Metformin to Treat Early-Stage Breast Cancer
Name of the Trial
Phase III Trial of Metformin versus Placebo in Early-Stage Breast Cancer (CAN-NCIC-MA.32). See the protocol summary.
Drs. Pamela J. Goodwin, Karen Gelmon, Kathleen Pritchard, Timothy Whelan, Lois Shepherd, Jennifer Ligibel, Dawn Hershman, Ingrid Mayer, Timothy Hobday, National Cancer Institute of Canada Clinical Trials Group; and Dr. Priya Rastogi, National Surgical Adjuvant Breast and Bowel Project
Why This Trial Is Important
Patients with early-stage breast cancer are usually treated with surgery to remove the affected breast (mastectomy) or just the tumor and a small amount of surrounding normal tissue (lumpectomy). Post-surgical, or adjuvant, therapy may include local treatment (radiation therapy) and/or systemic treatment (chemotherapy, hormone therapy, or both), depending on the type of surgery received and the clinical features of the tumor, such as its size, grade, and whether it has spread to nearby lymph nodes (lymph node-positive disease). In addition, if the tumor tests positive for overexpression of the HER2 gene, the patient will likely be treated with a drug or biological agent that targets the HER2 protein.
Although these treatments are effective in curing many patients with early-stage breast cancer, some patients will experience a relapse, and some will ultimately succumb to their disease. Consequently, doctors are eager to find new treatments for early-stage breast cancer or ways to improve the effectiveness of existing treatments.
The drug metformin (Glucophage) has been used for decades to treat people with diabetes. Researchers have found that diabetics taking metformin are less likely to develop cancer or die from the disease than diabetics who do not take metformin. In addition, women with early-stage breast cancer taking metformin for diabetes have higher response rates to presurgical, or neoadjuvant, therapies than diabetic patients not taking metformin or patients without diabetes. Recent results of studies in women with breast cancer who are waiting for surgery have shown that metformin may slow tumor cell growth. These observations have suggested that metformin may be helpful in preventing recurrences in women treated for early-stage breast cancer.
In this trial, nondiabetic women or men younger than age 75 who have been diagnosed with early-stage breast cancer within the previous 12 months and who have undergone surgery to remove their tumor will be randomly assigned to take metformin or placebo pills twice a day for 5 years. Participants in the trial may also receive adjuvant hormone and/or radiation therapy, but any chemotherapy (adjuvant or neoadjuvant) must have been completed prior to joining the study. Doctors will monitor the study participants to see if metformin improves disease-free survival, overall survival, and a number of other medical, biological, and quality-of-life endpoints.
“We think metformin may act against breast cancer through insulin-mediated or insulin-independent mechanisms of action, or both,” said Dr. Goodwin. “First, it may lower insulin levels, thereby reducing signaling through the PI3K [signaling] pathway, which is a growth/proliferation pathway in breast cancer cells. Secondly, independent of insulin, metformin alters metabolism in the mitochondria and turns on the [enzyme] AMP kinase, which then inhibits mTOR, a protein that helps regulate cell division and survival,” she explained.
“So, metformin is biologically a very interesting drug, and because it’s been used so widely, its side effects are well known,” Dr. Goodwin added. “In general, it’s a very safe and well-tolerated drug if you avoid its use in patients older than 80 and those with abnormal liver, kidney, or cardiac functions. The most common side effects are mild bloating and diarrhea that usually go away on their own after a few months, but we are starting off at half the dose of metformin for the first 4 weeks to help participants adjust.”