CYP2D6 gene variants and effectiveness of adjuvant tamoxifen in breast cancer

描述（由申请人提供）：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）的酶活性代谢为活性代谢物内毒素，该基因具有许多变异等位基因。在服用他莫昔芬的妇女中，无活性等位基因纯合子的血清内毒素水平低于具有两个功能等位基因的妇女。一些研究报告了CYP2D6失活等位基因纯合的女性乳腺癌复发或死亡的风险增加，但其他研究发现CYP2D6功能与预后之间没有关联。需要更大规模的研究，包括基于人群的研究。我们建议在Kaiser Permanente Northwest （KPNW）和Kaiser Permanente Hawaii （KPH）的大型健康计划成员人群中探索这个问题。我们将开展一项基于人群的病例对照研究，以评估以下假设：在对乳腺癌进行他莫昔芬辅助治疗后，CYP2D6基因型与他莫昔芬代谢不良相关的女性与CYP2D6基因型与他莫昔芬广泛代谢相关的女性相比，乳腺癌复发的风险更高。我们进一步假设CYP2D6基因型与他莫昔芬中度代谢相关的女性处于中等风险。研究对象将从1986年至2007年两项健康计划中诊断为激素受体阳性乳腺癌的所有妇女中抽取，这些妇女接受了他莫昔芬辅助治疗，并储存了福尔马林固定石蜡包埋（FFPE）组织供实验室分析。病例（600例）均为乳腺癌复发妇女。随机选择的对照组（1200名），乳腺癌未复发的妇女，将与病理和人口统计学特征的病例2:1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功能状态与乳腺癌复发的关系，考虑到其他可能改变这种关联的因素，特别是他莫昔芬的剂量和持续时间，以及伴随药物改变CYP2D6酶的活性。此次合作将Kaiser Permanente的两大健康计划成员群体、临床生物储存库、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在一起，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。

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.