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Association of Tamoxifen (TAM) and TAM Metabolite Concentrations with Self-Reported Side Effects of TAM in Women with Breast Cancer

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Abstract

The positive effects of tamoxifen (TAM) on breast cancer recurrence and survival as well as on overall mortality have led to its use as the predominant adjuvant therapy among women with breast cancer. However, the association of TAM intake with undesirable side effects has been reported in numerous studies. This analysis was carried out to assess whether the concentrations of TAM or TAM metabolites, N-desmethyltamoxifen (N-DMT) and 4-hydroxytamoxifen (4-OHT), were associated with self-reported side effects of TAM. Participants were 99 breast cancer patients who had been taking TAM for at least 30 days. Each participant completed a questionnaire that was used to ascertain whether she experienced certain specific symptoms while taking TAM. In addition, each woman provided a blood sample that was used to measure plasma concentrations of TAM, N-DMT, and 4-OHT by high performance liquid chromatography. Results of the analysis showed that women who experienced at least one TAM-related side effect had significantly higher levels of TAM than women not experiencing any TAM-related side effects. Furthermore, women who reported experiencing visual problems had significantly higher levels of both TAM and N-DMT compared to those women who reported experiencing no visual problems. The levels of 4-OHT were negatively associated with the occurrence of vaginal discharge. The results of this study suggest that the self-reported occurrence of certain symptoms during TAM treatment is related to TAM metabolism. Future studies should assess subgroups of women with specific TAM and TAM metabolite profiles to determine whether alternate, equally effective therapies would decrease their risk of experiencing certain undesirable side effects.

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References

  1. Mourits MJ, De Vries EG, Willemse PH, Ten Hoor KA, Hollema H, Van der Zee AG: Tamoxifen treatment and gynecologic side effects: a review. Obstet Gynecol 97: 855–866, 2001

    Google Scholar 

  2. Furr BJ, Jordan VC: The pharmacology and clinical uses of tamoxifen. Pharmacol Ther 25: 127–205, 1984

    Google Scholar 

  3. Early Breast Cancer Trialists’ Group: Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 351: 1451–1467, 1998

    Google Scholar 

  4. Crump M, Sawka CA, DeBoer G, Buchanan RB, Ingle JN, Forbes J, Meakin JW, Shelley W, Pritchard KI: An individual patient-based meta-analysis of tamoxifen versus ovarian ablation as first line endocrine therapy for premenopausal women with metastatic breast cancer. Breast Cancer Res Treat 44: 201–210, 1997

    Google Scholar 

  5. Ingle JN, Ahmann DL, Green SJ, Edmonson JH, Bisel HF, Kvols LK, Nichols WC, Creagan ET, Hahn RG, Rubin J, Frytak S: Randomized clinical trial of diethylstilbestrol versus tamoxifen in postmenopausal women with advanced breast cancer. N Engl J Med 304: 16–21, 1981

    Google Scholar 

  6. Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, Vogel V, Robidoux A, Dimitrov N, Atkins J, Daly M, Wieand S, Tan-Chiu E, Ford L, Wolmark N: Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90: 1371–1388, 1998

    Google Scholar 

  7. Mourits MJ, Bockermann I, de Vries EG, van der Zee AG, ten Hoor KA, van der Graaf WT, Sluiter WJ, Willemse PH: Tamoxifen effects on subjective and psychosexual well-being, in a randomised breast cancer study comparing high-dose and standard-dose chemotherapy. Br J Cancer 86: 1546–1550, 2002

    Google Scholar 

  8. Fellowes D, Fallowfield LJ, Saunders CM, Houghton J: Tolerability of hormone therapies for breast cancer: how informative are documented symptom profiles in medical notes for ‘well-tolerated’ treatments? Breast Cancer Res Treat 66: 73–81, 2001

    Google Scholar 

  9. Peyrade F, Frenay M, Etienne MC, Ruch F, Guillemare C, Francois E, Namer M, Ferrero JM, Milano G: Age-related difference in tamoxifen disposition. Clin Pharmacol Ther 59: 401–410, 1996

    Google Scholar 

  10. Jaiyesimi IA, Buzdar AU, Decker DA, Hortobagyi GN: Use of tamoxifen for breast cancer: twenty-eight years later. J Clin Oncol 13: 513–529, 1995

    Google Scholar 

  11. Mani C, Gelboin HV, Park SS, Pearce R, Parkinson A, Kupfer D: Metabolism of the antimammary cancer antiestrogenic agent tamoxifen. I. Cytochrome P-450-catalyzed Ndemethylation and 4-hydroxylation. Drug Metab Dispos 21: 645–656, 1993

    Google Scholar 

  12. 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: 171–178, 1997

    Google Scholar 

  13. Fabian C, Tilzer L, Sternson L: Comparative binding af-finities of tamoxifen, 4-hydroxytamoxifen, and desmethyltamoxifen for estrogen receptors isolated from human breast carcinoma: correlation with blood levels in patients with metastatic breast cancer. Biopharm Drug Dispos 2: 381–390, 1981

    Google Scholar 

  14. Jones RM, Yuan ZX, Lamb JH, Lim CK: On-line highperformance liquid chromatographic-electrospray ionization mass spectrometric method for the study of tamoxifen metabolism. J Chromatogr A 722: 249–255, 1996

    Google Scholar 

  15. Jones RM, Yuan ZX, Lim CK: Tamoxifen metabolism in rat liver microsomes: identification of a dimeric metabolite derived from free radical intermediates by liquid chromatography/ mass spectrometry. Rapid Commun Mass Spectrom 13: 211–215, 1999

    Google Scholar 

  16. SAS Institute Inc.: SAS/STAT Guide for Personal Computers, Version 6.04. SAS Institute, Inc., Cary, NC, 1987

    Google Scholar 

  17. Baker VL, Jaffe RB: Clinical uses of antiestrogens. Obstet Gynecol Surv 51: 45–59, 1996

    Google Scholar 

  18. Decensi A, Gandini S, Guerrieri-Gonzaga A, Johansson H, Manetti L, Bonanni B, Sandri MT, Barreca A, Costa A, Robertson C, Lien EA: Effect of blood tamoxifen concentrations on surrogate biomarkers in a trial of dose reduction in healthy women. J Clin Oncol 17: 2633–2638, 1999

    Google Scholar 

  19. Kaiser-Kupfer MI, Lippman ME: Tamoxifen retinopathy. Cancer Treat Rep 62: 315–320, 1978

    Google Scholar 

  20. Gorin MB, Day R, Costantino JP, Fisher B, Redmond CK, Wickerham L, Gomolin JE, Hargolese RG, Mathen MK, Bowman DM, Kaufman DI, Dimitrov NV, Singerman LJ, Bornstein R, Wolmark N, Kaufmann D: Long-term tamoxifen citrate use and potential ocular toxicity. Am J Ophthalmol 125: 493–501, 1998

    Google Scholar 

  21. Paganini-Hill A, Clark LJ: Eye problems in breast cancer patients treated with tamoxifen. Breast Cancer Res Treat 60: 167–172, 2000

    Google Scholar 

  22. Flaxel CJ, Mulholland B, Haynes B, Gregor ZJ: Intraocular penetration of tamoxifen. Ophthalmology 107: 2006–2009, 2000

    Google Scholar 

  23. Imperia PS, Lazarus HM, Lass JH: Ocular complications of systemic cancer chemotherapy. Surv Ophthalmol 34: 209–230, 1989

    Google Scholar 

  24. Greaves P, Goonetilleke R, Nunn G, Topham J, Orton T: Two-year carcinogenicity study of tamoxifen in Alderley Park Wistar-derived rats. Cancer Res 53: 3919–3924, 1993

    Google Scholar 

  25. Zhang JJ, Jacob TJ, Valverde MA, Hardy SP, Mintenig GM, Sepulveda FV, Gill DR, Hyde SC, Trezise AE, Higgins CF: Tamoxifen blocks chloride channels. A possible mechanism for cataract formation. J Clin Invest 94: 1690–1697, 1994

    Google Scholar 

  26. Buckley MM, Goa KL: Tamoxifen: A reappraisal of its pharmacodynamic and pharmacokinetic properties and therapeutic use. Drugs 37: 451–490, 1989

    Google Scholar 

  27. Etienne MC, Milano G, Fischel JL, Frenay M, Francois E, Formento JL, Gioanni J, Namer M: Tamoxifen metabolism: pharmacokinetic and in vitro study. Br J Cancer 60: 30–35, 1989

    Google Scholar 

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Gallicchio, L., Lord, G., Tkaczuk, K. et al. Association of Tamoxifen (TAM) and TAM Metabolite Concentrations with Self-Reported Side Effects of TAM in Women with Breast Cancer. Breast Cancer Res Treat 85, 89–97 (2004). https://doi.org/10.1023/B:BREA.0000021050.92539.b0

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  • DOI: https://doi.org/10.1023/B:BREA.0000021050.92539.b0

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