Tamoxifen Citrate in Patients With Breast Cancer

Tamoxifen Metabolism and the Impact of Tamoxifen Dose on the Level of the Active Metabolites in Endocrine Sensitive Breast Cancer Patients

RATIONALE: Estrogen can promote growth of endocrine sensitive breast cancer cells. Endocrine therapy with tamoxifen citrate may fight breast cancer by blocking the use of estrogen by the tumor cells. Pharmacokinetics and -genomics can have an impact on the efficacy of the treatment. PURPOSE: This phase III trial is studying blood samples to see if the level of active metabolites of tamoxifen can be improved in patients with breast cancer.

OBJECTIVES: Primary To determine how the increase of tamoxifen citrate dose influences the level of its major metabolites in patients with hormone-sensitive breast cancer. Secondary To characterize the population pharmacokinetic profile To investigate the role of the other CYPs To assess the relation between clinical symptoms and CYP2D6 genotypes and/or active metabolites levels To explore the correlation between genotypes/metabolites levels and clinical outcomes in terms of tumor relapse. To assess the feasibility, efficacy, and safety of concentration-guided adjustment of tamoxifen citrate dosage. To conduct other exploratory analysis based on the eventual new data coming up in the future. OUTLINE: Patients receive oral tamoxifen citrate (at a dose of 40 mg/day) daily for 4 months in the absence of disease progression or unacceptable toxicity. Blood samples are collected for PK, genotyping, phenotyping, and further analysis.

Determination of CYP2D6 genotype and determination of plasma concentrations of tamoxifen citrate and its metabolites (N-desmethyl-tamoxifen, 4-hydroxy-tamoxifen and endoxifen) under the 20 mg daily and 40 mg daily schedules

Characteristics of drug intake (date of tx initiation, current dosage and frequency, time of last intake) along with patient-reported adherence, assessed by questionnaire

DISEASE CHARACTERISTICS: Diagnosis of breast cancer Hormone-sensitive breast cancer defined as > 10% estrogen receptor and/or > 10% progesterone receptor positivity by immunohistochemistry Receiving treatment with tamoxifen citrate and must be eligible for exposure to higher doses PATIENT CHARACTERISTICS: No history of deep venous thrombosis or pulmonary embolism No history of endometrial carcinoma No known history of vaginal bleeding, endometriosis, endometrial hyperplasia, endometrial hypertrophy, and/or polyps Not pregnant or nursing No contraindication to tamoxifen citrate treatment No known allergy to midazolam or dextromethorphan PRIOR CONCURRENT THERAPY: See Disease Characteristics