Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients

Breast Cancer Research

Sten Wingren¹  Lars-Erik Rutqvist²  Lambert Skoog³  Bo Nordenskjöld⁴  Olle Stål⁴  Linda Vainikka¹  Pia Wegman¹ 

[1] Department of Biomedicine and Surgery, Division of Cellbiology, Faculty of Health Sciences, Linköping, Sweden;Department of Oncology, Huddinge University Hospital, Stockholm, Sweden;Division of Cytology, Karolinska Hospital, Stockholm, Sweden;Department of Biomedicine and Surgery, Division of Oncology, Faculty of Health Sciences, Linköping, Sweden

关键词: tamoxifen;    SULT1A1;    polymorphism;    CYP2D6;    breast cancer;   

Others  :  1114969
DOI  :  10.1186/bcr993

 received in 2004-08-17, accepted in 2004-12-20,  发布年份 2005

【 摘 要 】

Background

Tamoxifen is widely used as endocrine therapy for oestrogen-receptor-positive breast cancer. However, many of these patients experience recurrence despite tamoxifen therapy by incompletely understood mechanisms. In the present report we propose that tamoxifen resistance may be due to differences in activity of metabolic enzymes as a result of genetic polymorphism. Cytochrome P450 2D6 (CYP2D6) and sulfotransferase 1A1 (SULT1A1) are polymorphic and are involved in the metabolism of tamoxifen. The CYP2D6*4 and SULT1A1*2 genotypes result in decreased enzyme activity. We therefore investigated the genotypes of CYP2D6 and SULT1A1 in 226 breast cancer patients participating in a trial of adjuvant tamoxifen treatment in order to validate the benefit from the therapy.

Methods

The patients were genotyped using PCR followed by cleavage with restriction enzymes.

Results

Carriers of the CYP2D6*4 allele demonstrated a decreased risk of recurrence when treated with tamoxifen (relative risk = 0.28, 95% confidence interval = 0.11–0.74, P = 0.0089). A similar pattern was seen among the SULT1A1*1 homozygotes (relative risk = 0.48, 95% confidence interval = 0.21–1.12, P = 0.074). The combination of CYP2D6*4 and/or SULT1A1*1/*1 genotypes comprised 60% of the patients and showed a 62% decreased risk of distant recurrence with tamoxifen (relative risk = 0.38, 95% confidence interval = 0.19–0.74, P = 0.0041).

Conclusion

The present study suggests that genotype of metabolic enzymes might be useful as a guide for adjuvant endocrine treatment of postmenopausal breast cancer patients. However, results are in contradiction to prior hypotheses and the present sample size is relatively small. Findings therefore need to be confirmed in a larger cohort.

【 授权许可】

   
2005 Wegman et al., licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 3.

【 参考文献 】

• [1]Early Breast Cancer Trialist's Collaborative Group (EBCTCG): Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998, 352:1451-1467.
• [2]Fuqua SAW, Wiltschke C, Zhang QX, Borg Å, Castles CG, Friedrichs WE, Hopp T, Hilsenbeck S, Mohsin S, O'Connell P, Allred C: Hypersensitive estrogen receptor-α mutation in premalignant breast lesions. Cancer Res 2000, 60:4026-4029.
• [3]McClelland RA, Barrow D, Madden T-A, Dutkowski CM, Pamment J, Knowlden JM, Gee JMW, Nicholson RI: Enhanced epidermal growth factor receptor signalling in MCF-7 breast cancer cells after long-term culture in the presence of the pure antiestrogen ICI 182, 780 (Faslodex)*. Endocrinology 2001, 142:2776-2788.
• [4]Knowlden JM, Hutcheson IR, Jones HE, Madden T, Gee JMW, Harper ME, Barrow D, Wakeling AE, Nicholson RI: Elevated levels of epidermal growth factor receptor/c-erbB2 heterodimers mediate an autocrine growth regulatory pathway in tamoxifen-resistant MCF-7 Cells. Endocrinology 2003, 144:1032-1044.
• [5]Ali S, Coombes RC: Endocrine-responsive breast cancer and strategies for combating resistance. Nat Rev 2002, 2:101-112.
• [6]Fabian C, Tilzer L, Sternson L: Comparative binding affinities of tamoxifen, 4-hydroxytamoxifen, and desmethyltamoxifen for estrogen receptors isolated from human breast carcinoma: correlation with blood levels in patients with metastatic breast cancer. Biopharma Drug Dispos 1981, 2:381-390.
• [7]Coezy E, Borgna J-L, Rochefort H: Tamoxifen and metabolites in MCF7 cells: correlation between binding to estrogen receptor and inhibition of cell growth. Cancer Res 1982, 42:317-323.
• [8]Dehal SS, Kupfer D: CYP2D6 catalyzes tamoxifen 4-hydroxylation in human liver. Cancer Res 1997, 57:3402-3406.
• [9]Boocock DJ, Brown K, Gibbs AH, Sanchez E, Turteltaub KW, White INH: Identification of CYP forms involved in the activation of tamoxifen and irreversible binding to DNA. Carcinogenesis 2002, 23:1897-1901.
• [10]Falany CN, Wheeler J, Oh TS, Falany JL: Steroid sulfation by expressed human cytosolic sulfotransferases. J Steroid Biochem Mol Biol 1994, 48:369-375.
• [11]Seth P, Lunetta KL, Bell DW, Gray H, Nasser SM, Rhei E, Kaelin CM, Iglehart DJ, Marks JR, Garber JE, et al.: Phenol sulfotransferases: hormonal regulation, polymorphism, and age of onset of breast cancer. Cancer Res 2000, 60:6859-6863.
• [12]Sachse C, Brockmöller J, Bauer S, Roots I: Cytochrome P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequences. Am J Hum Genet 1997, 60:284-295.
• [13]Nowell S, Sweeney C, Winters M, Stone A, Lang NP, Hutchins LF, Kadlubar FF, Ambrosone CB: Association between sulfotransferase 1A1 genotype and survival of breast cancer patients receiving tamoxifen therapy. J Natl Cancer Inst 2002, 94:1635-1640.
• [14]Hanioka N, Kimura S, Meyer UA, Gonzalez FJ: The human CYP2D locus associated with a common genetic defect in drug oxidation: a G1934 → A base change in intron 3 of a mutant CYP2D6 allele results in an aberrant 3' splice recognition site. Am J Hum Genet 1990, 47:994-1001.
• [15]Raftogianis RB, Wood TC, Otterness DM, Van Loon JA, Weinshilboum RM: Phenol sulfotransferase pharmacogenetics in humans: Association of common SULT1A1 alleles with TS PST phenotype. Biochem Biophys Res Commun 1997, 239:298-304.
• [16]Rutqvist L-E, Cedermark B, Glas U, Johansson H, Rotstein S, Skoog L, Somell A, Theve T, Askergren J, Friberg S, et al.: Radiotherapy, chemotherapy, and tamoxifen as adjuncts to surgery in early breast cancer: a summary of three randomized trials. Int J Radiat Oncol Biol Phys 1989, 16:629-639.
• [17]Coughtrie MWH, Gilissen RAHJ, Shek B, Strange RC, Fryer AA, Jones PW, Bamber DE: Phenol sulphotransferase SULT1A1 polymorphism: molecular diagnosis and allele frequencies in Caucasian and African populations. Biochem J 1999, 337:45-49.
• [18]Longcope C, Flood C, Tast J: The metabolism of estrone sulphate in the female rhesus monkey. Steroids 1994, 59:270-273.
• [19]Coller JK, Krebsfanger N, Klein K, Endrizzi K, Wolbold R, Lang T, Nüssler A, Neuhaus P, Zanger UM, Eichelbaum M, Mürdter TE: The influence of CYP2B6, CYP2C9, and CYP2D6 genotypes on the formation of the potent antioestrogen Z-4-hydroxy-tamoxifen in human liver. Br J Clin Pharmacol 2002, 54:157-167.
• [20]Stearns V, Johnson M, Rae JM, Morocho A, Novielli A, Bhargava P, Hayes DF, Desta Z, Flockhart DA: Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst 2003, 95:1758-1764.
• [21]Crewe KH, Ellis W, Lennard MS, Tucker GT: Variable contribution of cytochrome P450 2D6, 2C9 and 3A4 to the 4-hydroxylation of tamoxifen by human liver microsomes. Biochem Pharmacol 1997, 53:171-178.
• [22]Bradford LD: CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. Pharmacogenomics 2002, 3:229-243.
• [23]Raimundo S, Fisher J, Eichelbaum M, Griese EU, Schwab M, Zang U: Elucidation of the genetic basis of the common 'intermediate metabolizer' phenotype for drug oxidation by CYP2D6. Pharmacogenetics 2000, 10:577-581.
• [24]Linder MW, Prough RA, Valdes R Jr: Pharmacogenetics: a laboratory tool for optimizing therapeutic efficiency. Clin Chem 1997, 43:254-266.