Use of Metformin to Reduce Cardiac Toxicity in Breast Cancer

This is a randomized, open-label, phase II design pilot study in patients with breast cancer
requiring neoadjuvant or adjuvant chemotherapy. Eligible patients will be equally randomized
to either receive metformin plus standard of care therapy or standard of care therapy alone.
Patients receiving metformin will continue drug until the doxorubicin-containing cycles are
complete, unless unacceptable toxicity occurs or the patient decides to withdraw from the
study. Both arms of the study will undergo echocardiograms with contrast at baseline, upon
completion of doxorubicin-containing cycles (within 28 days of completion), and at the
one-year and seven-year time points. Additionally biomarker labs will be obtained to explore
if there is a correlation between change in cardiac activity and the activity of metformin.
If willing, all enrolled patients will provide a sample of whole blood for further
exploratory analysis. Symptoms reported during the study will be correlated with know single
nucleotide polymorphisms (SNPs) found during an exploratory genomic analysis.

Inclusion Criteria:

- Breast cancer requiring neoadjuvant or adjuvant therapy with doxorubicin

- Complete metabolic panel demonstrating adequate organ functions as defined by the
following: AST less than 2.5 times ULN; ALt less than 2.5 times ULN; alkaline
phosphatase less than 2.5 times ULN; serum creatinine less than 1.5 mg/dL; serum
bilirubin less than ULN

- ECOG performance status of 0 or 1

- Age greater than or equal to 21 years

Exclusion Criteria:

- Known diabetes

- History of cardiac arrhythmias or symptomatic cardiac disease

- Currently taking antiarrhythmic medications, beta-blockers, or other rate controlling
cardiac medications

- Currently taking metformin and/or sulfonylureas

- Known hypersensitivity or intolerance to metformin

- Baseline ejection fraction of less than 50% measured by echocardiogram

- Known hypersensitivity to contrast used during echocardiogram

- Risk factors associated with increased risk of metformin-associated lactic acidosis
(e.g. congestive heard failure, history of acidosis, habitual intake of 3 or more
alcoholic beverages per day)

- Pregnant or breast feeding