Breast Cancer Research and Treatment

, Volume 154, Issue 3, pp 609–616 | Cite as

Benefit/risk for adjuvant breast cancer therapy with tamoxifen or aromatase inhibitor use by age, and race/ethnicity

  • R. T. ChlebowskiEmail author
  • R. Haque
  • H. Hedlin
  • N. Col
  • E. Paskett
  • J. E. Manson
  • J. T. Kubo
  • K. C. Johnson
  • J. Wactawski-Wende
  • K. Pan
  • G. Anderson


In early adjuvant breast cancer trial reports, aromatase inhibitors more effectively reduced breast recurrence with lower risk of thromboembolic events and endometrial cancer than tamoxifen, while aromatase inhibitors had higher fracture and cardiovascular disease risk. We used data from updated patient-level meta-analyses of adjuvant trials in analyses to summarize the benefits and risks of these agents in various clinical circumstances. Baseline incidence rates for health outcomes by age and race/ethnicity, absent aromatase inhibitor, or tamoxifen use were estimated from the Women’s Health Initiative. Aromatase inhibitor and tamoxifen effects on distant recurrence were obtained from a meta-analysis of the Arimidex, Tamoxifen, Alone or in Combination (ATAC) and Breast International Group (Big-1-98) clinical trials. Impact on other health outcomes were obtained from meta-analyses of randomized trials comparing aromatase inhibitor to tamoxifen use and from placebo-controlled chemoprevention trials. All health outcomes were given equal weight when modeling net benefit/risk for aromatase inhibitor compared to tamoxifen use by breast cancer recurrence risk, age (decade), race/ethnicity, hysterectomy (yes/no), and by prior myocardial infarction. Over a 10-year period, the benefit/risk index was more favorable for aromatase inhibitor than for tamoxifen as adjuvant breast cancer therapy in almost all circumstances regardless of patient age, race/ethnicity, breast cancer recurrence risk, or presence or absence of a uterus. Only in older women with prior myocardial infarction and low recurrence risk was an advantage for tamoxifen seen. Using a benefit/risk index for endocrine adjuvant breast cancer therapy in postmenopausal women, benefit was higher for aromatase inhibitor use in almost all circumstances.


Adjuvant breast cancer Benefit/risk assessment Endocrine therapy Aromatase inhibitor Tamoxifen Race/ethnicity 



We acknowledge the dedicated efforts of investigators and staff at the Women’s Health Initiative (WHI) clinical centres, the WHI Clinical Coordinating Center, and the National Heart, Lung and Blood program office (listing available at We also recognize the WHI participants for their extraordinary commitment to the WHI programme. The WHI programme was funded by the National Heart, Lung and Blood Institute, National Institutes of Health, Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. Additional funding support was provided by Kaiser Permanente Southern California award #13RHAqu-02-UCLA.

Compliance with ethical standards

Conflict of interest

RTC has received speaker’s fees and honorarium from Novartis and Genetech; honorarium for advisory boards and consulting for Novartis, Astra-Zeneca, Pfizer, Novo-Nordisk, Genentech, Genomic Health, and Amgen. No other author has conflicts to declare.

Supplementary material

10549_2015_3647_MOESM1_ESM.docx (23 kb)
Supplementary material 1 (DOCX 23 kb)


  1. 1.
    Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) (2015) Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomized trials. Lancet 386:1341–1352CrossRefGoogle Scholar
  2. 2.
    Braithwaite RS, Chlebowski RT, Lau J et al (2003) Meta-analysis of vascular and neoplastic events associated with tamoxifen. J Gen Intern Med 18:937–947PubMedCentralCrossRefPubMedGoogle Scholar
  3. 3.
    Cuppone F, Bria E, Verma S et al (2008) Do adjuvant aromatase inhibitors increase the cardiovascular risk in postmenopausal women with early breast cancer? Meta-analysis of randomized trails. Cancer 112:260–267CrossRefPubMedGoogle Scholar
  4. 4.
    Amir E, Seruga B, Niraula S et al (2011) Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: a systemic review and meta-analysis. J Natl Cancer Inst 103:1299–1309CrossRefPubMedGoogle Scholar
  5. 5.
    Dowsett M, Cuzick J, Ingle J et al (2010) Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. J Clin Oncol 28:509–518CrossRefPubMedGoogle Scholar
  6. 6.
    Chlebowski RT, Anderson GL, Geller M et al (2006) Coronary heart disease and stroke with aromatase inhibitor, tamoxifen, and menopausal hormone therapy use. Clin Breast Cancer Suppl 2:S58–S64CrossRefGoogle Scholar
  7. 7.
    Ligibel JA, O’Malley JA, Fisher M et al (2012) Risk of myocardial infarction, stroke, and fracture in a cohort of community-based breast cancer patients. Breast Cancer Res Treat 131(2):589–597CrossRefPubMedGoogle Scholar
  8. 8.
    Chapman JAW, Meng D, Shepherd L et al (2008) Competing causes of death from a randomized trial of extended adjuvant endocrine therapy for breast cancer. J Natl Cancer Inst 100:252–260PubMedCentralCrossRefPubMedGoogle Scholar
  9. 9.
    Ring A, Sestak I, Baum M et al (2011) Influence of comorbidities and age on risk of death with recurrence: a retrospective analysis of the Arimidex, Tamoxifen Alone or in Combination Trial. J Clin Oncol 29:4266–4427CrossRefPubMedGoogle Scholar
  10. 10.
    Puhalla S, Jankowitz RC, Davidson NE (2011) Adjuvant endocrine therapy for breast cancer: don’t ditch the switch. J Natl Cancer Inst 103:1280–1281CrossRefPubMedGoogle Scholar
  11. 11.
    Bardia A, Arieas ET, Zhang A et al (2012) Comparison of breast cancer recurrence risk and cardiovascular disease incidence risk among postmenopausal women with breast cancer. Breast Cancer Res Treat 131(3):907–914PubMedCentralCrossRefPubMedGoogle Scholar
  12. 12.
    Goss PE, Ingle JN, Ales-Martinez J et al (2011) Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med 364(25):2381–2391CrossRefPubMedGoogle Scholar
  13. 13.
    Cuzick J, Sestak I, Forbes JF et al (2014) Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial. Lancet 383(9922):1041–1048CrossRefPubMedGoogle Scholar
  14. 14.
    Freedman AN, Yu B, Gail MH et al (2011) Benefit/risk assessment for breast cancer chemoprevention with raloxifene or tamoxifen for women age 50 years or older. J Clin Oncol 29:2327–2333PubMedCentralCrossRefPubMedGoogle Scholar
  15. 15.
    Rossouw JE, Anderson GL, Prentice RL et al (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 288(3):321–333CrossRefPubMedGoogle Scholar
  16. 16.
    Anderson GL, Limacher M, Assaf AR et al (2004) Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 291(14):1701–1712CrossRefPubMedGoogle Scholar
  17. 17.
    The Women’s Health Initiative Study Group (1998) Design of the Women’s Health Initiative clinical trial and observational study. Control Clin Trials 19(1):61–109CrossRefGoogle Scholar
  18. 18.
    Anderson GL, Manson J, Wallace R et al (2003) Implementation of the Women’s Health Initiative study design. Ann Epidemiol 13(9 Suppl):S5–S17CrossRefPubMedGoogle Scholar
  19. 19.
    Wasan KM, Goss PE, Pritchard PH et al (2012) Lipid concentrations in postmenopausal women on letrozole after 5 years of tamoxifen: an NCIC CTG MA.17 sub-study. Breast Cancer Res Treat 136(3):769–776CrossRefPubMedGoogle Scholar
  20. 20.
    Visvanathan K, Hurley P, Bantug E et al (2013) Use of pharmacologic interventions for breast cancer risk reduction: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 31(23):2942–2962CrossRefPubMedGoogle Scholar
  21. 21.
    Fisher B, Costantino JP, Wickerham DL et al (1998) Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90(18):1371–1388CrossRefPubMedGoogle Scholar
  22. 22.
    Markopoulos C, Tzoracoleftherakis E, Polychronis A et al (2010) Management of anastrozole-induced bone loss in breast cancer patients with oral risedronate: results from the ARBI prospective clinical trial. Breast Cancer Res 12(2):R24PubMedCentralCrossRefPubMedGoogle Scholar
  23. 23.
    Coleman R, de Boer R, Eidtmann H et al (2013) Zoledronic acid (zoledronate) for postmenopausal women with early breast cancer receiving adjuvant letrozole (ZO-FAST study): final 60-month results. Ann Oncol 24(2):398–405CrossRefPubMedGoogle Scholar
  24. 24.
    Coleman RE, Rathbone E, Brown JE (2013) Management of cancer treatment-induced bone loss. Nat Rev Rheumatol 9(6):365–374CrossRefPubMedGoogle Scholar
  25. 25.
    Vogel VG, Costantino JP, Wickerham DL et al (2002) Re: tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 94(19):1504CrossRefPubMedGoogle Scholar
  26. 26.
    Chlebowski RT, Cuzick J, Amakye D et al (2009) Clinical perspectives on the utility of aromatase inhibitors for the adjuvant treatment of breast cancer. Breast Suppl 2:S1–S11CrossRefGoogle Scholar
  27. 27.
    Davies C, Pan H, Godwin J et al (2013) Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 381(9869):805–816PubMedCentralCrossRefPubMedGoogle Scholar
  28. 28.
    Gray RD, Rea DW, Handley K et al (2008) aTTom (adjuvant Tamoxifen—To offer more?): randomized trial of 10 versus 5 years of adjuvant tamoxifen among 6934 women with estrogen receptor-positive (ER+) or ER untested breast cancer—preliminary results. J Clin Oncol 26(155):513Google Scholar
  29. 29.
    Goss PE, Ingle JN, Martino S et al (2005) Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst 97(17):1262–1271CrossRefPubMedGoogle Scholar
  30. 30.
    Jakesz R, Greil R, Gnant M et al (2007) Extended adjuvant therapy with anastrozole among postmenopausal breast cancer patients: results from the randomized Austrian Breast and Colorectal Cancer Study Group Trial 6a. J Natl Cancer Inst 99(24):1845–1853CrossRefPubMedGoogle Scholar
  31. 31.
    Mamounas EP, Jeong JH, Wickerham DL et al (2008) Benefit from exemestane as extended adjuvant therapy after 5 years of adjuvant tamoxifen: intention-to-treat analysis of the National Surgical Adjuvant Breast and Bowel Project B-33 trial. J Clin Oncol 26(12):1965–1971CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • R. T. Chlebowski
    • 1
    Email author
  • R. Haque
    • 2
  • H. Hedlin
    • 3
  • N. Col
    • 4
  • E. Paskett
    • 5
  • J. E. Manson
    • 6
  • J. T. Kubo
    • 3
  • K. C. Johnson
    • 7
  • J. Wactawski-Wende
    • 8
  • K. Pan
    • 9
  • G. Anderson
    • 10
  1. 1.Los Angeles Biomedical Research Institute at Harbor-UCLA Medical CenterTorranceUSA
  2. 2.Department of Research and EvaluationSouthern California Permanente Medical GroupPasadenaUSA
  3. 3.Department of Medicine, Stanford Prevention Research CenterStanford UniversityStanfordUSA
  4. 4.School of Osteopathic MedicineUniversity of New EnglandBiddefordUSA
  5. 5.Division of Epidemiology, College of Public HealthThe Ohio State UniversityColumbusUSA
  6. 6.Brigham and Women’s Hospital, Harvard Medical SchoolBostonUSA
  7. 7.Department of Preventive MedicineUniversity of Tennessee Health Science CenterMemphisUSA
  8. 8.Department of Social and Preventive MedicineState University of New YorkBuffaloUSA
  9. 9.Harbor-UCLA Medical CenterTorranceUSA
  10. 10.Division of Public Health SciencesFred Hutchinson Cancer Research CenterSeattleUSA

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