Metformin and Nightly Fasting in Women With Early Breast Cancer

Inclusion Criteria:

• Women with histologically confirmed luminal (ER+ve and/or progesterone [PgR]+ve >= 1%) operable IBC (cT1-2, cN0-1, Mx) candidate to elective surgery and not toneo-adjuvant treatment. Women with larger tumors who refuse neo-adjuvantchemotherapy before surgery can also be eligible. Luminal HER2+ve (cT1, cN0) IBC andDCIS are also eligible

• Age >= 18 years

• Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

• Leukocytes >= 3,000/microliter

• Absolute neutrophil count >= 1,500/microliter

• Platelets >= 100,000/microliter

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 1.5 x institutional upper limit of normal

• Creatinine within normal institutional limits

• Creatinine clearance estimated with Cockcroft-Gault formula > 45 mL/min

• Female participants of child-bearing potential must agree to use contraception suchas barrier method of birth control or abstinence, prior to study entry and for theduration of study participation. Should a woman become pregnant or suspect she ispregnant while participating in this study, she has to inform her study physicianimmediately. The effects of metformin hydrochloride extended release on thedeveloping human fetus at the recommended therapeutic dose are unknown

• Ability to understand and the willingness to sign a written informed consentdocument

Exclusion Criteria:

• Body mass index (BMI) < 18.5 Kg/m^2

• Previous treatment for breast cancer including chemotherapy and endocrine therapy

• Women who are planned to receive neoadjuvant therapy (HER2+ve T2 or N+ve IBC orwomen < 50 years with luminal B IBC)

• Triple negative breast cancer (BC)

• Documented history of symptomatic hypoglycemia

• Diabetic patients or participants with fasting glucose level >= 126 mg/dL

• Known hypersensitivity or intolerance to metformin hydrochloride extended release

• Participants should not be receiving any other investigational agents

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, unstable angina pectoris, cardiacarrhythmia, or psychiatric illness/social situations that would limit compliancewith study requirements

• History of lactic acidosis

• Liver dysfunction including chronic active hepatitis and cirrhosis not compensated

• History of vitamin B12 deficiency or megaloblastic anemia

• Chronic use of large doses of diuretics (e.g., > 80 mg furosemide)

• Current use of oral hormonal contraceptives or female hormones in the last fourweeks or 5 half-lives, excluding vaginal creams and intrauterine devices (IUDs)

• Concomitant use of topiramate or other carbonic anhydrase inhibitors (e.g.,zonisamide, acetazolamide or dichlorphenamide)

• Pregnant women are excluded from this study because even though published data frompost-marketing studies have not reported a clear association between metforminhydrochloride extended release and major birth defects, miscarriage, or adversematernal or fetal outcomes when metformin hydrochloride extended release was usedduring pregnancy, these studies cannot definitely establish the absence of anymetformin hydrochloride extended release associated risk because of methodologicallimitations, including small sample size and inconsistent comparator groups. Becausethere is an unknown but potential risk for adverse events (AEs) in nursing infantssecondary to treatment of the mother with metformin hydrochloride extended release,breastfeeding should be discontinued if the mother is treated with metforminhydrochloride extended release. Moreover, prolonged fasting is not recommended inpregnant woman

• Women who practice any type of intermittent fasting program

• Women who will not have anyone available to assist them in case of need