Testing for Atypia in Random Periareolar Fine Needle Aspiration (RPFNA) Cytology after 12 months Metformin (1, 1-Dimethylbiguanide Hydrochloride) Chemoprevention versus Placebo Control in Premenopausal Women
Therese B. Bevers
Disease Group: Disorders of breast ,In situ neoplasms,Persons with health hazards related to family and personal history and cond. influencing hlth status
Treatment Agent: Metformin
Treatment Location: Both at MDACC & and Other Sites
Sponsor: National Cancer Institute,Susan G. Komen Promise Grant
Primary Objectives: 1) 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: 1) 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 p.o. bid (metformin group). 2) Compare Masood Cytology Score values at 0 and 12 months in right and left breasts from the same individual in the metformin and placebo group. 3) Test the reproducibility of RPPM in duplicate RPPM determinations from individual RPFNA specimens. 4) 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. 5) Determine the change in percent breast density from prior to the initiation of metformin or placebo treatment through therapy (i.e., at 12 and 24 months), and following therapy (i.e., 36 and 48 months). Correlative Research: 1) Test whether metformin alters RPFNA or blood biomarkers associated with breast cancer risk. Surrogate biomarkers of breast cancer risk include the following: Atypia - surrogate endpoint biomarker and risk biomarker Mammographic density - surrogate biomarker and risk biomarker Phosphoprotein expression - exploratory biomarker Circulating insulin growth factor (IGF) - surrogate biomarker and risk biomarker 2) Test whether metformin alters markers associated with obesity and insulin resistance. Markers of obesity and insulin resistance include the following: Waist to hip ratio Fasting serum insulin, fasting serum glucose Circulating serum Homeostatic Model Assessment (HOMA)- an estimate of insulin sensitivity calculated from a single measure of fasting insulin and glucose 3) Test other exploratory measures in RPFNA and serum including the following: Metformin levels Estrogen/Progesterone. 4) Banking: As part of ongoing research for Alliance Cancer Control studies, we are banking residual blood and RPFNA products for future studies.
IRB Review and Approval Date: 04/14/2016
Recruitment Status: Not Accepting
Projected Accrual: 300
1) Having had a prior biopsy demonstrating atypical hyperplasia, lobular
carcinoma in situ (LCIS), or ductal carcinoma in situ (DCIS) OR
2) A Gail Model Risk of greater than or equal to 1.66% over 5 years OR
3) A strong family history of breast and/or ovarian cancer which is defined as at least one of the following: 1) One first-degree relative with breast cancer before the age of 50 years 2) One first degree relative with bilateral breast cancer 3) Two or more first-degree relatives with breast cancer 4) One first degree relative and two or more second or third degree relatives with breast cancer 5) One first-degree relative with breast cancer and one or more relatives with ovarian cancer 6) Two second or third degree relatives with either breast cancer and one or more with ovarian cancer 7) One second or third degree relative with breast cancer and two or more with ovarian cancer 8) Three or more second or third degree relatives with breast cancer OR
4) Known BRCA1 or BRCA2 mutation carrier providing that the woman has 1) met with a Genetic Counselor to review genetic testing results, and 2) has been offered the opportunity to undergo prophylactic mastectomy and oophorectomy.
5) Age 25-55 years.
6) 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 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.
7) Digital mammogram within 180 days prior to pre-registration.
8) Mammograms must be read as not suspicious for breast cancer (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.
9) Must be non-pregnant and non-lactating for at least one year prior to preregistration.
10) If currently menstruating, subjects must use a reliable method of birth control.
11) Willing to provide RPFNA and blood samples for correlative research purposes (see Section 6.0 and 14.0).
12) Women with core biopsy or excisional biopsy containing DCIS, LCIS or atypia are eligible for this study.
13) Women eligible to take tamoxifen, must be offered tamoxifen prevention as part of their clinical care and have refused tamoxifen treatment.
1) Other active malignancy< or equal to 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.
2) 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) Currently receiving tamoxifen or raloxifene.
8) Administration of any investigational agent < or equal to 30 days prior to preregistration.
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 a1c > 6.3 or who are being actively treated for diabetes.
Information and next steps
Disorders of breast ,In situ neoplasms,Persons with health hazards related to family and personal history and cond. influencing hlth status
Therese B. Bevers
Clinical Cancer Prevention
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