The goal of this study is to test whether monitoring insulin levels and using pioglitazone to treat hyperglycemia and hyperinsulinemia in patients treated with Alpelisib for metastatic breast cancer is feasible and safe, and to assess the rates of glycemic control, dose reductions and treatment discontinuation and the progression free survival of patients treated with this regimen.

1. To assess the feasibility and safety of monitoring insulin levels alongside glucose levels and of directing antidiabetic treatment according to insulin and fasting glucose levels in patients treated with Alpelisib for metastatic breast cancer.
2. To assess the feasibility and safety of treatment with pioglitazone in these patients.
3. To assess the rate of severe (grade 3-4) hyperglycemia in patients treated according to this protocol.
4. To assess the rates of dose reductions and treatment discontinuation due to hyperglycemia in patients treated according to this protocol.
5. To assess the median progression free survival of patients treated according to this protocol

Inclusion Criteria:

• Patients with ER positive HER2 negative metastatic breast cancer, harboring an activating PIK3CA mutation, scheduled to start treatment with Alpelisib and fulvestrant.
• Ages 18 - 85
• ECOG performance status 0, 1 or 2
• Ability to understand and willingness to sign a written informed consent.

Exclusion Criteria:

• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of Alpelisib
• Uncontrolled diabetes mellitus, defined as HbA1c above 8%
• Diabetes mellitus controlled by insulin
• Uncontrolled intercurrent illness including, but not limited to: active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Pregnancy
• Known allergy to pioglitazone