Arzoxifene or Tamoxifen in Preventing Breast Cancer in Premenopausal Women at High Risk for Breast Cancer

OBJECTIVES:

• Compare the effect of arzoxifene vs tamoxifen vs placebo on surrogate endpoints biomarkers, especially systemic insulin-like growth factor levels, in women at high risk for breast cancer.
• Compare the toxic effects, biologic effects, clinical pharmacology, and pharmacodynamics of these drugs in these participants.
• Determine the effect of these drugs on surrogate endpoint biomarkers in participants with BRCA1 and BRCA2 mutations.
• Determine the feasibility of a chemoprevention study in participants with a strong family history of breast cancer.

OUTLINE: This is a randomized, placebo-controlled, double-blind study. Participants are randomized to 1 of 3 treatment arms.

• Arm I: Participants receive oral tamoxifen once daily.
• Arm II: Participants receive oral arzoxifene once daily.
• Arm III: Participants receive an oral placebo once daily. In all arms, treatment continues for 6 months in the absence of disease progression or unacceptable toxicity. After the completion of 6 months of treatment, participants are offered the opportunity to continue treatment with their assigned study drug for an additional 6 months. Participants randomized to receive placebo are offered treatment with arzoxifene for an additional 6 months.

After completion of study treatment, participants are followed annually.

PROJECTED ACCRUAL: A total of 120 participants will be accrued for this study.

DISEASE CHARACTERISTICS:

• Estimated probability of carrying a BRCA1 or BRCA2 mutation ≥ 10% AND meets one of the following criteria:

• Participants must have first-degree relatives (FDRs)* or second-degree relatives (SDRs)* (with an intervening male relative) with breast or ovarian cancer who satisfy one of the following criteria:

• High-risk breast/ovarian cancer (non-Jewish families)

• One FDR ≤ 40 years old** diagnosed with breast cancer
• At least two FDRs or SDRs diagnosed with breast cancer at ≤ 50 years old OR had bilateral breast cancer
• One FDR or one SDR diagnosed with breast cancer at ≤ 50 years old OR had bilateral breast cancer AND one FDR or SDR diagnosed with ovarian cancer
• Three FDRs and/or SDRs diagnosed with breast or ovarian cancer (at least one in case of ovarian cancer)
• Two FDRs and/or SDRs diagnosed with ovarian cancer
• One male FDR or SDR diagnosed with breast cancer and one FDR or SDR (male or female) diagnosed with breast or ovarian cancer
• Moderate-risk breast /ovarian cancer (non-Jewish families)

• Two FDRs diagnosed with breast cancer with one ≤ 50 years old and/or both < 60 years old
• One FDR and one SDR (mother or sister and maternal aunt or maternal grandmother) diagnosed with breast cancer if the sum of their ages is ≥ 118 years
• One FDR and one SDR (mother or sister and paternal aunt or paternal grandmother) diagnosed with breast cancer if the sum of their ages is ≥ 78 years
• Two SDRs (both maternal or both paternal) diagnosed with breast cancer if the sum of their ages is ≤ 98 years
• One FDR with ovarian cancer
• High-risk breast/ovarian cancer (Jewish families )

• At least one FDR or SDR diagnosed with breast cancer at ≤ 50 years old
• At least one FDR or SDR diagnosed with ovarian cancer
• At least one FDR or SDR diagnosed with breast cancer at any age AND one FDR or SDR diagnosed with breast and/or ovarian cancer
• At least one male FDR or SDR diagnosed with breast cancer NOTE: *FDRs are parents, siblings, and children of the participant; SDRs are aunts, uncles, grandparents, grandchildren, nieces, nephews, or half siblings of the participant

NOTE: **Age is approximated to the earliest age possible (e.g., a relative diagnosed in their 40's should be considered 40)

• Patterns of cancer cases must all be on the maternal or paternal side of the family
• Participants not meeting any of the above FDR or SDR criteria may provide medical documentation stating that they, a FDR, or a SDR carry BRCA1 or BRCA2 mutations

• Participants with a prior history of breast cancer are eligible provided they have a remaining breast that has not been irradiated, all therapy for breast cancer was completed more than 2 years ago, and they are premenopausal
• No ovarian cyst during screening
• No more than 12 months since prior Pap smear with normal cytological results OR human papilloma virus negative if atypical squamous cells of uncertain significance (ASCUS) present
• No higher degrees of atypia beyond ASCUS on Pap smear

• No known history of osteoporosis (bone mineral density > 1.5 standard deviations below young adult norms)
• Hormone receptor status
• Not specified

PATIENT CHARACTERISTICS:

Menopausal status

• Premenopausal, as defined by 1 of the following:

• Last menstrual period < 6 months ago
• Less than 45 years old AND underwent partial hysterectomy OR follicle-stimulating hormone within institutional pre-menopausal range within the past 3 months

Sex

• Female

Performance status

• ECOG 0-1

Life expectancy

• More than 2 years

Hematopoietic

• WBC ≥ 3,000/mm^3
• Platelet count ≥ 125,000/mm^3
• Hemoglobin ≥ 10 g/dL

Hepatic

• Bilirubin ≤ 1.5 mg/dL
• AST < 2 times upper limit of normal (ULN)
• Albumin ≥ 3.0 g/dL
• PT/PTT ≤ 1.25 times ULN

Renal

• Creatinine ≤ 1.5 mg/dL OR
• Creatinine clearance ≥ 60 mL/min

Cardiovascular

• No history of deep venous thrombosis

Pulmonary

• No history of pulmonary embolism

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile participants must use effective barrier-method contraception during and for 3 months after completion of study treatment
• No other malignancy within the past 2 years except curatively treated basal cell or squamous cell skin cancer or cervical cancer ≤ stage I
• No known addiction
• Not undergoing treatment for an illicit drug addiction
• Willing and able to undergo required study procedures (e.g., research-related breast biopsies)

PRIOR CONCURRENT THERAPY:

Chemotherapy

• More than 2 years since prior chemotherapy

Endocrine Therapy

• At least 3 months since prior oral contraceptives or intramuscular progestational agent
• At least 3 months since prior luteinizing-hormone releasing hormone (LHRH) agonists or antagonists if agent was administered daily or monthly
• At least 6 months since prior LHRH agonists or antagonists if agent was administered every 3 months
• At least 6 months since prior antiestrogens (e.g., tamoxifen, toremifene, and raloxifene)
• No concurrent progestational or contraceptive agents

Radiotherapy

• See Disease Characteristics
• More than 2 years since prior radiotherapy

Surgery

• No prior prophylactic bilateral mastectomy

Other

• No concurrent cholestyramine
• No concurrent routine warfarin, bromocriptine, or phenobarbital
• No other concurrent investigational agents