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Clinical Implications of CYP2D6 Genotypes Predictive of Tamoxifen Pharmacokinetics in Metastatic Breast Cancer

Hyeong-Seok Lim, Han Ju Lee, Keun Seok Lee, Eun Sook Lee, In-Jin Jang, Jungsil Ro

From the Research Institute and Hospital, National Cancer Center, Goyang, Gyeonggi; and Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea

Address reprint requests to Jungsil Ro, MD, Research Institute and Hospital, National Cancer Center, 809 Madu1-dong, Ilsan-gu, Goyang-si, Gyeonggi-do, 411-769, Republic of Korea; e-mail: jungsro{at}ncc.re.kr

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Purpose The CYP3A and CYP2D6 enzymes play a major role in converting tamoxifen to its active metabolites. CYP3A is a highly inducible enzyme, regulated mainly by pregnane X receptor (PXR). This study assessed the association between genetic polymorphisms of CYP2D6 and PXR, and tamoxifen pharmacokinetics (PK) and clinical outcomes in patients with breast cancer.

Patients and Methods Plasma concentrations of tamoxifen and its metabolites were measured. Common alleles of CYP2D6 and PXR were identified in 202 patients treated with tamoxifen 20 mg daily for more than 8 weeks. Twelve of the 202 patients and an additional nine patients with metastatic breast cancer receiving tamoxifen were assessed for clinical outcome in correlation with genotypes.

Results Patients carrying CYP2D6*10/*10 (n = 49) demonstrated significantly lower steady-state plasma concentrations of 4-hydroxy-N-desmethyltamoxifen and 4-hydroxytamoxifen than did those with other genotypes (n = 153; 4-hydroxy-N-desmethyltamoxifen: 7.9 v 18.9 ng/mL, P < .0001; 4-hydroxytamoxifen: 1.5 v 2.6 ng/mL, P < .0001), whereas no difference by PXR genotypes was found. CYP2D6*10/*10 was significantly more frequent among nonresponders with MBC (100% v 50%, P = .0186). In Cox proportional hazard analysis, CYP2D6 genotype and number of disease sites were significant factors affecting time to progression (TTP). The median TTP for patients receiving tamoxifen was shorter in those carrying CYP2D6*10/*10 than for others (5.0 v 21.8 months, P = .0032)

Conclusion CYP2D6*10/*10 is associated with lower steady-state plasma concentrations of active tamoxifen metabolites, which could possibly influence the clinical outcome by tamoxifen in Asian breast cancer patients.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Tamoxifen has been widely used for the treatment of patients with hormone-dependent breast cancer. Tamoxifen is converted to the active metabolites 4-hydroxytamoxifen and 4-hydroxy-N-desmethyltamoxifen (endoxifen), which is more than 100 times more potent than tamoxifen in antiestrogen effect.^1,2 The majority of tamoxifen is biotransformed to N-desmethyltamoxifen by cytochrome P450 (CYP) 3A enzymes. A portion of the desmethyltamoxifen metabolite is further metabolized to endoxifen by CYP2D6. A minor portion of tamoxifen is converted to 4-hydroxytamoxifen, which is performed mainly by CYP2D6.³

CYP2D6 plays a major role in the biotransformation of many drugs including neuroleptics, antiarrythmics, antidepressants, and selective serotonin reuptake inhibitors and blockers.⁴ There is a large interindividual and ethnic variability in the metabolism of drugs by CYP2D6 that can be explained largely by genetic polymorphisms affecting the enzyme's function and expression. The typical CYP2D6 phenotype is usually classified into three groups: poor metabolizers (PMs), extensive metabolizers (EMs) and ultrarapid metabolizers. The PM group is characterized by complete absence of CYP2D6 enzyme activity, found in less than 1% of Koreans, Japanese, or Chinese, and in 7% to 10% of whites.^5-8 CYP2D6*3, CYP2D6*4, CYP2D6*5, and CYP2D6*6 cause absence of enzyme activity, and 93% to 97.5% of the PMs can be predicted by these genotypes.⁹ CYP2D6*4 occurs with an allele frequency of 20% to 25% and is responsible for 70% to 90% of all PMs in whites, but is rare in Asians. The allele frequency of CYP2D6*5 in Asians is approximately 5%.¹⁰ The CYP2D6*10 is a major variant in Asians, and is associated with decreased CYP2D6 activity resulting from the formation of an unstable enzyme. Approximately 50% of Koreans carry this allele,^11,12 whereas only 2% of whites do,¹³ explaining why the median CYP2D6 enzyme activity is lower in East Asian EMs than in white EMs.^10,12 In contrast, hereditary duplication/multiplication of the CYP2D6*2 gene is related to extremely high CYP2D6 activity.¹⁴ The various polymorphisms of CYP2D6 could account for a wide range of tamoxifen pharmacokinetics (PK) and efficacies. Recent studies reported the association between CYP2D6 genotypes and the plasma concentration of endoxifen.^1,15 However, the study result on the association between CYP2D6 genotypes common in Asian population including *10 and tamoxifen biotransformation have not been reported yet. There have been controversies in the association of CYP2D6 genotypes and the efficacy of tamoxifen.^16-18

CYP3A is a highly xenobiotic-inducible enzyme,¹⁹ and transcription of the gene is regulated by nuclear hormone receptors. Pregnane X receptor (PXR) is a major transcriptional regulator of many drug-metabolizing enzymes including CYP3A.²⁰ PXR is highly expressed in liver and intestine and activated by endogenous and exogenous compounds.²¹ A previous study showed that three genetic variants of PXR, 7635G>A, 8055C>T, and –25385C>T, are functional ones.²² These variant alleles are frequently observed with ethnic differences.²² Tamoxifen and 4-hydroxytamoxifen are ligands for PXR and were shown to markedly increase the expression and activity of CYP3A4 through activation of PXR.²³ Hypothetically, the extent of induction of CYP3A by tamoxifen and its metabolite after repeated administration of tamoxifen could influence the conversion of tamoxifen to N-desmethyltamoxifen, a major metabolite mediated by CYP3A, thus the subsequent formation of endoxifen. Furthermore, extent of the induction might be different according to PXR genotypes, which could be ultimately associated with the plasma concentrations of N-desmethyltamoxifen and endoxifen.

In this study, we evaluated the association of CYP2D6 and PXR genetic polymorphisms common in Asian populations and the steady-state concentration of tamoxifen and its metabolites in breast cancer patients taking tamoxifen and subsequently applied to look for an association of this effect with the efficacy of tamoxifen in metastatic breast cancer (MBC) as a pilot trial.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Participants and Study Design
All of the participants in this study had histologically or cytologically diagnosed breast cancer. All patients were Korean females with a median age of 47 years (range, 25 to 73 years) with estrogen- or progesterone-receptor–positive tumors.

The current study consists of two parts. First, we evaluated the association between genotypes involving tamoxifen biotransformation and pharmacokinetics (genotype-PK study). On the basis of the results of the genotype-PK study, we evaluated the association between genotypes and efficacy of tamoxifen (genotype-efficacy study) in patients with MBC (Fig 1).

View larger version (23K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Study flow diagram. PK, pharmacokinetics; MBC, metastatic breast cancer.

Subsequently, we performed a genotype-efficacy study. Additional consecutive patients who were taking tamoxifen for MBC were enrolled. These patients were genotyped without PK analysis, and their clinical characteristics were analyzed together with those of patients with MBC in the genotype-PK study. The response was evaluated according to the Response Evaluation Criteria in Solid Tumors guidelines.²⁴

All samples were centrifuged at 2,000 x g for 10 minutes. Plasma and leukocyte portions of blood were separated into cryovials and stored at –70°C until analysis.

The study protocol was approved by the institutional review board of the National Cancer Center Hospital. All patients gave written informed consent before participating in the study.

Genotype Analysis
Genomic DNA was extracted from the peripheral whole blood of each patient using Qiagen DNA extraction kit (Qiagen, Hilden, Germany). CYP2D6*2xN, CYP2D6*5, and CYP2D6*10 were identified by polymerase chain reaction (PCR) methods as reported previously.^10,25,26 CYP2D6*2xN allele was determined by long PCR using two primer sets, 2D6-F/-R and 2D6dupl-F/-R, according to the method of Lundqvist et al.²⁵ CYP2D6*5 allele was detected in a similar fashion using long PCR with two primer sets, 2D6-F/-R and 2D6*5-F/-R, according to the method of Gaedigk et al.²⁶ For detection of CYP2D6*10 allele, PCR products were amplified using primers 9, 10, and 10B, and then digested with the restriction enzyme Hph I.^10,26 Two PXR alleles, 7635G>A and 8055C>T, were determined by single base extension method. Primers for the detection of 7635G>A were GAGAGGCAGCCAGACAGCA (forward), TGAATGAGGAGCAAGGCCAT (reverse), and ATGGGAAAGGAGCCATCCTCCCTCTTCCTCTC (extension), and for 8055C>T were GAGAGGCAGCCAGACAGCA (forward), TGAATGAGGAGCAAGGCCAT (reverse), and CTTGCTGAGAAGCTGCCCCTCCAT (extension). Amplification was carried out in a GeneAmp PCR System 9700 thermal cycler (Applied Biosystems, Foster City, CA).²⁷ Primer extension reactions were performed with the SNaPshot ddNTP Primer Extension Kit (Applied Biosystems).

Measurement of Plasma Concentration of Tamoxifen and Its Metabolites
Tamoxifen and its metabolites, N-desmethyltamoxifen, Z-4-hydroxy-N-desmethyltamoxifen, and Z-4-hydroxytamoxifen, in plasma were measured by high-performance liquid chromatography with online photocyclization as described previously with modification.²⁸ Z-4-hydroxytamoxifen (purity, 98%) and propranolol were purchased from Sigma-Aldrich (St Louis, MO). N-desmethyltamoxifen and tamoxifen were purchased from Toronto Research Chemicals (Toronto, Ontario, Canada). A mixture of E and Z isomers of Z-4-hydroxy-N-desmethyltamoxifen was provided by D.A. Flockhart at Indiana University School of Medicine (Indianapolis, IN), and the Z isomer was separated with a preparative column (5-µm particle size, 21.2 x 150 mm ID; Agilent Technologies, Palo Alto, CA) with a mobile phase of 35% acetonitrile in 20 mmol/L ammonium formate buffer (pH 3) at a flow rate of 5 mL/min. The compounds were separated through an analytic column (Capcell Pak C18: 5-µm particle size, 4.6 x 150 mm; Shiseido, Tokyo, Japan) with a mobile phase of 35% acetonitrile in 20 mmol/L potassium phosphate buffer (pH 3) at a flow-rate of 1 mL/min. A PHRED Photochemical Reactor (Sigma-Aldrich) supplied with a 20-m knitted reactor coil (0.25 mm ID; Sigma-Aldrich) and a 254-nm UV lamp (Sigma-Aldrich) was used to amplify the fluorescence. The fluorescence detector was set at an excitation wavelength of 256 nm and emission wavelength of 380 nm. The method was validated for each compound over 1 to approximately 40 ng/mL (Z-4-hydroxy N-desmethyltamoxifen), 0.5 to approximately 10 ng/mL (Z-4-hydroxytamoxifen), 15 to approximately 450 ng/mL (N-desmethyltamoxifen), and 15 to 450 ng/mL (tamoxifen) with the linearity established (r² > 0.9998 for each compound).

Statistical Analysis
The differences in plasma concentrations of tamoxifen and its metabolites by genotypes were compared using Wilcoxon rank sum test or analysis of variance. The association between patients' genotypes and clinical benefit, which was defined as complete response (CR), partial response (PR), or stable disease (SD) lasting as least 24 weeks during tamoxifen treatment, was tested with Fisher's exact test. Cox proportional hazard model analysis was performed to identify the significant factors associated with time to disease progression (TTP) during tamoxifen administration, defined as the time from the first day of tamoxifen to progression of the cancer. Kaplan-Meier estimates and log-rank test were used in univariate analysis of TTP.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Overall Study Flow
In the genotype-PK study, 212 patients who were taking tamoxifen, either for MBC or as adjuvant therapy at the National Cancer Center Hospital, Korea, were assessed to determine their eligibility for the study between June 2004 and June 2006. Of these, 202 were assessable for the genotype-PK association with tamoxifen. In the genotype-efficacy study, an additional nine patients with MBC were enrolled. These nine patients were genotyped without PK analysis, and their medical records were retrospectively reviewed together with those of the 12 MBC patients in the genotype-PK study (a total of 21 MBC patients) to evaluate the association between genotype and tamoxifen efficacy (Fig 2).

View larger version (20K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Steady-state plasma concentrations of endoxifen and 4-hydroxytamoxifen according to CYP2D6 genotypes (Box-Whisker plots). (A, B) Comparison by homozygous variant for *10 (*10/*10), heterozygote (Wt/*10) and homozygous wild-type (Wt/Wt) genotypes. (C, D) Comparison by homozygous variant for *10 and *5 (V/V), heterozygote (W/V) and homozygous wild (W/W) genotypes.

On the other hand, 21 metastatic patients in genotype-efficacy study showed a significantly higher proportion of CYP2D6*10/*10 genotypes, where 57.1% (n = 12) of patients were homozygous for CYP2D6*10 variant compared with 24.3% in the genotype-PK study (P = .0019).

Steady-State Plasma Concentrations of Tamoxifen and Its Metabolites by Genotypes
To analyze the effect of CYP2D6 genotypes on the plasma concentration of tamoxifen and its metabolites, we combined *10 and *5 into a variant genotype (V) such that the participants who carried *1/*10 or *1/*5 were grouped together into a wild-type/variant (W/V, where W is defined as a CYP2D6 allele not containing *5 and *10) group. However, considering the much higher frequency of the *10 allele among Koreans, we tested the effect of this once we grouped the participants according to *10 allele into homozygous (*10/*10), heterozygous (wild-type/*10 [wt/*10] where Wt is defined as a CYP2D6 allele not containing *10) and homozygous wild (wild-type/wild-type [Wt/Wt]) variants. The steady-state plasma concentrations of both endoxifen and 4-hydroxytamoxifen were significantly lower in patients carrying the CYP2D6*10/*10 genotype than in those with Wt/*10 or Wt/Wt (endoxifen, 7.9 v 19.9 or 18.1 ng/mL, P < .0001; 4-hydroxytamoxifen, 1.5 v 2.5 or 2.8 ng/mL, P < .0001; Table 2; Fig 2). The concentrations were comparable between Wt/*10 and Wt/Wt. The patients who were homozygous for *10 or *5 (V/V) also showed lower concentrations than those with W/V or W/W (endoxifen, 8.1 v 18.0 or 20.7 ng/mL, P < .0001; 4-hydroxytamoxifen, 1.5 v 2.5 or 2.9 ng/mL, P < .0001; Table 2; Fig 2). The mean concentrations of endoxifen and 4-hydroxytamoxifen in patients carrying the CYP2D6*2N allele (n = 4) were 18.2 and 2.4 ng/mL, respectively, which were not significantly different compared with the other genotypes for both compounds (data not shown). There was no significant association between the CYP2D6 genotype and the concentration of tamoxifen and N-desmethyltamoxifen.

Clinical Efficacy of Tamoxifen According to CYP2D6 Genotypes
Although patients with *10/*10 or who were homozygous variants for *10 or *5 showed distinctively lower concentrations of the active metabolites of tamoxifen, the frequency of *5/*5 or *10/*5 is low among Koreans. Therefore, the genotype-efficacy association study focused on the *10/*10, Wt/*10, and Wt/Wt genotype groups. Fifteen of the 21 patients with MBC achieved clinical benefit (CR + PR + SD 24 weeks) while receiving tamoxifen, whereas the remaining nine experienced progressive disease (PD) or SD with duration less than 24 weeks, with an overall TTP of 8.7 months (range, 2.1 to approximately 23.2+ months). All nine patients (100%) with CYP2D6 Wt/Wt or Wt/*10 genotypes, and six (50%) of the 12 patients with *10/*10 genotypes experienced clinical benefit (P = .0186). Nineteen patients had measurable lesions for response. All six patients with PD or SD lasting less than 24 weeks carried the *10/*10 genotype. One patient who experienced PR and eight patients with SD lasting at least 24 weeks had Wt/Wt or Wt/*10 (Table 3). With a median follow-up of 19.6 months (range, 6.6 to 53.8 months), the median TTP by Kaplan-Meier analysis was much shorter in patients who were CYP2D6*10/*10 homozygotes compared with the other genotypes evaluated (TTP: 5.03 v 21.8 months, P = .0032; Fig 3).

View larger version (12K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Time to disease progression in patients treated with tamoxifen for metastatic breast cancer.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

Recently, a few additional studies concerning genetic polymorphisms of CYP2D6 in association with tamoxifen metabolism have been reported. These data ought to be applied clinically to verify whether patients with a certain genotype cannot achieve clinical benefit with tamoxifen because of low plasma concentrations of the active metabolite. This study demonstrated that CYP2D6*10/*10 was significantly associated with lower plasma concentrations of endoxifen and 4-hydroxytamoxifen, two active metabolites of tamoxifen. We then applied this result to the small number of patients as a pilot study who took tamoxifen for MBC so that clinical outcomes could be readily evaluated in association with these polymorphisms. Indeed, the data demonstrated significant associations between the CYP2D6 genetic polymorphisms and the clinical outcomes of patients, where the CYP2D6*10/*10 genotype, along with the number of disease sites, was a significant factor affecting TTP by Cox proportional hazard analysis. The median TTP for patients with CYP2D6*10/*10 was shorter according to the Kaplan-Meier method, and the frequency of the CYP2D6*10/*10 genotype was higher in MBC patients with poor clinical outcomes. However, other genetic variants and clinical factors as well could affect the efficacy of tamoxifen in breast cancer patients.

Although the difference of efficacy on tamoxifen by CYP2D6 genotypes in the current study could be possibly explained by the differences in the rate of formation of tamoxifen active metabolites, it was previously reported that the efficacy of tamoxifen was not different between daily doses of 20 mg and 40 mg, although the serum concentration of tamoxifen was significantly higher in patients receiving 40 mg.³¹ Although one could not fully explain this disparity, one possible explanation might be that in dose ranges from 20 mg to 40 mg, the steady-state plasma concentration of tamoxifen active metabolites are within the plateau (ie, maximal effect in the concentration-response curve of maximum effect model³⁰), whereas those according to the CYP2D6 genotypes evaluated in this study on 20 mg/d of tamoxifen are within the rapidly changing region in the curve. In this case, we could observe the difference according to the CYP2D6 genotypes treated with 20 mg/d of tamoxifen, but not the significant difference between 20 mg/d and 40 mg/d of tamoxifen.

In a few randomized trials, the third-generation aromatase inhibitors have demonstrated superior efficacy compared with tamoxifen when used as adjuvant therapy in postmenopausal women with hormone receptor–positive breast cancer.^32-34 It could be assumed that the poorer outcome in tamoxifen arms may reflect the poorer outcome of patients carrying CYP2D6 variants that lead to a poor metabolizing phenotype.

In summary, our study suggests that the CYP2D6*10/*10 genotype is a marker that is associated with lower steady-state plasma concentrations of tamoxifen active metabolites, that could lead to reduced clinical benefits in Asian breast cancer patients on tamoxifen. Future research is warranted to compare tamoxifen at a higher dose or a different antiestrogen independent of the CYP2D6 genotype or aromatase inhibitors for the PM group of patients.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Hyeong-Seok Lim, In-Jin Jang, Jungsil Ro

Administrative support: Hyeong-Seok Lim, Jungsil Ro

Provision of study materials or patients: Hyeong-Seok Lim, Han Ju Lee, Keun Seok Lee, Eun Sook Lee, Jungsil Ro

Collection and assembly of data: Hyeong-Seok Lim, Han Ju Lee

Data analysis and interpretation: Hyeong-Seok Lim, Jungsil Ro

Manuscript writing: Hyeong-Seok Lim, Jungsil Ro

Final approval of manuscript: Jungsil Ro

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 

	ACKNOWLEDGMENTS

 
We acknowledge Kyun-Seop Bae at Asan Medical Center, Ji-Young Park, Kyoung-Ah Kim at Korea University College of Medicine, and Ka Heon Song at Seoul National University Hospital for their technical assistances with the HPLC analysis.

	NOTES

 
Supported by NCC Grants No. 0410590 and 0210150.

Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA, and the 29th Annual San Antonio Breast Cancer Symposium, December 14-17, 2006, San Antonio, TX.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted March 6, 2007; accepted June 8, 2007.

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