Breast Cancer Research and Treatment

, Volume 132, Issue 3, pp 1107–1118 | Cite as

Clinical and biomarker predictors of side effects from tamoxifen

  • Wendy Lorizio
  • Alan H. B. Wu
  • Mary S. Beattie
  • Hope Rugo
  • Simone Tchu
  • Karla Kerlikowske
  • Elad Ziv
Epidemiology

Abstract

Tamoxifen decreases breast cancer recurrence, mortality, and breast cancer risk in high-risk women. Despite these proven benefits, tamoxifen use is often limited due to side effects. We identified predictors of tamoxifen-induced side effects based on clinical variables and serum tamoxifen metabolite biomarkers in a cross-sectional study of patients taking tamoxifen. We enrolled 241 women and collected data on demographics, tamoxifen use and side effects, as well as potential clinical and serum predictors. We used logistic regression models and adjusted for age, body mass index, ethnicity, education, prior post-menopausal hormone therapy (HT), tamoxifen duration, and endoxifen levels to identify factors associated with side effects. Common tamoxifen attributed side effects were hot flashes (64%), vaginal dryness (35%), sleep problems (36%), weight gain (6%), and depression, irritability or mood swings (6%). In multi-variate models, tamoxifen duration, age, prior post-menopausal HT, and endoxifen levels all predicted side effects. Women who had been on tamoxifen for >12 months were less likely to report side effects (OR 0.15, 95% CI 0.04–0.58) or severe side effects (OR 0.05, 95% CI 0.005–0.58) compared to women on tamoxifen for <12 months. Compared to women younger than 50, women who were age 60–70 and older than 70 were less likely to report side effects (OR 0.22, 95% CI 0.03–1.35; OR 0.13, 95% CI 0.01–0.99; respectively). Women who previously took post-menopausal HT were more likely to report severe side effects. Women with higher endoxifen levels were more likely to report side effects (OR 1.67, 95% CI 1.01–2.77 per standard deviation increase in endoxifen). Clinicians should consider closely monitoring adherence in women taking tamoxifen, especially in younger women, and women who previously took HT. The association between endoxifen levels and side effects is consistent with the data that suggest that endoxifen is the most highly active metabolite of tamoxifen.

Keywords

Tamoxifen Side effects Predictors Biomarkers Endoxifen Breast cancer treatment 

Notes

Acknowledgments

This work was supported by the National Institute of General Medical Sciences (NIGMS) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Award T32 GM007546, University of California San Francisco, Clinical Pharmacology Fellowship Training Program (W. Lorizio); California Breast Cancer Research Program (CBCRP) Grant 14OB-0166 (E. Ziv); National Cancer Institute (NCI) Grant P50 CA58207 funded UCSF Breast SPORE; the Center for Translational and Policy Research in Personalized Medicine (TRANSPERS) National Institutes of Health/National Cancer Institute (NIH/NCI) Grant P01 CA130818-02A1 (M. S. Beattie), and materials and instrumentation for the AmpliChip CYP450 Test were donated by Roche Molecular Systems, Inc. We thank Viktoriya Krepkiy (Ziv Lab) for helping with participants and administrative support.

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Jordan VC (2003) Tamoxifen: a most unlikely pioneering medicine. Nat Rev Drug Discov 2(3):205–213PubMedCrossRefGoogle Scholar
  2. 2.
    Group EBCTC (2005) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365(9472):1687–1717CrossRefGoogle Scholar
  3. 3.
    Freedman AN, Graubard BI, Rao SR, McCaskill-Stevens W, Ballard-Barbash R, Gail MH (2003) Estimates of the number of US women who could benefit from tamoxifen for breast cancer chemoprevention. J Natl Cancer Inst 95(7):526–532PubMedCrossRefGoogle Scholar
  4. 4.
    Kloos I, Delaloge S, Pautier P, Di Palma M, Goupil A, Duvillard P, Cailleux PE, Lhomme C (2002) Tamoxifen-related uterine carcinosarcomas occur under/after prolonged treatment: report of five cases and review of the literature. Int J Gynecol Cancer 12(5):496–500PubMedCrossRefGoogle Scholar
  5. 5.
    Cuzick J, Powles T, Veronesi U, Forbes J, Edwards R, Ashley S, Boyle P (2003) Overview of the main outcomes in breast-cancer prevention trials. Lancet 361(9354):296–300PubMedCrossRefGoogle Scholar
  6. 6.
    Fisher B, Costantino JP, Redmond CK, Fisher ER, Wickerham DL, Cronin WM (1994) Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst 86(7):527–537PubMedCrossRefGoogle Scholar
  7. 7.
    Hendrick A, Subramanian VP (1980) Tamoxifen and thromboembolism. JAMA 243(6):514–515PubMedCrossRefGoogle Scholar
  8. 8.
    Love RR, Cameron L, Connell BL, Leventhal H (1991) Symptoms associated with tamoxifen treatment in postmenopausal women. Arch Intern Med 151(9):1842–1847PubMedCrossRefGoogle Scholar
  9. 9.
    Ganz PA, Rowland JH, Meyerowitz BE, Desmond KA (1998) Impact of different adjuvant therapy strategies on quality of life in breast cancer survivors. Recent Results Cancer Res 152:396–411PubMedCrossRefGoogle Scholar
  10. 10.
    Fisher B, Costantino J, Redmond C, Poisson R, Bowman D, Couture J, Dimitrov NV, Wolmark N, Wickerham DL, Fisher ER et al (1989) A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med 320(8):479–484PubMedCrossRefGoogle Scholar
  11. 11.
    Ganz PA (2001) Impact of tamoxifen adjuvant therapy on symptoms, functioning, and quality of life. J Natl Cancer Inst Monogr 30:130–134PubMedCrossRefGoogle Scholar
  12. 12.
    Day R, Ganz PA, Costantino JP, Cronin WM, Wickerham DL, Fisher B (1999) Health-related quality of life and tamoxifen in breast cancer prevention: a report from the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Clin Oncol 17(9):2659–2669PubMedGoogle Scholar
  13. 13.
    Kimmick GG, Lovato J, McQuellon R, Robinson E, Muss HB (2006) Randomized, double-blind, placebo-controlled, crossover study of sertraline (Zoloft) for the treatment of hot flashes in women with early stage breast cancer taking tamoxifen. Breast J 12(2):114–122PubMedCrossRefGoogle Scholar
  14. 14.
    Loprinzi CL, Kugler JW, Sloan JA, Mailliard JA, LaVasseur BI, Barton DL, Novotny PJ, Dakhil SR, Rodger K, Rummans TA, Christensen BJ (2000) Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial. Lancet 356(9247):2059–2063PubMedCrossRefGoogle Scholar
  15. 15.
    Loprinzi CL, Sloan JA, Perez EA, Quella SK, Stella PJ, Mailliard JA, Halyard MY, Pruthi S, Novotny PJ, Rummans TA (2002) Phase III evaluation of fluoxetine for treatment of hot flashes. J Clin Oncol 20(6):1578–1583PubMedCrossRefGoogle Scholar
  16. 16.
    Loprinzi CL, Sloan J, Stearns V, Slack R, Iyengar M, Diekmann B, Kimmick G, Lovato J, Gordon P, Pandya K, Guttuso T Jr, Barton D, Novotny P (2009) Newer antidepressants and gabapentin for hot flashes: an individual patient pooled analysis. J Clin Oncol 27(17):2831–2837PubMedCrossRefGoogle Scholar
  17. 17.
    Mortimer JE, Flatt SW, Parker BA, Gold EB, Wasserman L, Natarajan L, Pierce JP (2008) Tamoxifen, hot flashes and recurrence in breast cancer. Breast Cancer Res Treat 108(3):421–426PubMedCrossRefGoogle Scholar
  18. 18.
    Cuzick J, Sestak I, Cella D, Fallowfield L (2008) Treatment-emergent endocrine symptoms and the risk of breast cancer recurrence: a retrospective analysis of the ATAC trial. Lancet Oncol 9(12):1143–1148PubMedCrossRefGoogle Scholar
  19. 19.
    Lien EA, Solheim E, Lea OA, Lundgren S, Kvinnsland S, Ueland PM (1989) Distribution of 4-hydroxy-N-desmethyltamoxifen and other tamoxifen metabolites in human biological fluids during tamoxifen treatment. Cancer Res 49(8):2175–2183PubMedGoogle Scholar
  20. 20.
    Stearns V, Johnson MD, Rae JM, Morocho A, Novielli A, Bhargava P, Hayes DF, Desta Z, Flockhart DA (2003) Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst 95(23):1758–1764PubMedCrossRefGoogle Scholar
  21. 21.
    Wu X, Hawse JR, Subramaniam M, Goetz MP, Ingle JN, Spelsberg TC (2009) The tamoxifen metabolite, endoxifen, is a potent antiestrogen that targets estrogen receptor alpha for degradation in breast cancer cells. Cancer Res 69(5):1722–1727PubMedCrossRefGoogle Scholar
  22. 22.
    Johnson MD, Zuo H, Lee KH, Trebley JP, Rae JM, Weatherman RV, Desta Z, Flockhart DA, Skaar TC (2004) Pharmacological characterization of 4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen. Breast Cancer Res Treat 85(2):151–159PubMedCrossRefGoogle Scholar
  23. 23.
    Osborne CK (1998) Tamoxifen in the treatment of breast cancer. N Engl J Med 339(22):1609–1618PubMedCrossRefGoogle Scholar
  24. 24.
    Jordan VC, Collins MM, Rowsby L, Prestwich G (1977) A monohydroxylated metabolite of tamoxifen with potent antioestrogenic activity. J Endocrinol 75(2):305–316PubMedCrossRefGoogle Scholar
  25. 25.
    Desta Z, Ward BA, Soukhova NV, Flockhart DA (2004) Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther 310(3):1062–1075PubMedCrossRefGoogle Scholar
  26. 26.
    Jin Y, Desta Z, Stearns V, Ward B, Ho H, Lee KH, Skaar T, Storniolo AM, Li L, Araba A, Blanchard R, Nguyen A, Ullmer L, Hayden J, Lemler S, Weinshilboum RM, Rae JM, Hayes DF, Flockhart DA (2005) CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst 97(1):30–39PubMedCrossRefGoogle Scholar
  27. 27.
    Goetz MP, Rae JM, Suman VJ, Safgren SL, Ames MM, Visscher DW, Reynolds C, Couch FJ, Lingle WL, Flockhart DA, Desta Z, Perez EA, Ingle JN (2005) Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol 23(36):9312–9318PubMedCrossRefGoogle Scholar
  28. 28.
    Henry NL, Rae JM, Li L, Azzouz F, Skaar TC, Desta Z, Sikora MJ, Philips S, Nguyen AT, Storniolo AM, Hayes DF, Flockhart DA, Stearns V (2009) Association between CYP2D6 genotype and tamoxifen-induced hot flashes in a prospective cohort. Breast Cancer Res Treat 117(3):571–575PubMedCrossRefGoogle Scholar
  29. 29.
    Madlensky L, Flatt SW, Natarajan L, Lawrence HJ, Nikoloff DM, Fontecha M, Hao S, Hillman G, Johnson A, Parker BA JPP (2009) Hot flashes are associated with CYP2D6 genotype in breast cancer survivors taking tamoxifen. Cancer Res 69(Suppl):6045CrossRefGoogle Scholar
  30. 30.
    Leyland-Jones B, Regan MM, Bouzyk M, Kammler R, Tang W, Pagani O, Maibach R, Dell’Orto P, Thurlimann B, Price KN, Viale G; Group B-CGaIBCS (2010) Outcome according to CYP2D6 genotype among postmenopausal women with endocrine-responsive early invasive breast cancer randomized in the BIG 1-98 trial. Cancer Res 70 (24 Suppl 2):Abstract nr S1-8Google Scholar
  31. 31.
    Madlensky L, Natarajan L, Tchu S, Pu M, Mortimer J, Flatt SW, Nikoloff DM, Hillman G, Fontecha MR, Lawrence HJ, Parker BA, Wu AH, Pierce JP (2011) Tamoxifen metabolite concentrations, CYP2D6 genotype, and breast cancer outcomes. Clin Pharmacol Ther 89(5):718–725PubMedCrossRefGoogle Scholar
  32. 32.
    Rebsamen MC, Desmeules J, Daali Y, Chiappe A, Diemand A, Rey C, Chabert J, Dayer P, Hochstrasser D, Rossier MF (2009) The AmpliChip CYP450 test: cytochrome P450 2D6 genotype assessment and phenotype prediction. Pharmacogenomics J 9(1):34–41PubMedCrossRefGoogle Scholar
  33. 33.
    Gaedigk A, Simon SD, Pearce RE, Bradford LD, Kennedy MJ, Leeder JS (2008) The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype. Clin Pharmacol Ther 83(2):234–242PubMedCrossRefGoogle Scholar
  34. 34.
    Flockhart DA (2007) Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine. [http://medicine.iupui.edu/clinpharm/ddis/tableaspx]
  35. 35.
    Loprinzi CL, Zahasky KM, Sloan JA, Novotny PJ, Quella SK (2000) Tamoxifen-induced hot flashes. Clin Breast Cancer 1(1):52–56PubMedCrossRefGoogle Scholar
  36. 36.
    Perez DG, Zahasky KM, Loprinzi CL, Sloan J, Novotny P, Barton D, Pritchard KI (2007) Tamoxifen-associated hot flashes in women. Support Cancer Ther 4(3):152–156PubMedCrossRefGoogle Scholar
  37. 37.
    Demissie S, Silliman RA, Lash TL (2001) Adjuvant tamoxifen: predictors of use, side effects, and discontinuation in older women. J Clin Oncol 19(2):322–328PubMedGoogle Scholar
  38. 38.
    Rae JM, Drury S, Hayes DF, Stearns V, Thibert JN, Haynes BP, Salter J, Pineda S, Cuzick J, Dowsett M (2010) Lack of correlation between gene variants in tamoxifen metabolizing enzymes with primary endpoints in the ATAC trial. Cancer Res 70(24 Suppl 2):Abstract nr S1-7Google Scholar
  39. 39.
    Borges S, Desta Z, Li L, Skaar TC, Ward BA, Nguyen A, Jin Y, Storniolo AM, Nikoloff DM, Wu L, Hillman G, Hayes DF, Stearns V, Flockhart DA (2006) Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: implication for optimization of breast cancer treatment. Clin Pharmacol Ther 80(1):61–74PubMedCrossRefGoogle Scholar
  40. 40.
    Sideras K, Ingle JN, Ames MM, Loprinzi CL, Mrazek DP, Black JL, Weinshilboum RM, Hawse JR, Spelsberg TC, Goetz MP (2010) Coprescription of tamoxifen and medications that inhibit CYP2D6. J Clin Oncol 28(16):2768–2776PubMedCrossRefGoogle Scholar
  41. 41.
    Murdter TE, Schroth W, Bacchus-Gerybadze L, Winter S, Heinkele G, Simon W, Fasching PA, Fehm T, Eichelbaum M, Schwab M, Brauch H (2011) 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 89(5):708–717PubMedCrossRefGoogle Scholar
  42. 42.
    Fallowfield L (2005) Acceptance of adjuvant therapy and quality of life issues. Breast 14(6):612–616PubMedCrossRefGoogle Scholar
  43. 43.
    Bonanni B, Macis D, Maisonneuve P, Johansson HA, Gucciardo G, Oliviero P, Travaglini R, Muraca MG, Rotmensz N, Veronesi U, Decensi AU (2006) Polymorphism in the CYP2D6 tamoxifen-metabolizing gene influences clinical effect but not hot flashes: data from the Italian Tamoxifen Trial. J Clin Oncol 24(22):3708–3709 author reply 3709PubMedCrossRefGoogle Scholar
  44. 44.
    Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF, Hoctin-Boes G, Houghton J, Locker GY, Tobias JS (2005) Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 365(9453):60–62PubMedCrossRefGoogle Scholar
  45. 45.
    Coates AS, Keshaviah A, Thurlimann B, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Colleoni M, Lang I, Del Mastro L, Smith I, Chirgwin J, Nogaret JM, Pienkowski T, Wardley A, Jakobsen EH, Price KN, Goldhirsch A (2007) Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1–98. J Clin Oncol 25(5):486–492PubMedCrossRefGoogle Scholar
  46. 46.
    Staropoli CA, Flaws JA, Bush TL, Moulton AW (1998) Predictors of menopausal hot flashes. J Womens Health 7(9):1149–1155PubMedCrossRefGoogle Scholar
  47. 47.
    Wilbur J, Miller AM, Montgomery A, Chandler P (1998) Sociodemographic characteristics, biological factors, and symptom reporting in midlife women. Menopause 5(1):43–51PubMedCrossRefGoogle Scholar
  48. 48.
    Hunter MS (1993) Predictors of menopausal symptoms: psychosocial aspects. Baillieres Clin Endocrinol Metab 7(1):33–45PubMedCrossRefGoogle Scholar
  49. 49.
    Gold EB, Sternfeld B, Kelsey JL, Brown C, Mouton C, Reame N, Salamone L, Stellato R (2000) Relation of demographic and lifestyle factors to symptoms in a multi-racial/ethnic population of women 40–55 years of age. Am J Epidemiol 152(5):463–473PubMedCrossRefGoogle Scholar
  50. 50.
    Freeman EW, Sammel MD, Grisso JA, Battistini M, Garcia-Espagna B, Hollander L (2001) Hot flashes in the late reproductive years: risk factors for Africa American and Caucasian women. J Womens Health Gend Based Med 10(1):67–76PubMedCrossRefGoogle Scholar
  51. 51.
    Schwingl PJ, Hulka BS, Harlow SD (1994) Risk factors for menopausal hot flashes. Obstet Gynecol 84(1):29–34PubMedGoogle Scholar
  52. 52.
    Brown DE, Sievert LL, Morrison LA, Reza AM, Mills PS (2009) Do Japanese American women really have fewer hot flashes than European Americans? The Hilo Women’s Health Study. Menopause 16(5):870–876PubMedCrossRefGoogle Scholar
  53. 53.
    Avis NE, Stellato R, Crawford S, Bromberger J, Ganz P, Cain V, Kagawa-Singer M (2001) Is there a menopausal syndrome? Menopausal status and symptoms across racial/ethnic groups. Soc Sci Med 52(3):345–356PubMedCrossRefGoogle Scholar
  54. 54.
    Sievert LL, Morrison L, Brown DE, Reza AM (2007) Vasomotor symptoms among Japanese-American and European-American women living in Hilo, Hawaii. Menopause 14(2):261–269PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Wendy Lorizio
    • 1
    • 2
    • 3
    • 10
  • Alan H. B. Wu
    • 4
    • 11
  • Mary S. Beattie
    • 1
    • 3
    • 5
    • 6
    • 12
  • Hope Rugo
    • 3
    • 7
    • 13
  • Simone Tchu
    • 8
    • 11
  • Karla Kerlikowske
    • 9
    • 14
  • Elad Ziv
    • 1
    • 3
    • 5
    • 6
    • 10
  1. 1.Division of General Internal Medicine, Department of MedicineUniversity of California San FranciscoSan FranciscoUSA
  2. 2.Division of Clinical Pharmacology and Experimental Therapeutics, Department of MedicineUniversity of California San FranciscoSan FranciscoUSA
  3. 3.Helen Diller Family Comprehensive Cancer CenterUniversity of California San FranciscoSan FranciscoUSA
  4. 4.Department of Laboratory MedicineUniversity of California San FranciscoSan FranciscoUSA
  5. 5.Department of Epidemiology and BiostatisticsUniversity of California San FranciscoSan FranciscoUSA
  6. 6.Institute for Human GeneticsUniversity of California San FranciscoSan FranciscoUSA
  7. 7.Division of Hematology and Oncology, Department of MedicineUniversity of California San FranciscoSan FranciscoUSA
  8. 8.Department of Biopharmaceutical SciencesUniversity of California San FranciscoSan FranciscoUSA
  9. 9.Division of General Internal MedicineSan Francisco Veterans Affairs Medical CenterSan FranciscoUSA
  10. 10.UCSF Helen Diller Family Cancer Research BuildingSan FranciscoUSA
  11. 11.San Francisco General HospitalSan FranciscoUSA
  12. 12.UCSF Medical Center at Mount ZionSan FranciscoUSA
  13. 13.UCSF Medical Center at Mount ZionSan FranciscoUSA
  14. 14.Department of Medicine and Epidemiology and BiostatisticsUniversity of California San FranciscoSan FranciscoUSA

Personalised recommendations