CYP2D6 gene variants and effectiveness of adjuvant tamoxifen in breast cancer

CYP2D6基因变异和他莫昔芬辅助治疗乳腺癌的有效性

• 批准号: 8189263
• 负责人: CAROLYN SUE RICHARDS
• 金额: $ 66.72万
• 依托单位: KAISER FOUNDATION RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8189263
• 关键词: Address; Adherence; Adjuvant; Adjuvant Therapy; Adverse effects; Affect; Alleles; Aromatase Inhibitors; Bioinformatics; Breast Cancer Treatment; CYP2D6 gene; Case-Control Studies; Categories; Caucasians; Caucasoid Race; Cessation of life; Characteristics; Classification; Clinical; Clinical Trials; Collaborations; Computerized Medical Record; Cytochrome P450; Cytochromes; DNA; Data Analyses; Diagnosis; Diagnostic; Dose; ERBB2 gene; Effectiveness; Enzymes; Epidemiology; Epidermal Growth Factor Receptor; Estrogen Receptors; Estrogen receptor positive; Formalin; Gene Combinations; Genes; Genetic; Genetic Variation; Genomics; Genotype; Goals; Hawaii; Health Planning; Health Sciences; Heterogeneity; Hormone Receptor; Human; Individual; Inherited; Laboratories; Lead; Learning; Managed Care; Metabolism; Methods; Molecular; Molecular Genetics; Operative Surgical Procedures; Oregon; Osteoporosis; Outcome; Paraffin Embedding; Pathologic; Pharmaceutical Preparations; Pharmacy facility; Population; Postmenopause; Publishing; Records; Recurrence; Reporting; Research; Rest; Risk; Selective Estrogen Receptor Modulators; Serum; Study Subject; Subgroup; System; Tamoxifen; Testing; Therapeutic Agents; Tissue Sample; Tissues; Translational Research; Universities; Variant; Woman; base; biobank; cancer recurrence; cancer therapy; enzyme activity; functional status; genetic variant; malignant breast neoplasm; member; novel; patient population; population based; response; treatment response; tumor

DESCRIPTION (provided by applicant): Tamoxifen is a cornerstone of adjuvant therapy for hormone-receptor- positive breast cancer. Tamoxifen is metabolized to the active metabolite endoxifen through enzymatic activity of a P450 gene, cytochrome 2D6 (CYP2D6), which has numerous variant alleles. Among women who take tamoxifen, those homozygous for inactive alleles have lower levels of serum endoxifen than those with two functional alleles. Several studies have reported increased risk of breast cancer recurrence or death in women homozygous for CYP2D6 inactive alleles, but others have found no association between CYP2D6 function and outcome. Larger studies, including population-based studies, are needed. We propose to explore this question in the large health plan member populations of Kaiser Permanente Northwest (KPNW) and Kaiser Permanente Hawaii (KPH). We will conduct a population-based case-control study to evaluate the hypotheses that, after adjuvant tamoxifen treatment for breast cancer, women with CYP2D6 genotypes associated with poor metabolism of tamoxifen have an elevated risk of breast cancer recurrence compared to women with CYP2D6 genotypes associated with extensive metabolism of tamoxifen. We further hypothesize that women with CYP2D6 genotypes associated with intermediate metabolism of tamoxifen are at intermediate risk. Study subjects will be drawn from all women in the two health plans diagnosed with hormone-receptor positive breast cancer from 1986 to 2007 who received adjuvant tamoxifen treatment and for whom stored formalin-fixed paraffin-embedded (FFPE) tissue is available for laboratory analysis. Cases (600) will be women with breast cancer recurrence. Randomly selected controls (1,200), women whose breast cancers did not recur, will be matched 2:1 to cases on pathologic and demographic characteristics. The Oregon Health & Science University (OHSU) Molecular Genetics Laboratory will extract genomic DNA from stored formalin-fixed paraffin-embedded tissue blocks and will perform the molecular testing to accurately determine CYP2D6 variant status. We will analyze CYP2D6 functional status in relation to breast cancer recurrence, considering other factors that may alter the association, in particular tamoxifen dose and duration, as well as concomitant medications that alter the activity of the CYP2D6 enzyme. This collaboration brings together Kaiser Permanente's access to two large health plan member populations, clinical biorepositories, and sophisticated epidemiologic and bioinformatics capabilities with OHSU's extensive laboratory capabilities and expertise in molecular genetics to expand the spectrum of translational research. Our ultimate goal is to learn more about the genetic factors underlying breast cancer treatment response in order to make breast cancer treatment more targeted and more effective. PUBLIC HEALTH RELEVANCE: Women with estrogen-receptor positive breast cancer may benefit from treatment with tamoxifen. However, a significant proportion of women do not respond well to the drug. Research suggests that genetic factors may be the reason. We will assess whether women with CYP2D6 genetic variants respond differently to tamoxifen treatment for breast cancer in two large populations. Our project will examine tissue samples for 1,800 women who received tamoxifen therapy over 22+ years to determine whether women with CYP2D6 variations respond better, or more poorly, to tamoxifen. We willl use pharmacy records to learn which women took tamoxifen, as well as other medications that may interfere with tamoxifen. We will use the electronic medical records of two managed care organizations, Kaiser Permanente Northwest and Kaiser Permanente Hawaii. We will also make use of the laboratory capabilities of Oregon Health & Sciences University. Our goal is to understand the genetic factors that affect women's response to tamoxifen so that women can receive treatment for breast cancer that is more targeted and effective.

描述（由申请人提供）：他莫昔芬是乳腺癌受体阳性乳腺癌辅助治疗的基石。他莫昔芬通过P450基因细胞色素2D 6（CYP 2D 6）的酶活性代谢为活性代谢物内昔芬，该基因具有许多变体等位基因。在服用他莫昔芬的妇女中，那些非活性等位基因纯合子的血清内昔芬水平低于那些有两个功能等位基因的妇女。一些研究报道了CYP 2D 6非活性等位基因纯合子女性乳腺癌复发或死亡的风险增加，但其他研究发现CYP 2D 6功能与结果之间没有关联。需要更大规模的研究，包括基于人群的研究。我们建议探讨这个问题，在大型健康计划的成员人口凯撒永久西北（KPNW）和凯撒永久夏威夷（KPH）。我们将进行一项基于人群的病例对照研究，以评估以下假设：在乳腺癌辅助他莫昔芬治疗后，与他莫昔芬广泛代谢相关的CYP 2D 6基因型女性相比，与他莫昔芬代谢不良相关的CYP 2D 6基因型女性乳腺癌复发风险升高。我们进一步假设，与他莫昔芬中间代谢相关的CYP 2D 6基因型的妇女处于中等风险。研究受试者将从1986年至2007年两个健康计划中诊断为乳腺癌受体阳性的所有女性中抽取，这些女性接受了他莫昔芬辅助治疗，并且储存的福尔马林固定石蜡包埋（FFPE）组织可用于实验室分析。例（600）将是乳腺癌复发的妇女。随机选择的对照组（1，200名），乳腺癌未复发的女性，将与病理和人口统计学特征的病例进行2：1匹配。俄勒冈州健康与科学大学（OHSU）分子遗传学实验室将从储存的福尔马林固定石蜡包埋组织块中提取基因组DNA，并进行分子检测，以准确确定CYP 2D 6变体状态。我们将分析与乳腺癌复发相关的CYP 2D 6功能状态，考虑可能改变相关性的其他因素，特别是他莫昔芬剂量和持续时间，以及改变CYP 2D 6酶活性的合并用药。此次合作将Kaiser Permanente对两个大型健康计划成员群体的访问、临床生物储存库以及复杂的流行病学和生物信息学能力与OHSU广泛的实验室能力和分子遗传学专业知识结合起来，以扩大转化研究的范围。我们的最终目标是更多地了解乳腺癌治疗反应背后的遗传因素，以便使乳腺癌治疗更有针对性，更有效。 公共卫生相关性：雌激素受体阳性乳腺癌女性可能会从他莫昔芬治疗中受益。然而，很大一部分女性对药物反应不佳。研究表明，遗传因素可能是原因。我们将在两个大的人群中评估具有CYP 2D 6遗传变异的妇女对他莫昔芬治疗乳腺癌的反应是否不同。我们的项目将检查1,800名接受他莫昔芬治疗超过22年的妇女的组织样本，以确定CYP 2D 6变异的妇女对他莫昔芬的反应是否更好或更差。我们将使用药房记录来了解哪些妇女服用了他莫昔芬，以及其他可能干扰他莫昔芬的药物。我们将使用两个管理式医疗机构的电子病历，Kaiser Permanente Northwest和Kaiser Permanente夏威夷。我们还将利用俄勒冈州健康与科学大学的实验室能力。我们的目标是了解影响女性对他莫昔芬反应的遗传因素，以便女性能够接受更有针对性和有效的乳腺癌治疗。