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

Phase 2

Completed

• Conditions: Breast Cancer; Menopausal Symptoms
• Interventions: Drug: tamoxifen citrate; Genetic: gene expression analysis; Other: pharmacogenomic studies; Other: questionnaire administration; Procedure: quality-of-life assessment

• Registration Number: NCT00764322
• Lead Sponsor: UNC Lineberger Comprehensive Cancer Center

Brief Summary

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

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.

Study Timeline

• Study Start: 2008-06-18
• Study First Submitted: 2008-10-01
• Study First Submitted QC: 2008-10-01
• Study First Posted: 2008-10-02
• Primary Completion: 2010-09-28
• Study Completion: 2011-07-01
• Results First Submitted: 2017-03-31
• Results First Submitted QC: 2017-06-05
• Status Verified: 2017-07
• Results First Posted: 2017-07-02
• Last Update Submitted: 2017-07-03
• Last Update Posted: 2017-08-01

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 501

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Tamoxifen 40	tamoxifen citrate	This arm, containing the intermediate and poor metabolizer genotypes, receives escalated treatment with tamoxifen at 40mg.
Tamoxifen 20	pharmacogenomic studies	One arm, containing the ultra-rapid and extensive metabolizer genotypes, continues treatment with tamoxifen at 20mg.
Tamoxifen 20	tamoxifen citrate	One arm, containing the ultra-rapid and extensive metabolizer genotypes, continues treatment with tamoxifen at 20mg.
Tamoxifen 40	gene expression analysis	This arm, containing the intermediate and poor metabolizer genotypes, receives escalated treatment with tamoxifen at 40mg.
Tamoxifen 40	quality-of-life assessment	This arm, containing the intermediate and poor metabolizer genotypes, receives escalated treatment with tamoxifen at 40mg.
Tamoxifen 40	questionnaire administration	This arm, containing the intermediate and poor metabolizer genotypes, receives escalated treatment with tamoxifen at 40mg.
Tamoxifen 20	questionnaire administration	One arm, containing the ultra-rapid and extensive metabolizer genotypes, continues treatment with tamoxifen at 20mg.
Tamoxifen 40	pharmacogenomic studies	This arm, containing the intermediate and poor metabolizer genotypes, receives escalated treatment with tamoxifen at 40mg.
Tamoxifen 20	gene expression analysis	One arm, containing the ultra-rapid and extensive metabolizer genotypes, continues treatment with tamoxifen at 20mg.
Tamoxifen 20	quality-of-life assessment	One arm, containing the ultra-rapid and extensive metabolizer genotypes, continues treatment with tamoxifen at 20mg.

Primary Outcome Measures

Name	Time	Method
Endoxifen Concentrations in Participants Receiving Tamoxifen Citrate Dose of 20 mg or 40 mg Stratified by the Metabolizing CYP2D6 Genotypes	4 months	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.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Pulmonary Embolism (PE), Deep Vein Thrombosis (DVT), Stroke, and/or Endometrial Cancer	Approximately ten months from registration to last follow-up	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%.
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	Baseline and 4 months after dose increase	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.
CYP2D6 Allele Frequencies and Endoxifen Levels Among African-American Women Taking Tamoxifen Citrate	baseline	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.
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	Baseline and 4 months after dose increase	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
Patient Understanding of Pharmacogenomics	baseline	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%)

Trial Locations

Locations (7)

Moses Cone Regional Cancer Center at Wesley Long Community Hospital; 🇺🇸 Greensboro, North Carolina, United States

Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill; 🇺🇸 Chapel Hill, North Carolina, United States

Blumenthal Cancer Center at Carolinas Medical Center; 🇺🇸 Charlotte, North Carolina, United States

Duke Comprehensive Cancer Center; 🇺🇸 Durham, North Carolina, United States

Rex Cancer Center at Rex Hospital; 🇺🇸 Raleigh, North Carolina, United States

Gibbs Regional Cancer Center at Spartanburg Regional Medical Center; 🇺🇸 Spartanburg, South Carolina, United States

Leo W. Jenkins Cancer Center at ECU Medical School; 🇺🇸 Greenville, North Carolina, United States