treatment period, of whom 88 (86%) elected to continue treatment in the 6 month extension phase. Twenty-four subjects (15%) were considered treatment failures due to IGF-I level >1.3 ULN and terminated prior to the end of the core period. Seventeen subjects (11%) terminated for possible drug-related adverse events (AEs), consistent with known octreotide or disease-related AEs. Ten of the early terminations were due to GI symptoms (mostly mild to moderate nausea, diarrhea, or abdominal pain). Two deaths were reported: one of myocardial infarction in a patient with pancreatic carcinoma and obstructive jaundice, and another of suspected biliary obstruction and sepsis. Conclusions:Oral octreotide acetate exhibits efficacy in controlling IGF-I and GH levels in acromegaly patients treated for at least 7 months, following a switch from injectable SRLs with a safety profile consistent with approved SRLs. OOA is a viable option for administration as oral acromegaly monotherapy

Since its identification 20 years ago, the biological basis for the high breast cancer risk in women who have germline BRCA1 mutations has been an area of intense study for three reasons. First, BRCA1 was the first gene shown to associate with breast cancer risk, and therefore serves as model for understanding genetic susceptibility. Second, the type of breast cancer that occurs in these women has specific features that have engendered new hypotheses about the cancer biology. Third, it is hoped that understanding the origins of this disease may provide the means to prevent disease. Resolving this question has proven extremely challenging because the biology controlled by BRCA1 is complex. Our working model is that the high frequency of basal-like breast cancer in BRCA1 mutation carriers is the result of a self-perpetuating triad of cellular phenotypes consisting of: (i) intrinsic defects in DNA repair and centrosome regulation that lead to genomic instability and increases spontaneous transformation; (ii) aberrant lineage commitment; and (iii) increased proliferation due to in large part to increased IGF-1 activity. We propose that the last is key and is a potential entree for preventing breast cancer in BRCA1 mutation carriers.

Context: In clinical practice, the safety profile of GH replacement therapy for GH-deficient adults compared with no replacement therapy is unknown. Objective: The objective of this study was to compare adverse events (AEs) in GH-deficient adults who were GH-treated with those in GH-deficient adults who did not receive GH replacement. Design and Setting: This was a prospective observational study in the setting of US clinical practices. Patients and Outcome Measures: AEs were compared between GH-treated (n = 1988) and untreated (n = 442) GH-deficient adults after adjusting for baseline group differences and controlling the false discovery rate. The standardized mortality ratio was calculated using US mortality rates. Results: After a mean follow-up of 2.3 years, there was no significant difference in rates of death, cancer, intracranial tumor growth or recurrence, diabetes, or cardiovascular events in GH-treated compared with untreated patients. The standardized mortality ratio was not increased in either group. Unexpected AEs (GH-treated vs untreated, P