Letrozole in Breast Cancer Who Have Received 5 Years of Aromatase Inhibitor Therapy

Study Overview
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Brief Summary
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RATIONALE: Estrogen can cause the growth of breast cancer cells. Hormone therapy using letrozole may fight breast cancer by lowering the amount of estrogen the body makes. It is not yet known whether letrozole is more effective than a placebo in treating in women with breast cancer who have already received 5 years of aromatase inhibitor therapy. PURPOSE: This randomized phase III trial is studying letrozole to see how well it works compared with a placebo in treating women with primary breast cancer who have received 5 years of aromatase inhibitor therapy.

Detailed Description
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OBJECTIVES: Primary To compare the disease-free survival of women with primary breast cancer treated with letrozole vs placebo after completing approximately 5 years (i.e., 4½ - 6 years) of aromatase inhibitor therapy (e.g., letrozole, anastrozole, or exemestane). Secondary To compare the effect of these drugs on overall (all cause specific) mortality of these patients. To compare the incidence of contralateral breast cancer in patients treated with these drugs. To evaluate the long-term clinical and laboratory safety of aromatase inhibitor therapy, particularly cardiovascular morbidity and mortality (e.g., significant coronary artery disease, including myocardial infarction and angina requiring percutaneous transluminal coronary angioplasty or coronary artery bypass graft, fatal and nonfatal strokes, and all vascular deaths); incidence of all bone fractures (with particular emphasis on hip and wrist fractures as indicators of osteoporosis); changes in bone density; and common toxicities. To compare overall quality of life (QOL) and menopausal-specific QOL of patients treated with these drugs. OUTLINE: This is a multicenter study. Patients are stratified according to lymph node status at diagnosis (negative vs positive vs unknown), prior adjuvant chemotherapy (yes vs no), interval between last dose of aromatase inhibitor therapy and study randomization (< 6 months vs 6 months to 2 years), and duration of prior tamoxifen citrate use (0 vs < 2 years vs 2 - 4½ years vs > 4½ years). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive oral letrozole once daily for up to 5 years in the absence of unacceptable toxicity, disease recurrence, or development of a second malignancy. Arm II: Patients receive oral placebo once daily for up to 5 years in the absence of unacceptable toxicity, disease recurrence, or development of a second malignancy. Patients undergo bone mineral density measurement by DEXA scan at baseline (if not done within 12 months of study entry), at 24 and 48 months during study therapy, and at the completion of study therapy. Some patients also complete quality-of-life questionnaires at baseline and at 12, 24, 36, 48, and 60 months. After completion of study therapy, patients are followed annually.

Official Title
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A Double Blind Randomization to Letrozole or Placebo for Women Previously Diagnosed With Primary Breast Cancer Completing Five Years of Adjuvant Aromatase Inhibitor Either as Initial Therapy or After Tamoxifen (Including Those in The MA.17 Study)

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: Previously diagnosed with primary breast cancer Must have received 4½ - 6 years of aromatase inhibitor therapy (e.g., letrozole, anastrozole, or exemestane), either as initial therapy or after prior tamoxifen citrate, including treatment received as part of clinical trial CAN-NCIC-MA17 Completed aromatase inhibitor therapy ≤ 2 years ago No metastatic or recurrent disease, contralateral breast cancer, or ductal carcinoma in situ in either breast, as determined by the following: Clinical examination of the breast area, axillae, and neck within the past 60 days Mammogram within the past 12 months* Chest x-ray within the past 60 days Bone scan, if alkaline phosphatase > 2 times normal and/or there are symptoms of metastatic disease AND confirmatory x-ray, if bone scan results are questionable, within the past 60 days Abdominal ultrasound, liver scan, or CT scan of the abdomen within the past 60 days, if ALT, AST, or alkaline phosphatase > 2 times normal NOTE: *A baseline mammogram is not required for patients who have undergone bilateral complete mastectomy Hormone-receptor status: Estrogen receptor positive (ER+) and/or progesterone receptor positive (PR+) primary tumor at the time of diagnosis, defined as a tumor receptor content of > 10 fmol/mg protein or receptor positive by immunocytochemical assay (for patients not previously enrolled on clinical trial CAN-NCIC-MA17) ER+ and/or PR+ primary tumor OR hormone receptor status of primary tumor unknown (for patients previously enrolled on clinical trial CAN-NCIC-MA17) PATIENT CHARACTERISTICS: Menopausal status not specified ECOG performance status 0-2 Life expectancy ≥ 5 years WBC > 3.0 x 10^9/L OR granulocyte count (polymorphs + bands) ≥ 1.5 times 10^9/L Platelet count > 100 x 10^9/L AST and/or ALT < 2 times upper limit of normal (ULN)* Alkaline phosphatase < 2 times ULN* Able (i.e. sufficiently fluent) and willing to complete quality-of-life questionnaires in either English or French (NCIC CTG participating centers) Inability to complete questionnaires due to illiteracy in English or French, loss of sight, or other equivalent reason allowed Accessible for treatment and follow-up No other prior or concurrent malignancy except adequately treated, superficial squamous cell or basal cell skin cancer, carcinoma in situ of the cervix, or other cancer treated > 5 years ago that is presumed cured NOTE: *Elevated levels allowed provided imaging examinations have ruled out metastatic disease PRIOR CONCURRENT THERAPY: See Disease Characteristics No concurrent selective estrogen receptor modulator (e.g., raloxifene, idoxifene) No other concurrent anticancer therapy

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: Letrozole<br>Patients receive oral letrozole once daily for up to 5 years in the absence of unacceptable toxicity, disease recurrence, or development of a second malignancy. | Drug: letrozole<br>* Given orally<br>* Other names: femara;|
| Placebo Comparator: Placebo<br>Patients receive oral placebo once daily for up to 5 years in the absence of unacceptable toxicity, disease recurrence, or development of a second malignancy. | Other: placebo<br>* Given orally<br>* Other names: sugar pill;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-free Survival (DFS) | It is defined as the months from the day of randomization to the earliest date when a recurrence of the primary disease (recurrence in the breast, chest wall and nodal sites or the development of metastatic disease) or a contralateral breast cancer was observed. Subjects who died without recurrence of the primary disease or the development of the contralateral breast cancer were censored at their death date. If a patient has not recurred, developed a contralateral breast cancer, or died, disease-free survival was censored on the date of the last day the patient was known to be alive. Probability of disease free survival at 5 years is estimated and reported. | Unitil the end of study with a median follow up of 75 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Contralateral Breast Cancer | The annual incidence rate was estimated based on the time to the development of contralateral breast cancer, which was calculated in months from the day of randomization to the diagnosis date of contralateral breast cancer for subjects who had developed the contralateral breast cancer, to the time of death for the patient who died, or to the last day the patient was known alive for subjects without contralateral breast cancer | 10 years | 
| Overall Survival (OS) | For subjects who died, overall survival was calculated in months from the day of randomization to the date of death. Otherwise, survival was censored at the last day the patient was known to be alive. Probability of overall survival at 5 years is estimated and reported. | Until the end of study with a median follow-up of 75 months | 
| Change From Baseline in Role Function- Physical Scale on SF(Short Form)-36 Health Survey | Difference between post baseline scores and baseline score of role function-physical scale on SF-36 Health Survey (scale range between 0 and 100 with higher score indicating better quality of life). | 8 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, stage IIIB breast cancer, stage IIIC breast cancer