Breast Cancer Research and Treatment

, Volume 125, Issue 2, pp 505–510 | Cite as

Potent CYP2D6 Inhibiting drugs do not increase relapse rate in early breast cancer patients treated with adjuvant tamoxifen

  • Nava Siegelmann-Danieli
  • Daniel Kurnik
  • Yossi Lomnicky
  • Janet Vesterman-Landes
  • Itzhak Katzir
  • Martin Bialik
  • Ronen Loebstein


Endoxifen, the most active metabolite of the prodrug tamoxifen, is produced by cytochrome P450 CYP2D6. Breast cancer patients treated with tamoxifen who have reduced CYP2D6 activity, related to either genetic variation or drug inhibition, may have inferior outcomes. To assess the effect of concomitant CYP2D6 inhibiting drug use on clinical outcomes of breast cancer patients treated with adjuvant tamoxifen. We conducted a retrospective database analysis. Women with non-metastatic estrogen receptor positive tumors who had completed adjuvant tamoxifen therapy for 2 years, without treatment with adjuvant aromatase inhibitors or early relapse, were included. Patients were classified as users of CYP2D6 inhibitors if they purchased strong CYP2D6 inhibiting drugs for ≥4 consecutive months during tamoxifen treatment. Tumors were classified as “high risk” if adjuvant chemotherapy was prescribed. Primary endpoint was disease free (DFS) and secondary endpoint was overall survival (OS). 902 patients treated with tamoxifen (median duration, 4.9 years) were followed for a median period of 5.9 years. Fifty-nine (6.5%) patients were users of CYP2D6 inhibitors (median duration, 23 months). DFS at 3 years (corresponding to 5 years after tamoxifen initiation) did not differ between users and non-users of CYP2D6 inhibiting drugs (92.7 vs. 93.0%, respectively; adjusted P = 0.44). OS at 3 years was lower in the patients using CYP2D6 inhibiting drugs: 89.4 vs. 93.8%, but after adjustment for age and comorbidities this difference was not significant (P = 0.20). Overall recurrence rates did not differ between users and non-users of CYP2D6 inhibiting drugs (11.8 vs. 19.0% respectively, P = 0.23). Concomitant prolonged therapy with strong CYP2D6 inhibiting drugs does not affect adversely DFS and recurrence rates in tamoxifen-treated early breast cancer patients.


Tamoxifen CYP2D6 inhibition Disease-free survival Overall survival Drug interaction 


  1. 1.
    Borges S, Desta Z, Li Z et al (2006) Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: Implication for optimization of breast cancer treatment. Clin Pharamacol Ther 80(1):64–74Google Scholar
  2. 2.
    Wu X, Howse JR, Subramaniam M, Goetz MP, Ingle JN, Spelbsberg TC (2009) The tamoxifen metabolite, endoxifen, is a potent antiestrogen that targets estrogen receptor α for degradation in breast cancer cells. Cancer Res 69(5):1722–1727CrossRefPubMedGoogle Scholar
  3. 3.
    Kiyotani K, Mushiroda T, Sasa M et al (2008) Impact of CYP2D6*10 on recurrence-free survival in breast cancer patients receiving adjuvant tamoxifen therapy. Cancer Sci 99(5):995–999CrossRefPubMedGoogle Scholar
  4. 4.
    Schroth W, Goetz MP, Hamann U et al (2009) Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with Tamoxifen. J Am Med Assoc 302(13):1429–1436CrossRefGoogle Scholar
  5. 5.
    Scott SA, Edelmann L, Kornreich R, Erazo M, Desnick R (2007) CYP2C9, CYP2C19 and CYP2D6 allele frequencies in the Ashkenazi Jewish population. Pharmacogenomics 8(7):721–730CrossRefPubMedGoogle Scholar
  6. 6.
    Schroth W, Antoniadou L, Fritz P et al (2007) Breast cancer treatment outcome with adjuvant Tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. J Clin Oncol 25(33):5187–5193CrossRefPubMedGoogle Scholar
  7. 7.
    Bonnani B, Macis D, Maisonneuve P et al (2006) Polymorphism in the CYP2D6 metabolizing gene influences clinical effect but not hot flashes: data from the Italian Tamoxifen trial. J Clin Onc 24(22):3708–3709CrossRefGoogle Scholar
  8. 8.
    Goetz MP, Knox SK, Suman VJ et al (2007) The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant Tamoxifen. Breast Cancer Res Treat 101(1):113–121CrossRefPubMedGoogle Scholar
  9. 9.
    Lim HS, Ju Lee H, Seok Lee K et al (2007) Clinical implications of CYP2D6 genotypes predictive of tamoxifen pharmacokinetics in metastatic breast cancer. J Clin Oncol 25(25):3837–3845CrossRefPubMedGoogle Scholar
  10. 10.
    Nowell SA, Ahn J, Rae JM et al (2005) 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):249–258CrossRefPubMedGoogle Scholar
  11. 11.
    Wegman P, Elingarami S, Carstensen J, Stal O, Nordenskjold B, Wingren S (2007) Genetic variants of the CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal patients with breast cancer. Breast Cancer Res 91(1):R7CrossRefGoogle Scholar
  12. 12.
    Rae JM, Thibert J, Sikora MJ et al (2009) Lack of correlation between genetic polymorphism in tamoxifen metabolizing enzymes with primary endpoints in the IMPACT trial. Cancer Res 69(Suppl):24 (Abstract 2011)Google Scholar
  13. 13.
    Ahern TP, Pedersen L, Cronin-Fenton DP, Sorensen HT, Lash TL (2009) No increase in breast cancer recurrence with concurrent use of Tamoxifen and some CYP2D6-inhibiting medications. Cancer Epidemiol Biomarker Prev 18(9):2562–2564 Google Scholar
  14. 14.
    Aubert RE, Stanek J, Yao J et al (2009) Risk of breast cancer recurrence in women initiating Tamoxifen with CYP2D6 inhibitors. J Clin Oncol 28(188):CRA508Google Scholar
  15. 15.
    Dezentje V, Van Blijderveen NJ, Gelderblom H et al (2009) Concomitant CYP2D6 inhibitor use and tamoxifen adherence in early-stage breast cancer: a pharmacoepidemiologic study. J Clin Oncol 28(188):CRA509Google Scholar
  16. 16.
    Kelly CM, Juurlink DN, Gomes T, Duong-Hua M, Pritchard KI, Austin PC, Paszat LF (2010) Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study. Br Med J 340:c693CrossRefGoogle Scholar
  17. 17.
    Crewe HK, Lennard MS, Tucker GT, Woods FR, Haddock RE (1992) The effect of selective serotonin re-uptake inhibitors on cytochrome P4502D5 (CYP2D6) activity in human liver microsomes. Br J Clin Pharmacol 34(3):262–265PubMedGoogle Scholar
  18. 18.
    P450 Drug Interaction Table. Division of Clinical Pharmacology. School of Medicine, Indiana University. Available at Accessed June 16, 2010
  19. 19.
    Early Breast Cancer Trialists Collaborative Group (EBCTCG) (9472) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15 year survival: an overview of the randomized trials. Lancet 365(9472):1687–1717Google Scholar
  20. 20.
    Lash TL, Pedersen L, Cronin-Fenton D, Ahern TP, Rosenberg CL, Lunetta KL, Silliman RA, Hamilton-Dutoit S, Garne JP, Ewertz M, Sorensen HT (2008) Tamoxifen’s protection against breast cancer recurrence is not reduced by concurrent use of the SSRI citalopram. Br J Cancer 99:616–621CrossRefPubMedGoogle Scholar
  21. 21.
    Lash TL, Cronin-Fenton D, Ahern TP, Rosenberg CL, Lunetta KL, Silliman RA, Hamilton-Dutoit S, Garne JP, Ewertz M, Sorensen HT, Pedersen L (2010) Breast cancer recurrence risk related to concurrent use of SSRI antidepressants and tamoxifen. Acta Oncol 49:305–312CrossRefPubMedGoogle Scholar
  22. 22.
    Lash TL, Lien EA, Sorensen HT, Hamilton-Dutoit S (2009) Genotype-guided tamoxifen therapy: time to pause for reflection? Lancet Oncol 10:825–833CrossRefPubMedGoogle Scholar
  23. 23.
    Shi L, Dong B, Li Z et al (2009) Expression of ER-α36, a novel variant of estrogen receptor α and resistance to Tamoxifen treatment in breast cancer. J Clin Oncol 27(21):3423–3429CrossRefPubMedGoogle Scholar
  24. 24.
    Hawse JR, Wu X, Subramaniam M et al (2009) The impact of estrogen receptor-beta on the actions of endoxifen in breast cancer cells. Cancer Res 69(Suppl):24 (Abstract 405)Google Scholar
  25. 25.
    Coombes RC, Hall E, Gibson LJ et al (2004) A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Eng J Med 350(11):1081–1092CrossRefGoogle Scholar
  26. 26.
    Goetz MP, Berry DA, Klein TE et al (2009) Adjuvant tamoxifen treatment outcome according to cytochrome P450 2D6 (CYP2D6) phenotype in early stage breast cancer: findings from the International Tamoxifen Pharmacogenomics Consortium. Cancer Res 69(Suppl):24 (Abstract 33)Google Scholar

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Nava Siegelmann-Danieli
    • 1
  • Daniel Kurnik
    • 2
    • 3
  • Yossi Lomnicky
    • 2
  • Janet Vesterman-Landes
    • 2
  • Itzhak Katzir
    • 2
  • Martin Bialik
    • 2
  • Ronen Loebstein
    • 2
    • 3
  1. 1.Department of Specialized MedicineMaccabi Healthcare ServicesTel AvivIsrael
  2. 2.Department of Pharmaceutics and Clinical PharmacologyMaccabi Healthcare ServicesTel AvivIsrael
  3. 3.Sackler School of MedicineTel Aviv UniversityTel AvivIsrael

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