Letrozole in Preventing Breast Cancer in Postmenopausal Women

Study Overview
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Brief Summary
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RATIONALE: Chemoprevention therapy is the use of certain drugs to try to prevent the development or recurrence of cancer. Letrozole may be effective in preventing the development or recurrence of breast cancer in postmenopausal women who are at increased risk of developing breast cancer because of elevated estradiol levels. PURPOSE: This randomized phase II trial is studying how well letrozole works in preventing breast cancer in postmenopausal women with elevated estradiol levels.

Detailed Description
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OBJECTIVES: Primary The primary outcome of the study is the change in bone mineral density following a year on letrozole vs. a year on placebo. Secondary Compare the safety, acceptability, and adherence to letrozole vs placebo in postmenopausal women at increased risk for the development or recurrence of breast cancer based on elevated plasma estradiol levels through evaluation of menopausal symptoms (including hot flushes, weight changes, sexual functioning, and genitourinary effects), blood lipid levels, markers of bone turnover, and multidimensional quality of life. Determine the effect of letrozole-induced reduction of plasma estradiol levels on mammographic percent breast density. Obtain background information for a future large chemoprevention trial to address the question of whether a reduction in plasma estradiol levels can reduce the risk of breast cancer in postmenopausal women. OUTLINE: This is a pilot, randomized, double-blind, placebo-controlled, multicenter study. Patients are randomized to 2:1 (experimental treatment: placebo arms). PROJECTED ACCRUAL: A total of 110 patients (73 for arm I and 37 for arm II) will be accrued for this study.

Official Title
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A Pilot Study of Aromatase Inhibitors for Women at Increased Risk of Breast Cancer Based on Estradiol Levels

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: At increased risk for the development or recurrence of breast cancer, defined as an estradiol level ≥ 9 pg/mL No evidence of suspicious or malignant disease, based on the following examinations: Clinical bilateral breast examination within the past 6 months Bilateral* mammogram within 3 months before randomization OR within 30 days after randomization Pelvic exam normal within the past 5 years General physical exam within the past 6 months NOTE: *Unilateral mammogram of the uninvolved breast for patients with prior invasive breast cancer or ductal carcinoma in situ (DCIS) Bone density scan within 2 standard deviations from normal within the past 30 days Bone density scan ≥ 2 standard deviations below normal allowed if approved by the study physician At least 1 breast that has not been previously treated with radiotherapy or surgery (for patients with prior invasive breast cancer or DCIS) Hormone receptor status: Not specified PATIENT CHARACTERISTICS: Age 35 and over Sex Female Menopausal status Postmenopausal, defined by any of the following criteria: At least 12 months without spontaneous menstrual bleeding Prior hysterectomy and bilateral salpingo-oophorectomy ≥ 55 years of age with a prior hysterectomy with or without oophorectomy < 55 years of age with a prior hysterectomy without oophorectomy OR the status of the ovaries is unknown AND follicle-stimulating hormone (FSH) level is in the postmenopausal range Performance status Normal activity must not be restricted for a significant portion of the day Life expectancy At least 10 years Hematopoietic Complete blood count with differential normal Prior benign neutropenia allowed provided the granulocyte count is ≥ 1,500/mm^3 Hepatic Bilirubin normal Alkaline phosphatase normal SGOT and SGPT normal Renal Creatinine normal Cardiovascular No uncontrolled cardiovascular disease Other Not pregnant No other malignancy within the past 5 years except basal cell or squamous cell skin cancer or carcinoma in situ of the cervix No osteoporosis No hyperlipidemia No mental health status resulting in cognitive or emotional impairment that would preclude study participation PRIOR CONCURRENT THERAPY: Biologic therapy Not specified Chemotherapy Not specified Endocrine therapy More than 30 days since prior AND no concurrent use of any of the following hormonal agents: Estrogen or progesterone replacement therapy Oral contraceptives Raloxifene or other plasma estrogen receptor modulators (SERMs) Androgens (e.g., danazol) Luteinizing hormone-releasing hormone (LHRH) analogs (e.g., goserelin or leuprolide) Prolactin inhibitors (e.g., bromocriptine) Antiandrogens (e.g., cyproterone) More than 60 days since prior AND no concurrent tamoxifen No prior aromatase inhibitors (for patients with prior invasive breast cancer or DCIS) No concurrent phytoestrogenic dietary supplements (e.g., soy, ginseng, or other natural products) Dietary soy allowed Radiotherapy See Disease Characteristics Surgery See Disease Characteristics No prior bilateral mastectomy Other More than 60 days since prior treatment for invasive breast cancer or DCIS More than 30 days since prior bisphosphonates or calcitonin No prior or concurrent participation on a treatment study for invasive breast cancer or DCIS No concurrent participation in any other cancer prevention study or osteoporosis prevention study involving pharmacologic agents No concurrent calcitonin No concurrent bisphosphonate therapy Concurrent cholecalciferol (vitamin D) and calcium to augment bone mineral density allowed

Ages Eligible for Study
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Minimum Age: 35 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Letrozole<br>Participants in this arm received 2.5 mg of letrozole per day for a duration of 12 months; followed by an optional 4 years. Treatment continued in the absence of unacceptable toxicity or diagnosis of invasive breast cancer, ductal carcinoma in situ, or any non-breast primary cancer. | Drug: Letrozole<br> <br> * Other names: Femara;|
| Placebo Comparator: Placebo<br>Participants in this arm received 1 tablet per day which contained the inert ingredients from the letrozole tablet, for a duration of 12 months; followed by an optional 5 years of letrozole.Treatment continued in the absence of unacceptable toxicity or diagnosis of invasive breast cancer, ductal carcinoma in situ, or any non-breast primary cancer. | Other: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Lumbar Density From Baseline to 12 Months | The bone mineral density (BMD) test was comprised of the following 4 measurements [total density (g/cm^2)]: lumbar, femoral neck, trochanter, hip. | Evaluation occurred at treatment initiation (BL) and after 12-months of treatment. | 
| Change in Femoral Neck Density From Baseline to 12 Months | The bone mineral density (BMD) test was comprised of the following 4 measurements [total density (g/cm^2)]: lumbar, femoral neck, trochanter, hip. | Evaluation occurred at treatment initiation (BL) and after 12-months of treatment. | 
| Change in Trochanter Density From Baseline to 12 Months | The bone mineral density (BMD) test was comprised of the following 4 measurements [total density (g/cm^2)]: lumbar, femoral neck, trochanter, hip. | Evaluation occurred at treatment initiation (BL) and after 12-months of treatment. | 
| Change in Hip Density From Baseline to 12 Months | The bone mineral density (BMD) test was comprised of the following 4 measurements [total density (g/cm^2)]: lumbar, femoral neck, trochanter, hip. | Evaluation occurred at treatment initiation (BL) and after 12-months of treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Worst Grade Hot Flashes | Participants reported worst grade hot flashes: 01: mild (<1qd) or 02: moderate (>1qd) during 12 months of treatment. | Heath assessments during treatment were administered at 3- and 9-months by telephone contact and during clinic visits at 6- and12-months. | 
| Worst Grade Muscle Aches/Pains | Participants reported worst grade muscle aches/pains defined as grade 01: mild, 02: moderate, 03: severe (CTCAEv3) or 04: disabling (CTCAEv3) during 12 months of treatment. | Heath assessments during treatment were administered at 3- and 9-months by telephone contact and during clinic visits at 6- and12-months. | 
| Worst Grade Nausea | Participants reported worst grade nausea grade 01: able to eat, 02: oral intake significantly decreased, 03: no significant intake, requiring IV fluids during 12 months of treatment. | Heath assessments during treatment were administered at 3- and 9-months by telephone contact and during clinic visits at 6- and12-months. | 
| Worst Grade Vomiting | Participants reported worst grade vomiting grade 01: 1x in 24 hours, 02: 2-5x in 24 hours, 03: >/= 6x in 24 hours, grade 04: requiring parenteral nutrition/intensive care during 12 months of treatment. | Heath assessments during treatment were administered at 3- and 9-months by telephone contact and during clinic visits at 6- and12-months. | 
| Worst Grade Abdominal Pain | Participants reported worst grade abdominal pain: 01: mild, 02: moderate, 03: severe (CTCAEv3), 04: disabling (CTCAEv3) during 12 months of treatment. | Heath assessments during treatment were administered at 3- and 9-months by telephone contact and during clinic visits at 6- and12-months. | 
| Worst Grade Bone Pain | Participants reported worst grade bone pain: 01: mild, 02: moderate, 03: severe (CTCAEv3), 04: disabling (CTCAEv3) during 12 months of treatment. | Heath assessments during treatment were administered at 3- and 9-months by telephone contact and during clinic visits at 6- and12-months. | 
| Worst Grade Headache | Participants reported worst grade headache: 01: mild, 02: moderate, 03: severe (CTCAEv3), 04: disabling (CTCAEv3) during 12 months of treatment. | Heath assessments during treatment were administered at 3- and 9-months by telephone contact and during clinic visits at 6- and12-months. | 
| Worst Grade Fatigue | Participants reported worst grade fatigue: 01: mild, 02: moderate, 03: severe (CTCAEv3), 04: disabling (CTCAEv3) during 12 months of treatment. | Heath assessments during treatment were administered at 3- and 9-months by telephone contact and during clinic visits at 6- and12-months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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breast cancer, stage I breast cancer, stage II breast cancer, stage IIIA breast cancer, stage IIIB breast cancer, stage IIIC breast cancer, stage IV breast cancer, breast cancer in situ, ductal breast carcinoma in situ