Effects of CYP2D6*10 polymorphism on tamoxifen pharmacokinetics in patients with breast cancer in Asia: a meta-analysis
- 220 Downloads
Insufficient serum metabolite concentrations of tamoxifen can compromise treatment efficacy in patients with breast cancer. The purpose of this meta-analysis was to explore correlations between cytochrome P450 (CYP) 2D6*10 gene polymorphisms and serum concentrations of tamoxifen and its active metabolites in patients with breast cancer in Asia.
The study included a systematic literature search for cohort studies published before March 2018 in English databases (PubMed, Embase, Cochrane Library, and Web of Science) and Chinese databases (Chinese National Knowledge Infrastructure and Wan Fang database). The meta-analysis was performed using RevMan 5.3 software. Pooled means and standard deviations were calculated with 95% confidence intervals. Publication bias and sensitivity analyses were also performed using STATA 14.0.
In total, 7 studies and 552 patients were included in the meta-analysis. Serum concentrations of endoxifen were significantly different in each CYP2D6*10 genotype group (p < 0.05). The CC genotype was associated with higher concentrations of 4-OH-TAM than the CT/TT genotype (p < 0.05). However, there were no statistically significant between-group differences in serum concentrations of TAM (p > 0.05). Publication bias and sensitivity analyses confirmed that the meta-analysis results were stable and reliable.
CYP2D6*10 polymorphisms influence the pharmacokinetics of tamoxifen in patients with breast cancer in Asia.
KeywordsBreast cancer CYP2D6*10 Pharmacokinetics Polymorphism Tamoxifen
We would like to thank Editage (http://www.editage.com) for English language editing and publication support.
This study was supported by grants from the National Key Technologies R&D Program (no. 2016YFC0904900).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflicts of interest.
For this type of study, a formal consent is not required. This study does not involve any human participants or animals.
- 5.Woo HI, Lee SK, Kim J, Kim SW, Yu J, Bae SY, Lee JE, Nam SJ, Lee SY (2017) Variations in serum concentrations of tamoxifen metabolites and the effects of genetic polymorphisms on tamoxifen metabolism in Korean patients with breast cancer. Oncotarget 8:100296–100311. https://doi.org/10.18632/oncotarget.22220 Google Scholar
- 9.Johnson MD, Zuo H, Lee KH, Trebley JP, Rae JM, Weatherman RV, Desta Z, Flockhart DA, Skaar TC (2004) Pharmacological characterization of 4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen. Breast Cancer Res Treat 85:151–159. https://doi.org/10.1023/B:BREA.0000025406.31193.e8 CrossRefGoogle Scholar
- 11.Saladores P, Murdter T, Eccles D, Chowbay B, Zqheib NK, Winter S, Ganchew B, Eccles B, Gerty S, Tfayli A, Lim JS, Yap YS, Nq RC, Wong NS, Dent R, Habbal MZ, Schaeffeler E, Eichelbaum M, Schroth W, Schwab M, Brauch H (2015) Tamoxifen metabolism predicts drug concentrations and outcome in premenopausal patients with early breast cancer. Pharmacogenom J 15(1):84–94CrossRefGoogle Scholar
- 12.Schroth W, Winter S, Mürdter T, Schaeffeler E, Eccles D, Eccles B, Chowbay B, Khor CC, Tfayli A, Zgheib NK, Eichelbaum M, Schwab M, Brauch H (2017) Improved prediction of endoxifen metabolism by CYP2D6 genotype in breast cancer patients treated with tamoxifen. Front Pharmacol 8:582. https://doi.org/10.3389/fphar.2017.00582 CrossRefGoogle Scholar
- 13.Goetz MP, Sangkuhl K, Guchelaar HJ, Schwab M, Province M, Whirl-Carrillo M, Symmans WF, McLeod HL, Ratain MJ, Zembutsu H, Gaedigk A, van Schaik RH, Ingle JN, Caudle KE, Klein TE (2018) Clinical pharmacogenetics implementation consortium (CPIC) guideline for CYP2D6 and tamoxifen therapy. Clin Pharmacol Ther 103:770–777. https://doi.org/10.1002/cpt.1007 CrossRefGoogle Scholar
- 15.Sirachainan E, Jaruhathai S, Trachu N, Panvichian R, Sirisinha T, Ativitavas T, Ratanatharathorn V, Chamnanphon M, Sukasem C (2012) CYP2D6 polymorphisms influence the efficacy of adjuvant tamoxifen in Thai breast cancer patients. Pharmgenom Pers Med 5:149–153. https://doi.org/10.2147/PGPM.S32160 Google Scholar
- 16.Yin SJ, Ni YB, Wang SM, Wang X, Lou YQ, Zhang GL (2012) Differences in genotype and allele frequency distributions of polymorphic drug metabolizing enzymes CYP2C19 and CYP2D6 in mainland Chinese Mongolian, Hui and Han populations. J Clin Pharm Ther 37:364–369. https://doi.org/10.1111/j.1365-2710.2011.01298.x CrossRefGoogle Scholar
- 17.Lan B, Ma F, Zhai X, Li Q, Chen S, Wang J, Fan Y, Luo Y, Cai R, Yuan P, Zhang P, Li Q, Xu B (2018) The relationship between the CYP2D6 polymorphisms and tamoxifen efficacy in adjuvant endocrine therapy of breast cancer patients in Chinese Han population. Int J Cancer. https://doi.org/10.1002/ijc.31291 Google Scholar
- 22.Tian C, Yang Y, Li H (2014) Clinical analysis of CYP2D6 gene polymorphism with serum concentration of tamoxifen and 4-hydroxytamoxifen. Sichuan Med J 35(1):4–6Google Scholar
- 26.Zhang YX, Li YF, Chen B, Zhang WX, Cai WM (2010) Correlation between polymorphisms of CYP3A5 and CYP2D6 genotypes with concentration of tamoxifen and its activity metabolism 4-hydroxytamoxifen in Chinese breast cancer patients. China Pharmacist 13(9):1229–1232Google Scholar
- 27.Lim JS, Chen XA, Singh O, Yap YS, Ng RC, Wong NS, Wong M, Lee EJ, Chowbay B (2011) Impact of CYP2D6, CYP3A5, CYP2C9 and CYP2C19 polymorphisms on tamoxifen pharmacokinetics in Asian breast cancer patients. Br J Clin Pharmacol 71:737–750. https://doi.org/10.1111/j.1365-2125.2011.03905.x CrossRefGoogle Scholar
- 28.Kiyotani K, Mushiroda T, Imamura CK, Tanigawara Y, Hosono N, Kubo M, Sasa M, Nakamura Y, Zembutsu H (2012) Dose-adjustment study of tamoxifen based on CYP2D6 genotypes in Japanese breast cancer patients. Breast Cancer Res Treat 131:137–145. https://doi.org/10.1007/s10549-011-1777-7 CrossRefGoogle Scholar
- 29.Yang X, Luo B, Wu B (2013) Association between CYP2D6 polymorphism and serum concentration of endoxifen in breast cancer patients. Chin J Cancer Prev Treat 20(12):922–925Google Scholar
- 30.Lei L, Wang X, Wu XD, Wang Z, Chen ZH, Zheng YB, Wang XJ (2016) Association of CYP2D6*10 (c.100C>T) polymorphisms with clinical outcome of breast cancer after tamoxifen adjuvant endocrine therapy in Chinese population. Am J Transl Res 8:3585–3592Google Scholar
- 33.Chamnanphon M, Pechatanan K, Sirachainan E, Trachu N, Chantratita W, Pasomsub E, Noonpakdee W, Sensorn I, Sukasem C (2013) Association of CYP2D6 and CYP2C19 polymorphisms and disease-free survival of Thai post-menopausal breast cancer patients who received adjuvant tamoxifen therapy. Pharmgenom Pers Med 6:37–47Google Scholar
- 35.Helland T, Henne N, Bifulco E, Naume B, Borgen E, Kristensen VN, kvaløy JT, Lash TL, Alnæs GIG, van Schaik RH, Janssen EAM, Hustad S, Lien EA, Mellgren G, Søiland H (2017) Serum concentration of active tamoxifen metabolites predict long-term survival in adjuvantly treated breast cancer patients. Breast Cancer Res 19(1):125CrossRefGoogle Scholar
- 38.Neven P, Jongen L, Lintermans A, Van AK, Blomme C, Lambrechts D, Poppe A, Wildiers H, Dieudomne AS, Brouckaert O, Decloedt J, Berteloot P, Verhoeven D, Joerger M, Vuylsteke P, Wynendaele W, Casteels M, Van HS, Lybaert W, Van GJ, Paridaens R, Vergote I, Dezentje VO, Van CB, Guchelaar HJ (2018) Tamoxifen metabolism and efficacy in breast cancer: a prospective multicenter trial. Clin Cancer Res 24(10):2312–2318CrossRefGoogle Scholar