Impact of CYP2D6 Polymorphisms in Predicting Occurrence of Adverse Effect to Tamoxifen and Developing Recurrence in ER+ Breast Cancer Patients
Abstract
Background: Breast cancer is a major public health in Algeria. Tamoxifen has been approved for the treatment of ER+ breast cancer. Some of the negative side effects of tamoxifen are frequently a reason for discontinuation of therapy during treatment, which would otherwise be potentially lifesaving. In the current study, we assessed the association between CYP2D6 polymorphisms and tamoxifen efficacy in the Algerian population receiving tamoxifen as adjuvant therapy in ER+ breast cancer.
Methods: A total of 76 Algerian hormone receptor-positive premenopausal breast cancer patients with adjuvant tamoxifen treatment were investigated (45.36±6.13). DNA genotyping was performed by TaqMan Open Array technology. Tamoxifen and its metabolite levels were measured by ultra-high-performance liquid chromatography (UHPLC) followed by electro-spray tandem mass spectrometry (LC-MS/MS).
Results: A significant association between the presence of a deficit copy of enzyme activity and the development of adverse effects after the commencement of tamoxifen therapy. Low plasma endoxifen was observed in patients categorized as (NM/PM), (IM/ IM), (IM/PM) and (PM/PM). Patients with increased plasma endoxifen concentrations were significantly more likely than patients with reduced or null activity to not report recurrences (P<0.05). We realized that the combination genotypes NM/PM, IM/IM, IM/PM, with PM/PM were more strongly associated with disease recurrence and adverse effects than NM carriers of CYP2D6*1 allele (P<0.05).
Conclusion: Our results affirm that CYP2D6 polymorphism should be considered in predicting the occurrence of adverse effects of fatty liver in women treated with tamoxifen. Thus, alternative treatment can be intended and lifestyle modifications can be implemented.
Full text article
References
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians, 71(3), 209-249 (2021). doi: 10.3322/caac.21660.
Adeoye PA.. Epidemiology of breast cancer in sub-Saharan Africa. 2023; In Breast Cancer Updates. IntechOpen. doi: 10.5772/intechopen.109361.
WHO.CancerTomorrow.Availableonline:https://gco.iarc.fr/tomorrow/graphicisotype?type=0&type_sex=0&mode=population&sex=2&populations=900&cancers=20&age_group=value&apc_male=0&apc_female=0&single_unit=500000&print=0 (accessed on 19 September 2020.
Cronin-Fenton DP, Damkier P. Tamoxifen and CYP2D6: a controversy in pharmacogenetics. Advances in pharmacology, 2018; 83, 65-91(2018). doi:10.1016/bs.apha.2018.03.001.
Nardin JM, Schroth W, Almeida TA, Mürdter T, Picolotto S, Vendramini ECL, et al. The Influences of Adherence to Tamoxifen and CYP2D6 Pharmacogenetics on Plasma Concentrations of the Active Metabolite (Z)‐Endoxifenxifenxifen in Breast Cancer. 2020; Clinical and translational science, 13(2), 284-292 (2020). doi:10.1111/cts.12707.
Tornio A, Backman J. Cytochrome P450 in Pharmacogenetics: An Update; Advances in Pharmacology; 2018. pp. 3–32. doi:10.1016/bs.apha.2018.04.007.
Gaedigk A, Dinh JC, Jeong H, Prasad B, Leeder JS. Ten years’ experience with the CYP2D6 activity score: a perspective on future investigations to improve clinical predictions for precision therapeutics. 2018; Journal of personalized medicine, 8(2), 15. doi:10.3390/jpm8020015.
Gaedigk A, Simon S, Pearce R, Bradford L, Kennedy M, Leeder J. The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype. Clin. Pharmacol. Ther. 2008; 83, 234–242.
Agema BC, Buijs SM, Sassen SD, Mürdter TE, Schwab M, Koch BC, et al. Toward model-informed precision dosing for tamoxifen: A population-pharmacokinetic model with a continuous CYP2D6 activity scale. Biomedicine & Pharmacotherapy, 2023; 160, 114369. doi:10.1016/j.biopha.2023.114369
Sidibe M, Tazzite A, Jouhadi H, Dehbi H. Impact of CYP2D6, CYP2C9/19, CYP3A4, UGT, and SULT Variability on Tamoxifen Metabolism in Breast Cancer Treatment. Journal of Current Oncology, 2024; 25898892231223300. doi:10.1177/25898892231223
Caudle KE, Sangkuhl K, Whirl‐Carrillo M, Swen JJ, Haidar CE, Klein TE, et al. Standardizing CYP 2D6 genotype to phenotype translation: consensus recommendations from the clinical pharmacogenetics implementation consortium and Dutch pharmacogenetics working group. Clin. Transl Sci. 2020; 13, 116–124. doi:10.1111/cts.12692.
Schuurman TN, Witteveen PO, van der Wall E, Passier JLM, Huitema ADR, Amant F, et al. Tamoxifen and pregnancy: an absolute contraindication? Breast Cancer Res. Treat. 175, 17–25; 2019. doi:10.1007/s10549-019-05154-7.
Klingman L, Younus J. Management of hot flashes in women with breast cancer. CurrOncol; 17(1):81–86 2010. doi:10.3747/co.v17i1.473.
Cole LK, Jacobs RL, Vance DE. Tamoxifen induces triacylglycerol accumulation in the mouse liver by activation of fatty acid synthesis. Hepatology;52(4):1258–1265 (2010). doi:10.1002/hep.23813.
Shahriari-Ahmadi M, Masouleh MN, Kaveh V. Tamoxifen-Induced Fatty Liver is observed in New Zealand White Rabbit by Ultrasonography. Biomedical Research and Therapy, 2023; 10(12), 6075-6085. doi: 10.15419/bmrat.v10i12.849.
Nardelli MJ, Monteiro MJSD, Cançado GGL, Cal TCMF, Lima AQR, Pontine VP, et al. Risk of fatty liver and hepatic fibrosis associated with long-term use of tamoxifen or anastrozole may be overestimated in patients with breast cancer. 2024. doi: 10.21203/rs.3.rs-4185141/v1.
Gudbrandsen OA, Rost TH, Berge RK. Causes and prevention of tamoxifen-induced accumulation of triacylglycerol in rat liver. J Lipid Res;47(10):2223–2232 (2006). doi:10.1194/jlr.M600148-JLR200.
Farrell GC. Drugs and steatohepatitis. SeminLiver Dis; 22(2):185–194; 2002. doi:10.1055/s-2002-30106.
Larosche I, Letteron P, Fromenty B, et al. Tamoxifen inhibits topoisomerases, depletes mitochondrial DNA, and tiggers steatosis in mouse liver. J PharmacolExp Ther;321(2):526–535; 2007. doi: 10.1124/jpet.106.114546.
Probst-Schendzielorz, Kristina, Roberto Viviani, Julia C. Stingl. Effect of Cytochrome P450 polymorphism on the action and metabolism of selective serotonin reuptake inhibitors. Expert opinion on drug metabolism&toxicology. 2015; 11.8 :1219-1232. doi: 10.1517/17425255.2015.1052791.
Prevalence, incidence and risk factors of tamoxifen-related non-alcoholic fatty liver disease: A systematic review and meta-analysis.
Miller SA, Dykes DD, Polesky HF A simple salting out procedure for extracting DNA from human nucleated cells. Nucl Acids Res 16(3):55404 (1988). doi: 10.1093/nar/16.3.1215.
Bobin-Dubigeon C, Campone M, Rossignol E, Salaun E, Amiand MB, Bard JM. New UPLC–MS/MS assay for the determination of tamoxifen and its metabolites in human plasma, application to patients. Future science OA, 5(5), FSO374 (2019). doi: 10.2144/fsoa-2018-0113.
National Cancer Control Program. Cancer Incidence Data Sri Lanka 2010. 12th pub. Colombo: National Cancer Control Program, Ministry of Health, Nutrition and Indigenous Medicine; 2016. doi: 10.2139/ssrn.3253316.
Zafra-Ceres M, de Haro T, Farez-Vidal E, et al. Influence of CYP2D6 polymorphisms on serum levels of tamoxifen metabolites in Spanish women with breast cancer. Int J Med Sci;10(7):932–937 (2013). doi: 10.7150/ijms.5708.
Hoskins JM, Carey LA, McLeod HL. CYP2D6 and tamoxifen: DNA matters in breast cancer. Nat Rev Cancer;9(8):576–586 (2009). doi:10.1038/nrc2683.
Rang HP, Dale MM, Ritter JM, et al. Anticancer drugs. In: Rang and Dale’s Pharmacology. 7th ed. Spain: Elsevier Inc; 673–688 (2012).
Brunton LL, Parker KL, editors. Goodman and Gilman’s Manual of Pharmacology and Therapeutics. 7th ed. New York, NY: McGraw-Hill; 2008.
Dean L. Tamoxifen therapy and CYP2D6 Genotype. medical genetics summaries. Avialbale from: http://www.ncbi.nlm.nih.gov/books/ NBK247013. AccessedSeptember 6, 2016. 28520357.
Briest S, Stearns V. Tamoxifen metabolism and its effect on endoxifenxifencrine treatment of breast cancer. Clin AdvHematol Oncol;7(3):185–192 (2009). 19398943.
Ribeiro MP, Santos AE, Custódio JB. Mitochondria: the gateway for tamoxifen-induced liver injury. Toxicology, 2014; 323, 10-18. doi: 10.1016/j.tox.2014.05.009.
Schroth W, Goetz MP, Hamann U, Fasching PA, Schmidt M, Winter S, et al. Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen. Jama, 2009; 302(13), 1429-1436. doi: 10.1001/jama.2009.1420.
Schroth W, Antoniadou L, Fritz P, Schwab M, Muerdter T, Zanger UM, et al. Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. J ClinOncol. 2007; 25:5187–5193 (2007). doi: 10.1200/JCO.2007.12.2705.
Owen JR, Nemeroff CB. New antidepressants and the cytochrome P450 system: focus on venlafaxine, nefazodone, and mirtazapine. Depression and anxiety, 1998; 7(S1), 24-32 (1998). 9597349.
Authors
Copyright (c) 2024 Archives of Breast Cancer
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Copyright©. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International License, which permits copy and redistribution of the material in any medium or format or adapt, remix, transform, and build upon the material for any purpose, except for commercial purposes.