Impacts of Cytochrome P450 2D6 (CYP2D6) Genetic Polymorphism in Tamoxifen Therapy for Breast Cancer

Abstract

Tamoxifen (TMX) is the main drug used both in pre and postmenopausal women as adjuvant treatment for hormone receptor-positive breast cancer. An important barrier to the use of TMX is the development of drug resistance caused by molecular processes related to genetic and epigenetic mechanisms, such as the actions of cytochrome P450 2D6 (CYP2D6) polymorphisms and of its metabolites. The present study aimed to review recent findings related to the impact of CYP2D6 polymorphisms and how they can affect the results of TMX in breast cancer treatment. The keywords CYP2D6, tamoxifen, and breast cancer were searched in the PubMed, Scopus, The Cochrane Library, Scielo, and Bireme databases. Studies related to other types of neoplasms or based on other isoenzymes from cytochrome P450, but not on CYP2D6, were excluded. The impact of CYP2D6 polymorphisms in the TMX resistance mechanism remains unclear. The CYP2D6 gene seems to contribute to decreasing the efficacy of TMX, while the main mechanism responsible for therapy failure, morbidity, and mortality is the progression of the disease.

Resumo

O tamoxifeno é a principal droga que pode ser utilizada como tratamento hormonal adjuvante em pacientes portadoras de câncer de mama receptor hormonal positivo tanto na pré- quanto na pós-menopausa. Uma das maiores barreiras em seu uso é o desenvolvimento de resistência medicamentosa causada por meio de processos moleculares relacionados a mecanismos genéticos e epigenéticos, como a ação dos polimorfismos do gene citocromo P450 2D6 (CYP2D6) e seus metabólitos. O presente estudo busca revisar as descobertas recentes acerca dos impactos dos polimorfismos do gene CYP2D6 e de como eles podem afetar os resultados do tamoxifeno na terapêutica do câncer de mama. As palavras-chave CYP2D6, tamoxifeno e câncer de mama foram buscadas nas bases de dados Pubmed, Scopus, The Cochrane Library, Scielo e Bireme. Estudos relacionados com outros tipos de câncer ou relacionados a outras isoenzimas do citocromo P450 que não o CYP2D6 foram excluídos. O impacto do polimorfismo do CYP2D6 nos mecanismos de resistência ao tamoxifeno permanecem controversos. O gene CYP2D6 parece reduzir a eficácia do TMX; entretanto, os principais fatores associados a falha terapêutica são morbimortalidade e a progressão da doença

Keywords

cytochrome P-450 CYP2D6 - polymorphism genetic - tamoxifen - breast neoplasms - therapeutic uses

Palavras-chave

citocromo P-450 CYP2D6 - polimorfismo genético - tamoxifeno - neoplasias da mama - usos terapêuticos

• References

• 1 Shagufta AI, Ahmad I. Tamoxifen a pioneering drug: An update on the therapeutic potential of tamoxifen derivatives. Eur J Med Chem 2018; 143: 515-531 Doi: 10.1016/j.ejmech.2017.11.056
• 2 Jahangiri R, Mosaffa F, Emami Razavi A, Teimoori-Toolabi L, Jamialahmadi K. Altered DNA methyltransferases promoter methylation and mRNA expression are associated with tamoxifen response in breast tumors. J Cell Physiol 2018; 233 (09) 7305-7319 Doi: 10.1002/jcp.26562
• 3 Shah N, Mohammad AS, Saralkar P. , et al. Investigational chemotherapy and novel pharmacokinetic mechanisms for the treatment of breast cancer brain metastases. Pharmacol Res 2018; 132: 47-68 Doi: 10.1016/j.phrs.2018.03.021
• 4 Allan AL, Vantyghem SA, Tuck AB, Chambers AF. Tumor dormancy and cancer stem cells: implications for the biology and treatment of breast cancer metastasis. Breast Dis 2006–2007– 2007; 26: 87-98 Doi: 10.3233/BD-2007-26108
• 5 Souza RDM, Martins DMF, Chein MBC, Brito LMO. Importância do CYP2D6 em usuárias de tamoxifeno no câncer de mama. Femina 2011; 39: 267-274
• 6 Drăgănescu M, Carmocan C. Hormone therapy in breast cancer. Chirurgia (Bucur) 2017; 112 (04) 413-417 Doi: 10.21614/chirurgia.112.4.413
• 7 Abdel-Hafiz HA. Epigenetic mechanisms of tamoxifen resistance in luminal breast cancer. Diseases 2017; 5 (03) E16 Doi: 10.3390/diseases5030016
• 8 Fleeman N, Payne K, Newman WG. , et al. Are health technology assessments of pharmacogenetic tests feasible? A case study of CYP2D6 testing in the treatment of breast cancer with tamoxifen. Per Med 2013; 10 (06) 601-611 Doi: 10.2217/pme.13.60
• 9 Bachelot T, Bourgier C, Cropet C. , et al. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J Clin Oncol 2012; 30 (22) 2718-2724 Doi: 10.1200/JCO.2011.39.0708
• 10 Bekele RT, Venkatraman G, Liu RZ. , et al. Oxidative stress contributes to the tamoxifen-induced killing of breast cancer cells: implications for tamoxifen therapy and resistance. Sci Rep 2016; 6: 21164 Doi: 10.1038/srep21164
• 11 Viedma-Rodríguez R, Baiza-Gutman L, Salamanca-Gómez F. , et al. Mechanisms associated with resistance to tamoxifen in estrogen receptor-positive breast cancer (review). Oncol Rep 2014; 32 (01) 3-15 Doi: 10.3892/or.2014.3190
• 12 Thota K, Prasad K, Basaveswara Rao MV. Detection of cytochrome p450 polymorphisms in breast cancer patients may impact on tamoxifen therapy. Asian Pac J Cancer Prev 2018; 19 (02) 343-350 Doi: 10.22034/APJCP.2018.19.2.343
• 13 Hansten PD. The Underrated Risks of Tamoxifen Drug Interactions. Eur J Drug Metab Pharmacokinet 2018; 43 (05) 495-508 Doi: 10.1007/s13318-018-0475-9
• 14 Lyon E, Gastier Foster J, Palomaki GE. , et al; working group of the Molecular Genetics Subcommittee on behalf of the American College of Medical Genetics and Genomics ACMG) Laboratory Quality Assurance Committee. Laboratory testing of CYP2D6 alleles in relation to tamoxifen therapy. Genet Med 2012; 14 (12) 990-1000 Doi: 10.1038/gim.2012.108
• 15 Chin FW, Chan SC, Abdul Rahman S, Noor Akmal S, Rosli R. CYP2D6 Genetic polymorphisms and phenotypes in different ethnicities of Malaysian breast cancer patients. Breast J 2016; 22 (01) 54-62 Doi: 10.1111/tbj.12518
• 16 Lan B, Ma F, Zhai X. , et al. The relationship between the CYP2D6 polymorphisms and tamoxifen efficacy in adjuvant endocrine therapy of breast cancer patients in Chinese Han population. Int J Cancer 2018; 143 (01) 184-189 Doi: 10.1002/ijc.31291
• 17 Wellmann R, Borden BA, Danahey K. , et al. Analyzing the clinical actionability of germline pharmacogenomic findings in oncology. Cancer 2018; 124 (14) 3052-3065 Doi: 10.1002/cncr.31382
• 18 Del Re M, Rofi E, Citi V, Fidilio L, Danesi R. Should CYP2D6 be genotyped when treating with tamoxifen?. Pharmacogenomics 2016; 17 (18) 1967-1969 Doi: 10.2217/pgs-2016-0162
• 19 Goetz MP, Kamal A, Ames MM. Tamoxifen pharmacogenomics: the role of CYP2D6 as a predictor of drug response. Clin Pharmacol Ther 2008; 83 (01) 160-166 Doi: 10.1038/sj.clpt.6100367
• 20 Monteagudo E, Gándola Y, González L, Bregni C, Carlucci AM. Development, characterization, and in vitro evaluation of tamoxifen microemulsions. J Drug Deliv 2012; 2012: 236713 Doi: 10.1155/2012/236713
• 21 Khan BA, Robinson R, Fohner AE. , et al. Cytochrome P450 genetic variation associated with tamoxifen biotransformation in American Indian and Alaska native people. Clin Transl Sci 2018; 11 (03) 312-321 Doi: 10.1111/cts.12542
• 22 Wegman P, Vainikka L, Stål O. , et al. Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients. Breast Cancer Res 2005; 7 (03) R284-R290 Doi: 10.1186/bcr993
• 23 Nowell SA, Ahn J, Rae JM. , et al. Association of genetic variation in tamoxifen-metabolizing enzymes with overall survival and recurrence of disease in breast cancer patients. Breast Cancer Res Treat 2005; 91 (03) 249-258 Doi: 10.1007/s10549-004-7751-x
• 24 Hertz DL, Kidwell KM, Hilsenbeck SG. , et al. CYP2D6 genotype is not associated with survival in breast cancer patients treated with tamoxifen: results from a population-based study. Breast Cancer Res Treat 2017; 166 (01) 277-287 Doi: 10.1007/s10549-017-4400-8
• 25 Teh LK, Mohamed NI, Salleh MZ. , et al. The risk of recurrence in breast cancer patients treated with tamoxifen: polymorphisms of CYP2D6 and ABCB1. AAPS J 2012; 14 (01) 52-59 Doi: 10.1208/s12248-011-9313-6
• 26 Dean L. Tamoxifen therapy and CYP2D6 genotype. In: Pratt V, McLeod H, Rubinstein W. , et al., eds. Medical Genetics Summaries. Bethesda, MD: National Center for Biotechnology Information; 2014: 1-12 https://www.ncbi.nlm.nih.gov/books/NBK247013/pdf/Bookshelf_NBK247013.pdf . Accessed November 12, 2017.
• 27 Moyer AM, Suman VJ, Weinshilboum RM. , et al. SULT1A1, CYP2C19 and disease-free survival in early breast cancer patients receiving tamoxifen. Pharmacogenomics 2011; 12 (11) 1535-1543 Doi: 10.2217/pgs.11.97
• 28 Kiyotani K, Mushiroda T, Nakamura Y, Zembutsu H. Pharmacogenomics of tamoxifen: roles of drug metabolizing enzymes and transporters. Drug Metab Pharmacokinet 2012; 27 (01) 122-131 Doi: 10.2133/dmpk.DMPK-11-RV-084
• 29 Lim JSL, Chen XA, Singh O. , et al. Impact of CYP2D6, CYP3A5, CYP2C9 and CYP2C19 polymorphisms on tamoxifen pharmacokinetics in Asian breast cancer patients. Br J Clin Pharmacol 2011; 71 (05) 737-750 Doi: 10.1111/j.1365-2125.2011.03905.x
• 30 Motamedi S, Majidzadeh K, Mazaheri M, Anbiaie R, Mortazavizadeh SMR, Esmaeili R. Tamoxifen resistance and CYP2D6 copy numbers in breast cancer patients. Asian Pac J Cancer Prev 2012; 13 (12) 6101-6104
• 31 Zembutsu H, Nakamura S, Akashi-Tanaka S. , et al. Significant effect of polymorphisms in CYP2D6 on response to tamoxifen therapy for breast cancer: a prospective multicenter study. Clin Cancer Res 2017; 23 (08) 2019-2026 Doi: 10.1158/1078-0432.CCR-16-1779
• 32 Regan MM, Leyland-Jones B, Bouzyk M. , et al; Breast International Group (BIG) 1-98 Collaborative Group. CYP2D6 genotype and tamoxifen response in postmenopausal women with endocrine-responsive breast cancer: the breast international group 1-98 trial. J Natl Cancer Inst 2012; 104 (06) 441-451 Doi: 10.1093/jnci/djs125
• 33 De Ameida Melo M, De Vasconcelos-Valença RJ, Neto FM. , et al. CYP2D6 gene polymorphisms in Brazilian patients with breast cancer treated with adjuvant tamoxifen and its association with disease recurrence. Biomed Rep 2016; 5 (05) 574-578 Doi: 10.3892/br.2016.771
• 34 Facina G, Baracat EC, Lima GR, Gebrim LH. Effects of different tamoxifen doses on mammary epithelium proliferation. Rev Bras Ginecol Obstet 2003; 25: 185-191 Doi: 10.1590/S0100-72032003000300007
• 35 Reinert T, Barrios CH. Overall survival and progression-free survival with endocrine therapy for hormone receptor-positive, HER2-negative advanced breast cancer: review. review Ther Adv Med Oncol 2017; 9 (11) 693-709 Doi: 10.1177/1758834017728928
• 36 Bonneterre J, Thürlimann B, Robertson JF. , et al. Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study. J Clin Oncol 2000; 18 (22) 3748-3757 Doi: 10.1200/JCO.2000.18.22.3748
• 37 Bonneterre J, Buzdar A, Nabholtz JM. , et al; Arimidex Writing Committee; Investigators Committee Members. Anastrozole is superior to tamoxifen as first-line therapy in hormone receptor positive advanced breast carcinoma. Cancer 2001; 92 (09) 2247-2258 Doi: 10.1002/1097-0142(20011101)92:9<2247::AID-CNCR1570>3.0.CO;2-Y
• 38 Nabholtz JM, Bonneterre J, Buzdar A, Robertson JF, Thürlimann B. Anastrozole (Arimidex) versus tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: survival analysis and updated safety results. Eur J Cancer 2003; 39 (12) 1684-1689 Doi: 10.1016/S0959-8049(03)00326-5