Studying Blood Samples From Women With Breast Cancer or Ductal Carcinoma In Situ Who Are Receiving Tamoxifen

Study Overview
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Brief Summary
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RATIONALE: Studying samples of blood from patients with cancer in the laboratory may help doctors learn more about differences in DNA and predict how well patients will respond to treatment and plan better treatment. PURPOSE: This clinical trial is studying blood samples from women with breast cancer or ductal carcinoma in situ who are receiving tamoxifen.

Detailed Description
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OBJECTIVES: Primary To evaluate the change in endoxifen levels after an increase in tamoxifen citrate dose from 20 mg to 40 mg in women with breast cancer or ductal breast carcinoma in situ with intermediate-metabolizing CYP2D6 genotypes. Secondary To evaluate the tolerability of increasing the dose of tamoxifen citrate from 20 to 40 mg per day in these patients. To assess the feasibility of obtaining pharmacogenomic information from patients in the clinical setting and using it to guide changes in therapy. To examine CYP2D6 allele frequencies and endoxifen levels among African-American women taking tamoxifen citrate. To evaluate the change in plasma endoxifen levels after an increase in the tamoxifen citrate dose from 20 mg to 40 mg daily in patients with poor-metabolizing genotypes. To study patient understanding of pharmacogenomics and obstacles to participation in clinical trials based upon germline DNA. OUTLINE: This is a multicenter study. Blood samples are collected at baseline to determine CYP2D6 genotype and tamoxifen citrate metabolic status: poor-metabolizing (PM), intermediate-metabolizing (IM), or extensive-metabolizing (EM) alleles. Samples are also analyzed for plasma levels of endoxifen and N-desmethyltamoxifen and for endoxifen/N-desmethyltamoxifen ratio. Patients found to be IM or PM are notified to increased tamoxifen citrate to 40 mg/day for 4 months (in the absence of unacceptable toxicity) with repeat endoxifen and N-desmethyltamoxifen levels (and the ratio) at the end of this time. All patients complete Quality Of Life (QOL) and Menopausal Symptoms Scale (MSS) questionnaires at baseline and after 4 months of treatment. Toxicities are assessed at the end of 4 months. Patients undergo repeat questionnaire assessment of their understanding of the use of pharmacogenomics in clinical decision-making. Some patients also undergo a 30-minute, baseline interview regarding attitudes and experience towards participation in a pharmacogenomics study. Patients who choose to be informed of the results of their genotyping are contacted by letter, along with their physicians, and offered genetic counseling to discuss the significance of these results. After completion of study therapy, patients are followed at 3-6 months, including toxicity assessment and QOL and MSS questionnaires.

Official Title
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Validating CYP2D6 Genotype-Guided Tamoxifen Therapy for a Multiracial U.S. Population

Conditions
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Breast Cancer, Menopausal Symptoms

Intervention / Treatment
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* Drug: tamoxifen citrate
* Genetic: gene expression analysis
* Other: pharmacogenomic studies
* Other: questionnaire administration
* Procedure: quality-of-life assessment


Participation Criteria
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Eligibility Criteria
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Inclusion: Histologically confirmed invasive carcinoma of the breast or ductal breast carcinoma in situ Has been receiving tamoxifen citrate at a dose of 20 mg/day for at least 4 months either for the treatment of invasive or non-invasive carcinoma of the breast or for breast cancer recurrence prevention Expected duration of tamoxifen citrate treatment at least 6 months Hormone receptor status not specified Concurrent participation in non-treatment studies allowed provided it will not interfere with participation in this study Menopausal status not specified Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Life expectancy ≥ 6 months Absolute Neutrophil Count (ANC) ≥ 1.0 x 10^9/L Platelet count ≥ 100 x 10^9/L Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 2.5 times Upper Limit of Normal (ULN) Total bilirubin ≤ 2.5 times ULN Creatinine clearance ≥ 50 mL/min Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: No limitations to number of prior therapies No limitations for prior radiotherapy More than 14 days since prior and no other concurrent investigational agent Exclusion: Not pregnant or nursing No active, serious infection or medical or psychiatric illness likely to preclude study participation No psychiatric conditions that would preclude study compliance or informed consent No history of venous thromboembolism, transient ischemic attack, or cerebral vascular accident No history of allergic reaction to tamoxifen citrate or any of its reagents No concurrent coumadin No concurrent medications known to inhibit CYP2D6, including any of the following: Amiodarone Haloperidol Indinavir Ritonavir Quinidine No concurrent selective serotonin reuptake inhibitors, except the following: Venlafaxine Citalopram

Ages Eligible for Study
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Minimum Age: 21 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tamoxifen 20<br>One arm, containing the ultra-rapid and extensive metabolizer genotypes, continues treatment with tamoxifen at 20mg. | Drug: tamoxifen citrate<br>* Women found to be IM or PM will undergo increased tamoxifen to 40 mg/day (20 mg bid). Drug is given orally on a daily basis.<br>* Other names: Soltamox;Genetic: gene expression analysis<br>* Genetic analysis of blood sample.<br>Other: pharmacogenomic studies<br>* Genetic analysis of blood sample.<br>Other: questionnaire administration<br>* Questionnaire called the survey of participants. Questionnaires is self administered on paper documents and given pre-study, and at 4 months<br>Procedure: quality-of-life assessment<br>* Self administration of a multiquestion questionnaire called the Functional Assessment of Cancer Therapy -Breast (FACT-B). Given pre-study, at 4 months and at 8-10 months.<br>|
| Active Comparator: Tamoxifen 40<br>This arm, containing the intermediate and poor metabolizer genotypes, receives escalated treatment with tamoxifen at 40mg. | Drug: tamoxifen citrate<br>* Women found to be IM or PM will undergo increased tamoxifen to 40 mg/day (20 mg bid). Drug is given orally on a daily basis.<br>* Other names: Soltamox;Genetic: gene expression analysis<br>* Genetic analysis of blood sample.<br>Other: pharmacogenomic studies<br>* Genetic analysis of blood sample.<br>Other: questionnaire administration<br>* Questionnaire called the survey of participants. Questionnaires is self administered on paper documents and given pre-study, and at 4 months<br>Procedure: quality-of-life assessment<br>* Self administration of a multiquestion questionnaire called the Functional Assessment of Cancer Therapy -Breast (FACT-B). Given pre-study, at 4 months and at 8-10 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Endoxifen Concentrations in Participants Receiving Tamoxifen Citrate Dose of 20 mg or 40 mg Stratified by the Metabolizing CYP2D6 Genotypes | Measurements of plasma concentrations of the key active metabolite of tamoxifen, endoxifen, were measured at baseline and after 4 months of treatment; The most common CYP2D6 alleles have been grouped by functional activity classifications with descending activity: ultra-rapid (UM), extensive (EM), intermediate (IM) or poor (PM) metabolism. A given patient has two alleles, giving them 10 possible allelic combinations, or diplotypes (UM/UM, UM/EM, EM/EM, etc.). These diplotypes are collapsed into four phenotypes, UM, EM, IM or PM. | 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Pulmonary Embolism (PE), Deep Vein Thrombosis (DVT), Stroke, and/or Endometrial Cancer | The doubling of tamoxifen dose is defined as unacceptable (i.e., not tolerable) if the prevalence of Pulmonary embolism (PE), Deep vein thrombosis (DVT), stroke, or endometrial cancer, either individually or in any combination, is greater than 2%. | Approximately ten months from registration to last follow-up | 
| Change in Median Endoxifen Concentrations to Determine Feasibility of Obtaining Pharmacogenomic Information From Patients in the Clinical Setting and Using it to Guide Changes in Therapy | If the key active tamoxifen metabolite, endoxifen, could be significantly increased by genotype-guided tamoxifen dosing in patients with intermediate CYP2D6 metabolism (by increasing tamoxifen dosing based on CYP2D6 genotype), then the study would be deemed feasible and the accrual expanded. | Baseline and 4 months after dose increase | 
| CYP2D6 Allele Frequencies and Endoxifen Levels Among African-American Women Taking Tamoxifen Citrate | Mean endoxifen levels by CYP2D6 genotype among African Americans. Measurements of plasma concentrations of the key active metabolite of tamoxifen, endoxifen, were measured at baseline.The most common CYP2D6 alleles have been grouped by functional activity classifications with descending activity: ultra-rapid (UM), extensive (EM), intermediate (IM) or poor (PM) metabolism. A given patient has two alleles, giving them 10 possible allelic combinations, or diplotypes (UM/UM, UM/EM, EM/EM, etc.). These diplotypes are collapsed into four phenotypes, UM, EM, IM or PM. | baseline | 
| Change in Plasma Endoxifen Levels After an Increase in Tamoxifen Citrate Dose From 20 mg to 40 mg Daily in Patients With Poor-metabolizing Genotypes | The intrapatient change in median endoxifen levels were calculated between baseline and 4 months after the increase in dose of Tamoxifen from 20mg/day to 40 mg/day | Baseline and 4 months after dose increase | 
| Patient Understanding of Pharmacogenomics | To examine patients' beliefs about how hypothetical genotype information would affect their perceived recurrence risk and benefits of tamoxifen therapy, participants were given experimentally manipulated 6 vignettes to describe hypothetical tamoxifen treatment (no or yes) and hypothetical genotype (EM, IM or PM). For each vignette, participants gave their perceived recurrence risk (RR; 0-100%) | baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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menopausal symptoms, recurrent 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, ductal breast carcinoma in situ, breast cancer in situ