Individualization of tamoxifen therapy: Much more than just CYP2D6 genotyping

Cancer Treatment Reviews

Volumn 41, Issue 3, 2015, Pages 289-299

  Binkhorst, Lisette ^a,b   Mathijssen, Ron H J ^a   Jager, Agnes ^a   van Gelder, Teun ^b  

^a ERASMUS MC CANCER INSTITUTE   (Netherlands)

^b ERASMUS MEDICAL CENTER   (Netherlands)

Author keywords

CYP2D6; Endoxifen; Pharmacogenetics; Pharmacokinetics; Tamoxifen; Therapeutic drug monitoring

Indexed keywords

AFIMOXIFENE; AROMATASE; CYTOCHROME P450 2C; CYTOCHROME P450 2C19; CYTOCHROME P450 2C9; CYTOCHROME P450 2D6; CYTOCHROME P450 2D6 INHIBITOR; CYTOCHROME P450 3A; CYTOCHROME P450 3A4; CYTOCHROME P450 3A5; ENDOXIFEN; SEROTONIN NORADRENALIN REUPTAKE INHIBITOR; SEROTONIN UPTAKE INHIBITOR; TAMOXIFEN;

BODY MASS; BREAST CANCER; CIRCADIAN RHYTHM; DISEASE FREE SURVIVAL; DRUG BLOOD LEVEL; DRUG EFFICACY; DRUG METABOLISM; DRUG MONITORING; GENETIC POLYMORPHISM; GENETIC VARIABILITY; GENOTYPE; GLUCURONIDATION; HUMAN; MEDICATION COMPLIANCE; PERSONALIZED MEDICINE; PHARMACOGENETICS; PHENOTYPE; PROGRESSION FREE SURVIVAL; RECURRENCE FREE SURVIVAL; REVIEW; SEASONAL VARIATION; SULFATION; UNSPECIFIED SIDE EFFECT; ANIMAL; BREAST NEOPLASMS; ENZYMOLOGY; FEMALE; GENETICS; GENOTYPING TECHNIQUE; METABOLISM;

ANIMALS; BREAST NEOPLASMS; CYTOCHROME P-450 CYP2D6; FEMALE; GENOTYPING TECHNIQUES; HUMANS; INDIVIDUALIZED MEDICINE; TAMOXIFEN;

EID: 84923204072     PISSN: 03057372     EISSN: 15321967     Source Type: Journal    
DOI: 10.1016/j.ctrv.2015.01.002     Document Type: Review

References (100)

1. 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. Lancet 2005, 365:1687-1717.
2. Early Breast Cancer Trialists' Collaborative Group Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet 2011, 378:771-784.
3. Massarweh S., Schiff R. Unraveling the mechanisms of endocrine resistance in breast cancer: new therapeutic opportunities. Clin Cancer Res 2007, 13:1950-1954.
4. Burstein H.J., Griggs J.J., Prestrud A.A., Temin S. American society of clinical oncology clinical practice guideline update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Oncol Pract 2010, 6:243-246.
5. Gray R.G. aTTom: long-term effects of continuing adjuvant tamoxifen to 10years versus stopping at 5years in 6,953 women with early breast cancer. J Clin Oncol 2013, 31. aTTom Collaborative Group, (RD).
6. Schiavon G., Smith I.E. Endocrine therapy for advanced/metastatic breast cancer. Hematol Oncol Clin North Am 2013, 27:715-736. (viii).
7. Bardia A., Stearns V. Personalized tamoxifen: a step closer but miles to go. Clin Cancer Res 2010, 16:4308-4310.
8. Hoskins J.M., Carey L.A., McLeod H.L. CYP2D6 and tamoxifen: DNA matters in breast cancer. Nat Rev Cancer 2009, 9:576-586.
9. Murdter T.E., Schroth W., Bacchus-Gerybadze L., et al. Activity levels of tamoxifen metabolites at the estrogen receptor and the impact of genetic polymorphisms of phase I and II enzymes on their concentration levels in plasma. Clin Pharmacol Ther 2011, 89:708-717.
10. Nowell S.A., Ahn J., Rae J.M., 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, 91:249-258.
11. Lien E.A., Solheim E., Lea O.A., Lundgren S., Kvinnsland S., Ueland P.M. Distribution of 4-hydroxy-N-desmethyltamoxifen and other tamoxifen metabolites in human biological fluids during tamoxifen treatment. Cancer Res 1989, 49:2175-2183.
12. Stearns V., Johnson M.D., Rae J.M., et al. Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst 2003, 95:1758-1764.
13. CYP2D6 allele nomenclature: . (accessed November 24). http://www.cypalleles.ki.se/cyp2d6.htm.
14. Zanger U.M., Raimundo S., Eichelbaum M. Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemistry. Naunyn Schmiedebergs Arch Pharmacol 2004, 369:23-37.
15. 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 2006, 80:61-74.
16. Lim H.S., Ju Lee H., Seok Lee K., Seok Lee E., Jang I.J., Ro J. Clinical implications of CYP2D6 genotypes predictive of tamoxifen pharmacokinetics in metastatic breast cancer. J Clin Oncol 2007, 25:3837-3845.
17. Jin Y., Desta Z., Stearns V., et al. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst 2005, 97:30-39.
18. Gjerde J., Hauglid M., Breilid H., et al. Effects of CYP2D6 and SULT1A1 genotypes including SULT1A1 gene copy number on tamoxifen metabolism. Ann Oncol 2008, 19:56-61.
19. Teft W.A., Gong I.Y., Dingle B., et al. CYP3A4 and seasonal variation in vitamin D status in addition to CYP2D6 contribute to therapeutic endoxifen level during tamoxifen therapy. Breast Cancer Res Treat 2013, 139:95-105.
20. Fernandez-Santander A., Gaibar M., Novillo A., et al. Relationship between genotypes Sult1a2 and Cyp2d6 and tamoxifen metabolism in breast cancer patients. PLoS One 2013, 8:e70183.
21. Madlensky L., Natarajan L., Tchu S., et al. Tamoxifen metabolite concentrations, CYP2D6 genotype, and breast cancer outcomes. Clin Pharmacol Ther 2011, 89:718-725.
22. Kiyotani K., Mushiroda T., Imamura C.K., et al. Significant effect of polymorphisms in CYP2D6 and ABCC2 on clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients. J Clin Oncol 2010, 28:1287-1293.
23. Lim J.S., Chen X.A., 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, 71:737-750.
24. Goetz M.P., Rae J.M., Suman V.J., et al. Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol 2005, 23:9312-9318.
25. *4 genotype on progression free survival in tamoxifen breast cancer treatment. Curr Med Res Opin 2010, 26:2535-2542.
26. *4 polymorphism affects breast cancer survival in tamoxifen users. Breast Cancer Res Treat 2009, 118:125-130.
27. *10 genotype and survival of breast cancer patients receiving tamoxifen treatment. Ann Oncol 2008, 19:1423-1429.
28. 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 2007, 25:5187-5193.
29. Schroth W., Goetz M.P., Hamann U., et al. Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen. JAMA 2009, 302:1429-1436.
30. Margolin S., Lindh J.D., Thoren L., et al. CYP2D6 and adjuvant tamoxifen: possible differences of outcome in pre- and post-menopausal patients. Pharmacogenomics 2013, 14:613-622.
31. Karle J., Bolbrinker J., Vogl S., et al. Influence of CYP2D6-genotype on tamoxifen efficacy in advanced breast cancer. Breast Cancer Res Treat 2013, 139:553-560.
32. Damodaran S.E., Pradhan S.C., Umamaheswaran G., Kadambari D., Reddy K.S., 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 2012, 70:75-81.
33. Teh L.K., Mohamed N.I., Salleh M.Z., et al. The risk of recurrence in breast cancer patients treated with tamoxifen: polymorphisms of CYP2D6 and ABCB1. AAPS J 2012, 14:52-59.
34. Ramony Cajal T., Altes A., Pare L., et al. Impact of CYP2D6 polymorphisms in tamoxifen adjuvant breast cancer treatment. Breast Cancer Res Treat 2010, 119:33-38.
35. Goetz M.P., Suman V.J., Hoskin T.L., et al. CYP2D6 metabolism and patient outcome in the Austrian Breast and Colorectal Cancer Study Group trial (ABCSG) 8. Clin Cancer Res 2013, 19:500-507.
36. Lammers L.A., Mathijssen R.H., van Gelder T., et al. The impact of CYP2D6-predicted phenotype on tamoxifen treatment outcome in patients with metastatic breast cancer. Br J Cancer 2010, 103:765-771.
37. 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 2005, 7:R284-R290.
38. 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 2007, 9:R7.
39. Lash T.L., Cronin-Fenton D., Ahern T.P., et al. CYP2D6 inhibition and breast cancer recurrence in a population-based study in Denmark. J Natl Cancer Inst 2011, 103:489-500.
40. Okishiro M., Taguchi T., Jin Kim S., 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. Cancer 2009, 115:952-961.
41. *10 genotype and survival of node-negative Japanese breast cancer patients receiving adjuvant tamoxifen treatment. Jpn J Clin Oncol 2009, 39:651-656.
42. Newman W.G., Hadfield K.D., Latif A., et al. Impaired tamoxifen metabolism reduces survival in familial breast cancer patients. Clin Cancer Res 2008, 14:5913-5918.
43. Abraham J.E., Maranian M.J., Driver K.E., 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 2010, 12:R64.
44. Park H.S., Choi J.Y., Lee M.J., et al. Association between genetic polymorphisms of CYP2D6 and outcomes in breast cancer patients with tamoxifen treatment. J Korean Med Sci 2011, 26:1007-1013.
45. Park I.H., Ro J., Park S., et al. Lack of any association between functionally significant CYP2D6 polymorphisms and clinical outcomes in early breast cancer patients receiving adjuvant tamoxifen treatment. Breast Cancer Res Treat 2012, 131:455-461.
46. Thompson A.M., 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 2011, 125:279-287.
47. Regan M.M., 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 2012, 104:441-451.
48. Rae J.M., Drury S., Hayes D.F., et al. CYP2D6 and UGT2B7 genotype and risk of recurrence in tamoxifen-treated breast cancer patients. J Natl Cancer Inst 2012, 104:452-460.
49. Dezentje V.O., van Schaik R.H., Vletter-Bogaartz J.M., et al. CYP2D6 genotype in relation to tamoxifen efficacy in a Dutch cohort of the tamoxifen exemestane adjuvant multinational (TEAM) trial. Breast Cancer Res Treat 2013, 140:363-373.
50. Morrow P.K., Serna R., Broglio K., et al. Effect of CYP2D6 polymorphisms on breast cancer recurrence. Cancer 2012, 118:1221-1227.
51. Chamnanphon M., Pechatanan K., Sirachainan E., et al. Association of CYP2D6 and CYP2C19 polymorphisms and disease-free survival of Thai post-menopausal breast cancer patients who received adjuvant tamoxifen. Pharmgenomics Pers Med 2013, 6:37-48.
52. Mwinyi J., Vokinger K., Jetter A., et al. Impact of variable CYP genotypes on breast cancer relapse in patients undergoing adjuvant tamoxifen therapy. Cancer Chemother Pharmacol 2014, 73:1181-1188.
53. Markkula A., Hjertberg M., Rose C., Ingvar C., Jernstrom H. No association found between CYP2D6 genotype and early breast cancer events in tamoxifen-treated patients. Acta Oncol 2014, 53:195-200.
54. Goetz M.P., Ingle J.N. CYP2D6 genotype and tamoxifen: considerations for proper nonprospective studies. Clin Pharmacol Ther 2014, 96:141-144.
55. Stanton V. 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 2012, 104:1265-1266. (author reply 6-8).
56. Province M.A., Goetz M.P., Brauch H., et al. CYP2D6 genotype and adjuvant tamoxifen: meta-analysis of heterogeneous study populations. Clin Pharmacol Ther 2014, 95:216-227.
57. Jeppesen U., Gram L.F., Vistisen K., Loft S., Poulsen H.E., Brosen K. Dose-dependent inhibition of CYP1A2, CYP2C19 and CYP2D6 by citalopram, fluoxetine, fluvoxamine and paroxetine. Eur J Clin Pharmacol 1996, 51:73-78.
58. Binkhorst L., Mathijssen R.H., van Herk-Sukel M.P., et al. Unjustified prescribing of CYP2D6 inhibiting SSRIs in women treated with tamoxifen. Breast Cancer Res Treat 2013, 139:923-929.
59. Kelly C.M., Juurlink D.N., Gomes T., et al. Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study. BMJ 2010, 340:c693.
60. Binkhorst L., Bannink M., de Bruijn P., et al. First intra-patient comparison of antidepressant use among tamoxifen patients. Ann Oncol 2014, 25(Suppl. 4). (iv106).
61. Aubert R.E., Yao J., Teagarden J.R., et al. Risk of breast cancer recurrence in women initiating tamoxifen with CYP2D6 inhibitors. J Clin Oncol 2009, 27. (suppl; abstr CRA508).
62. Dezentje V.O., van Blijderveen N.J., 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 2010, 28:2423-2429.
63. Azoulay L., Dell'Aniello S., Huiart L., du Fort G.G., Suissa S. Concurrent use of tamoxifen with CYP2D6 inhibitors and the risk of breast cancer recurrence. Breast Cancer Res Treat 2011, 126:695-703.
64. 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 2011, 125:505-510.
65. Lash T.L., Cronin-Fenton D., Ahern T.P., et al. Breast cancer recurrence risk related to concurrent use of SSRI antidepressants and tamoxifen. Acta Oncol 2010, 49:305-312.
66. Dusetzina S.B., Alexander G.C., Freedman R.A., Huskamp H.A., Keating N.L. Trends in co-prescribing of antidepressants and tamoxifen among women with breast cancer, 2004-2010. Breast Cancer Res Treat 2013, 137:285-296.
67. Dieudonne A.S., De Nys K., Casteels M., Wildiers H., Neven P. How often did Belgian physicians co-prescribe tamoxifen with strong CYP2D6 inhibitors over the last 6years?. Acta Clin Belg 2014, 69:47-52.
68. Gjerde J., Geisler J., Lundgren S., et al. Associations between tamoxifen, estrogens, and FSH serum levels during steady state tamoxifen treatment of postmenopausal women with breast cancer. BMC Cancer 2010, 10:313.
69. Wang D., Guo Y., Wrighton S.A., Cooke G.E., Sadee W. Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs. Pharmacogenomics J 2011, 11:274-286.
70. Binkhorst L., van Gelder T., Loos W.J., et al. Effects of CYP induction by rifampicin on tamoxifen exposure. Clin Pharmacol Ther 2012, 92:62-67.
71. Gryn S.E., Teft W.A., Kim R.B. Profound reduction in the tamoxifen active metabolite endoxifen in a patient on phenytoin for epilepsy compared with a CYP2D6 genotype matched cohort. Pharmacogenet Genomics 2014, 24:367-369.
72. *2 genotype predicts tamoxifen treatment outcome in advanced breast cancer patients. Pharmacogenomics 2011, 12:1137-1146.
73. Moyer A.M., Suman V.J., Weinshilboum R.M., et al. SULT1A1, CYP2C19 and disease-free survival in early breast cancer patients receiving tamoxifen. Pharmacogenomics 2011, 12:1535-1543.
74. Ahern T.P., Christensen M., Cronin-Fenton D.P., et al. Functional polymorphisms in UDP-glucuronosyl transferases and recurrence in tamoxifen-treated breast cancer survivors. Cancer Epidemiol Biomarkers Prev 2011, 20:1937-1943.
75. Nowell S., Sweeney C., Winters M., et al. Association between sulfotransferase 1A1 genotype and survival of breast cancer patients receiving tamoxifen therapy. J Natl Cancer Inst 2002, 94:1635-1640.
76. Lien E.A., Soiland H., Lundgren S., et al. Serum concentrations of tamoxifen and its metabolites increase with age during steady-state treatment. Breast Cancer Res Treat 2013, 141:243-248.
77. Wu A.H., Pike M.C., Williams L.D., et al. Tamoxifen, soy, and lifestyle factors in Asian American women with breast cancer. J Clin Oncol 2007, 25:3024-3030.
78. Binkhorst L., Kloth J.S.L., de Bruijn P., et al. Tamoxifen pharmacokinetics influenced by circadian rhythm. Eur J Cancer 2013, 49(Suppl. 2).
79. Wu X., Hawse J.R., Subramaniam M., Goetz M.P., Ingle J.N., Spelsberg T.C. The tamoxifen metabolite, endoxifen, is a potent antiestrogen that targets estrogen receptor alpha for degradation in breast cancer cells. Cancer Res 2009, 69:1722-1727.
80. Hawse J.R., Subramaniam M., Cicek M., et al. Endoxifen's molecular mechanisms of action are concentration dependent and different than that of other anti-estrogens. PLoS One 2013, 8:e54613.
81. Saladores P., Murdter T., Eccles D., et al. Tamoxifen metabolism predicts drug concentrations and outcome in premenopausal patients with early breast cancer. Pharmacogenomics J 2014.
82. Gong I.Y., Teft W.A., Ly J., et al. Determination of clinically therapeutic endoxifen concentrations based on efficacy from human MCF7 breast cancer xenografts. Breast Cancer Res Treat 2013, 139:61-69.
83. Love R.R., Desta Z., Flockhart D., et al. CYP2D6 genotypes, endoxifen levels, and disease recurrence in 224 Filipino and Vietnamese women receiving adjuvant tamoxifen for operable breast cancer. Springerplus 2013, 2:52.
84. de Graan A.J., Teunissen S.F., de Vos F.Y., et al. Dextromethorphan as a phenotyping test to predict endoxifen exposure in patients on tamoxifen treatment. J Clin Oncol 2011, 29:3240-3246.
85. ter Heine R., Binkhorst L., de Graan A.J., et al. Population pharmacokinetic modelling to assess the impact of CYP2D6 and CYP3A metabolic phenotypes on the pharmacokinetics of tamoxifen and endoxifen. Br J Clin Pharmacol 2014, 78:572-586.
86. Opdam F.L., Dezentje V.O., den Hartigh J., et al. The use of the 13C-dextromethorphan breath test for phenotyping CYP2D6 in breast cancer patients using tamoxifen: association with CYP2D6 genotype and serum endoxifen levels. Cancer Chemother Pharmacol 2013, 71:593-601.
87. Gjerde J., Gandini S., Guerrieri-Gonzaga A., et al. Tissue distribution of 4-hydroxy-N-desmethyltamoxifen and tamoxifen-N-oxide. Breast Cancer Res Treat 2012, 134:693-700.
88. Lorizio W., Wu A.H., Beattie M.S., et al. Clinical and biomarker predictors of side effects from tamoxifen. Breast Cancer Res Treat 2012, 132:1107-1118.
89. Jager N.G., Koornstra R.H., Vincent A.D., et al. Hot flashes are not predictive for serum concentrations of tamoxifen and its metabolites. BMC Cancer 2013, 13:612.
90. van Leeuwen F.E., Benraadt J., Coebergh J.W., et al. Risk of endometrial cancer after tamoxifen treatment of breast cancer. Lancet 1994, 343:448-452.
91. Barginear M.F., Jaremko M., Peter I., et al. Increasing tamoxifen dose in breast cancer patients based on CYP2D6 genotypes and endoxifen levels: effect on active metabolite isomers and the antiestrogenic activity score. Clin Pharmacol Ther 2011, 90:605-611.
92. Irvin W.J., Walko C.M., Weck K.E., et al. Genotype-guided tamoxifen dosing increases active metabolite exposure in women with reduced CYP2D6 metabolism: a multicenter study. J Clin Oncol 2011, 29:3232-3239.
93. Jager N.G., Rosing H., Schellens J.H., Linn S.C., Beijnen J.H. Tamoxifen dose and serum concentrations of tamoxifen and six of its metabolites in routine clinical outpatient care. Breast Cancer Res Treat 2014, 143:477-483.
94. Ahmad A., Shahabuddin S., Sheikh S., et al. Endoxifen, a new cornerstone of breast cancer therapy: demonstration of safety, tolerability, and systemic bioavailability in healthy human subjects. Clin Pharmacol Ther 2010, 88:814-817.
95. Dickschen K., Eissing T., Murdter T., Schwab M., Willmann S., Hempel G. Concomitant use of tamoxifen and endoxifen in postmenopausal early breast cancer: prediction of plasma levels by physiologically-based pharmacokinetic modeling. Springerplus 2014, 3:285.
96. Murphy C.C., Bartholomew L.K., Carpentier M.Y., Bluethmann S.M., Vernon S.W. Adherence to adjuvant hormonal therapy among breast cancer survivors in clinical practice. a systematic review. Breast Cancer Res Treat 2012, 134:459-478.
97. Pagani O., Gelber S., Colleoni M., Price K.N., Simoncini E. Impact of SERM adherence on treatment effect: International Breast Cancer Study Group Trials 13-93 and 14-93. Breast Cancer Res Treat 2013, 142:455-459.
98. van Herk-Sukel M.P., van de Poll-Franse L.V., Voogd A.C., Nieuwenhuijzen G.A., Coebergh J.W., Herings R.M. Half of breast cancer patients discontinue tamoxifen and any endocrine treatment before the end of the recommended treatment period of 5years: a population-based analysis. Breast Cancer Res Treat 2010, 122:843-851.
99. Lash T.L., Fox M.P., Westrup J.L., Fink A.K., Silliman R.A. Adherence to tamoxifen over the five-year course. Breast Cancer Res Treat 2006, 99:215-220.
100. Jager N.G., Rosing H., Schellens J.H., Beijnen J.H., Linn S.C. Use of dried blood spots for the determination of serum concentrations of tamoxifen and endoxifen. Breast Cancer Res Treat 2014, 146:137-144.