Zoledronate in Preventing Bone Loss in Postmenopausal Women Who Are Receiving Letrozole for Stage I, Stage II, or Stage IIIA Breast Cancer

OBJECTIVES:

• Compare the effectiveness of zoledronate vs standard care in reducing bone loss during the first 12 months of study treatment in postmenopausal women with stage I-IIIA breast cancer initiating letrozole after prior treatment with tamoxifen.
• Compare the effect of immediate vs delayed zoledronate, annually at 2-5 years post-baseline, in reducing bone loss in these patients.

OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified according to duration of prior tamoxifen therapy (≤ 2 years vs > 2 years); time since tamoxifen therapy was discontinued (< 1 vs ≥ 1 year); prior adjuvant chemotherapy (yes vs no); and baseline total lumbar spine or femoral neck bone mineral density (BMD) T-score (> -1 standard deviation [SD] vs between -1 to -2 SD). Patients are randomized to 1 of 2 treatment arms.

• Arm I (immediate therapy): Patients receive oral letrozole once daily. Patients also receive zoledronate IV over 15 minutes once every 6 months.
• Arm II (delayed therapy): Patients receive oral letrozole as in arm I. Patients with radiologic evidence of bone loss after 1 year of letrozole therapy receive zoledronate as in arm I.

In both arms, treatment continues for up to 5 years in the absence of disease progression or unacceptable toxicity.

PROJECTED ACCRUAL: A total of 550 patients (275 per treatment arm) will be accrued for this study within 28 months.

DISEASE CHARACTERISTICS:

• Diagnosis of breast cancer

• Stage I, II, or IIIA disease
• Completed ≤ 6 years of adjuvant tamoxifen therapy
• Total baseline lumbar spine or femoral neck bone mineral density T-score below -2.0 standard deviation (e.g., a patient with a T-score of -2.1 in ineligible; a patient with a T-score of -1.9 is eligible)
• No clinical or radiological evidence of recurrent or metastatic disease
• Hormone receptor status:

• Estrogen receptor- and/or progesterone receptor-positive

PATIENT CHARACTERISTICS:

Age

• Postmenopausal

Sex

• Female

Menopausal status

• Postmenopausal, defined by 1 of the following:

• Over 55 years of age with cessation of menses
• 55 years of age and under with spontaneous cessation of menses for > 1 year
• 55 years of age and under with spontaneous cessation of menses for ≤ 1 year, but amenorrheic (e.g., spontaneous or secondary to hysterectomy) with postmenopausal estradiol levels (< 5 ng/dL)
• Undergone bilateral oophorectomy

Performance status

• ECOG 0-2

Life expectancy

• At least 5 years

Hematopoietic

• WBC ≥ 3,000/mm^3
• Platelet count ≥ 100,000/mm^3

Hepatic

• Alkaline phosphatase ≤ 3 times upper limit of normal (ULN)
• AST ≤ 3 times ULN

Renal

• Creatinine < 2.0 mg/dL
• No hypercalcemia (i.e., calcium > 1 mg/dL above ULN within the past 6 months)
• No hypocalcemia (i.e., calcium > 0.5 mg/dL below lower limit of normal within the past 6 months)

Other

• No uncontrolled infection
• No uncontrolled diabetes mellitus
• No uncontrolled thyroid dysfunction
• No disease affecting bone metabolism (e.g., hyperparathyroidism, hypercortisolism, Paget's disease, or osteogenesis imperfecta)
• No malabsorption syndrome
• No uncontrolled seizure disorder associated with falls
• No known hypersensitivity to zoledronate or other bisphosphonates, letrozole, calcium, or cholecalciferol (vitamin D)
• No mental illness that would preclude giving informed consent
• No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
• No other non-malignant systemic disease
• No clinical or radiologic evidence of existing fracture in the lumbar spine and/or total hip
• No history of fracture with low intensity or not associated with trauma
• No contraindication to spinal dual energy x-ray absorptiometry (DEXA) due to any of the following:

• History of surgery at the lumbosacral spine, with or without implantable devices
• Scoliosis with a Cobb angle > 15° at the lumbar spine
• Immobility, hyperostosis, or sclerotic changes at the lumbar spine
• Evidence of sufficient sclerotic abdominal aorta that would interfere with DEXA scan
• Any disease of the spine that would preclude proper acquisition of a lumbar spine DEXA
• Considered reliable

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• No concurrent chemotherapy

Endocrine therapy

• See Disease Characteristics
• Prior parathyroid hormone allowed provided it was not administered for > 1 week
• More than 6 months since prior anabolic steroids or growth hormone
• More than 12 months since prior endocrine therapy (including estrogen) except for the following:

• Tamoxifen
• Insulin
• Oral hypoglycemics
• Thyroid hormone
• Steroid inhalers
• More than 12 months since prior systemic corticosteroids except short-term corticosteroids to prevent or treat chemotherapy-induced nausea and vomiting or acute respiratory illness

• Concurrent short-term corticosteroids allowed
• No other concurrent hormonal therapy
• No concurrent parathyroid hormone

Radiotherapy

• Not specified

Surgery

• Not specified

Other

• Prior systemic sodium fluoride allowed provided it was not administered for > 3 months within the past 2 years
• More than 3 weeks since prior oral bisphosphonates
• More than 2 weeks since prior and no concurrent drugs known to affect the skeleton (e.g., calcitonin, mithramycin, or gallium nitrate)
• More than 30 days since prior systemic investigational drugs and/or devices
• More than 7 days since prior topical investigational drugs
• No prior IV bisphosphonates
• No prior aromatase inhibitor therapy
• No concurrent calcitonin, sodium fluoride, or Tibolone
• No other concurrent anticancer therapy
• No other concurrent bisphosphonates
• No other concurrent investigational drugs or devices