Patient case: 73-year-old female with breast cancer; genetic feature: CDKN2A

Clinical trial: Metformin Hydrochloride in Patients With Atypical Hyperplasia or In Situ Breast Cancer to Placebo in Decreasing Atypical Cells in Patients With Atypical Hyperplasia or in Situ Breast Cancer

Summary: The purpose of this research study is to test whether metformin, a drug commonly used to treat diabetes, is able to get rid of atypia (early cell changes that are thought to be a marker of breast cancer risk) in women at increased risk for breast cancer. There will be testing for the presence of atypia in the breast after metformin is given to see if it can get rid of atypia. The study will compare the effects, good and/or bad, of metformin or placebo on atypia to find out which is better.
  Note: The standard drug used for the "breast cancer prevention" is tamoxifen. If the patient is eligible to take tamoxifen, he/she must be offered tamoxifen prevention as part of clinical care. Metformin and tamoxifen are not similar and function differently. This study is not investigating the use of tamoxifen. Metformin is not approved for preventing breast cancer, but is currently being tested to determine if it can prevent breast cancer.

Detailed description: A total of 400 premenopausal women (200 per arm) will be pre-registered, among which 300 patients with atypia (Masood Score 14-17) on random periareolar fine needle aspiration (RPFNA) at baseline are expected to be randomized between Metformin and placebo control arm. It is expected that the accrual rate will be 5 to 10 patients per month and that accrual will be completed about 4 years after study activation. The randomization will be stratified for known BRCA mutation (BRCA1 or BRCA2 mutation vs. no mutation), prior excisional biopsy (atypical epithelial hyperplasia, atypical lobular hyperplasia, flat epithelial hyperplasia vs. DCIS vs. LCIS), and baseline fasting insulin > 2x ULN vs. ≤ 2x ULN.
  The primary and secondary objectives are described below.
  Primary Objective:
  • Test for the presence or absence of cytological atypia in RPFNA bilateral 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) for women receiving metformin versus placebo control. The presence of cytological atypia means any atypia in any RPFNA specimen.
  Secondary Objectives:
  -  Use the Masood Cytology Index Score to test for the presence of cytological atypia or disappearance of cytological atypia in RPFNA bilateral 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 PO BID (metformin group).
  -  Compare Masood Cytology Score values at 0 and 12 months in the right and left breasts from the same individual in the metformin and placebo groups.
  -  Test the reproducibility of reverse phase protein microarray (RPPM) in duplicate RPPM determinations from individual RPFNA specimens.
  -  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.
  -  Determine the change in percent breast density from prior to the initiation of metformin or placebo treatment through therapy (ie, at 12 and 24 months), and following therapy (ie, 36 and 48 months).
  Follow up visits will be performed at 36 and 48 months after the start of treatment.

Eligibility: Pre-Registration Inclusion Criteria:
  1. 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 as defined in the study protocol.
  -  Known breast cancer BRCA1 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
  2. 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.
  3. Digital mammogram within 180 days prior to pre-registration.
  4. 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.
  5. Must be non-pregnant and non-lactating for at least one year prior to pre-registration.
  6. If currently menstruating, subjects must use a reliable method of birth control.
  7. Willing to provide RPFNA and blood samples for correlative research purposes.
  8. Women with core biopsy or excisional biopsy containing DCIS, LCIS or atypia are eligible for this study.
  9. Women eligible to take tamoxifen must be offered tamoxifen prevention as part of their clinical care and have refused tamoxifen treatment.
  Pre-registration Exclusion Criteria:
  1. 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 of prior malignancy, they must not be receiving other specific treatment, i.e., other hormonal therapy, for their cancer.
  2. Body mass index (BMI) < 25.
  3. Receiving warfarin.
  4. Bilateral breast implants or autologous breast flap reconstruction.
  5. Active diagnosis of alcoholism.
  6. Contraindication to metformin prevention such as acute hypersensitivity or allergic reaction to metformin.
  7. Receiving tamoxifen or raloxifene.
  8. Administration of any investigational agent ≤ 30 days prior to pre-registration.
  9. Previous radiation to both breasts.
  10. 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.
  11. 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.
  12. Receiving pyrimethamine, cimetidine, rifampin or cephalexin.
  13. Women who have a core biopsy or excisional biopsy containing invasive cancer.
  14. Women who have taken metformin within the past 90 days.
  15. Patients with hemoglobin alc > 6.3 or who are being actively treated for diabetes.
  Registration/Randomization Inclusion Criteria:
  1. Qualifying cytological atypia in RPFNA, Masood score of 14-17.
  2. Required laboratory values obtained no more than 30 days prior to registration/randomization.
  1. Hemoglobin ≥ 9 g/dL.
  2. Absolute neutrophil count (ANC) ≥ 1500/mm^3.
  3. Platelet count ≥ 75,000/mm^3.
  4. Creatinine ≤ 1.4 mg/dL
  5. Total bilirubin ≤ 3.0 mg/dL.
  6. Aspartate trasaminase (AST) ≤ 3 x upper limit of normal (ULN).
  7. Alanine transaminase (ALT) ≤ 3 x ULN.
  3. 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 (ie, has had menses at any time in the preceding 12 consectuve imonths).

Relevance to patient case: not relevant