Metformin Hydrochloride in Preventing Breast Cancer in Patients With Atypical Hyperplasia or In Situ Breast Cancer

This randomized phase III trial studies metformin hydrochloride to see how well it works compared to placebo in preventing breast cancer in patients with atypical hyperplasia or in situ breast cancer. Chemoprevention is the use of certain drugs to keep cancer from forming. The use of metformin hydrochloride may prevent breast cancer.

I. Test for the presence or absence of cytological atypia (as measured by a Masood Cytology Index Score of 14-17) in unilateral or bilateral random periareolar fine needle aspiration (RPFNA) aspirates after 12 and 24 months (24 month is optional for placebo-only group for patients who remain on placebo arm and will not receive metformin \[metformin hydrochloride\]) for women receiving metformin versus placebo control. The presence of cytological atypia means any atypia in any RPFNA specimen.

SECONDARY OBJECTIVES:

I. Use the Masood Cytology Index Score to test for the presence of cytological atypia or disappearance of cytological atypia in RPFNA aspirates after 12 months for both arms, and 24 months (24 month is optional for placebo-only group for patients who remain on placebo arm and will not receive metformin, and mandatory for crossover patients) for women receiving metformin 850 mg orally (PO) twice daily (BID) (metformin group).

II. Compare Masood Cytology Score values at 0 and 12 months in right and left breasts (if both breasts were aspirated) from the same individual in the metformin and placebo group.

III. Test the reproducibility of reverse phase protein microarray (RPPM) in duplicate RPPM determinations from individual RPFNA specimens.

IV. Correlate baseline RPPM values with presence of atypia (as measured by Masood Cytology Index Score) at month 12 and month 24 (month 24 optional for placebo-only group; for patients who remain on placebo arm and will not receive metformin) RPFNA.

TERTIARY OBJECTIVES:

I. Test whether metformin alters RPFNA or blood biomarkers associated with breast cancer risk.

II. Test whether metformin alters markers associated with obesity and insulin resistance.

III. Test other exploratory measures in RPFNA and serum including metformin levels and estrogen/progesterone.

IV. Banking: As part of ongoing research for Alliance Cancer Control studies, banking residual blood and RPFNA products for future studies.

Eligibility Criteria:
* PRE-REGISTRATION-INCLUSION CRITERIA
* Must be at increased risk for breast cancer, defined as at least one of the following four criteria:

  * Having had a prior biopsy demonstrating atypical hyperplasia, lobular carcinoma in situ (LCIS), or ductal carcinoma in situ (DCIS)
  * A Gail Model Risk of \>= 1.66% over 5 years
  * A strong family history of breast and/or ovarian cancer which is defined as at least one of the following:

    * One first-degree relative with breast cancer before the age of 50 years
    * One first degree relative with bilateral breast cancer
    * Two or more first-degree relatives with breast cancer
    * One first degree relative and two or more second or third degree relatives with breast cancer
    * One first-degree relative with breast cancer and one or more relatives with ovarian cancer
    * Two second or third degree relatives with either breast cancer and one or more with ovarian cancer
    * One second or third degree relative with breast cancer and two or more with ovarian cancer
    * Three or more second or third degree relatives with breast cancer
  * Known breast cancer (BRCA)1 or BRCA2 mutation carrier providing that the woman has

    * Met with a genetic counselor to review genetic testing results, and
    * Has been offered the opportunity to undergo prophylactic mastectomy and oophorectomy
* Pre-menopausal women as defined as four menstrual cycles within the last six months prior to pre-registration; women with less than 4 menses within 6 months prior to pre-registration, or women who have had a hysterectomy with ovaries intact will be considered premenopausal if follicle-stimulating hormone (FSH) level is \< 20; women who are using hormonal contraceptives that cause amenorrhea (e.g. injectable and extended oral contraceptives, hormone containing contraceptive ring, or hormone containing intrauterine device) will be considered eligible if they had a minimum of 4 menstrual cycles within the last six months prior to starting on the contraceptive
* Digital mammogram within 365 days prior to pre-registration
* Mammograms must be read as not suspicious for breast cancer (American College of Rheumatology \[ACR\] class I-III); subjects with a class IV mammogram may be enrolled once they have been evaluated by a breast surgeon and there is no evidence of invasive malignancy
* Must be non-pregnant and non-lactating for at least one year prior to pre-registration
* If currently menstruating, subjects must use a reliable method of birth control
* Willing to provide RPFNA and blood samples for correlative research purposes
* REGISTRATION/RANDOMIZATION INCLUSION CRITERIA:
* Qualifying cytological atypia in RPFNA, Masood score of 14-17; the qualifying RPFNA (of one or both breasts) must be send to Dr. Seewaldt's laboratory for cytological scoring and proteomic analysis; score results must be received from Dr. Seewaldt's lab prior to patient registration/randomization; test must be done =\< 90 days prior to registration/randomization

  \* Note: Only the contralateral breast can be aspirated in women with DCIS and those undergoing surgery for an atypical lesion; the decision to aspirate the contralateral breast is at the discretion of the woman's surgeon
* Hemoglobin \>= 9 g/dL
* Absolute neutrophil count (ANC) \>= 1500/mm\^3
* Platelet count \>= 75,000/mm\^3
* Creatinine =\< 1.4 mg/dL
* Total bilirubin =\< 3.0 mg/dL
* Aspartate transaminase (AST) =\< 3 x upper limit of normal (ULN)
* Alanine transaminase (ALT) =\< 3 x ULN
* Negative pregnancy test done =\< 7 days prior to registration/randomization, for women of childbearing potential only

  \* A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months)
* Women eligible to take tamoxifen must be offered tamoxifen prevention as part of their clinical care and have refused tamoxifen treatment

Exclusion Criteria

* Other active malignancy =\< 5 years prior to pre-registration; EXCEPTIONS: non-melanotic skin cancer or carcinoma-in-situ of the cervix; NOTE: if there is a history or prior malignancy, they must not be receiving other specific treatment, i.e., other hormonal therapy, for their cancer
* Body mass index (BMI) \< 25
* Receiving Warfarin
* Bilateral breast implants or autologous breast flap reconstruction
* Active diagnosis of alcoholism
* Contraindication to metformin prevention such as acute hypersensitivity or allergic reaction to metformin
* Currently receiving tamoxifen or raloxifene
* Administration of any investigational agent =\< 30 days prior to pre-registration
* Previous radiation to both breasts
* Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
* Receiving pyrimethamine, cimetidine, rifampin or cephalexin
* Women who have a core biopsy or excisional biopsy containing invasive cancer
* Women who have taken metformin within the past 90 days
* Patients with hemoglobin a1c \> 6.3 or who are being actively treated for diabetes