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: 8309965
• 负责人: CAROLYN SUE RICHARDS
• 金额: $ 61.38万
• 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/8309965
• 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.

描述(申请人提供)：他莫昔芬是激素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2D6(CYP2D6)的酶活性代谢成活性代谢物Enoxifen，该基因有许多变异的等位基因。在服用他莫昔芬的女性中，那些携带非活性等位基因的纯合子的女性的血清内毒素水平低于那些携带两个功能等位基因的女性。一些研究报告称，携带CYP2D6非活性等位基因纯合的女性会增加乳腺癌复发或死亡的风险，但其他研究发现，CYP2D6功能与预后之间没有关联。需要进行更大规模的研究，包括基于人群的研究。我们建议在Kaiser Permanente Northwest(KPNW)和Kaiser Permanente Hawaii(KPH)的大型健康计划成员群体中探索这个问题。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：在辅助他莫昔芬治疗乳腺癌后，携带与他莫昔芬代谢不良相关的CYP2D6基因的女性与携带与广泛代谢他莫昔芬相关的CYP2D6基因的女性相比，乳腺癌复发的风险更高。我们进一步假设，携带与他莫昔芬中间代谢相关的CYP2D6基因的女性处于中等风险。研究对象将从1986至2007年间两个健康计划中被诊断为激素受体阳性乳腺癌的所有接受三苯氧胺辅助治疗且可用于实验室分析的福尔马林固定石蜡包埋(FFPE)组织的妇女中抽取。病例(600例)将是乳腺癌复发的妇女。随机选择的对照组(1200名)，即乳腺癌没有复发的女性，将在病理和人口学特征上与病例进行2：1的匹配。俄勒冈健康与科学大学(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，并将进行分子测试，以准确确定CYP2D6变异状态。我们将分析CYP2D6的功能状态与乳腺癌复发的关系，考虑可能改变这种联系的其他因素，特别是他莫昔芬的剂量和持续时间，以及改变CYP2D6酶活性的伴随药物。这一合作将Kaiser Permanente与OHSU在分子遗传学方面的广泛实验室能力和专业知识相结合，将Kaiser Permanente接触到两大健康计划成员群体、临床生物库和复杂的流行病学和生物信息学能力结合在一起，以扩大翻译研究的范围。我们的最终目标是更多地了解乳腺癌治疗反应的遗传因素，以便使乳腺癌治疗更有针对性和更有效。