Acolbifene in Preventing Cancer in Premenopausal Women at High Risk of Breast Cancer

PRIMARY OBJECTIVES:

I. To determine the effect of six months of acolbifene 20 mg/day on Ki-67 in high risk premenopausal women with baseline hyperplasia +/- atypia and Ki-67 positivity of >= 2%..

SECONDARY OBJECTIVES:

I. To determine the effect of six months of acolbifene 20 mg/day on mammographic breast density in high risk premenopausal women.

II. To determine the effect of six months of acolbifene 20 mg/day on serum levels of follicular phase bioavailable estradiol, and luteal phase progesterone, testosterone, and fasting IGF-1/IGFBP-3.

III. To determine the effect of six months of acolbifene 20 mg/day on epithelial cell cytomorphology and molecular markers such as ER, PgR, and pS2.

IV. To determine the effect of six months of acolbifene on markers of cardiovascular risk (C-reactive protein, functional AntiThrombin III, and fasting lipid profile) and bone turnover markers associated with bone mineral density gain or loss (serum osteocalcin and N-telopeptide crosslinks).

V. To assess any increase in reported hot flashes, menstrual cycle irregularities, pelvic pain, musculoskeletal complaints, and fatigue from baseline.

OUTLINE:

Patients receive oral acolbifene hydrochloride once daily for 6 months in the absence of unacceptable toxicity.

Patients undergo symptom assessment (hot flashes, menstrual abnormalities, pelvic pain, muscle and joint pain, and fatigue) at baseline, 6-8 weeks, monthly for 6 months, and then at 2 weeks after completion of study treatment.

Patients undergo random periareolar fine needle aspiration between days 1-10 of menstrual cycle at baseline and at 6 months. Patients also undergo blood sample collection between days 1-10 and days 20-24 of menstrual cycle at baseline and at 6 months. Samples taken between days 1-10 of menstrual cycle are analyzed for Ki-67 expression, cytomorphology, molecular markers (estrogen receptor, progesterone receptor, and pS2 expression), and bioavailable estradiol levels. Samples taken between days 20-24 of menstrual cycle are analyzed for progesterone, testosterone, IGF-1, IGFBP-3, lipid profile, bone-turnover markers (osteocalcin and N-telopeptide crosslinks), C-reactive protein, and functional antithrombin III.

After completion of study treatment, patients are followed at 2 weeks.

Inclusion criteria

• Gail risk >= 1.7% and/or relative risk >= 3 times that for 5-year age group
• Premenopausal
• More than 6 months since initiating or discontinuing oral contraceptives
• At increased risk for breast cancer, as indicated by >= 1 of the following risk factors:
• BRCA1/2 mutation characterized as deleterious or of uncertain significance
• Prior atypical ductal hyperplasia, ductal carcinoma in situ, or lobular carcinoma in situ
• Prior random periareolar fine needle aspiration (RPFNA) showing atypical hyperplasia
• Family history consistent with hereditary breast cancer, as indicated by 1 of the following criteria:

• >= 4 relatives with breast cancer
• >= 2 relatives diagnosed with breast cancer at ≤ 50 years of age
• Breast and ovarian cancer diagnosed in same relative
• No suspicion for breast cancer on baseline mammogram performed between days 1-10 of menstrual cycle within 3 months prior to screening baseline RPFNA
• Exhibits hyperplasia with or without atypia (Masood score >= 14) with >= 500 cells AND Ki-67 positivity >= 2% by RPFNA performed within 6 months prior to initiation of study drug
• Estimated visual mammographic breast density category >= 5% on mammogram performed within 6 months prior to initiation of study drug
• Has regular menstrual cycles (between 21 and 35 days) unless using extended regimen oral contraceptives or a contraceptive device (e.g., Mirena IUD) Values for metabolic profile and blood count within normal limits
• Absolute granulocyte count > 1,000/mm^3
• Platelets > 100,000/mm^3
• Hemoglobin > 10 g/dL
• Bilirubin < 2.0 mg/dL
• AST < 2 times upper limit of normal (ULN)
• Albumin > 3.0 g/dL
• Creatinine < 1.5 mg/dL
• Alkaline phosphatase < 2 times ULN
• Concurrent hormonal contraceptives allowed provided patient remains on the same hormonal regimen from 3 months prior to baseline aspiration until the completion of study treatment
• Fertile patients must use effective contraception during and for 3 months after completion of study treatment
• Willing to ingest recommended dose of calcium and vitamin D for premenopausal bone health (1,200 mg calcium and 800 IU vitamin D daily)
• Negative pregnancy test prior to receiving study agent

Exclusion criteria

• pregnant or nursing
• nursing within the past 6 months
• Known osteoporosis or severe osteopenia (T-score -2 or worse by DEXA)
• History of symptomatic endometriosis with pelvic pain, poorly controlled migraines, or hot flashes
• History of deep venous thrombosis
• History of allergic reactions attributed to compounds of similar chemical or biological composition to the study agent
• Other condition or concurrent illness that, in the opinion of the investigator, would make the patient a poor candidate for RPFNA
• Less than 1 year since prior use of aromatase inhibitors (e.g., anastrozole, exemestane, or letrozole) or selective estrogen receptor modulators (e.g., tamoxifen citrate, raloxifene, or arzoxifene hydrochloride)
• Other concurrent chemopreventive agents
• Concurrent anticoagulants
• Other concurrent investigational agents
• Bilateral breast implants