Annals of Oncology Advance Access originally published online on April 11, 2008
Annals of Oncology 2008 19(8):1423-1429; doi:10.1093/annonc/mdn155
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breast cancer |
Association between CYP2D6 *10 genotype and survival of breast cancer patients receiving tamoxifen treatment
1 Breast Center
2 Department of Traditional Chinese Medicine, Beijing Cancer Hospital & Institute, Peking University School of Oncology, Beijing, People's Republic of China
3 Department of Biochemistry and Molecular Biology, Beijing Cancer Hospital & Institute, Peking University School of Oncology, Beijing, People's Republic of China
* Correspondence to: Dr Y. Xie and Dr P. Li, Beijing Cancer Hospital and Institute, Peking University School of Oncology, 100036, Beijing, P. R. China; Tel: +86-10-88196362; E-mail: zlxyt2{at}bjmu.edu.cn or lppma123{at}yahoo.com.cn
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Abstract |
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Background: Human cytochrome P450 2D6 (CYP2D6) genotype may affect the efficacy of tamoxifen treatment in Caucasian women with breast cancer. The most common polymorphism of CYP2D6 in Chinese women is variant 10 (188 C to T).
Patients and methods: Tamoxifen and 4-hydroxytamoxifen (4OHtam) were measured in the serum of 37 women with breast cancer who were receiving tamoxifen treatment. The association between CYP2D6 *10 genotype and survival was determined in a cohort of 293 women with breast cancer who received tamoxifen (n = 152) or who did not (n = 141).
Results: The serum 4OHtam concentrations were significantly lower in women with the CYP2D6 *10 homozygous variant T/T genotype than in those with the homozygous wild-type C/C genotype (P = 0.04). Among tamoxifen-treated women, women with the T/T genotype had a significantly worse disease-free survival (DFS) than those with the C/C or C/T genotype, and the T/T genotype remained an independent prognostic factor of DFS in multivariate analysis (hazard ratio = 4.7; 95% confidence interval = 1.1–20.0; P = 0.04). Among women who did not receive tamoxifen, there was no significant association between CYP2D6 *10 genotype and survival.
Conclusion: In tamoxifen-treated patients, women with the CYP2D6 *10 T/T genotype have a lower 4OHtam level in the serum and a worse clinical outcome.
Key words: breast cancer, CYP2D6 *10 genotype, survival, tamoxifen
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingReferences |
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Tamoxifen, a selective estrogen receptor modulator (SERM), is the first-line endocrine drug in the treatment of all stages of estrogen receptor (ER)-positive breast cancer and is also widely used for breast cancer prevention in high-risk women [1]. However, the clinical response to tamoxifen therapy varies widely from patients to patients, and roughly 35% of patients with ER-positive tumors do not respond to tamoxifen therapy and eventually relapse in the disease [2]. It has been indicated that tamoxifen is a parent drug and its active metabolites have a potent role in inhibiting tumor cell growth. Thus, differences in patient outcomes might be due to individual variation in metabolism of tamoxifen.
Tamoxifen is metabolized by human liver enzymes to several metabolites. The major metabolite, N-desmethyltamoxifen, is produced primarily by cytochrome P450 3A4 (CYP3A4), but this metabolite has a low affinity for the ER [3]. Two minor metabolites of tamoxifen, 4-hydroxytamoxifen (4OHtam) and 4-hydroxy-N-desmethyl tamoxifen (endoxifen), are predominantly catalyzed by cytochrome P450 2D6 (CYP2D6) [3–6]; these two metabolites have much greater affinity for the ER than either tamoxifen or N-desmethyltamoxifen. For instance, 4OHtam exhibits 140-fold greater affinity for the ER and 30- to 100-fold greater potency in suppressing estrogen-dependent tumor cell growth when compared with tamoxifen [7, 8].
CYP2D6 encodes a phase I enzyme and is highly polymorphic in humans, with >90 allelic variants described (http://www.imm.ki.se/cypalleles/) [9]. The most common CYP2D6 variants in Caucasians are variant *3, *4, and *5, resulting in a decreased enzyme activity and leading to poor metabolizer phenotypes [10–12]. The frequency of these variants, however, is <5% in Chinese population [13, 14]. Among Chinese women, the most common polymorphism in CYP2D6 is allelic variant *10 (formerly defined as CYP2D6 Ch1) [13–16], which generates a 188 C to T transition in exon 1, leading to a Proline 34 to Serine amino acid substitution and resulting in an unstable enzyme with lower catalytic activity [15].
Recent studies have showed that women who are homozygous for CYP2D6 *4/*4 genotype have significantly lower plasma endoxifen concentrations and worse clinical outcome than do women who are heterozygous or homozygous for the common allele in Caucasian women who received tamoxifen therapy [4, 5, 17]. Therefore, it would be of great interest to investigate whether CYP2D6 *10 genotype affects the efficacy of tamoxifen in Chinese women who receive tamoxifen treatment. To test this hypothesis, we determined whether CYP2D6 *10 genotype affects the conversion of tamoxifen to 4OHtam in Chinese women. Furthermore, we investigated whether the CYP2D6 *10 genotype is associated with the clinical outcome of breast cancer patients who received tamoxifen (n = 152) or who did not (n = 141).
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patients and methods |
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study subjects
The primary objective in this study was to determine the correlation between CYP2D6 *10 genotype and serum concentrations of tamoxifen and 4OHtam. Eligible women were recruited from the Breast Center at Peking University School of Oncology. Pre- and postmenopausal women (30 years
age 65 years) with newly diagnosed breast cancer who were starting tamoxifen (20 mg/day orally) as standard adjuvant therapy were included in this study. The eligible women had completed all primary surgery, adjuvant chemotherapy, and radiation, and the women had been taking tamoxifen for at least 4 weeks before entering this study. Patients were excluded from the study if they had started tamoxifen therapy concurrently with received cytotoxic chemotherapy, endocrine therapy other than tamoxifen, or radiation therapy. No eligible women were taking concomitant medicines that are known to inhibit CYP2D6 activity. All subjects provided written consent before study entry. Thus, 37 eligible patients were enrolled in this study. The detailed information of these patients is presented in the supplementary table 1 (available online). At the study day, all 37 patients took tamoxifen 10 mg in the morning, 2 h later, a 3-ml blood sample was collected, the serum was isolated for measuring the tamoxifen and 4OHtam concentrations, and the DNA was extracted from the blood cells for CYP2D6 *10 genotyping analysis. No selection of patients by genotype was made, and no otherwise eligible patients were excluded on the basis of CYP2D6 genotype. A secondary objective was to investigate the correlation between the CYP2D6 *10 genotype and survival in breast cancer patients who received tamoxifen treatment or those who did not (received chemotherapy). From December 1994 through November 2005, a total of 161 patients with primary breast cancer were only receiving adjuvant tamoxifen treatment after completion of primary surgery or radiation at Peking University School of Oncology. The blood samples or fresh-frozen tumor tissues were used as a source of DNA for CYP2D6 *10 genotyping if available; otherwise, paraffin-embedded achieved normal lymph nodes were used. Among the 161 patients, DNA was isolated from blood samples in 25 patients, from fresh-frozen tumors in 11 patients, and from the achieved normal lymph nodes in 125 patients. In nine of 161 available specimens, a PCR product could not be obtained because of poor-quality DNA (all nine patients from the achieved normal lymph nodes). Thus, 152 patients with primary early-stage breast cancer were included in this study. Patients received 5-year tamoxifen (20 mg/day orally) treatment after completion of surgery and/or radiation; no women received either pre- or post-adjuvant chemotherapy. The follow-up data were available for all patients, with a median follow-up of 63 months (range, 4 to 122 months); during the follow-up period, 17 patients had developed distant metastases or died of breast cancer.
To investigate the correlation between the CYP2D6 *10 genotype and survival in patients who did not receive tamoxifen treatment (received chemotherapy, either FAC or CMF regimen), fresh tumor samples were collected from January 1985 to September 1996 at Peking University School of Oncology. A total of 385 patients with operable primary breast cancer had fresh-frozen tumor samples for investigation, of whom 166 received chemotherapy (without tamoxifen) and CYP2D6 *10 genotype was successfully determined in these 166 patients.
In this subgroup of patients, the follow-up data were available for 141 patients, with a median follow-up of 120 months (range, 4 to 193 months); during the follow-up period, 54 patients had developed distant metastases or died of breast cancer.
To investigate the concordance of CYP2D6 *10 genotype between the fresh tumors and blood samples, we determined CYP2D6 *10 genotype in 30 patients (from January 2004 to December 2004) whose fresh-frozen tumors and blood samples are available.
This study was approved by the Research and Ethical Committee of Peking University School of Oncology.
hormone receptors
From 1985 to 1999, the levels of ER and progesterone receptor (PR) were measured by the dextran-coated charcoal method. ER or PR was considered positive when the samples contain at least 10 fmol/mg protein. The ER or PR status was determined by immunohistochemistry assay after 1999 and ER or PR was considered positive when 
10% of tumor cells showed positive staining. In addition, the C-erbB2 expression was determined by immunohistochemistry as described elsewhere [18].
measurement of serum concentrations of tamoxifen and 4OHtam
Tamoxifen and 4OHtam concentrations in serum were determined using high-performance liquid chromatography and mass spectrometry assay (LC/MS) as described elsewhere [19, 20], with minor modifications. In brief, this method allowed rapid extraction of tamoxifen and 4OHtam using hexane (95%)–isopropyl alcohol (5%). The mobile phase was composed of solvent A (0.01% formic acid in de-ionized water) and solvent B (0.01% formic acid in methanol). Separation was carried out on a HiQ sil C18W column (2.1 x 150 mm, 5 µm particle size; KYA TECH, Japan) by gradient elution from 40% to 95% solvent B at a flow rate of 0.2 ml/min. The LC/MS system was fitted with electrospray ionization source and the signal was optimized on the 4OHtam ion current in MS/MS mode. Under these conditions, the retention times of propranolol (internal standard), tamoxifen, and 4OHtam were 8.35, 9.25, and 10.10 min, respectively. The limits of quantification were 10 and 1 ng/ml for tamoxifen and 4OHtam, respectively.
DNA extraction and CYP2D6 *10 genotyping
DNA was extracted from blood samples, fresh-frozen tumors, or paraffin-embedded negative axillary lymph nodes by using phenol–chloroform assay.
CYP2D6 *10 genotype was detected using PCR restriction fragment length polymorphism assay as described previously [16]. In brief, PCR reaction was composed of 100 ng of DNA, 0.8 mM deoxyribonucleotide triphosphate, 1.5 mM MgCl2, 1.0x PCR buffer, 0.5 µM each primer (forward: 5'-CCA TTT GGT AGT GAG GCA GGT AT-3'; reverse: 5'-CAC CAT CCA TGT TTG CTT CTG GT-3'), 1.0x Q-solution, and 0.4 unit HotStar Taq DNA polymerase (Qiagen, Chatsworth, CA) in a total volume of 20 µl. The reaction condition was first 94°C for 15 min to activate HotStar Taq DNA polymerase, followed by denaturation at 94°C for 30 s, annealing 57°C for 45 s, and extension 72°C for 45 s. The PCR was run for 35 cycles and finally elongated for 10 min. Ten microliters of PCR product was digested with Hph I restriction enzyme (New England Biolabs, Inc.) for 1 h at 37°C. The digestion products were then resolved on a 2.5% agarose gel containing ethidium bromide.
statistical analysis
The correlation between the genotype variants and clinicopathologic characteristics was determined using Pearson's 
2 test. The differences of the serum concentrations of tamoxifen and 4OHtam between the genotype groups were analyzed using a one-way analysis of variance (ANOVA) test. Disease-free survival (DFS) was defined as the time from date of diagnosis to first distant metastasis or death from breast cancer without a recorded relapse. Disease-specific survival (DSS) was defined as the time from date of diagnosis to death where breast cancer was the primary or underlying cause of death. Patients who were alive at the last follow-up were censored at the last follow-up date, and patients who died from causes other than breast cancer were censored at the time of death. Survival curves were estimated with the Kaplan–Meier method, and the curves were compared by log-rank tests. A Cox regression model was applied to determine whether a factor was an independent predictor of survival in multivariate analysis. All statistical tests were two-sided, P values <0.05 were considered as statistically significant, and the statistical analyses were carried out using SPSS 13.0 software.
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association between CYP2D6 *10 genotype and serum concentrations of tamoxifen and 4OHtam
The serum concentrations of tamoxifen and 4OHtam in 37 breast cancer patients who received tamoxifen are presented in supplementary table 1 (available online). The patient's clinicopathological characteristics, menopausal status, age and body mass index were not significantly different between the genotype groups (data not shown). The levels of serum tamoxifen and 4OHtam concentrations represented normal distribution (P = 0.67 and P = 0.92, respectively, Shapiro–Wilk test) in the 37 patients. Thus, the differences in the serum concentrations of tamoxifen and 4OHtam between the genotype groups were compared using one-way ANOVA test. The mean serum concentration of tamoxifen was not significantly different between the genotype groups (C/C versus C/T or T/T: P = 0.07 or 0.78, respectively) (Table 1). In contrast, the mean serum concentrations of 4OHtam were statistically significantly lower in women with the homozygous variant T/T genotype than in women with the homozygous wild-type C/C genotype (P = 0.04) (Table 1). The serum concentrations of 4OHtam were not significantly different between the homozygous wild-type C/C and heterozygous C/T genotype groups (P = 0.96) (Table 1). Thus, we combined the C/C and C/T genotype on the following survival analysis.
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frequency of CYP2D6 *10 genotype and genotype concordance between tumors and blood samples
CYP2D6 *10 genotype was determined in a total of 293 patients who received adjuvant tamoxifen treatment or who did not. Twenty-four percent (70 of 293) of the patients were homozygous for wild-type C/C genotype, 28% (83 of 293) were heterozygous for C/T genotype, and 48% (140 of 293) were homozygous for variant T/T genotype (Table 2). The frequency of genotypes was similar to our previous study [21]. In addition, we determined the CYP2D6 *10 genotype in 30 patients who have both tumors and blood samples and the concordance of genotype between tumors and blood samples was 100% (30/30); this result was consistent with a previous report [17].
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association between CYP2D6 *10 genotype and survival in patients who received tamoxifen treatment
Among 152 patients who were only receiving adjuvant tamoxifen treatment, no significant associations between the CYP2D6 *10 genotype and age, tumor size, clinical stage, lymph node involvement, adjuvant therapy, surgery, C-erbB2 status, and ER or PR status were found (Table 2). The CYP2D6 *10 genotype was significantly associated with 5-year DFS (Figure 1A), but not with 5-year DSS (Figure 1B) in this subgroup; women with the homozygous variant T/T genotype had a lower 5-year DFS rate than those with the homozygous wild-type C/C or heterozygous C/T genotype (89% versus 96%, P = 0.005) (Figure 1A).
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In multivariate analysis, as compared with the C/T or C/C genotype, the T/T genotype remained an independent prognostic marker of DFS (hazard ratio = 4.7; 95% confidence interval = 1.1–20.0; P = 0.04) (Table 3) after adjusting for age, clinical stage, lymph node involvement, tumor size, adjuvant therapy, surgery, C-erbB2 status, and ER or PR status in this subgroup of 152 patients.
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When the group of women who were receiving tamoxifen was restricted to patients with ER-positive tumors (n = 125), women with the T/T genotype still had a worse DFS than did women with the C/T or C/C genotype (P = 0.03) (Figure 1C), and the T/T genotype remained an independent prognostic factor of DFS in this subgroup of patients (data not shown). Similarly, there was no significant association between the genotype and DSS in these 125 patients (P = 0.18) (Figure 1D).
CYP2D6 *10 genotype and survival in patients who did not receive tamoxifen treatment
Next we investigated whether there was an association between the CYP2D6 *10 genotype and survival in women who did not receive tamoxifen (n = 141). As compared with the group of patients who received tamoxifen, the majority of patients in this subgroup represented ER-negative tumors. Similarly, there was no significant association between CYP2D6 *10 genotype and clinicopathological characteristics in this subgroup of patients (Table 2). Furthermore, the CYP2D6 *10 genotype was not significantly associated with DFS and DSS in this subgroup (P = 0.99 and P = 0.78, respectively) (Figure 2A and B).
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discussion |
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To our knowledge, this is the first study to address the correlation between the CYP2D6 *10 genotype and clinical outcome in Chinese women who received tamoxifen treatment. The CYP2D6 *10 genotype is the most common polymorphism of CYP2D6 in Chinese population. The homozygous variant T/T genotype accounted for
48% of all subjects tested in the present study, which was consistent with previous reports [13–15, 21]. In vitro experiments have shown that the homozygous variant T/T genotype produces an unstable enzyme with shorter half-life and lower activity, and the catalytic activity of the T/T genotype is 1/40th of the activity of the wild-type C/C genotype [15]. Although recent studies showed that endoxifen is a new member of active metabolite of tamoxifen [4, 5], 4OHtam is well documented to be an important active metabolite of tamoxifen [1, 6]. In the present study, we showed that the serum concentration of 4OHtam was influenced by CYP2D6 *10 genotype; patients with the homozygous variant T/T genotype had a lower serum concentration of 4OHtam than did patients with the homozygous wild-type C/C genotype. Based on the results that CYP2D6 *10 genotype may influence the convention of tamoxifen to 4OHtam, we investigated whether these effects contribute to clinical outcome in patients who received adjuvant tamoxifen treatment. In a cohort of 152 breast cancer patients who were receiving tamoxifen treatment, we found that patients with the homozygous variant T/T genotype had a worse DFS than did those with the wild-type C/C or heterozygous C/T genotype, and the T/T genotype remained an independent poor prognostic factor of DFS in this cohort of patients. Our results are similar to the recent findings of Goetz et al. [17] that Caucasian women who carry the CYP2D6 *4/*4 genotype had a worse relapse-free time and DFS than did women with wild-type/*4 or wild-type/wild-type genotype when the women received adjuvant tamoxifen treatment of breast cancer. Other studies, however, found no association between the CYP2D6 genotype and survival in breast cancer patients treated with tamoxifen [22, 23]; the reason for this discrepancy is currently unclear, it may be due to different sample size or patient's selection.
To test the specificity of the association between the CYP2D6 *10 genotype and survival in women receiving tamoxifen treatment, we investigate the association between the CYP2D6 *10 genotype and survival in 141 women who did not receive tamoxifen. There was no significant association between the CYP2D6 *10 genotype and survival in this subgroup, indicating that the CYP2D6 *10 genotype per se was not a prognostic marker. Thus, our present results indicated that disruption of CYP2D6 activity may affect the conversion of tamoxifen to its active metabolites and leads to poor clinical outcome in Chinese women who receive tamoxifen treatment, and women with the variant T/T genotype had a worse DFS, which was likely due, at least in part, to a lower 4OHtam concentration.
We noted that there are several limitations in our study. First, recent study showed that endoxifen is as effective as 4OHtam in suppressing estrogen-dependent tumor cell growth [4]. Due to lack of a standard endoxifen, we did not determine the serum concentrations of endoxifen. It was unclear whether there was a correlation between CYP2D6 *10 genotype and serum endoxifen concentrations. Secondly, other CYP2D6 alleles, like variant *3, *4, *5, *6, and genetic polymorphisms of CYP2C9 and CYP3A5 may also influence the metabolisms of tamoxifen [5]; we did not determine these genetic variants in the present study. The frequency of CYP2D6 variant *3, *4, *5, and *6 is quite rare in Chinese populations [13, 14]; these variants might not play an important role in the tamoxifen metabolism in Chinese women. Thirdly, we found that CYP2D6 *10 genotype is only associated with DFS but not with DSS; it could be due to a relatively small sample size (n = 152) and/or short follow-up (median: 63 months) in tamoxifen-treated group. Therefore, it should be carefully interpreted in our results, and the CYP2D6 *10 genotype should not apply in clinical practice until the data from prospective studies are available.
In summary, we found that CYP2D6 *10 genotype affects the efficacy of tamoxifen treatment in Chinese women; women with the CYP2D6 *10 variant T/T genotype have a worse clinical outcome when receiving tamoxifen treatment. Although the aromatase inhibitors have been increasingly common for postmenopausal women with ER-positive tumors [24], tamoxifen would still be commonly used in both premenopausal and postmenopausal women in the foresee future. Therefore, analysis of CYP2D6 *10 genotype may be useful in identifying patients who are more likely to benefit from tamoxifen treatment in Chinese women. Nevertheless, further studies with large sample size are warranted to confirm our findings.
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Program for New Century Excellent Talents in University (985-2-067-113 to Y.X.); National Natural Science Foundation of China (30672419).
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These authors have contributed equally to the work. 
Received for publication November 11, 2007. Revision received March 10, 2008. Accepted for publication March 10, 2008.
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