Metabolism and transport of tamoxifen in relation to its effectiveness: new perspectives on an ongoing controversy

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References

• 1  Jordan VC. Tamoxifen: catalyst for the change to targeted therapy. Eur. J. Cancer44(1),30–38 (2008).
  Medline CASGoogle Scholar
• 2  Osborne CK. Tamoxifen in the treatment of breast cancer. N. Engl. J. Med.339(22),1609–1618 (1998).
  Medline CASGoogle Scholar
• 3  Burstein HJ, Prestrud AA, Seidenfeld J et al. American society of clinical oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J. Clin. Oncol.28(23),3784–3796 (2010).
  MedlineGoogle Scholar
• 4  Goldhirsch A, Ingle JN, Gelber RD, Coates AS, Thurlimann B, Senn HJ. Thresholds for therapies: highlights of the St Gallen international expert consensus on the primary therapy of early breast cancer 2009. Ann. Oncol.20(8),1319–1329 (2009).•• Guidelines for clinical practice recommend tamoxifen for premenopausal women whose breast tumors express the ER, and some postmenopausal women. CYP2D6 genetic testing is not recommended in routine clinical practice.
  Medline CASGoogle Scholar
• 5  Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Davies C, Godwin J, Gray J et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet378(9793),771–784 (2011).
  Medline CASGoogle Scholar
• 6  Early Breast Cancer Trialists’ Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet365(9472),1687–1717 (2005).
  MedlineGoogle Scholar
• 7  Jordan VC, Collins MM, Rowsby L, Prestwich G. A monohydroxylated metabolite of tamoxifen with potent antioestrogenic activity. J. Endocrinol.75(2),305–316 (1977).
  Medline CASGoogle Scholar
• 8  Lien EA, Solheim E, Kvinnsland S, Ueland PM. Identification of 4-hydroxy-N-desmethyltamoxifen as a metabolite of tamoxifen in human bile. Cancer Res.48(8),2304–2308 (1988).
  Medline CASGoogle Scholar
• 9  Adam HK, Douglas EJ, Kemp JV. The metabolism of tamoxifen in human. Biochem. Pharmacol.28(1),145–147 (1979).
  Medline CASGoogle Scholar
• 10  Stearns V, Johnson MD, Rae JM et al. Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J. Natl Cancer Inst.95(23),1758–1764 (2003).
  Medline CASGoogle Scholar
• 11  Coller JK, Krebsfaenger N, Klein K et al. 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.54(2),157–167 (2002).
  Medline CASGoogle Scholar
• 12  Lim YC, Desta Z, Flockhart DA, Skaar TC. 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(5),471–478 (2005).
  Medline CASGoogle Scholar
• 13  Lazarus P, Blevins-Primeau AS, Zheng Y, Sun D. Potential role of UGT pharmacogenetics in cancer treatment and prevention: focus on tamoxifen. Ann. NY Acad. Sci.1155,99–111 (2009).
  Medline CASGoogle Scholar
• 14  Ahern TP, Christensen M, Cronin-Fenton DP et al. Functional polymorphisms in UDP-glucuronosyl transferases and recurrence in tamoxifen-treated breast cancer survivors. Cancer Epidemiol. Biomarkers Prev.20(9),1937–1943 (2011).
  Medline CASGoogle Scholar
• 15  Gjerde J, Hauglid M, Breilid H et al. Effects of CYP2D6 and SULT1A1 genotypes including SULT1A1 gene copy number on tamoxifen metabolism. Ann. Oncol.19(1),56–61 (2008).•• Polymorphisms in genes encoding enzymes that metabolize tamoxifen affect the concentration of tamoxifen’s metabolites.
  Medline CASGoogle Scholar
• 16  International Transporter Consortium; Giacomini KM, Huang SM, Tweedie DJ et al. Membrane transporters in drug development. Nat. Rev. Drug Discov.9(3),215–236 (2010).
  Medline CASGoogle Scholar
• 17  Lai Y, Varma M, Feng B et al. Impact of drug transporter pharmacogenomics on pharmacokinetic and pharmacodynamic variability – considerations for drug development. Expert Opin. Drug Metab. Toxicol.8(6),723–743 (2012).
  Medline CASGoogle Scholar
• 18  Leslie EM, Deeley RG, Cole SP. Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense. Toxicol. Appl. Pharmacol.204(3),216–237 (2005).
  Medline CASGoogle Scholar
• 19  Reed K, Parissenti AM. The effect of ABCB1 genetic variants on chemotherapy response in HIV and cancer treatment. Pharmacogenomics12(10),1465–1483 (2011).
  CASGoogle Scholar
• 20  Amiri-Kordestani L, Basseville A, Kurdziel K, Fojo AT, Bates SE. Targeting MDR in breast and lung cancer: discriminating its potential importance from the failure of drug resistance reversal studies. Drug Resist. Updat.15(1–2),50–61 (2012).
  Medline CASGoogle Scholar
• 21  Clarke R, Leonessa F, Trock B. Multidrug resistance/P-glycoprotein and breast cancer: review and meta-analysis. Semin. Oncol.32(6 Suppl. 7),S9–S15 (2005).
  Medline CASGoogle Scholar
• 22  Teft WA, Mansell SE, Kim RB. Endoxifen, the active metabolite of tamoxifen, is a substrate of the efflux transporter P-glycoprotein (multidrug resistance 1). Drug Metab. Dispos.39(3),558–562 (2011).•• Highlights that tamoxifen is a substrate of P-glycoprotein.
  Medline CASGoogle Scholar
• 23  Iusuf D, Teunissen SF, Wagenaar E, Rosing H, Beijnen JH, Schinkel AH. P-glycoprotein (ABCB1) transports the primary active tamoxifen metabolites endoxifen and 4-hydroxytamoxifen and restricts their brain penetration. J. Pharmacol. Exp. Ther.337(3),710–717 (2011).
  Medline CASGoogle Scholar
• 24  Biglia N, Torta R, Roagna R et al. Evaluation of low-dose venlafaxine hydrochloride for the therapy of hot flushes in breast cancer survivors. Maturitas52(1),78–85 (2005).
  Medline CASGoogle Scholar
• 25  Henry NL, Rae JM, Li L et al. Association between CYP2D6 genotype and tamoxifen-induced hot flashes in a prospective cohort. Breast Cancer Res. Treat.117(3),571–575 (2009).
  MedlineGoogle Scholar
• 26  Demissie S, Silliman RA, Lash TL. Adjuvant tamoxifen: predictors of use, side effects, and discontinuation in older women. J. Clin. Oncol.19(2),322–328 (2001).
  Medline CASGoogle Scholar
• 27  Baum M, Budzar AU, Cuzick J et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet359(9324),2131–2139 (2002).
  Medline CASGoogle Scholar
• 28  Deitcher SR, Gomes MP. The risk of venous thromboembolic disease associated with adjuvant hormone therapy for breast carcinoma: a systematic review. Cancer101(3),439–449 (2004).
  MedlineGoogle Scholar
• 29  Fisher B, Costantino JP, Wickerham DL et al. Tamoxifen for the prevention of breast cancer: Current status of the national surgical adjuvant breast and bowel project P-1 study. J. Natl Cancer Inst.97(22),1652–1662 (2005).
  Medline CASGoogle Scholar
• 30  Swerdlow AJ, Jones ME. Tamoxifen treatment for breast cancer and risk of endometrial cancer: a case–control study. J. Natl Cancer Inst.97(5),375–384 (2005).
  Medline CASGoogle Scholar
• 31  Crewe HK, Ellis SW, Lennard MS, Tucker GT. Variable contribution of cytochromes P450 2D6, 2C9 and 3A4 to the 4-hydroxylation of tamoxifen by human liver microsomes. Biochem. Pharmacol.53(2),171–178 (1997).
  Medline CASGoogle Scholar
• 32  Crewe HK, Lennard MS, Tucker GT, Woods FR, Haddock RE. The effect of selective serotonin re-uptake inhibitors on cytochrome P4502D6 (CYP2D6) activity in human liver microsomes. Br. J. Clin. Pharmacol.34(3),262–265 (1992).
  Medline CASGoogle Scholar
• 33  Jeppesen U, Gram LF, Vistisen K, Loft S, Poulsen HE, Brosen K. Dose-dependent inhibition of CYP1A2, CYP2C19 and CYP2D6 by citalopram, fluoxetine, fluvoxamine and paroxetine. Eur. J. Clin. Pharmacol.51(1),73–78 (1996).
  Medline CASGoogle Scholar
• 34  Jin Y, Desta Z, Stearns V et al.CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J. Natl Cancer Inst.97(1),30–39 (2005).•• Selective serotonin reuptake inhibitors and polymorphisms in genes encoding enzymes that metabolize tamoxifen affect the serum concentration of tamoxifen’s metabolites.
  Medline CASGoogle Scholar
• 35  Cronin-Fenton D, Lash TL, Sorensen HT. Selective serotonin reuptake inhibitors and adjuvant tamoxifen therapy: risk of breast cancer recurrence and mortality. Future Oncol.6(6),877–880 (2010).
  CASGoogle Scholar
• 36  Sideras K, Ingle JN, Ames MM et al. Coprescription of tamoxifen and medications that inhibit CYP2D6. J. Clin. Oncol.28(16),2768–2776 (2010).
  Medline CASGoogle Scholar
• 37  Borges S, Desta Z, Jin Y et al. Composite functional genetic and comedication CYP2D6 activity score in predicting tamoxifen drug exposure among breast cancer patients. J. Clin. Pharmacol.50(4),450–458 (2010).
  Medline CASGoogle Scholar
• 38  Borges S, Desta Z, Li L et al. Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: implication for optimization of breast cancer treatment. Clin. Pharmacol. Ther.80(1),61–74 (2006).
  Medline CASGoogle Scholar
• 39  Ahern TP, Pedersen L, Cronin-Fenton DP, Sorensen HT, Lash TL. No increase in breast cancer recurrence with concurrent use of tamoxifen and some CYP2D6-inhibiting medications. Cancer Epidemiol. Biomarkers Prev.18(9),2562–2564 (2009).
  Medline CASGoogle Scholar
• 40  Lash TL, Cronin-Fenton D, Ahern TP et al. Breast cancer recurrence risk related to concurrent use of SSRI antidepressants and tamoxifen. Acta Oncol.49(3),305–312 (2010).
  Medline CASGoogle Scholar
• 41  Lash TL, Pedersen L, Cronin-Fenton D et al. Tamoxifen’s protection against breast cancer recurrence is not reduced by concurrent use of the SSRI citalopram. Br. J. Cancer99(4),616–621 (2008).
  Medline CASGoogle Scholar
• 42  Lash TL, Cronin-Fenton D, Ahern TP et al. CYP2D6 inhibition and breast cancer recurrence in a population-based study in Denmark. J. Natl Cancer Inst.103(6),489–500 (2011).
  Medline CASGoogle Scholar
• 43  Kelly CM, Juurlink DN, Gomes T et al. Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study. BMJ340,c693 (2010).
  MedlineGoogle Scholar
• 44  Morrow PK, Serna R, Broglio K et al. Effect of CYP2D6 polymorphisms on breast cancer recurrence. Cancer118(5),1221–1227 (2012).
  Medline CASGoogle Scholar
• 45  Wegman P, Elingarami S, Carstensen J, Stal O, Nordenskjold B, Wingren S. Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal patients with breast cancer. Breast Cancer Res.9(1),R7 (2007).
  MedlineGoogle Scholar
• 46  Wegman P, Vainikka L, Stal O et al. Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients. Breast Cancer Res.7(3),R284–R290 (2005).
  Medline CASGoogle Scholar
• 47  Okishiro M, Taguchi T, Jin KS, Shimazu K, Tamaki Y, Noguchi S. Genetic polymorphisms of CYP2D6*10 and CYP2C19*2,*3 are not associated with prognosis, endometrial thickness, or bone mineral density in japanese breast cancer patients treated with adjuvant tamoxifen. Cancer115(5),952–961 (2009).
  Medline CASGoogle Scholar
• 48  Oesterreich S, Hilsenbeck SH, Skaar T et al. Correlations between genetic variants in CYP2D6 and UGT2B7 and survival in breast cancer patients treated with or without tamoxifen: results from a large cohort study. Presented at: San Antonio Breast Cancer Symposium. San Antonio, TX, USA, 8–12 December 2010.
  Google Scholar
• 49  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.91(3),249–258 (2005).
  Medline CASGoogle Scholar
• 50  Regan MM, Leyland-Jones B, Bouzyk M et al.CYP2D6 genotype and tamoxifen response in postmenopausal women with endocrine-responsive breast cancer: the Breast International Group 1-98 trial. J. Natl Cancer Inst.104(6),441–451 (2012).
  Medline CASGoogle Scholar
• 51  Abraham JE, Maranian MJ, Driver KE et al.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 (2010).
  MedlineGoogle Scholar
• 52  Gor PP, Su HI, Gray RJ et al. Cyclophosphamide-metabolizing enzyme polymorphisms and survival outcomes after adjuvant chemotherapy for node-positive breast cancer: a retrospective cohort study. Breast Cancer Res.12(3),R26 (2010).
  MedlineGoogle Scholar
• 53  Rae JM, Drury S, Hayes DF et al.CYP2D6 and UGT2B7 genotype and risk of recurrence in tamoxifen-treated breast cancer patients. J. Natl Cancer Inst.104(6),452–460 (2012).
  Medline CASGoogle Scholar
• 54  Park HS, Choi JY, Lee MJ et al. Association between genetic polymorphisms of CYP2D6 and outcomes in breast cancer patients with tamoxifen treatment. J. Korean Med. Sci.26(8),1007–1013 (2011).
  MedlineGoogle Scholar
• 55  Stingl JC, Parmar S, Huber-Wechselberger A et al. Impact of CYP2D6*4 genotype on progression free survival in tamoxifen breast cancer treatment. Curr. Med. Res. Opin.26(11),2535–2542 (2010).
  Medline CASGoogle Scholar
• 56  Schroth W, Goetz MP, Hamann U et al. Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen. JAMA302(13),1429–1436 (2009).
  Medline CASGoogle Scholar
• 57  Goetz MP, Suman VJ, Hoskin TL et al. CYP2D6 metabolism and patient outcome in the Austrian Breast and Colorectal Cancer Study Group trial (ABCSG) 8. Clin. Cancer Res.19(2),500–507 (2013).
  Medline CASGoogle Scholar
• 58  Sirachainan E, Jaruhathai S, Trachu N et al.CYP2D6 polymorphisms influence the efficacy of adjuvant tamoxifen in Thai breast cancer patients. Pharmgenomics Pers. Med.5,149–153 (2012).
  Medline CASGoogle Scholar
• 59  Thompson AM, Johnson A, Quinlan P et al. Comprehensive CYP2D6 genotype and adherence affect outcome in breast cancer patients treated with tamoxifen monotherapy. Breast Cancer Res. Treat.125(1),279–287 (2011).
  Medline CASGoogle Scholar
• 60  Newman WG, Hadfield KD, Latif A et al. Impaired tamoxifen metabolism reduces survival in familial breast cancer patients. Clin. Cancer Res.14(18),5913–5918 (2008).
  Medline CASGoogle Scholar
• 61  Bijl MJ, van Schaik RH, Lammers LA et al. The CYP2D6*4 polymorphism affects breast cancer survival in tamoxifen users. Breast Cancer Res. Treat.118(1),125–130 (2009).
  Medline CASGoogle Scholar
• 62  Ramón y Cajal YC, Altes A, Pare L et al. Impact of CYP2D6 polymorphisms in tamoxifen adjuvant breast cancer treatment. Breast Cancer Res. Treat.119(1),33–38 (2010).
  Medline CASGoogle Scholar
• 63  Sukasem C, Sirachainan E, Chamnanphon M et al. Impact of CYP2D6 polymorphisms on tamoxifen responses of women with breast cancer: a microarray-based study in Thailand. Asian Pac. J. Cancer Prev.13(9),4549–4553 (2012).
  MedlineGoogle Scholar
• 64  Xu Y, Sun Y, Yao L et al. Association between CYP2D6 *10 genotype and survival of breast cancer patients receiving tamoxifen treatment. Ann. Oncol.19(8),1423–1429 (2008).
  Medline CASGoogle Scholar
• 65  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.14(1),52–59 (2012).
  Medline CASGoogle Scholar
• 66  Kiyotani K, Mushiroda T, Imamura CK et al. Significant effect of polymorphisms in CYP2D6 and ABCC2 on clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients. J. Clin. Oncol.28(8),1287–1293 (2010).
  Medline CASGoogle Scholar
• 67  Schroth W, Antoniadou L, Fritz P et al. Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. J. Clin. Oncol.25(33),5187–5193 (2007).
  Medline CASGoogle Scholar
• 68  Kiyotani K, Mushiroda T, Sasa M et al. Impact of CYP2D6*10 on recurrence-free survival in breast cancer patients receiving adjuvant tamoxifen therapy. Cancer Sci.99(5),995–999 (2008).
  Medline CASGoogle Scholar
• 69  Goetz MP, Knox SK, Suman VJ et al. The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen. Breast Cancer Res. Treat.101(1),113–121 (2007).
  Medline CASGoogle Scholar
• 70  Schroth W, Hamann U, Fasching PA et al. CYP2D6 polymorphisms as predictors of outcome in breast cancer patients treated with tamoxifen: expanded polymorphism coverage improves risk stratification. Clin. Cancer Res.16(17),4468–4477 (2010).•• Comprehensive genotyping of the CYP2D6 gene increases the strength of the association between reduced function CYP2D6 and breast cancer recurrence.
  Medline CASGoogle Scholar
• 71  Toyama T, Yamashita H, Sugiura H, Kondo N, Iwase H, Fujii Y. No association between CYP2D6*10 genotype and survival of node-negative Japanese breast cancer patients receiving adjuvant tamoxifen treatment. Jpn J. Clin. Oncol.39(10),651–656 (2009).
  MedlineGoogle Scholar
• 72  Kim H, Shin HC, Yom CK et al. Lack of significant association between CYP2D6 polymorphisms and clinical outcomes of adjuvant tamoxifen therapy. Presented at: San Antonio Breast Cancer Symposium. San Antonio, TX, USA, 8–12 December 2010.
  Google Scholar
• 73  Lash TL. Association between CYP2D6 polymorphisms and breast cancer outcomes. JAMA303(6),516 (2010).
  Medline CASGoogle Scholar
• 74  Damodaran SE, Pradhan SC, Umamaheswaran G, Kadambari D, Reddy KS, Adithan C. Genetic polymorphisms of CYP2D6 increase the risk for recurrence of breast cancer in patients receiving tamoxifen as an adjuvant therapy. Cancer Chemother. Pharmacol.70(1),75–81 (2012).
  Medline CASGoogle Scholar
• 75  Chubak J, Buist DS, Boudreau DM, Rossing MA, Lumley T, Weiss NS. Breast cancer recurrence risk in relation to antidepressant use after diagnosis. Breast Cancer Res. Treat.112(1),123–132 (2008).
  Medline CASGoogle Scholar
• 76  Azoulay L, Dell’aniello S, Huiart L, du Fort GG, Suissa S. Concurrent use of tamoxifen with CYP2D6 inhibitors and the risk of breast cancer recurrence. Breast Cancer Res. Treat.126(3),695–703 (2011).
  Medline CASGoogle Scholar
• 77  Rothman KJ, Greenland S, Lash TL. Validity in epidemiologic studies. In: Modern Epidemiology. Rothman KJ, Greenland S, Lash TL (Eds). Lippincott Williams and Wilkins, PA, USA, 115–134 (2008).
  Google Scholar
• 78  Aubert RE, Stanek EJ, Yao J et al. Risk of breast cancer recurrence in women initiating tamoxifen with CYP2D6 inhibitors. J. Clin. Oncol.27,18S (2009).
  Google Scholar
• 79  Dusetzina SB, Alexander GC, Freedman RA, Huskamp HA, Keating NL. Trends in co-prescribing of antidepressants and tamoxifen among women with breast cancer, 2004–2010. Breast Cancer Res. Treat.137(1),285–296 (2013).
  MedlineGoogle Scholar
• 80  Binkhorst L, Mathijssen RH, van Herk-Sukel MP et al. Unjustified prescribing of CYP2D6 inhibiting SSRIs in women treated with tamoxifen. Breast Cancer Res. Treat.139(3),923–929 (2013).
  Medline CASGoogle Scholar
• 81  Stanton V Jr. Re: CYP2D6 genotype and tamoxifen response in postmenopausal women with endocrine-responsive breast cancer: the Breast International Group 1-98 trial. J. Natl Cancer Inst.104(16),1265–1266; author reply 1266–1268 (2012).
  Medline CASGoogle Scholar
• 82  Kelly CM, Pritchard KI. CYP2D6 genotype as a marker for benefit of adjuvant tamoxifen in postmenopausal women: lessons learned. J. Natl Cancer Inst.104(6),427–428 (2012).
  Medline CASGoogle Scholar
• 83  Pharoah PD, Abraham J, Caldas C. Re: CYP2D6 genotype and tamoxifen response in postmenopausal women with endocrine-responsive breast cancer: the Breast International Group 1-98 trial and Re: CYP2D6 and UGT2B7 genotype and risk of recurrence in tamoxifen-treated breast cancer patients. J. Natl Cancer Inst.104(16),1263–1264; author reply 1266–1268 (2012).
  Medline CASGoogle Scholar
• 84  Nakamura Y, Ratain MJ, Cox NJ, McLeod HL, Kroetz DL, Flockhart DA. Re: CYP2D6 genotype and tamoxifen response in postmenopausal women with endocrine-responsive breast cancer: the Breast International Group 1-98 trial. J. Natl Cancer Inst.104(16),1264; author reply 1266–1268 (2012).
  Medline CASGoogle Scholar
• 85  Ellsworth RE, Ellsworth DL, Lubert SM, Hooke J, Somiari RI, Shriver CD. High-throughput loss of heterozygosity mapping in 26 commonly deleted regions in breast cancer. Cancer Epidemiol. Biomarkers Prev.12(9),915–919 (2003).
  Medline CASGoogle Scholar
• 86  Hirano A, Emi M, Tsuneizumi M et al. Allelic losses of loci at 3p25.1, 8p22, 13q12, 17p13.3, and 22q13 correlate with postoperative recurrence in breast cancer. Clin. Cancer Res.7(4),876–882 (2001).
  Medline CASGoogle Scholar
• 87  Benetkiewicz M, Piotrowski A, Diaz De Stahl T et al. Chromosome 22 array-CGH profiling of breast cancer delimited minimal common regions of genomic imbalances and revealed frequent intra-tumoral genetic heterogeneity. Int. J. Oncol.29(4),935–945 (2006).
  Medline CASGoogle Scholar
• 88  Rodriguez S, Gaunt TR, Day IN. Hardy–Weinberg equilibrium testing of biological ascertainment for mendelian randomization studies. Am. J. Epidemiol.169(4),505–514 (2009).
  MedlineGoogle Scholar
• 89  Salanti G, Amountza G, Ntzani EE, Ioannidis JP. Hardy–Weinberg equilibrium in genetic association studies: an empirical evaluation of reporting, deviations, and power. Eur. J. Hum. Genet.13(7),840–848 (2005).
  Medline CASGoogle Scholar
• 90  Trikalinos TA, Salanti G, Khoury MJ, Ioannidis JP. Impact of violations and deviations in Hardy–Weinberg equilibrium on postulated gene-disease associations. Am. J. Epidemiol.163(4),300–309 (2006).
  MedlineGoogle Scholar
• 91  Ahern TP, Christensen M, Cronin-Fenton D et al. Concordance of metabolic enzyme genotypes assayed from paraffin-embedded, formalin-fixed breast tumors and normal lymphatic tissue. Clin. Epidemiol.2,241–246 (2010).
  MedlineGoogle Scholar
• 92  Rae JM, Cordero KE, Scheys JO, Lippman ME, Flockhart DA, Johnson MD. Genotyping for polymorphic drug metabolizing enzymes from paraffin-embedded and immunohistochemically stained tumor samples. Pharmacogenetics13(8),501–507 (2003).
  Medline CASGoogle Scholar
• 93  Lash TL, Lien EA, Sorensen HT, Hamilton-Dutoit S. Genotype-guided tamoxifen therapy: time to pause for reflection? Lancet Oncol.10(8),825–833 (2009).•• Gene–drug and drug–drug interactions affect the concentration profile of tamoxifen’s metabolites but these changes may have little clinical impact on tamoxifen’s effectiveness. The clinical epidemiology to date is widely heterogeneous, without adequate explanation, and with an average association near the null.
  Medline CASGoogle Scholar
• 94  Lash TL, Ahern TP, Cronin-Fenton D, Garne JP, Hamilton-Dutoit S, Sorensen HT. Comment on ‘impact of CYP2D6*10 on recurrence-free survival in breast cancer patients receiving adjuvant tamoxifen therapy’. Cancer Sci.99(8),1706–1707 (2008).
  Medline CASGoogle Scholar
• 95  Dunn BK, Greene MH, Kelley JM et al. Novel pathway analysis of genomic polymorphism-cancer risk interaction in the breast cancer prevention trial. Int. J. Mol. Epidemiol. Genet.1(4),332–349 (2010).•• Analysis of the complete tamoxifen metabolic pathway will give insights into the association between tamoxifen metabolism and breast cancer outcomes.
  Medline CASGoogle Scholar
• 96  Lash TL, Ahern TP. Bias analysis to guide new data collection. Int. J. Biostat. doi:10.2202/1557,4679.1345 (2012) (Epub ahead of print).
  MedlineGoogle Scholar
• 97  Jordan VC. Metabolites of tamoxifen in animals and man: identification, pharmacology, and significance. Breast Cancer Res. Treat.2(2),123–138 (1982).
  Medline CASGoogle Scholar
• 98  Baurley JW, Conti DV, Gauderman WJ, Thomas DC. Discovery of complex pathways from observational data. Stat. Med.29(19),1998–2011 (2010).
  MedlineGoogle Scholar
• 99  Jordan VC, Dowse LJ. Tamoxifen as an anti-tumour agent: effect on oestrogen binding. J. Endocrinol.68(02),297–303 (1976).
  Medline CASGoogle Scholar
• 100  Johnson MD, Zuo H, Lee KH et al. Pharmacological characterization of 4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen. Breast Cancer Res. Treat.85(2),151–159 (2004).
  Medline CASGoogle Scholar
• 101  Sherman BM, Chapler FK, Crickard K, Wycoff D. Endocrine consequences of continuous antiestrogen therapy with tamoxifen in premenopausal women. J. Clin. Invest.64(2),398–404 (1979).
  Medline CASGoogle Scholar
• 102  Saladores P, Schroth W, Eccles D, Tapper W, Gerty S, Brauch H. CYP2D6 polymorphisms are not associated with tamoxifen outcome in premenopausal women with ER positive breast cancer of the POSH cohort. Am. Assoc. Cancer Res.72(8 Suppl. 1),2671 (2012).
  Google Scholar
• 103  American Cancer Society. Breast Cancer Facts and Figures 2009–2010. American Cancer Society, Inc., Atlanta, GA, USA (2009).
  Google Scholar
• 104  Surowiak P, Materna V, Matkowski R et al. Relationship between the expression of cyclooxygenase 2 and MDR1/P-glycoprotein in invasive breast cancers and their prognostic significance. Breast Cancer Res.7(5),R862–R870 (2005).
  Medline CASGoogle Scholar
• 105  Filipits M, Pohl G, Rudas M et al. Clinical role of multidrug resistance protein 1 expression in chemotherapy resistance in early-stage breast cancer: the Austrian Breast and Colorectal Cancer Study Group. J. Clin. Oncol.23(6),1161–1168 (2005).
  Medline CASGoogle Scholar
• 106  Lash TL, Cole SR. Immortal person-time in studies of cancer outcomes. J. Clin. Oncol.27(23),e55–e56 (2009).
  MedlineGoogle Scholar
• 107  Sai K, Saito Y, Itoda M et al. Genetic variations and haplotypes of ABCC2 encoding MRP2 in a Japanese population. Drug Metab. Pharmacokinet.23(2),139–147 (2008).
  Medline CASGoogle Scholar
• 108  Choi HK, Yang JW, Roh SH, Han CY, Kang KW. Induction of multidrug resistance associated protein 2 in tamoxifen-resistant breast cancer cells. Endocr. Relat. Cancer14(2),293–303 (2007).
  Medline CASGoogle Scholar
• 109  Siegelmann-Danieli N, Kurnik D, Lomnicky Y et al. Potent CYP2D6 inhibiting drugs do not increase relapse rate in early breast cancer patients treated with adjuvant tamoxifen. Breast Cancer Res. Treat.125(2),505–510 (2011).
  Medline CASGoogle Scholar
• 110  Dezentjé VO, van Blijderveen NJ, Gelderblom H et al. Effect of concomitant CYP2D6 inhibitor use and tamoxifen adherence on breast cancer recurrence in early-stage breast cancer. J. Clin. Oncol.28(14),2423–2429 (2010).
  Medline CASGoogle Scholar
• 111  Lehmann D, Nelsen J, Ramanath V, Newman N, Duggan D, Smith A. Lack of attenuation in the antitumor effect of tamoxifen by chronic CYP isoform inhibition. J. Clin. Pharmacol.44(8),861–865 (2004).
  Medline CASGoogle Scholar
• 201  The Human Cytochrome P450 (CYP) Allele Nomenclature Database. www.cypalleles.ki.se
  Google Scholar
• 202  National Cancer Institure. Tamoxifen citrate in treating patients with metastatic or recurrent breast cancer. www.cancer.gov/clinicaltrials/search/view?cdrid=672523&version=healthprofessional
  Google Scholar
• 203  NCCN practice guidelines in oncology, breast cancer – v.2.2011. Invasive breast cancer, adjuvant endocrine therapy (2010). www.nccn.org
  Google Scholar