Chemotherapy and/or Hormone Therapy With or Without Zoledronate in Treating Women With Stage II or Stage III Breast Cancer

Study Overview
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Brief Summary
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RATIONALE: Zoledronate may delay or prevent the formation of bone metastases. It is not yet known whether chemotherapy and/or hormone therapy are more effective with or without zoledronate in preventing cancer recurrence and bone metastases in women with breast cancer. PURPOSE: This randomized phase III trial is studying giving chemotherapy and/or hormone therapy together with zoledronate to see how well they work compared to chemotherapy and/or hormone therapy alone in preventing cancer recurrence and bone metastases in women with stage II or stage III breast cancer.

Detailed Description
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OBJECTIVES: Primary Compare disease-free survival of women with stage II or III breast cancer at high risk of relapse treated with neoadjuvant or adjuvant chemotherapy and/or hormonal therapy with vs without zoledronate. Secondary Compare time to bone metastases, as first recurrence, in patients treated with these regimens. Compare time to bone metastases, per se, in patients treated with these regimens. Compare time to distant metastases in patients treated with these regimens. Compare overall survival in patients treated with these regimens. Compare the reduction in skeletal-related events (fractures, spinal cord compression, radiotherapy to the bone, surgery to the bone, and hypercalcemia) before and after the development of bone metastases in patients treated with these regimens. Determine the safety and toxicity of zoledronate in patients treated with these regimens. Correlate prognostic factors, such as estrogen-receptor and progesterone-receptor status, TNM stage, tumor grade, HER2/neu status, and menopausal status with treatment outcome in patients treated with these regimens. Determine more specific prognostic indicators for the development of bone metastases and factors that are able to predict specific benefit from bisphosphonate treatment using proteomics, tissue micro-array, and other modern techniques in these patients. OUTLINE: This is a randomized, open-label, parallel-group, multicenter study. Patients are stratified according to participating center. Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive neoadjuvant or adjuvant chemotherapy and/or hormonal therapy. Patients also receive concurrent zoledronate IV over 15 minutes every 3-4 weeks for 6 doses, every 3 months for 8 doses, and then every 6 months for 5 doses in the absence of disease progression or unacceptable toxicity. Arm II: Patients receive neoadjuvant or adjuvant chemotherapy and/or hormonal therapy alone. After completion of study treatment, patients are followed annually for 5 years. PROJECTED ACCRUAL: A total of 3,300 patients (1,650 per treatment arm) will be accrued for this study within 3 years.

Official Title
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Does Adjuvant Zoledronic Acid Reduce Recurrence in Patients With High Risk Localized Breast Cancer?

Conditions
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Breast Cancer, Metastatic Cancer

Intervention / Treatment
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* Drug: zoledronic acid
* Procedure: adjuvant therapy
* Procedure: neoadjuvant therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of primary breast cancer, meeting 1 of the following staging criteria: Stage II Stage III T stage ≥ T1 Receiving OR scheduled to receive chemotherapy and/or endocrine therapy For patients receiving neoadjuvant therapy Tumor > 5 cm (T3), features of locally advanced disease (T4), OR biopsy-proven lymph node involvement (N1) Scheduled to proceed to definitive surgery and/or radical radiotherapy with curative intent within 6 months of starting neoadjuvant therapy No more than 30 days between initiation of neoadjuvant therapy and start of study drug For patients receiving adjuvant therapy Must have undergone complete primary tumor resection and treatment of axillary lymph nodes* Must have lymph node involvement No prior neoadjuvant therapy** No more than 60 days since prior definitive surgery NOTE: *Patients whose treatment plan includes further primary tumor resection and/or treatment of the axillary lymph nodes (e.g., clearance or radiotherapy) with curative intent after completion of chemotherapy are eligible provided the treatment is completed within 9 months of study entry NOTE: **Preoperative endocrine therapy with a duration of < 30 days is not considered prior neoadjuvant therapy No evidence of recurrent or metastatic disease No history of breast cancer, except ductal carcinoma in situ or lobular carcinoma in situ Hormone receptor status: Not specified PATIENT CHARACTERISTICS: Age 18 and over Sex Female Menopausal status Premenopausal or postmenopausal Performance status Karnofsky 80-100% OR ECOG 0-1 Life expectancy Not specified Hematopoietic Not specified Hepatic Not specified Renal Creatinine ≤ 1.5 times upper limit of normal Other Not pregnant or nursing Fertile patients must use effective contraception No active dental problems, including dental abscess or infection of the jaw bone (e.g., maxilla or mandible) No prior or current diagnosis of osteonecrosis of the jaw No other malignancy within the past 5 years (including prior contralateral breast cancer) except nonmelanoma skin cancer or curatively treated carcinoma in situ of the cervix No history of disease with influence on bone metabolism, including any of the following: Paget's disease of the bone Primary hyperparathyroidism Osteoporosis requiring treatment or likely to require treatment within the next 6 months No other severe physical or psychological disease that would preclude study compliance No known hypersensitivity to bisphosphonates PRIOR CONCURRENT THERAPY: Chemotherapy See Disease Characteristics Endocrine therapy See Disease Characteristics Radiotherapy See Disease Characteristics Surgery See Disease Characteristics More than 4 weeks since prior and no concurrent dental or jaw surgery (e.g., extractions or implants) Dental fillings, teeth scaling and polishing, or minor gingival surgery within the past 4 weeks are allowed Other More than 1 year since prior bisphosphonates More than 30 days since prior investigational drugs No concurrent investigational drugs (i.e., not locally approved for any indication)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: zoledronic acid|nan|
|Procedure: adjuvant therapy|nan|
|Procedure: neoadjuvant therapy|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-free survival as assessed annually for 10 years |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to bone metastases as first recurrence assessed annually for 10 years |  |  | 
| Time to bone metastases per se as assessed annually for 10 years |  |  | 
| Time to distant metastases as assessed annually for 10 years |  |  | 
| Overall survival as assessed by final analysis at 10 years |  |  | 
| Skeletal-related events prior to development of bone metastases as assessed annually for 10 years |  |  | 
| Skeletal-related events following development of bone metastases as assessed annually for 10 years |  |  | 
| Safety and toxicity of zoledronic acid as assessed annually for 10 years |  |  | 
| Evaluation of the influence of prognostic factors (e.g., estrogen receptor or progesterone receptor [ER/PR] status, TNM stage, tumor grade, HER2/neu, and menopausal status) on treatment outcome |  |  | 
| Analysis of tumor-specific mutations, proteomics and gene expression changes in tumor cells |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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bone metastases, stage II breast cancer, stage IIIA breast cancer, stage IIIB breast cancer, stage IIIC breast cancer