S0307 Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary Breast Cancer.

OBJECTIVES:

• Compare disease-free survival and overall survival of women with resected primary stage I-III adenocarcinoma of the breast treated with adjuvant zoledronate vs clodronate vs ibandronate.
• Compare the distributions of sites of first disease recurrence in patients treated with these drugs.
• Compare adverse events in patients treated with these drugs.
• Correlate parathyroid hormone related protein status and N-telopeptide levels at baseline with disease-free survival and sites of first recurrence in patients treated with these drugs.
• Investigate whether there is an association between inherited germ-line single nucleotide polymorphisms (SNP, rs2297480) in farnesyl diphosphate synthase (FDPS) and the adverse event of acute phase reactions in these patients.

OUTLINE: This is a randomized, multicenter study. Patients are randomized to 1 of 3 treatment arms.

• Arm I: Patients receive zoledronate IV over 15 minutes once a month for 6 months and then once every 3 months for 2.5 years.
• Arm II: Patients receive oral clodronate once daily for 35 months.
• Arm III: Patients receive oral ibandronate once daily for 35 months. Treatment in all arms continues in the absence of disease recurrence or unacceptable toxicity.

After completion of study treatment, patients are followed every 6 months until disease recurrence and then annually for up to 10 years.

PROJECTED ACCRUAL: A total of 5,400 will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically confirmed primary adenocarcinoma of the breast

• Stage I-III disease
• No evidence of metastatic disease
• Must have undergone lumpectomy or total mastectomy for primary disease within the past 12 weeks, or have completed chemotherapy within the past 8 weeks

• Axillary evaluation per institutional standards
• Currently receiving or planning to receive standard adjuvant systemic therapy comprising chemotherapy, hormonal therapy, or combined chemotherapy/hormonal therapy for breast cancer

• Patients who are at low risk for disease recurrence and for whom adjuvant systemic therapy will not be prescribed are not eligible
• Patients who receive biologic agents only or local radiotherapy only (without chemotherapy and/or hormone therapy) are not eligible
• Additional therapies are allowed including radiotherapy and biologic agents (e.g., trastuzumab [Herceptin^®], bevacizumab, or hematopoietic growth factors)
• Neoadjuvant therapy or hormonal therapy alone is allowed provided study entry occurs ≥ 12 weeks after completion of surgery
• Patients with skeletal pain are eligible provided bone scan and/or roentgenological exam are negative for metastatic disease

• Suspicious findings must be confirmed as benign by x-ray, MRI, or biopsy
• Hormone receptor status:

• Not specified

PATIENT CHARACTERISTICS:

Age

• 18 and over

Sex

• Female

Menopausal status

• Not specified

Performance status

• Zubrod 0-2

Life expectancy

• Not specified

Hematopoietic

• Not specified

Hepatic

• Not specified

Renal

• Creatinine ≤ 2 times upper limit of normal
• Creatinine clearance ≥ 30 mL/min
• No renal failure

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No history of esophageal stricture or motility disorders

• Gastroesophageal reflux disorder allowed
• No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, or adequately treated stage I or II cancer in complete remission

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Prior or concurrent hematopoietic growth factors allowed
• HER-2-targeted therapies allowed
• Antiangiogenics allowed

Chemotherapy

• See Disease Characteristics

Endocrine therapy

• See Disease Characteristics

Radiotherapy

• Concurrent radiotherapy to the breast, chest wall, or lymph node group allowed at the discretion of the treating physician

Surgery

• See Disease Characteristics

Other

• Prior neoadjuvant therapy allowed
• Prior bisphosphonates for bone density allowed
• No other concurrent bisphosphonates as adjuvant therapy or for treatment of osteoporosis
• No concurrent enrollment in clinical trials with bone density as an endpoint

• Concurrent enrollment on any other locoregional or systemic therapy breast cancer study (including cooperative group studies) allowed