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

UNC Lineberger Comprehensive Cancer Center

Status and phase: Completed; Phase 2

Conditions: Breast Cancer; Menopausal Symptoms

Treatments: Procedure: quality-of-life assessment; Other: questionnaire administration; Drug: tamoxifen citrate; Other: pharmacogenomic studies; Genetic: gene expression analysis

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT00764322

08-0483 (Other Identifier)

LCCC 0801

P30CA016086 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 501 patients

Sex: Female

Ages: 21 to 120 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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501 participants in 2 patient groups

Tamoxifen 20

Experimental group

Description:

One arm, containing the ultra-rapid and extensive metabolizer genotypes, continues treatment with tamoxifen at 20mg.

Treatment:

Genetic: gene expression analysis

Other: pharmacogenomic studies

Drug: tamoxifen citrate

Other: questionnaire administration

Procedure: quality-of-life assessment

Tamoxifen 40

Active Comparator group

Description:

This arm, containing the intermediate and poor metabolizer genotypes, receives escalated treatment with tamoxifen at 40mg.

Treatment:

Genetic: gene expression analysis

Other: pharmacogenomic studies

Drug: tamoxifen citrate

Other: questionnaire administration

Procedure: quality-of-life assessment