Abstract
Purpose
Individual differences in cytochrome P-450 efficiency partly explain their variations in resistance to tamoxifen and estrogen metabolism. Two polymorphisms of the CYP1A1 gene—A4889G and T6235C—are known to affect activation of estrone and estradiol and to deregulate concentration of highly active tamoxifen metabolites. However, the clinicopathologic implications of these findings have not yet been evaluated.
Objective
The objective of this study is to evaluate whether T6235C and A4889G gene polymorphisms are related to pathological presentations and clinical outcomes of ER+/PR+ breast cancer (BC) in women using tamoxifen.
Methods
We included 405 women with ER+/PR+ tumors, who used tamoxifen as their primary therapy, and for whom 5-year follow-up data were available. We evaluated associations within clinicopathologic features, including overall 5-year survival, with CYP1A1 gene status.
Results
Univariate analysis showed that a slightly higher proportion of women with AG/GG genotypes were of European descent (P = 0.05) and that TC/CC genotype was significantly associated with premenopausal status (P = 0.01); however, no significant association remained after multivariate adjustment. Women with CYP1A1 genotypes other than AA and TT were more prone to develop low-grade tumors; 85.9 % of tumors in AA and TT genotype groups were grade III, but only 76.1 % of tumors in carriers of the polymorphisms were grade III (adjusted P = 0.02; OR 0.51 for grade III disease; 95 % CI 0.28–0.93). After 60 months of follow-up, ~75 % of the women were alive. There was no significant difference in survival related to the CYP1A1 gene status.
Conclusions
Breast cancer patients carrying CYP1A1 gene polymorphisms developed less aggressive tumors, but showed no evidence of better prognoses.
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References
Stearns V, Johnson MD, Rae JM et al (2003) Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst 95:1758–1764
Johnson MD, Zuo H, Lee KH et al (2004) Pharmacological characterization of 4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen. Breast Cancer Res Treat 85:151–159
Lim YC, Desta Z, Flockhart DA, Skaar TC (2005) Endoxifen (4-hydroxy-N-desmethyl-tamoxifen) has anti-estrogenic effects in breast cancer cells with potency similar to 4-hydroxy-tamoxifen. Cancer Chemother Pharmacol 55:471–478
MacCallum J, Cummings J, Dixon JM, Miller WR (2000) Concentrations of tamoxifen and its major metabolites in hormone responsive and resistant breast tumours. Br J Cancer 82:1629–1635
Kisanga ER, Gjerde J, Guerrieri-Gonzaga A et al (2004) Tamoxifen and metabolite concentrations in serum and breast cancer tissue during three dose regimens in a randomized preoperative trial. Clin Cancer Res 10:2336–2343
Sharma M, Shubert DE, Sharma M et al (2003) Biotransformation of tamoxifen in a human endometrial explant culture model. Chem Biol Interact 146:237–249
Parte P, Kupfer D (2005) Oxidation of tamoxifen by human flavin-containing monooxygenase (FMO) 1 and FMO3 to tamoxifen-N-oxide and its novel reduction back to tamoxifen by human cytochromes P450 and hemoglobin. Drug Metab Dispos 33:1446–1452
van Schaik RH (2008) CYP450 pharmacogenetics for personalizing cancer therapy. Drug Resist Updat 11:77–98
Desta Z, Ward BA, Soukhova NV, Flockhart DA (2004) Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther 310:1062–1075
Sun D, Sharma AK, Dellinger RW et al (2007) Glucuronidation of active tamoxifen metabolites by the human UDP glucuronosyltransferases. Drug Metab Dispos 35:2006–2014
Nishiyama T, Ogura K, Nakano H et al (2002) Reverse geometrical selectivity in glucuronidation and sulfation of cis- and trans-4-hydroxytamoxifens by human liver UDP-glucuronosyltransferases and sulfotransferases. Biochem Pharmacol 63:1817–1830
Nowell S, Falany CN (2006) Pharmacogenetics of human cytosolic sulfotransferases. Oncogene 25:1673–1678
Seruga B, Amir E (2010) Cytochrome P450 2D6 and outcomes of adjuvante tamoxifen therapy: results of a meta-analysis. Breast Cancer Res Treat 122(3):609–617
Abrahan JE, Maranian MJ, Driver KE et al (2010) CYP2D6 gene variants: association with breast cancer specific survival in a cohort of breast cancer patients from the United Kingdom treated with adjuvant tamoxifen. Breast Cancer Res 12(4):R64
Parl FF, Dawling S, Roodi N, Crooke PS (2009) Estrogen metabolism and breast cancer: a risk model. Ann NY Acad Sci 1155:68–75
Tsuchiya Y, Nakajima M, Yokoi T (2005) Cytochrome P450-mediated metabolism of estrogens and its regulation in human. Cancer Lett 227:115–124
Oliveira C, Lourenço GJ, Silva PM et al (2011) Polymorphisms in the 5′- and 3′-untranslated region of the VEGF gene and sporadic breast cancer risk and clinicopathologic characteristics. Tumour Biol 32:295–300
Cardoso-Filho C, Lourenço GJ, Shinzato JY, Zeferino LC, Costa FF (2008) Clinical and pathological implications of GSTM1 and GSTT1 gene deletions in sporadic breast cancer. Oncol Rev 2:36–43
Woodhead JL, Fallon R, Figuered H, Longdale J, Malcom AD (1986) Alternative methodology of gene diagnosis. In: Davies KE (ed) Human genetic diseases: a practical approach. IRL Press, Oxford, pp 51–64
Canalle R, Burim RV, Tone LG, Takahashi CS (2004) Genetic polymorphisms and susceptibility to childhood acute lymphoblastic leukemia. Environ Mol Mutagen 43:100–109
Wang J, Deng Y, Li L et al (2003) Association of GSTM1, CYP1A1 and CYP2E1 genetic polymorphisms with susceptibility to lung adenocarcinoma: a case-control study in Chinese population. Cancer Sci 94:448–452
Joseph T, Kusumakumary P, Chacko P, Abraham A, Radhakrishna Pillai M (2004) Genetic polymorphisms of CYP1A1, CYP2D6, GSTM1, GSTT1 and susceptibility to acute lymphoblastic leukaemia in Indian children. Pediatr Blood Cancer 43:560–567
Schneider J, Huh MM, Bradlow LH, Fishman J (1984) Antiestrogen action of 2-hydroxyestrone on MCF-7 human breast cancer cells. J Biol Chem 259:4840–4845
Fotsis T, Zhang Y, Pepper MS et al (1994) Endogenous estrogen metabolite 2-methoxyestradiol inhibits angiogenesis and suppresses tumor growth. Nature 368:237–239
Cushman M, He HM, Katzenellenbogan JA, Lin CM, Hamel E (1995) Synthesis, antitubulin and antimitotic activity, and cytotoxicity of analogs of 2-methoxyestradiol, an endogenous mammalian metabolite of estradiol that inhibits tubulin polymerization by binding to the colchicine binding site. J Med Chem 38:2041–2049
Lopez-Garcia MA, Geyer FC, Lacroix-Triki M, Marchió C, Reis-Filho JS (2010) Breast cancer precursors revisited: molecular features and progression pathways. Histopathology 57(2):171–192
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Cardoso-Filho, C., Sarian, L.O., de Oliveira, C.B.M. et al. Clinical effects of A4889G and T6235C polymorphisms in cytochrome P-450 CYP1A1 for breast cancer patients treated with tamoxifen: implications for tumor aggressiveness and patient survival. Cancer Chemother Pharmacol 72, 529–535 (2013). https://doi.org/10.1007/s00280-013-2221-y
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DOI: https://doi.org/10.1007/s00280-013-2221-y