LY353381 in Preventing Breast Cancer in Women With Hyperplasia

A Phase II Clinical Trial of a Selective Estrogen Receptor Modulator (LY353381*HCl) in High Risk Women With Fine Needle Aspiration Cytologic Evidence of Hyperplasia

RATIONALE: Chemoprevention therapy is the use of certain drugs to try to prevent the development or recurrence of cancer. The use of LY353381 may be an effective way to prevent the development of breast cancer in women who have hyperplasia.

PURPOSE: Randomized phase II trial to study the effectiveness of LY353381 in preventing breast cancer in women who have hyperplasia.

OBJECTIVES:

• Determine if LY353381 hydrochloride improves baseline cytology in women at high risk for breast cancer.
• Determine if this drug modulates other potential surrogate endpoint biomarkers or drug effect biomarkers.
• Determine if cytologic improvement is associated with initial presentation of the various stratification factors.
• Determine whether cytology is correlated with other potential surrogate endpoint biomarkers or drug effect biomarkers and whether change in cytology is correlated with change in the other biomarkers.
• Monitor the effects of this drug in terms of quality of life and women's health.

OUTLINE: This is a randomized, double-blind, multicenter study followed by an open-label study for both arms. Patients are stratified according to cytologic status (hyperplasia with atypia vs hyperplasia without atypia), mutation status (known carrier for BRCA1 or BRCA2 genes vs known not to be a carrier of mutant genes), menopausal status (premenopausal vs postmenopausal), estrogen-receptor status, and participating center. Patients are randomized to one of two treatment arms.

• Arm I: Patients receive oral LY353381 hydrochloride once daily for 6 months.
• Arm II: Patients receive oral placebo once daily for 6 months. Patients in both arms then receive oral LY353381 hydrochloride for an additional 6 months.

Quality of life is assessed at baseline and then at 6 and 12 months.

Patients are followed at 2 weeks and then annually for 5 years.

PROJECTED ACCRUAL: A total of 210-220 patients will be accrued for this study within 2.5-3 years.

DISEASE CHARACTERISTICS:

• Current random fine needle breast aspiration (FNA) evidence of 1 of the following:

  • Hyperplasia with atypia
  • Hyperplasia without atypia but with a 10-year modified Gail risk of at least 4%
  • Hyperplasia without atypia but with a BRCAPRO risk of at least 25%
  • Hyperplasia without atypia but with a known mutation in BRCA1 or BRCA2
  • Hyperplasia without atypia but with a history of contralateral ductal carcinoma in situ or invasive breast cancer

• FNA must have been taken during days 1-14 of the menstrual cycle for premenopausal women

• Classified as ACR class I-III on mammogram with stepwedge within past 6 months If intact uterus and/or ovaries, must have color doppler transvaginal pelvic sonogram within past 6 months showing endometrial thickening no greater than 13 mm premenopausal or no greater than 8 mm postmenopausal

  • No ovarian cysts felt to be possibly or probably non-physiologic that have not resolved to gynecologist's satisfaction on repeat sonogram

• Must agree to have or have had genetic counseling and genetic testing performed for BRCA1 and BRCA2

• No active cancer (e.g., detectable disease)

• Hormone receptor status:

  • Not specified

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Sex:

• Female

Menopausal status:

• Any

Performance status:

• Not specified

Life expectancy:

• At least 12 months

Hematopoietic:

• Hemoglobin greater than 10 g/dL
• Granulocyte count greater than 1,000/mm^3
• No deficiencies in protein C, protein S, or antithrombin III
• No activated protein C resistance

Hepatic:

• Albumin greater than 3.0 g/dL
• Bilirubin less than 1.5 mg/dL
• AST less than 100 U/L
• Alkaline phosphatase less than 200 U/L

Renal:

• Creatinine less than 1.5 mg/dL

Cardiovascular:

• No history of deep venous thrombosis not related to trauma or pregnancy
• No severe coronary artery disease
• No history of prior stroke

Other:

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 3 months after study
• No other active cancer
• No retinal vein thrombosis
• No concurrent severe poorly controlled migraine
• No factor V Leiden mutation carrier

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• At least 12 months since prior immunotherapy

Chemotherapy:

• At least 3 months between completion of prior KUMC phase II difluoromethylornithine (DFMO) study and baseline aspiration
• At least 12 months since prior chemotherapy

Endocrine therapy:

• Must not have started or stopped hormone replacement therapy or oral contraceptives within 6 months of baseline aspiration
• Must continue all hormone replacement therapy and/or oral contraceptives that were being taken at time of baseline aspiration
• At least 12 months since prior tamoxifen, raloxifene, or other antihormonal therapy

Radiotherapy:

• At least 3 months since prior radiotherapy

Surgery:

• At least 6 months between prior oophorectomy and baseline aspiration

Other:

• At least 2 weeks since the start of other new medication that would be ingested for 1 or more months