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.     

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.     

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.     

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.     

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.     

The relationship between the CYP2D6 polymorphisms and tamoxifen efficacy in adjuvant endocrine therapy of breast cancer patients in Chinese Han population

Variants of the CYP2D6 gene may lead to a poor prognosis of tamoxifen (TAM)‐treated patients. Our study validated the association between the CYP2D6 genotype and outcomes of patients receiving TAM in adjuvant endocrine therapy. A total of 778 breast cancer patients who received adjuvant TAM (n = 325) or aromatase inhibitors (AIs) (n = 453) at the National Cancer Center were analyzed. Nine single nucleotide polymorphisms (SNPs) in the CYP2D6 gene were selected from online databases. The associations of each SNP genotype with disease‐free survival (DFS) and clinicopathological characteristics were analyzed. A total of 167 (21.5%) patients carried the CYP2D6*10 (c.100C>T) T/T genotype. Among the 325 patients who received TAM, the 5‐year DFS rate was considerably lower in CYP2D6*10 T/T genotype patients than C/C or C/T patients (54.9% vs. 70.9%, p = 0.007). The T/T genotype for CYP2D6*10 was a significant prognostic marker for DFS in multivariate analysis (hazard ratio = 1.87; p = 0.006). The CYP2D6*10 genotype in women who received AIs was not significantly associated with DFS (p = 0.332). Other SNPs were not related to the survival of patients who received TAM. Our finding showed patients with CYP2D6*10 T/T received less benefit from TAM adjuvant treatment. This conclusion may optimize the individualized treatments for this subgroup of patients.     

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.     

CYP2C19*17 is associated with decreased breast cancer risk

Cytochrome P450 2C19 (CYP2C19) plays an important role in the metabolism of xenobiotics and drugs and contributes to the catabolism of endogenous substrates like estradiol. Genetic variability impacts expression and activity of CYP2C19 and therefore can influence catabolism of estrogens. In the present study we analyzed the association of three polymorphisms of CYP2C19 namely CYP2C19*2 (CYP2C19_681_G>A, rs4244285), CYP2C19*3 (CYP2C19_636_G>A, rs57081121) and CYP2C19*17 (CYP2C19_-806_C>T, rs12248560), with breast cancer susceptibility. We genotyped 1,015 breast cancer cases and 1,021 age-matched, population-based controls of the German GENICA study by matrix assisted laser desorption/ionization time-of-flight mass spectrometry. Risk estimates were calculated by logistic regression. All tests were two-sided. We observed a decreased breast cancer risk for carriers of the CYP2C19*17 allele (OR 0.77, 95% CI: 0.65–0.93; P = 0.005). In subgroup analysis we observed a significant decreased breast cancer risk for women using hormone therapy for ten years or longer who were carriers of the CYP2C19*17 allele (OR 0.57, 95% CI: 0.39–0.83; P = 0.003). Since CYP2C19*17 defines an ultra rapid metabolizer phenotype we suggest that an increased catabolism of estrogens by CYP2C19 may lead to decreased estrogen levels and therefore reduces breast cancer risk. This protective effect seems to be stronger in combination with long-term intake of supplemental estrogens during hormone therapy.     

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。     

CYP2W1, CYP4F11 and CYP8A1 polymorphisms and interaction of CYP2W1 genotypes with risk factors in Mexican women with breast cancer

Breast cancer (BCa) is the leading type of cancer in Mexican women. Genetic factors, such as single nucleotide polymorphisms (SNP) of P450 system, have been reported in BCa. In this report, and for the first time in the literature, we analyzed the rs3735684 (7021 G>A), rs11553651 (15016 G>T) and rs56195291 (60020 C>G) polymorphisms in the CYP2W1, 4F11 and 8A1 genes in patients with BCa and in healthy Mexican women to identify a potential association between these polymorphisms and BCa risk. Patients and controls were used for polymorphism analysis using an allelic discrimination assay with TaqMan probes and confirmed by DNA sequencing. Links with clinic-pathological characteristics were also analyzed. Statistical analysis was performed using the standard χ2 or Fisher exact test statistic. No significant differences were observed in the distributions of CYP2W1 (OR 8.6, 95%CI 0.43-172.5 P>0.05; OR 2.0, 95%CI 0.76-5.4, P>0.05) and CYP4F11 (OR 0.3, 95%CI 0.01-8.4 P>0.05) genotypes between the patients and controls. Only the CYP8A1 CC genotype was detected in patients with BCa and the controls. All polymorphism frequencies were in Hardy-Weinberg Equilibrium (HWE) in the controls (P>0.05). We found a significant association between BCa risk and smoking, use of oral contraceptives or hormonal replacement therapy (HRT), obesity, hyperglycemia, chronic diseases, family history of cancer and menopausal status in the population studied (P<0.05). Tobacco, oral contraceptive or HRT, chronic diseases and obesity or overweight were strongly associated with almost eight, thirty-five, nine and five-fold increased risk for BCa. Tobaco, obesity and hyperglycemia significantly increased the risk of BCa in the patients carrying variant genotypes of CYP2W1 (P<0.05). These results indicate that the CYP2W1 rs3735684, CYP4F11 rs11553651 and CYP8A1 rs56195291 SNPs are not a key risk factor for BCa in Mexican women. This study did not detect an association between the CYP2W1, 4F11 and 8A1 genes polymorphisms and BCa risk in a Mexican population. However, some clinico-pathological risk factors interact with CYP2W1 genotypes and modifies susceptibility to BCa.     

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.     

The TP53 Arg72Pro and MDM2 309G>T polymorphisms are not associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers

Background:

The TP53 pathway, in which TP53 and its negative regulator MDM2 are the central elements, has an important role in carcinogenesis, particularly in BRCA1- and BRCA2-mediated carcinogenesis. A single nucleotide polymorphism (SNP) in the promoter region of MDM2 (309T>G, rs2279744) and a coding SNP of TP53 (Arg72Pro, rs1042522) have been shown to be of functional significance.

Methods:

To investigate whether these SNPs modify breast cancer risk for BRCA1 and BRCA2 mutation carriers, we pooled genotype data on the TP53 Arg72Pro SNP in 7011 mutation carriers and on the MDM2 309T>G SNP in 2222 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analysed using a Cox proportional hazards model within a retrospective likelihood framework.

Results:

No association was found between these SNPs and breast cancer risk for BRCA1 (TP53: per-allele hazard ratio (HR)=1.01, 95% confidence interval (CI): 0.93–1.10, P_trend=0.77; MDM2: HR=0.96, 95%CI: 0.84–1.09, P_trend=0.54) or for BRCA2 mutation carriers (TP53: HR=0.99, 95%CI: 0.87–1.12, P_trend=0.83; MDM2: HR=0.98, 95%CI: 0.80–1.21, P_trend=0.88). We also evaluated the potential combined effects of both SNPs on breast cancer risk, however, none of their combined genotypes showed any evidence of association.

Conclusion:

There was no evidence that TP53 Arg72Pro or MDM2 309T>G, either singly or in combination, influence breast cancer risk in BRCA1 or BRCA2 mutation carriers.