Low-Dose Tamoxifen Citrate in Reducing Breast Cancer Risk in Radiation-Induced Cancer Survivors

Study Overview
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Brief Summary
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Estrogen can cause the growth of breast cancer cells. Hormone therapy using tamoxifen citrate may fight breast cancer by blocking the use of estrogen by the tumor cells This phase IIb trial studies how well low-dose tamoxifen citrate works in reducing breast cancer risk in radiation-induced cancer survivors.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the impact of a two-year course of low-dose tamoxifen (tamoxifen citrate) administered at 5 mg per day on surrogate endpoint biomarkers of breast cancer (BC) risk, including: mammographic breast density (MBD), an established radiographic biomarker of BC risk; cytomorphology and proliferative index, tissue biomarkers closely linked to BC risk; and sex steroid hormones and insulin growth factors, circulating biomarkers of BC risk. II. To establish safety and tolerability of this low-dose tamoxifen regimen, assessing both objective measures (lipid profiles, clotting factors and bone metabolism markers) and patient-reported outcomes. III. To examine the modifying effect of demographic, clinical, and molecular characteristics on the risk: benefit ratio from this two-year low dose tamoxifen intervention. IV. To explore the relationship between this low-dose tamoxifen regimen and clinical measures of efficacy (new breast cancer and ductal carcinoma in situ [DCIS] diagnoses) and toxicity (thromboembolic events, reports of hot flashes and gynecological symptoms, liver function abnormalities, and other cancer diagnoses). OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive tamoxifen citrate orally (PO) once daily for 24 months in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive placebo PO once daily for 24 months in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up periodically for up to 10 years.

Official Title
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Low-Dose Tamoxifen for Radiation-Induced Breast Cancer Risk Reduction: A Phase IIB Randomized Placebo-Controlled Trial

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Tamoxifen Citrate
* Drug: Placebo
* Procedure: Digital mammography
* Other: immunohistochemistry staining method
* Other: pharmacological study
* Other: laboratory biomarker analysis
* Genetic: protein expression analysis
* Other: pharmacogenomic studies
* Other: questionnaire administration
* Procedure: Fine needle aspiration
* Other: Quality of Life Assessment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Exposure to radiation therapy (RT) delivered to the chest, axilla, and/or supraclavicular areas at a cumulative dose of 12 Gy or more by age 40 years; in addition, patients who received total body irradiation by age 40 may be considered No evidence of active disease from their primary cancer for at least 2 continuous years prior to registration; the indication for RT is not specified but cannot be for primary breast cancer; common examples include, but are not limited to: lymphoma, leukemia, sarcoma, and Wilms tumor occurring in pediatric patients, and lymphoma, leukemia, and sarcoma occurring in young adults; primary cancer therapy must have been completed at least 6 months prior to registration Well-defined menopausal status falling into one of the following categories: Premenopausal, defined as age at registration 45 years old or younger with regular monthly period for at least 6 consecutive months prior to registration Postmenopausal, defined as continuous absence of menstruation for 12 months OR status-post bilateral oophorectomy OR follicle stimulating hormone (FSH) level in the postmenopausal range Exclusion Criteria: Subsequent malignant neoplasm (SMN) other than those listed below diagnosed within 2 years of study entry; patients with the listed indolent or pre-invasive neoplasms may be eligible if diagnosed within 2 years and all treatment was completed at least 6 months prior to registration: Non-melanoma cancers of the skin Thyroid cancer Cervical cancer confined to the cervix or cervical intraepithelial neoplasia (CIN) Ductal carcinoma in situ (DCIS) or breast intraepithelial neoplasia (IEN) (includes atypical hyperplasia and lobular carcinoma in situ [LCIS]), or Superficial or non-invasive transitional cell carcinoma of the bladder For women with a prior history of DCIS or breast IEN, only one breast could have been involved and all therapy must have been completed at least 6 months prior to registration; in addition women with a prior history of invasive breast cancer may also be eligible, as long as only one breast was involved, they were diagnosed at least 2 years prior to study entry, and therapy was completed at least 6 months prior to study entry Bilateral breast implants or status-post bilateral prophylactic mastectomy Evidence of malignant breast disease on any form of breast imaging; the study only requires annual mammography; however, annual breast magnetic resonance imaging (MRI) is considered standard of care in this patient population (per Children's Oncology Group [COG] or National Comprehensive Cancer Network [NCCN] follow-up guidelines), and breast ultrasound may be indicated if a palpable lesion is detected on screening clinical breast exam; abnormal imaging may require additional radiographs and/or breast biopsy; patients who are found to have benign breast disease with or without atypia may continue on study as long as there is no evidence of malignancy; if there is evidence of malignancy, and only one breast is involved, they may be reapproached 6 months after completion of therapy for consideration of the trial Baseline categorical mammographic density scored as BIRAD 1, or extremely fatty, in both breasts; if the patient has a prior history of IEN (DCIS, LCIS, or atypical hyperplasia), the contralateral breast must not have a mammographic density score of BIRAD 1; this determination will be made at the local site Current or recent use (within 6 months of registration or baseline mammogram, whichever is first) of any of the following: systemic hormone replacement therapy (includes oral or transdermal formulations); Vagifem and Estring, two formulations of locally applied vaginal estrogen associated with minimal systemic absorption, may be allowed; other estrogen-containing vaginal creams, while not an exclusion, should be avoided whenever possible; patients with a history of hormone modifying herbal supplements are eligible, but patients will be asked to avoid their use after on study Current or recent use (within 6 months of registration or baseline mammogram, whichever is first) of any of the following: hormonal forms of contraception (includes oral, transdermal, implanted, and injectable formulations): selective estrogen receptor modifiers; aromatase inhibitors; GnRH analogs; androgens or antiandrogens Concurrent use of warfarin and strong inhibitors or CYP2D6 will not be allowed A personal history or a strong family of thromboembolism, including deep venous thrombosis (DVT), pulmonary embolus (PE), or cerebrovascular accident (CVA); a personal history of transient ischemic attack (TIA) or retinal vein thrombosis will also not be allowed; in addition, patients with a condition known to increase hypercoagulability, such as Factor V Leiden disease, will be excluded; patients with atrial fibrillation will be excluded, due to risk of CVA, but patients with coronary artery disease or congestive heart failure without atrial fibrillation will be allowed to participate Current intrauterine pregnancy or plans to become pregnant within two years; in addition, currently nursing mothers will be excluded Serum creatinine > 2X the institutional norm Total bilirubin > 2X the institutional norm Serum glutamic oxaloacetic transaminase (SGOT) or serum glutamic pyruvic transaminase (SGPT) > 2X the institutional norm Unable to provide consent

Ages Eligible for Study
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Minimum Age: 25 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (tamoxifen citrate)<br>Patients receive tamoxifen citrate PO QD for 24 months in the absence of disease progression or unacceptable toxicity. | Drug: Tamoxifen Citrate<br>* 5 mg PO Daily<br>* Other names: ICI 46,474;Procedure: Digital mammography<br>* Correlative studies<br>Other: immunohistochemistry staining method<br>* Correlative Studies<br>Other: pharmacological study<br>* Correlative Studies<br>Other: laboratory biomarker analysis<br>* Correlative Studies<br>Genetic: protein expression analysis<br>* correlative studies<br>Other: pharmacogenomic studies<br>* correlative studies<br>Other: questionnaire administration<br>* Ancillary studies<br>Procedure: Fine needle aspiration<br> <br> * Other names: Correlative studies;Other: Quality of Life Assessment<br>* Ancillary Studies<br>|
| Placebo Comparator: Arm II (placebo)<br>Patients receive placebo PO QD for 24 months in the absence of disease progression or unacceptable toxicity. | Drug: Placebo<br>* 1 tablet daily<br>Procedure: Digital mammography<br>* Correlative studies<br>Other: immunohistochemistry staining method<br>* Correlative Studies<br>Other: pharmacological study<br>* Correlative Studies<br>Other: laboratory biomarker analysis<br>* Correlative Studies<br>Genetic: protein expression analysis<br>* correlative studies<br>Other: pharmacogenomic studies<br>* correlative studies<br>Other: questionnaire administration<br>* Ancillary studies<br>Procedure: Fine needle aspiration<br> <br> * Other names: Correlative studies;Other: Quality of Life Assessment<br>* Ancillary Studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mammographic Breast Density | Mammographic density was quantified as percentage of fibroglandular tissue. Using an intention-to-treat analysis, mammographic breast density (MBD) was compared between patients in the low dose tamoxifen intervention and placebo group by applying the linear mixed effects model for normally distributed data. | At year two post treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin Growth Factor Levels (IGF1) | IGF1 will be treated as a continuous measure. The linear mixed effects model for between group comparisons of measures from 3 time points will be applied. The unstructured mean model and linear in time model will be employed. | Up to 2 years | 
| Number of Grade 2-4 Toxicities | Will be tabulated by treatment arm. Differences by treatment arm will be evaluated using Fisher exact tests. | Up to 2 years | 
| Biomarker Levels | Total cholesterol, low and high density lipoprotein, triglycerides, and anti-thrombin III enzymatic assay measurements will be treated as continuous variables. Transformed to normality as appropriate, the linear mixed effects model will be applied, using the unstructured mean model and linear in time model to assess the effects of low-dose tamoxifen on these measurements over time. | Up to 2 years | 
| Percentage of Pills Taken Out of the Total Prescribed | The number of pills taken out of the total prescribed in a 3-month period will be modeled as a random effects binomial regression model. The binomial rates from 8 time points (month 3-24) will be modeled as unstructured mean model with 7 indicator variables as well as polynomial models over time. The random-intercept and the random intercept and slope models will be considered. The significance of the time indicators or parameters by treatment interaction will be evaluated for treatment difference in compliance. | Up to 2 years | 
| Number of Participants With Different Patient Reported Symptoms, Measured by Questionnaire | The outcomes will be scored as a 5-point Likert-type scale (0-4) in response to questions on how much the patients are bothered by certain symptoms. The questionnaire will be administered every 6 months. The responses will be treated as normally distributed, as ordinal or dichotomized variable, and the linear mixed effects of general linear mixed model (GLMM) methods will be applied to compare changes between treatment groups. Piecewise models will also be fitted with join point at 6 months, considering linear and curvilinear trajectories between 6 and 24 month time points. | Up to 2 years | 
| Insulin Growth Factor Levels (IGF3 ) | IGF3 will be treated as a continuous measure. The linear mixed effects model for between group comparisons of measures from 3 time points will be applied. The unstructured mean model and linear in time model will be employed. | Up to 2 years | 
| Biomarker Levels - Alkaline Phosphatase | Serum bone-specific alkaline phosphatase measurements will be treated as continuous variables. Transformed to normality as appropriate, the linear mixed effects model will be applied, using the unstructured mean model and linear in time model to assess the effects of low-dose tamoxifen on these measurements over time. | Up to 2 years | 
| Biomarker Levels - Urine N-telopeptide | Urine n-telopeptide measurements will be treated as continuous variables. Transformed to normality as appropriate, the linear mixed effects model will be applied, using the unstructured mean model and linear in time model to assess the effects of low-dose tamoxifen on these measurements over time. | Up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cancer survivors, Low Dose Tamoxifen, Breast Cancer Risk Reduction