CYP2D6基因多态性与乳腺癌内分泌治疗

CYP2D6是细胞色素P450的一种同工酶,代谢许多临床常用药物。其基因的多态性可以影响他莫昔芬的代谢,从而导致携带不同基因型的乳腺癌患者对他莫昔芬的反应性不同。本文简要综述了CYP2D6基因多态性与他莫昔芬代谢和疗效的关系,药物间的相互作用对他莫昔芬代谢的影响,以及针对不同患者选择个体化内分泌治疗方案。     

乳腺癌患者CYP2D6基因多态性与他莫昔芬代谢相关性研究

目的 探究乳腺癌患者CYP2D6基因多态性与他莫昔芬药物代谢产物浓度之间的关系。方法 收集2010年1月—2012年12月我院乳腺癌患者的外周血样本,检测CYP2D6基因上rs16947,rs1065852和rs28371725三种单核苷酸多态性(Single nucleotide polymorphism,SNP)位点的基因型及他莫昔芬代谢产物在血液中的浓度。应用非参数检验中的独立样本Kruskal-Wallis检验进行统计学分析。结果 CYP2D6基因上rs16947位点不同基因型携带者间他莫昔芬代谢产物4-OH-N-D-TAM和4'OH-N-D-TAM在血液中的浓度具有统计学差异(P=0.049),表明CYP2D6基因上的rs16947位点影响他莫昔芬药物在人体内的代谢。结论 乳腺癌患者CYP2D6基因rs16947位点的基因型与部分他莫昔芬代谢产物的血液浓度有关。     

CYP2D6基因多态性与乳腺癌患者盐酸表柔比星治疗疗效的相关性研究

目的 探讨CYP2D6基因多态性对乳腺癌患者盐酸表柔比星治疗预后的影响.方法 筛选125例雌激素受体阳性的乳腺癌患者,采用常规酚-氯仿法行全血基因组DNA提取,采用TaqMan MGB RT-PCR法进行CYP2D6基因多态性检测,利用分析软件确定各个样本的基因分型结果(C/C:野生型,C/T:突变杂合子,T/T:突变型).结果 125例乳腺癌患者中,野生型46例(36.8％),突变杂合子55例(44.0％),突变型24例(19.2％).不同CYP2D6*10基因突变型患者的盐酸表柔比星不良反应发生率比较,差异无统计学意义(P﹥0.05).T/T组患者的盐酸表柔比星不良反应发生率低于C/C+C/T组.T/T、C/C和C/T组患者的生存时间比较,差异有统计学意义(P﹤0.05),C/C+C/T组患者的生存时间短于T/T组患者,差异有统计学意义(P﹤0.05).肿瘤最大直径为2～5 cm、淋巴结转移个数≥4、孕激素受体(+++)、CYP2D6(C/T)是影响患者生存时间的独立危险因素.结论CYP2D6*10基因多态性与静脉滴注盐酸表柔比星的雌激素受体阳性的乳腺癌患者生存期缩短有相关性.     

Impact of CYP2D*6 in the adjuvant treatment of breast cancer patients with tamoxifen

Biotransformation of tamoxifen to the potent antiestrogen endoxifen is performed by cytochrome P450 (CYP) enzymes, in particular the CYP2D6 isoform. CYP2D6*4 is one of the most frequent alleles associated with loss of enzymatic activity. The incidence of CYP2D6*4 among Caucasians is estimated up to 27%, while it is present in up to 90% of all poor metabolizers within the Caucasian population. The hypothesis under question is whether the presence of one or two non-functioning (null) alleles predicts an inferior outcome in postmenopausal women with breast cancer receiving adjuvant treatment with tamoxifen. The numerous existing studies investigating the association of CYP2D6 with treatment failure in breast cancer are inconsistent and give rather conflicting results. Currently, routine CYP2D6 testing among women with breast cancer is not recommended and the significance of CYP2D6 phenotype in decision making regarding the administration of tamoxifen is unclear. The present study summarizes current literature regarding clinical studies on CYP2D6*4, particularly in terms of response to tamoxifen therapy and breast cancer outcome.     

CYP2D6与他莫昔芬疗效相关性的研究进展

CYP2D6是一种重要的P450系氧化代谢酶,是他莫昔芬在体内代谢成更强抗雌激素作用代谢产物endoxifen的重要代谢酶,因此,强代谢乳腺癌患者服用他莫昔芬后引起明显的潮热症状,而潮热症状的发生与他莫昔芬疗效正相关。除了CYP2D6基因多态性可能影响他莫昔芬体内的代谢外,帕罗西汀（paroxetine）可竞争性抑制CYP2D6对他莫昔芬的代谢,使乳腺癌患者对他莫昔芬疗效明显降低。     

甘肃地区乳腺癌患者的CYP2D6基因多态性及代谢表型特征分析

目的:分析乳腺癌患者的CYP2D6基因多态性和代谢表型,为乳腺癌患者进行他莫西芬（TAM）个体化临床治疗提供参考依据。方法:选取2018年1月至2019年1月于我院乳腺科确诊的170例乳腺癌患者外周血,通过Sanger测序技术对CYP2D6基因的9个外显子进行全面具体分析。结果:本研究主要发现有5个CYP2D6等位基因变异位点:CYP2D6*10、CYP2D6*4、CYP2D6*7、CYP2D6*41和CYP2D6*5,其对应的发生频率分别为66.5%、5.9%、2.4%、0.6%和0.6%;其中,CYP2D6*10/*10基因型在乳腺癌患者中占据主导地位,发生频率为60.6%。结论:中国甘肃地区乳腺癌患者,多以CYP2D6*10等位基因、CYP2D6*10/*10基因型、TAM中间代谢型为主,这可为乳腺癌患者选择相应的个体化药物治疗方案以及本地区乳腺癌患者今后大规模的药物遗传基因组学研究提供参考数据。     

Effect of CYP2D6 polymorphisms on breast cancer recurrence

BACKGROUND:

Previous studies evaluating the effect of cytochrome P450 2D6 (CYP2D6) polymorphisms on outcomes of adjuvant tamoxifen therapy have been conflicting due to differences in study design, concomitant medications that alter CYP2D6 metabolism, and tamoxifen adherence.

METHODS:

The authors performed CYP2D6 genotyping from whole blood and fresh frozen tumor samples (n 106) in patients at The University of Texas MD Anderson Cancer Center who were receiving, or had received, tamoxifen as adjuvant therapy for early breast cancer (EBC), using the AmpliChip CYP450 Test. Each patient's medical history was assessed for drugs that affected CYP2D6. Fifty‐five patients who had experienced breast cancer recurrence were matched (by date of diagnosis, menopausal status, clinical stage [TNM Staging System], and race) to patients without recurrence.

RESULTS:

Unadjusted for other patient characteristics, the odds ratio for disease recurrence associated with CYP2D6 functional status was 1.0 (95% confidence interval, 0.35‐2.85). After adjustment for stage, CYP2D6 inhibitors (moderate or strong vs none), and follow‐up time, no significant association was found between CYP2D6 genotype and breast cancer recurrence in patients who were treated with adjuvant tamoxifen for EBC.

CONCLUSIONS:

This case‐control study demonstrated no significant effect of CYP2D6 genotype on risk of recurrence in breast cancer patients who received adjuvant tamoxifen therapy. Cancer 2012;. © 2011 American Cancer Society.     

The impact of CYP2D6-predicted phenotype on tamoxifen treatment outcome in patients with metastatic breast cancer

Background:

Cytochrome P450 2D6 (CYP2D6) has a crucial role in the metabolic conversion of tamoxifen into the active metabolite endoxifen. In this cohort study, the effect of CYP2D6-predicted phenotype, defined as the combined effect of CYP2D6 genetic variation and concomitant use of CYP2D6-inhibiting medication, on time to breast cancer progression (TTP) and overall survival (OS) in women who use tamoxifen for metastatic breast cancer (MBC) was examined.

Methods:

We selected patients treated with tamoxifen (40 mg per day) for hormone receptor-positive MBC from whom a blood sample for pharmacogenetic analysis (CYP2D6*3, *4, *5, *6, *10 and *41) was available. Patient charts (n=102) were reviewed to assess TTP and OS, and to determine whether CYP2D6 inhibitors were prescribed during tamoxifen treatment.

Results:

OS was significantly shorter in patients with a poor CYP2D6 metaboliser phenotype, compared with extensive metabolisers (HR=2.09; P=0.034; 95% CI: 1.06–4.12). Co-administration of CYP2D6 inhibitors alone was also associated with a worse OS (HR=3.55; P=0.002; 95% CI: 1.59–7.96) and TTP (HR=2.97; P=0.008; 95% CI: 1.33–6.67) compared with patients without CYP2D6 inhibitors.

Conclusion:

CYP2D6 phenotype is an important predictor of treatment outcome in women who are receiving tamoxifen for MBC. Co-administration of CYP2D6 inhibitors worsens treatment outcome of tamoxifen and should therefore be handled with care.     

Relationships between CYP2D6 phenotype, breast cancer and hot flushes in women at high risk of breast cancer receiving prophylactic tamoxifen: results from the IBIS-I trial

Background:

Several studies have reported discordant results regarding the impact of the CYP2D6 phenotype on both the effectiveness and the degree of endocrine symptoms associated with tamoxifen. Other studies have suggested that menopausal symptoms may be a predictive factor to tamoxifen response.

Methods:

We investigated the relationship between the CYP2D6-predicted phenotype and tamoxifen response in a nested case–control study among women from the International Breast cancer Intervention Study (IBIS-I), which evaluated tamoxifen in the preventive setting.

Results:

In this retrospective analysis of the tamoxifen-treated women in the IBIS-I study, 9 women (16.6%) who developed oestrogen receptor-positive invasive breast cancer had a 2D6 poor or intermediate metaboliser phenotype compared with 45 (20.6%) controls. Adjusted matched logistic regression revealed no significant difference between cases and controls for extensive vs intermediate metaboliser phenotype (OR=0.81 (0.30–2.23), P=0.7) or extensive vs poor metaboliser phenotype (OR=1.02 (0.31–3.32), P=0.9). Controls in the tamoxifen group with a poor metaboliser phenotype developed nonsignificantly fewer hot flushes compared with those with an extensive metaboliser phenotype (OR=0.40 (0.12–1.31)), but those with the intermediate phenotype developed nonsignificantly more hot flushes (OR=1.38 (0.58–3.29)) in an unadjusted analysis.

Conclusion:

Data from the preventive IBIS-I study did not support an association between the CYP2D6 phenotype and breast cancer outcome or the development of endocrine symptoms in tamoxifen-treated women.     

CYP2D6基因多态性对他莫昔芬及托瑞米芬代谢和疗效影响的研究进展

他莫昔芬和托瑞米芬均为选择性的雌激素受体调节剂,通过竞争性结合雌激素受体发挥抗癌作用,是绝经前乳腺癌最常用的辅助内分泌治疗药物,能够显著降低乳腺癌患者的复发和死亡风险。多项研究发现CYP2D6*10基因的突变会影响他莫昔芬的代谢导致预后不良。而托瑞米芬的代谢受CYP2D6基因多态性的影响较小,治疗乳腺癌的疗效与他莫昔芬相当,甚至优于他莫昔芬。本文就CYP2D6基因多态性与两种内分泌药物代谢和疗效的相关性研究作系统阐述。     

新疆汉族与维吾尔族乳腺癌CYP2D6和CYP2C19基因多态性差异研究

目的 探讨新疆汉族与维吾尔族绝经前乳腺癌患者CYP2D6和CYP2C19基因频率分布及他莫昔芬代谢类型以指导临床合理用药.方法 选取2011-06-01-2013-12-01新疆医科大学附属肿瘤医院绝经前激素受体阳性乳腺癌患者中汉族125例和维吾尔族121例,对CYP450中常见突变位点利用TaqMan(R)-MGB技术进行基因检测并确定他莫昔芬代谢类型.结果 CYP2D6(* 1/* 10)、CYP2D6(* 10/* 10)及CYP2C19(* 1/*1)基因型在汉族、维吾尔族两组患者中表达差异有统计学意义,x2值分别为1.123、9.746和5.935,P值分别为0.029、0.002和0.015;而CYP2D6(* 1/*5)、CYP2D6(* 5/*5)、CYP2D6(* 5/* 10)、CYP2C19(* 3/*3)基因型在两组患者中均无表达,差异无统计学意义,P＞0.05.两组中CYP2D6(* 1/*1)、CYP2C19(* 1/*2)、CYP2C19(* 2/*2)、CYP2C19(* 1/*3)和CYP2C19(* 2/*3)基因型差异无统计学意义,P＞0.05.汉族患者他莫昔芬快、中、慢代谢型者比例分别为72.0％、24.0％和4.0％,维吾尔族分别为76.9％、17.4％和5.7％,P＞0.05.结论 汉族、维吾尔族乳腺癌患者中CYP2C19*2、CYP2C19*3基因频率均差异无统计学意义;而CYP2D6* 10等位基因的频率差异有统计学意义;他莫昔芬的代谢类型均以快代谢类型为主,两组之间差异无统计学意义.     

CYP2B6*6 is associated with increased breast cancer risk

The cytochrome P450 2B6 (CYP2B6) is involved in the metabolism of testosterone. Functional changes in this enzyme may influence endogenous hormone exposure, which has been associated with risk of breast cancer. To assess potential associations between two functional polymorphisms CYP2B6_516_G>T (rs3745274) and CYP2B6_785_A>G (rs2279343) and breast cancer risk, we established a specific matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry assay. The GENICA breast cancer case–control study showed associations between the variant genotypes CYP2B6_516_TT and CYP2B6_785_GG and breast cancer risk with odds ratios (ORs) of 1.34 (p = 0.001) and 1.31 (p = 0.002), respectively. A similar effect was observed for carriers of the CYP2B6_516_T allele in a validation study including four independent studies from Germany, Sweden and USA. In a pooled analysis of all five studies involving 4,638 breast cancer cases and 3,594 controls of European ancestry, carriers of the CYP2B6_516_G and the CYP2B6_785_G variant had an increased breast cancer risk with ORs of 1.10 (p = 0.027) and 1.10 (p = 0.031), respectively. We conclude that the genetic variants CYP2B6_516_G and CYP2B6_785_G (designated CYP2B6*6), which are known to decrease activity of the CYP2B6 enzyme, contribute to an increased breast cancer risk.     

Genetic polymorphisms of CYP2D6*10 and CYP2C19*2,*3 are not associated with prognosis,endometrial thickness,or bone mineral density in Japanese breast cancer patients treated with adjuvant tamoxifen

BACKGROUND:

The authors investigated the impact of the genetic polymorphisms cytochrome P450 (CYP) family 2, subfamily D, polypeptide 6, allele *10 (CYP2D6*10) and CYP family 2, subfamily C, polypeptide 19, allele *2,*3 (CYP2C19*2,*3) on disease recurrence in patients with breast cancer who received adjuvant tamoxifen and evaluated the impact of those polymorphisms on endometrial thickness, bone mineral density (BMD), and serum total cholesterol levels.

METHODS:

Patients with primary breast cancer (n=173) who had hormone receptor‐positive tumors and who also received adjuvant tamoxifen were included in the current study. Genetic polymorphisms of CYP2D6*10 and CYP2C19*2,*3 were analyzed.

RESULTS:

Recurrence‐free survival (RFS) rates did not differ significantly between patients with the CYP2D6 *10/*10 genotype (n=40) and patients with the CYP2D6 wild‐type (wt)/wt or wt/*10 genotype (n=133) or between patients with the CYP2C19 *2/*2, *2/*3, or *3/*3 genotypes (n=41) and patients with the CYP2C19 wt/wt, wt/*2, or wt/*3 genotype (n=132). Multivariate analysis indicated that, even after adjustment for well established prognostic factors, these CYP2D6 or CYP2C19 genotypes were not associated significantly with the RFS rate. Moreover, these genotypes did not affect endometrial thickness, BMD, or total cholesterol levels 1 year after the start of tamoxifen treatment.

CONCLUSIONS:

Neither the CYP2D6 *10/*10 genotype nor the CYP2C19 genotype is likely to have a clinically significant impact on prognosis, endometrial thickness, BMD, or total cholesterol levels in Japanese patients with breast cancer who are treated with adjuvant tamoxifen. Cancer 2009. © 2009 American Cancer Society.     

CYP2D6 Genotype and Risk of Recurrence in Tamoxifen Treated Breast Cancer Patients

Background: Despite consistent pharmacogenetic effects of CYP2D6 on tamoxifen exposure, there isconsiderable controversy regarding the validity of CYP2D6 as a predictor of tamoxifen outcome. Understandingthe current state of evidence in this area and its limitations is important for the care of patients who requireendocrine therapy for breast cancer. Materials and Methods: A total of 101 patients with breast cancer whoreceived tamoxifen therapy for at least 3 years, were genotyped for common alleles of the CYP2D6 gene bynested-PCR and restriction fragment length polymorphism PCR. Patients were classified as extensive or poormetabolizers (PM) based on CYP2D6*4 alleles in 3 different groups according to the menopause, Her2-neustatus, and stage 3. Results: The mean age of the patients with the disease recurrence was 50.8±6.4 and in nonrecurrent patients was 48.2±6.8. In this study 63.3% (n=64) patients were extensive metabolizers and 36.6%(n=37) were poor metabolizers. Sixty four of the 101 patients (63.3%) were Her2-neu positive. For tamoxifentreatedpatients, no statistically significant difference in rate of recurrence observed between CYP2D6 metabolicvariants in stage 3 and post-menopausal patients. However, there was a significant association between CYP2D6genotype and recurrence in tamoxifen-treated Her2-neu positive patients. Compared with other women withbreast cancer, those with Her2-neu positive breast cancer and extensive metabolizer alleles had a decreasedlikelihood of recurrence. Conclusions: This study for the first time demonstrated significant effects of CYP2D6extensive metabolizer alleles on risk of recurrence in Her2-neu positive breast cancer patients receiving adjuvanttamoxifen therapy. Therefore, CYP2D6 metabolism, as measured by genetic variation, can be a predictor ofbreast cancer outcome in Her2-neu positive women receiving tamoxifen.     

Impact of cytochrome P450 2D6 polymorphisms on decision-making and clinical outcomes in adjuvant hormonal therapy for breast cancer

BACKGROUNDThere are concerns that tamoxifen is less effective in Asian women because of the high prevalence of impaired function cytochrome P450 2D6 (CYP2D6) polymor-phisms.AIMTo evaluate how knowledge of CYP2D6 genotype impacted the choice of hormonal agent and how CYP2D6 genotype and agent were associated with clinical outcomes.METHODSEighty-two women were recruited. Seventy-eight completed CYP2D6 genotyping and were categorized into poor, intermediate (IM) and extensive or ultra metabolizer phenotypes. Women with poor metabolizer and IM phenotypes were recommended aromatase inhibitors as the preferred agent.RESULTSMore than 70% of the women had an IM phenotype, 32% an extensive or ultra metabolizer phenotype, and 0% had a poor metabolizer phenotype. Regardless of genotype, more women opted for aromatase inhibitors. Overall, 80% of women completed 5 years of hormonal therapy. Five women developed recurrence, 3 contralateral breast cancer, 5 died, and 1 was diagnosed with a second primary cancer. Five-year recurrence-free and overall survival were slightly better in women with the extensive or ultra metabolizer phenotype compared to those with the IM phenotype, though not statistically significant [P = 0.743, hazard ratio (HR): 1.441, 95% confidence interval (CI): 0.191 to 10.17 and P = 0.798, HR: 1.327, 95%CI: 0.172 to 9.915, respectively]. Women receiving aromatase inhibitors also appeared to have a better, but also nonsignificant, 5-year recurrence-free and overall survival (P = 0.253, HR: 0.368, 95%CI: 0.031 to 0.258 and P = 0.292, HR: 0.252, 95%CI: 0.005 to 4.951, respectively).CONCLUSIONThe IM phenotype was highly prevalent but was not associated with clinical outcome.     

FGFR2 gene polymorphisms are associated with breast cancer risk in the Han Chinese population

Aims and background: Breast cancer is one of the most common neoplasms among women in many developing countries including China, and is the leading cause of female cancer-related deaths worldwide. Methods: In the current study, we analyzed the relationship between 14 tag single-nucleotide polymorphisms (tSNPs) and breast cancer risk in the Han Chinese population including 185 breast cancer patients and 199 healthy women controls on the different types of breast cancer and menopausal status. Results: Overall, we found rs2981579 in the FGFR2 gene, and rs2380205 were associated with breast cancer susceptibility.Conclusions:These findings indicate that FGFR2 was associated with breast cancer risk in the Han Chinese population, support the hypothesis that the applicability of a common susceptibility locus must be confirmed among genetically different populations.     

Effect of CYP2D6 genetic polymorphism on the population pharmacokinetics of tipifarnib

Objective: Evaluate the effect of CYP2D6 genotype on the pharmacokinetics of tipifarnib. Methods: A total of 268 subjects included in six clinical trials were treated orally with tablet formulation of tipifarnib, as a single dose or as multiple b.i.d. doses (range 50–600 mg), and/or intravenously following 1, 2, and 24 h infusions. A total of 2,575 tipifarnib concentrations were fitted to an open three-compartment linear disposition model with sequential zero-order input into the depot compartment, followed by a first-order absorption process, and lag time, using NONMEM V. The effect of CYP2D6 genotype was explored as a covariate for tipifarnib systemic clearance and absolute bioavailability. Likelihood ratio test was used to compare these parameters in homozygous extensive metabolizers (EM) (N=152), heterozygous EM (N=97), or poor metabolizers (PM) (N=19). Computer simulations were undertaken to explore the CYP2D6 genotype effect on the tipifarnib pharmacokinetics. Results: The ratio of tipifarnib systemic clearance for the heterozygous EM and the PM subjects, relative to the homozygous EM group, were 0.95 (95%CI 0.87–1.03) and 0.96 (95%CI 0.82–1.11), respectively (χ²=2.376, df=2, P=0.305). The ratio of tipifarnib absolute bioavailability for the heterozygous EM and the PM, relative to the homozygous EM, were 1.06 (95%CI 0.83–1.30) and 0.95 (95%CI 0.55–1.34), respectively (χ²=1.398, df=2, P=0.497). Conclusions: These results indicate that CYP2D6 genetic polymorphism does not appreciably influence the pharmacokinetics of tipifarnib. Hence, concomitant administration of potent CYP2D6 inhibitors is anticipated to have little or no significant impact on the systemic exposure to tipifarnib.Supported by Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Raritan, NJ     

Effects of CYP2D6 and SULT1A1 genotypes including SULT1A1 gene copy number on tamoxifen metabolism.

BACKGROUND: Tamoxifen is hydroxylated by cytochrome P450 (CYP) 2D6 to the potent metabolites 4-hydroxytamoxifen (4OHtam) and 4-hydroxy-N-demethyltamoxifen (4OHNDtam), which are both conjugated by sulphotransferase (SULT)1A1. Clinical studies indicate that CYP2D6 and SULT1A1 genotypes are predictors for treatment response to tamoxifen. Therefore, we examined the relationship between CYP2D6 genotype, SULT1A1 genotype, SULT1A1 copy number and the pharmacokinetics of tamoxifen. PATIENTS AND METHODS: The serum levels of tamoxifen and metabolites of 151 breast cancer patients were measured by high-pressure liquid chromatography-tandem mass spectrometry. The CYP2D6 and SULT1A1 polymorphisms and SULT1A1 copy number were determined by long PCR, PCR-based restriction fragment length polymorphism, DNA sequencing and fluorescence-based PCR. RESULTS: The levels of 4OHtam, 4OHNDtam and N-demethyltamoxifen were associated with CYP2D6 predicted enzymatic activity (P < 0.05). The SULT1A1 genotype or copy number did not influence the levels of tamoxifen and its metabolites. However, the ratios of N-demethyltamoxifen/tamoxifen and N-dedimethyltamoxifen/N-demethyltamoxifen were related to SULT1A1 genotype. CONCLUSION: CYP2D6 and SULT1A1 genotypes may partly explain the wide inter-individual variations in the serum levels of tamoxifen and its metabolites. We propose that therapeutic drug monitoring should be included in studies linking CYP2D6 and SULT1A1 genotypes to clinical outcome.