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.
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References
Sung, H., Ferlay, J., Siegel, R. L., 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, P. A. (2023). Epidemiology of breast cancer in sub-Saharan Africa. 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, D. P., &Damkier, P. (2018). Tamoxifen and CYP2D6: a controversy in pharmacogenetics. Advances in pharmacology, 83, 65-91(2018). DOI:10.1016/bs.apha.2018.03.001
Nardin, J. M., Schroth, W., Almeida, T. A., Mürdter, T., Picolotto, S., Vendramini, E. C. L., ...&Casali‐da‐Rocha, J. C. (2020). The Influences of Adherence to Tamoxifen and CYP2D6 Pharmacogenetics on Plasma Concentrations of the Active Metabolite (Z)‐Endoxifenxifenxifen in Breast Cancer. Clinical and translational science, 13(2), 284-292 (2020). DOI : 10.1111/cts.12707.
Tornio, A., Backman, J., 2018. Cytochrome P450 in Pharmacogenetics: An Update, in: Advances in Pharmacology. pp. 3–32. DOI: 10.1016/bs.apha.2018.04.007.
Gaedigk, A., Dinh, J. C., Jeong, H., Prasad, B., & Leeder, J. S. (2018). Ten years’ experience with the CYP2D6 activity score: a perspective on future investigations to improve clinical predictions for precision therapeutics. Journal of personalized medicine, 8(2), 15. DOI: 10.3390/jpm8020015.
Gaedigk, A., Simon, S., Pearce, R., Bradford, L., Kennedy, M., and Leeder, J. (2008). The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype. Clin. Pharmacol. Ther. 83, 234–242.
Agema, B. C., Buijs, S. M., Sassen, S. D., Mürdter, T. E., Schwab, M., Koch, B. C., ... & Koolen, S. L. (2023). Toward model-informed precision dosing for tamoxifen: A population-pharmacokinetic model with a continuous CYP2D6 activity scale. Biomedicine & Pharmacotherapy, 160, 114369. DOI : 10.1016/j.biopha.2023.114369
Sidibe, M., Tazzite, A., Jouhadi, H., & Dehbi, H. (2024). Impact of CYP2D6, CYP2C9/19, CYP3A4, UGT, and SULT Variability on Tamoxifen Metabolism in Breast Cancer Treatment. Journal of Current Oncology, 25898892231223300. DOI: 10.1177/25898892231223
Caudle, K. E., Sangkuhl, K., Whirl‐Carrillo, M., Swen, J. J., Haidar, C. E., Klein, T. E., et al. (2020).Standardizing CYP 2D6 genotype to phenotype translation: consensus recommendations from the clinical pharmacogenetics implementation consortium and Dutch pharmacogenetics working group. Clin. Transl Sci. 13, 116–124. DOI: 10.1111/cts.12692
Schuurman, T.N., Witteveen, P.O., van der Wall, E., Passier, J.L.M., Huitema, A.D.R., Amant, F., Lok, C.A.R. 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, M. N., & Kaveh, V. (2023). Tamoxifen-Induced Fatty Liver is observed in New Zealand White Rabbit by Ultrasonography. Biomedical Research and Therapy, 10(12), 6075-6085.DOI : 10.15419/bmrat.v10i12.849.
Nardelli, M. J., Monteiro, M. J. S. D., Cançado, G. G. L., Cal, T. C. M. F., Lima, A. Q. R., Pontine, V. P., ... & Couto, C. A. (2024). Risk of fatty liver and hepatic fibrosis associated with long-term use of tamoxifen or anastrozole may be overestimated in patients with breast cancer. 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, and Julia C. Stingl. "Effect of Cytochrome P450 polymorphism on the action and metabolism of selective serotonin reuptake inhibitors. » Expert opinion on drug metabolism&toxicology 11.8 :1219-1232 (2015). 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, M. B., & Bard, J. M. 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 [Internet]. [Created October 7, 2014. Last Update: May 3, 2016]. 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, M. P., Santos, A. E., &Custódio, J. B. (2014). Mitochondria: the gateway for tamoxifen-induced liver injury. Toxicology, 323, 10-18 (2014). DOI : 10.1016/j.tox.2014.05.009
Schroth, W., Goetz, M. P., Hamann, U., Fasching, P. A., Schmidt, M., Winter, S., ...&Brauch, H. (2009). Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen. Jama, 302(13), 1429-1436 (2009). DOI: 10.1001/jama.2009.1420
Schroth W, Antoniadou L, Fritz P, Schwab M, Muerdter T, Zanger UM, Simon W, Eichelbaum M, Brauch H (2007) Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. J ClinOncol 25:5187–5193 (2007). DOI: 10.1200/JCO.2007.12.2705
Owen, J. R., &Nemeroff, C. B. (1998). New antidepressants and the cytochrome P450 system: focus on venlafaxine, nefazodone, and mirtazapine. Depression and anxiety, 7(S1), 24-32 (1998). 9597349
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