Genetic Study of CYP2D6 Enzyme and Therapeutic Drug Monitoring of Tamoxifen in Premenopausal Women With Breast Cancer
试验速览
- 阶段
- 不适用
- 入组人数
- 100
- 主要终点
- Estimate the frequency of Cyp2D6*1 and *4 alleles in Egyptian patients maintained on tamoxifen (20 mg/day) for management of ER +ve breast cancer.
研究概览
简要总结
Aim of work:
- To estimate the frequency of Cyp2D6*1 and *4 alleles in Egyptian patients maintained on tamoxifen (20 mg/day) for management of ER +ve breast cancer.
- To measure levels of tamoxifen, 4-hydroxy tamoxifen, N-desmethyl-tamoxifen and 4- hydroxyl-N-desmethyl-tamoxifen (endoxifen) in the serum of these patients.
- To correlate between the levels of tamoxifen/active metabolite enoxifen ratio and CYP2D6*1,*4 genotyping.
- To investigate which is more valuable investigatory tool for prediction of the clinical outcome (response and/or toxicity) in these patients; either the measurements related to pharmacokinetics: tamoxifen/endoxifen levels or the pharmacogenetic analysis of CYP2D6 *1,*4.
详细描述
Breast cancer is considered to be the most common cancer among women worldwide. The majority of breast cancer cases (almost 80%) are classified as hormone-dependent cancer, since estrogen, acting via estrogen receptor alpha (ER-α) or estrogen receptor beta (ER-β), is the major inducer of the development and growth of the tumor. These are also called ER-positive breast cancers. The remaining cases are not induced by estrogen and are classified as hormone-independent, or ER-negative, cancers. Since the growth of hormone-dependent cancer cells can be down-regulated by the oppositely active hormones, several endocrine therapies that limit the actions of estrogen (through blocking its production or its receptors) have been developed over the past years. These endocrine therapies have played an important part in treating and improving the outcomes of women with all stages of the disease . Selective estrogen receptor modulators (SERMs) have also been studied for their anti-cancer activity.
Selective estrogen receptor modulators (SERMs) are a class of drugs that act on the estrogen receptor (ER); a characteristic that distinguishes these substances from pure ER agonists and antagonists as their action is different in various tissues, thereby granting the possibility to selectively inhibit or stimulate estrogen-like action in various tissues .
Tamoxifen, which is a SERM, is important for the treatment and prevention of estrogen receptor (ER) positive breast cancer commonly in premenopausal women. It has been shown to decrease disease recurrence and mortality rates by as much as 50% and 30% respectively. It has been also used as a prophylactic treatment for patients who are at high risk of developing breast cancer. Post-menopausal breast cancer patients are commonly treated nowadays with aromatase inhibitors (AIs) for 5 years, alone or combined with tamoxifen for a 3-5 year period. Tamoxifen monotherapy in postmenopausal women with breast cancer may be used for 10 years if the side effects from AIs are too bothersome .
Besides acting as SERMs, it has recently been found that some of tamoxifen's metabolites (as norendoxifen) also act as aromatase inhibitors in vitro. Aromatase converts steroids (e.g., testosterone to estradiol), the inhibition of which severely decreases the amount of available estrogen in the body .
The most common side effects of Tamoxifen:
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 20 Years 至 50 Years（Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Premenopausal patients will be included in this study, with hormone receptor positive tumors.
- •The hormone receptor positive tumor is diagnosed by microscopic examination if ≥ 10% of the cells are positive for estrogen by immunohistochemistry analysis.
- •All patients with normal hepatic and renal function, aspartate aminotransferase and alanine aminotransferase (≤2 upper normal limit) and serum creatinine (≤1.2 mg/dl).
排除标准
- •Patients treated with other hormonal therapy, radiation or chemotherapy will be excluded from the study.
- •Pregnant or breast feeding women will be excluded from the study.
- •Patients who are taking drugs that are known to inhibit CYP2D6 activity as SSRIs will be excluded from the study.
研究组 & 干预措施
responding
patients who received Tamoxifen 20 mg daily for at least 3 years with good response (no relapse) to tamoxifen. Both genotyping assessment and TDM of tamoxifen and its metabolites will be performed and correlated with the records. Follow up for these patients for further assessment of tamoxifen effectiveness will be carried out for 1- 2 years.
干预措施: Tamoxifen 20 mg (Drug)
relapse
patients who received Tamoxifen 20 mg daily for at least 3 years who were good responder to the drug but then the response has been diminished (relapse) and they have been shifted to another therapy. They will be exposed to genotyping study of CYP 2D6 to recognize the phenotyping style of that patient that may explain diminishing of response to tamoxifen therapy.
干预措施: Tamoxifen 20 mg (Drug)
tamoxifen resistant
patients who received Tamoxifen 20 mg daily for not more than 1 year with poor response to tamoxifen (early relapse) and clinically will be shifted to use another medication as they were diagnosed as tamoxifen resistant. Like the second group, they will be exposed to genotyping study of CYP2D6 with the same concept.
干预措施: Tamoxifen 20 mg (Drug)
结局指标
主要结局
Estimate the frequency of Cyp2D6*1 and *4 alleles in Egyptian patients maintained on tamoxifen (20 mg/day) for management of ER +ve breast cancer.
时间窗: 6 months
The CYP2D6 genotypes will be determined using the TaqMan Allelic Discrimination Assay.
次要结局
- measuring levels of tamoxifen, 4-hydroxy tamoxifen, N-desmethyl-tamoxifen and 4- hydroxyl-N-desmethyl-tamoxifen (endoxifen) in the serum ofbreast cancer patients.(2 months)
研究者
Amira Fawzy Taha
Assistant Lecturer
Assiut University