Letrozole in Preventing Breast Cancer in Postmenopausal Women

OBJECTIVES:

Primary

- The primary outcome of the study is the change in bone mineral density following a year
on letrozole vs. a year on placebo.

Secondary

- Compare the safety, acceptability, and adherence to letrozole vs placebo in
postmenopausal women at increased risk for the development or recurrence of breast
cancer based on elevated plasma estradiol levels through evaluation of menopausal
symptoms (including hot flushes, weight changes, sexual functioning, and genitourinary
effects), blood lipid levels, markers of bone turnover, and multidimensional quality of
life.

- Determine the effect of letrozole-induced reduction of plasma estradiol levels on
mammographic percent breast density.

- Obtain background information for a future large chemoprevention trial to address the
question of whether a reduction in plasma estradiol levels can reduce the risk of breast
cancer in postmenopausal women.

OUTLINE: This is a pilot, randomized, double-blind, placebo-controlled, multicenter study.
Patients are randomized to 2:1 (experimental treatment: placebo arms).

PROJECTED ACCRUAL: A total of 110 patients (73 for arm I and 37 for arm II) will be accrued
for this study.

DISEASE CHARACTERISTICS:

- At increased risk for the development or recurrence of breast cancer, defined as an
estradiol level ≥ 9 pg/mL

- No evidence of suspicious or malignant disease, based on the following examinations:

- Clinical bilateral breast examination within the past 6 months

- Bilateral* mammogram within 3 months before randomization OR within 30 days after
randomization

- Pelvic exam normal within the past 5 years

- General physical exam within the past 6 months NOTE: *Unilateral mammogram of the
uninvolved breast for patients with prior invasive breast cancer or ductal
carcinoma in situ (DCIS)

- Bone density scan within 2 standard deviations from normal within the past 30 days

- Bone density scan ≥ 2 standard deviations below normal allowed if approved by the
study physician

- At least 1 breast that has not been previously treated with radiotherapy or surgery
(for patients with prior invasive breast cancer or DCIS)

- Hormone receptor status:

- Not specified

PATIENT CHARACTERISTICS:

Age

- 35 and over

Sex

- Female

Menopausal status

- Postmenopausal, defined by any of the following criteria:

- At least 12 months without spontaneous menstrual bleeding

- Prior hysterectomy and bilateral salpingo-oophorectomy

- ≥ 55 years of age with a prior hysterectomy with or without oophorectomy

- < 55 years of age with a prior hysterectomy without oophorectomy OR the status of
the ovaries is unknown AND follicle-stimulating hormone (FSH) level is in the
postmenopausal range

Performance status

- Normal activity must not be restricted for a significant portion of the day

Life expectancy

- At least 10 years

Hematopoietic

- Complete blood count with differential normal

- Prior benign neutropenia allowed provided the granulocyte count is ≥ 1,500/mm^3

Hepatic

- Bilirubin normal

- Alkaline phosphatase normal

- SGOT and SGPT normal

Renal

- Creatinine normal

Cardiovascular

- No uncontrolled cardiovascular disease

Other

- Not pregnant

- No other malignancy within the past 5 years except basal cell or squamous cell skin
cancer or carcinoma in situ of the cervix

- No osteoporosis

- No hyperlipidemia

- No mental health status resulting in cognitive or emotional impairment that would
preclude study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

- Not specified

Chemotherapy

- Not specified

Endocrine therapy

- More than 30 days since prior AND no concurrent use of any of the following hormonal
agents:

- Estrogen or progesterone replacement therapy

- Oral contraceptives

- Raloxifene or other plasma estrogen receptor modulators (SERMs)

- Androgens (e.g., danazol)

- Luteinizing hormone-releasing hormone (LHRH) analogs (e.g., goserelin or
leuprolide)

- Prolactin inhibitors (e.g., bromocriptine)

- Antiandrogens (e.g., cyproterone)

- More than 60 days since prior AND no concurrent tamoxifen

- No prior aromatase inhibitors (for patients with prior invasive breast cancer or DCIS)

- No concurrent phytoestrogenic dietary supplements (e.g., soy, ginseng, or other
natural products)

- Dietary soy allowed

Radiotherapy

- See Disease Characteristics

Surgery

- See Disease Characteristics

- No prior bilateral mastectomy

Other

- More than 60 days since prior treatment for invasive breast cancer or DCIS

- More than 30 days since prior bisphosphonates or calcitonin

- No prior or concurrent participation on a treatment study for invasive breast cancer
or DCIS

- No concurrent participation in any other cancer prevention study or osteoporosis
prevention study involving pharmacologic agents

- No concurrent calcitonin

- No concurrent bisphosphonate therapy

- Concurrent cholecalciferol (vitamin D) and calcium to augment bone mineral density
allowed