Letrozole After Tamoxifen in Treating Women With Breast Cancer

Study Overview
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Brief Summary
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RATIONALE: Estrogen can stimulate the growth of breast cancer cells. Hormone therapy using letrozole may fight breast cancer by reducing the production of estrogen. PURPOSE: This randomized phase III trial is studying letrozole to see how well it works in treating women with breast cancer who have received tamoxifen for at least 5 years.

Detailed Description
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OBJECTIVES: Primary Compare the disease-free survival and overall survival of postmenopausal women with primary breast cancer who have completed at least five years of adjuvant aromatase inhibitor as initial therapy or after tamoxifen treated with letrozole or placebo. Secondary Compare the incidence of contralateral breast cancer in patients treated with these regimens. Evaluate the long-term clinical and laboratory safety of letrozole, in terms of lipid profile, cardiovascular morbidity and mortality, incidence of bone fractures, change in bone density, and common toxic effects, in this patient population. Compare the quality of life of patients treated with these regimens. Re-randomization Primary Compare disease-free survival of patients who, after receiving at least 4.5 years of letrozole, are re-randomized to receive an additional 5 years of letrozole vs placebo. Secondary Determine whether common genetic polymorphisms for genes encoding proteins involved in pharmacokinetic and/or pharmacodynamic pathways for letrozole contribute to individual variation in toxicity and efficacy of letrozole therapy. OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to receptor status (positive vs unknown), lymph node status (negative vs positive vs unknown), prior adjuvant chemotherapy (yes vs no), interval between last dose of aromatase inhibitor therapy and randomization (< 6 months vs 6 months-2 years), and duration of prior tamoxifen use (0 years vs < 2 years vs 2-4.5 years vs > 4.5 years). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive oral letrozole once daily. Arm II: Patients receive oral placebo once daily. In both arms, treatment continues for 5 years in the absence of disease progression or unacceptable toxicity. Patients in arm II may then be offered oral letrozole once daily for up to 5 years. Quality of life is assessed at baseline, at 6 months, and then annually for 4.5 years. Double-blind, re-randomization: Patients who complete ≥ 4.5 years of letrozole (arm I) and who did not experience recurrent disease or new primary breast cancer, including ductal carcinoma in situ, may participate in the double-blind, placebo-controlled, re-randomization portion of the study. Patients are stratified according to lymph node status at enrollment (negative vs positive vs unknown), prior adjuvant chemotherapy (yes vs no), and interval between last dose of letrozole and re-randomization (<6 months vs 6 months to 2 years). Common genetic single nucleotide polymorphisms for genes encoding proteins involved in pharmacokinetic and/or pharmacodynamic pathways for letrozole are analyzed in order to determine if these single nucleotide polymorphisms contribute to individual variation in toxicity and efficacy of letrozole therapy. Quality of life is assessed as during the first randomization. Patients are followed annually. PROJECTED ACCRUAL: A total of 4,700 patients will be accrued for this study.

Official Title
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A Phase III Randomized Double Blind Study of Letrozole Versus Placebo in Women With Primary Breast Cancer Completing Five or More Years of Adjuvant Tamoxifen

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: letrozole
* Other: placebo


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically or cytologically confirmed primary invasive breast carcinoma resected at time of original diagnosis No ductal carcinoma in situ Axillary lymph node negative, positive, or unknown No evidence of metastases No localized or distant breast cancer recurrence Not registered on protocol NCCTG-893052, any other IBCSG protocol, or protocol SWOG-S9623 Hormone receptor status: Estrogen or progesterone receptor positive as defined by tumor receptor content at least 10 fmol/mg protein or receptor positive by ERICA or PgRICA Unknown status allowed if effort to determine status has been made by immunocytochemistry No contralateral breast cancer PATIENT CHARACTERISTICS: Age: Postmenopausal Sex: Female Menopausal status: Postmenopausal defined by one of the following: Age 50 or over at start of adjuvant tamoxifen Under age 50 and considered postmenopausal by treating physician at start of adjuvant tamoxifen Under age 50 at start of adjuvant tamoxifen and had bilateral oophorectomy (surgical or radiation) Under age 50 and premenopausal at start of adjuvant tamoxifen, but became amenorrheic during tamoxifen and remained amenorrheic for at least 1 year Considered postmenopausal by physician with LH/FSH levels under the treatment center's postmenopausal limits Performance status: ECOG 0-2 Life expectancy: At least 5 years Hematopoietic: WBC ≥ 3,000/mm^3 OR Granulocyte count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Hepatic: AST and/or ALT < 2 times upper limit of normal (ULN) (unless imaging examinations have ruled out metastatic disease) Alkaline phosphatase < 2 times ULN (unless imaging examinations have ruled out metastatic disease) Renal: Not specified Other: No concurrent medical or psychiatric condition that would preclude study participation No other malignancy within the past 5 years except adequately treated superficial squamous cell or basal cell skin cancer or carcinoma in situ of the cervix Able to swallow study drug Adequate oral intake PRIOR CONCURRENT THERAPY: Biologic therapy: Not specified Chemotherapy: Prior adjuvant chemotherapy allowed No concurrent chemotherapy Endocrine therapy: Completed at least 4.5 but no more than 6 years of adjuvant tamoxifen after resection Completed at least 4.5-6 years of adjuvant aromatase inhibitor as initial therapy or after tamoxifen No more than 3 months since prior adjuvant tamoxifen No concurrent hormone replacement therapy (e.g., megestrol) No concurrent selective estrogen-receptor modulators (e.g., raloxifene or idoxifene) Concurrent intermittent vaginal estrogens (e.g., Estring) allowed if other local measures for intractable vaginal atrophy are insufficient No other concurrent aromatase inhibitors No more than 2 years since prior aromatase inhibitor therapy (re-randomization) Radiotherapy: Prior radiotherapy allowed Surgery: See Disease Characteristics Other: At least 1 month since prior investigational drugs Prior treatment on a clinical trial for breast cancer allowed if permission has been obtained from the sponsors of the original study for their patient to participate on MA.17/JMA.17/BIG-97-01 No prior placebo on core protocol No concurrent anticancer therapy Concurrent thyroid medication, calcium, vitamin D, and bisphosphonates allowed

Ages Eligible for Study
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Minimum Age: 0 Years
Maximum Age: 120 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive oral letrozole once daily. | Drug: letrozole<br>* Given orally<br>* Other names: Femara;|
| Placebo Comparator: Arm II<br>Patients receive oral placebo once daily. | Other: placebo<br>* Given orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-free survival |  | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage I breast cancer, stage II breast cancer, stage IIIA breast cancer