This phase III trial evaluates how often women develop insulin resistance and type-2 diabetes and compares metformin with usual care to usual care alone in treating insulin resistance in women with stage I-III breast cancer after chemotherapy. Insulin resistance occurs when cells stop responding to insulin and is a risk factor for developing diabetes and heart disease. Higher levels of insulin have been shown to be associated with aggressive breast cancer. Metformin hydrochloride decreases the amount of glucose (a type of sugar) released into the bloodstream from the liver and increases the body's use of the glucose. Metformin as well as standard of care diet and exercise education is known to lower blood sugar. However, chemotherapy may accelerate metabolic disorders, such as high blood sugar, and the impact of metformin in these breast cancer survivors is not known. Giving metformin with usual care may be more effective than usual care alone in preventing or reversing insulin resistance in women with stage I-III breast cancer after chemotherapy.

PRIMARY OBJECTIVE:

I. To determine if extended release metformin hydrochloride (metformin) can normalize glycosylated hemoglobin (HgbA1c) (< 5.7%) for women breast cancer survivors with HgbA1c between 5.7-6.4%.

EXPLORATORY OBJECTIVES:

I. To investigate whether metformin treatment of insulin resistance (versus standard of care alone) alters epigenetic changes (chromatin acetylation, chromatin opening, and methylation) and the level of inflammatory cytokines. (Pilot) II. To investigate whether normalization of HgbA1c alters epigenetic changes (chromatin acetylation, chromatin opening, and methylation) and the level of inflammatory cytokines. (Pilot)

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive standard of care healthy diet and exercise handouts and extended release metformin orally (PO) once daily (QD) for 12 months in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection throughout the study.

ARM II: Patients receive standard of care healthy diet and exercise handouts on study. Additionally, patients undergo blood sample collection throughout the study.

After completion of study treatment, patients are followed up at 30 days and in 12 months.

Inclusion Criteria:

• Documented informed consent of the participant and/or legally authorized representative

• Agreement to allow lab draw of approximately 26 mL of blood (less than 2 tablespoons)

  • To check blood counts, organ function and disease at baseline and 12 months
  • Review of clinical charts at pre-registration* (refer to Study Calendar), baseline, 3 months, 6 months,12 months, and 24 months
  • Research labs at baseline, 6 months,12 months, and 24 months

• Age: ≥ 18 years

• Female sex assigned at birth

• Ability to read and understand English or Spanish for questionnaires

• Diagnosis of invasive breast cancer stages I-III

• Completed adjuvant treatment for Stage 1-3 breast cancer within 5 years and are disease free.

• Women who receive drugs for weight loss - e.g. semaglutide - prior to diagnosis are eligible for this protocol and can continue the drug during the intervention.

Exclusion Criteria:

• Currently taking metformin or any other oral antidiabetic medications. Weight loss medications are permitted - e.g. semaglutide
• Taking tamoxifen or aromatase inhibitor
• Contraindication to metformin prevention such as acute hypersensitivity or allergic reaction to metformin
• Participants with acute or chronic renal insufficiency (a glomerular filtration rate [GFR] < 60 mL/min/1.73m^2) or those with acute renal insufficiency of any severity due to hepato-renal syndrome or in the peri-operative liver transplantation period
• Bilirubin of >2.5 mg/dL (normal range 0.1-1.2 mg/dL).
• Previously diagnosed type 1 or type 2 diabetes
• Patients pregnant or within 1 year of pregnancy and completion of lactation (to be determined at randomization).
• Other active malignancy. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
• An employee who is under the direct/indirect supervision of the principal investigator (PI)/a co-investigator/the study manager and/or a direct study team member
• Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

Female sex assigned at birth