PIK3CA Mutations Drive Therapeutic Resistance in Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer.

The phosphatidylinositol 3-kinase (PI3K) pathway is an intracellular pathway activated in response to progrowth signaling, such as human epidermal growth factor receptor 2 (HER2) and other kinases. Abnormal activation of PI3K has long been recognized as one of the main oncogenic drivers in breast cancer, including HER2-positive (HER2+) subtype. Somatic activating mutations in the gene encoding PI3K alpha catalytic subunit (PIK3CA) are present in approximately 30% of early-stage HER2+ tumors and drive therapeutic resistance to multiple HER2-targeted agents. Here, we review currently available agents targeting PI3K, discuss their potential role in HER2+ breast cancer, and provide an overview of ongoing trials of PI3K inhibitors in HER2+ disease. Additionally, we review the landscape of PIK3CA mutational testing and highlight the gaps in knowledge that could present potential barriers in the effective application of PI3K inhibitors for treatment of HER2+ breast cancer.

Phase II study of paclitaxel given once per week along with trastuzumab and pertuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer.

PURPOSE: The CLEOPATRA (Clinical Evaluation of Trastuzumab and Pertuzumab) study demonstrated superior progression-free survival (PFS) and overall survival when pertuzumab was added to trastuzumab and docetaxel. Paclitaxel given once per week is effective and less toxic than docetaxel. We performed a phase II study to evaluate the efficacy and safety of pertuzumab and trastuzumab with paclitaxel given once per week. PATIENTS AND METHODS: Patients with metastatic human epidermal growth factor receptor 2-positive breast cancer with zero to one prior therapy were enrolled. Treatment consisted of paclitaxel 80 mg/m(2) once per week plus trastuzumab (8 mg/kg loading dose → 6 mg/kg) once every 3 weeks plus pertuzumab (840 mg loading dose → 420 mg) once every 3 weeks, all given intravenously. The primary end point was 6-month PFS assessed by Kaplan-Meier methods. RESULTS: From January 2011 to December 2013, we enrolled 69 patients: 51 (74%) and 18 (26%) treated in first- and second-line metastatic settings, respectively. At a median follow-up of 21 months (range, 3 to 38 months), 6-month PFS was 86% (95% CI, 75% to 92%). The median PFS was 19.5 months (95% CI, 14 to 26 months) overall. PFS was 24.2 months (95% CI, 14 months to not reached [NR]) and 16.4 months (95% CI, 8.5 months to NR) for those without and with prior treatment, respectively. At 1 year, Kaplan-Meier PFS was 70% (95% CI, 56% to 79%) overall, 71% (95% CI, 55% to 82%) for those without prior therapy, and 66% (95% CI, 40% to 83%) for those with prior therapy. Treatment was well-tolerated; there was no febrile neutropenia or symptomatic left ventricular systolic dysfunction. CONCLUSION: Paclitaxel given once per week with trastuzumab and pertuzumab is highly active and well tolerated and seems to be an effective alternative to docetaxel-based combination therapy.

Treatment of type 2 diabetes in childhood using a very-low-calorie diet.

OBJECTIVE: Pharmacologic agents currently approved for use in children with type 2 diabetes (metformin and insulin) are less than optimal for some patients. We evaluated the use of a ketogenic, very-low-calorie diet (VLCD) in the treatment of type 2 diabetes. RESEARCH DESIGN AND METHODS: We conducted a chart review of 20 children (mean age 14.5 +/- 0.4 years) who consumed a ketogenic VLCD in the treatment of type 2 diabetes. Several response variables (BMI, blood pressure, HbA(1c), blood glucose, and treatment regimens) were examined before, during, and up to 2 years after the diet and compared with a matched diabetic control group. RESULTS: Before starting the diet, 11 of 20 patients were treated with insulin and 6 with metformin. Mean daily blood glucose values fell from 8.9 +/- 1.1 to 5.5 +/- 0.38 mmol/l (P < 0.0001) in the first 3 days of the VLCD, allowing insulin and oral agents to be discontinued in all but one subject. BMI fell from 43.5 +/- 1.8 to 39.3 +/- 1.8 kg/m(2) (P < 0.0001) and HbA(1c) dropped from 8.8 +/- 0.6 to 7.4 +/- 0.6% (P < 0.005) as the diet was continued for a mean of 60 +/- 8 days (range 4-130 days), and none required resumption of antidiabetic medications. Sustained decreases in BMI and insulin requirements were observed in patients remaining on the VLCD for at least 6 weeks when compared with those of the control group. CONCLUSIONS: The ketogenic VLCD is an effective short-term, and possibly long-term, therapy for pediatric patients with type 2 diabetes. Blood glucose control and BMI improve, allowing the discontinuation of exogenous insulin and other antidiabetic agents. This diet, although strict, has potential as an alternative to pharmacologic therapies for this emerging subset of diabetic individuals.