Efficacy and Safety of Letrozole vs. Letrozole Plus Zoledronic Acid as Endocrine Therapy Before Surgery in Postmenopausal Patients With Breast Cancer

Study Overview
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Brief Summary
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This study will evaluate the safety/efficacy of zoledronic acid when given by intravenous infusion every 4 weeks in addition to letrozole as endocrine therapy in postmenopausal patients with hormone responsive breast cancer

Detailed Description
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Open-label, multicenter, randomized phase II trial over approx 6.5 months of neoadjuvant treatment with letrozole with or without zoledronic acid in postmenopausal patients with primary breast cancer. A total of approximately 850 patients were originally planned to be enrolled; primary study endpoint was the objective response rate (according to modified RECIST criteria) after 6 months of treatment. After the core study, patients willing to participate were followed-up for further 5 years.

Official Title
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Neoadjuvant Therapy for Postmenopausal Women With ER and/or PgR Positive Breast Cancer. A Randomized Open Phase II Trial Evaluating the Efficacy of a 6 Months Preoperative Treatment With Letrozole (2.5 mg/Day) With or Without Zoledronic Acid (4 mg Every 4 Weeks)

Conditions
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Breast Neoplasms

Intervention / Treatment
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* Drug: Letrozole
* Drug: Zolendronic Acid


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Postmenopausal women with primary invasive breast cancer, histologically confirmed by core needle biopsy, whose tumors are estrogen (ER) and / or progesterone (PgR) positive Clinical Stage T1c (Size ≥ 1.5 cm), T2, T3, T4a, b, c, N0 or N1, M0 (TNM Classification). According to the modified RECIST criteria, tumors of size ≥ 1.5 cm are considered measurable by mammography and can be determined as target lesions). Tumor measurable by mammography, sonography and clinical examination. Adequate bone marrow, renal and hepatic function Good health status (ECOG Performance status of 0, 1 or 2) Exclusion criteria: Prior treatment with letrozole or bisphosphonates. Prior and concomitant anti-breast-cancer treatments such as chemotherapy, immunotherapy / biological response modifiers (BRM's), endocrine therapy other than letrozole (including steroids), and radiotherapy. Patients who have received hormone replacement therapy (HRT) will NOT be excluded, provided that HRT is discontinued at least 2 weeks prior to entry into the study. Patients with unstable angina, or uncontrolled cardiac disease (e.g. Class III and IV New York Heart Association's Functional Classification, see Appendix 9) or uncontrolled endocrine disorders. Evidence of inflammatory breast cancer or distant metastasis. Current active dental problems including infection of the teeth or jawbone (maxilla or mandibular); dental or fixture trauma, or a current or prior diagnosis of osteonecrosis of the jaw (ONJ), of exposed bone in the mouth, or of slow healing after dental procedures. Recent (within 6 weeks) or planned dental or jaw surgery (e.g. extraction, implants). History of diseases with influence on bone metabolism, such as Paget's disease, Osteogenesis Imperfecta, and primary or secondary hyperthyroidism within the 12 months prior to study entry Other protocol-defined inclusion/exclusion criteria may apply

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
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Letrozole<br>Letrozole 2.5 mg/day oral letrozole for approximately 6.5 months neoadjuvent treatment | Drug: Letrozole<br>* 2.5 mg.tablet.<br>|
| Experimental: Zolendronic Acid + Letrozole<br>2.5 mg/day oral letrozole for approximately 6.5 months neoadjuvant treatment plus zoledronic acid 4 mg i.v. q4w | Drug: Letrozole<br>* 2.5 mg.tablet.<br>Drug: Zolendronic Acid<br>* 4 mg or an adjusted dose based on renal function in 100 ml physiologic (o.9%) normal saline, (as an intravenous infusion over no less than 15 minutes)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor Response Rate (Complete Response (CR) or Partial Response (PR)) Based on MRI- or Mammography and/or Sonography According to Modified RECIST Criteria at Month 6 | Sum of longest diameter for all target lesions was reported as baseline sum LD. Baseline sum LD was used as reference to characterize objective tumor response. Response Evaluation Criteria in Solid Tumors has 4 response categories. CR (complete response) = disappearance of all target lesions, PR (partial response)= 30% decrease in sum of longest diameter of target lesions, PD (progressive disease) = 20% increase in the sum of the longest diameter of target lesions and SD(stable disease)=small changes that do not meet criteria. Analysis was underpowered due to insufficient recruitment rate. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best RECIST Response Based on Central Review at 6 Mos | Best response is defined as the best response the patients has reached during the 6 months of treatment. Response Evaluation Criteria in Solid Tumors (RECIST) has 4 response categories. CR (complete response) = disappearance of all target lesions, PR (partial response) = 30% decrease in the sum of the longest diameter of target lesions, PD (progressive disease) = 20% increase in the sum of the longest diameter of target lesions and SD (stable disease) = small changes that do not meet criteria. | 6 Months | 
| Number of Patients With Breast Conserving Surgery at 6 Months |  | Every 6 months | 
| Change From Baseline in Tumor Size (Longest Diameter) at Month 6 | Tumor size (sum of longest diameter)was analyzed based on the diameters values provided with the central review. | Baseline, Month 6 | 
| Mean Changes From Baseline in FACT-B Total Score at 6 Months (ITT, Data as Observed) | The FACT-B total score is calculated by summing all five unweighted subscale scores, with total scores in the range of 0-144.To Derive a FACT-B total score: all sections added together The higher the score the better the QoL + __________ + __________ + __________ + __________ =________=FACT-B Total score (PWB score) (SWB score) (EWB score) (FWB score) (BCS score) | baseline and 6 mos | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast cancer, Anti tumor potential, Letrozole, Zoledronic acid, Neoadjuvant treatment, Hormone responsive breast cancer