Breast Cancer Research and Treatment

, Volume 174, Issue 3, pp 785–794 | Cite as

Aromatase inhibitor and tamoxifen use and the risk of venous thromboembolism in breast cancer survivors

  • Xiaoqing Xu
  • Rowan T. Chlebowski
  • Jiaxiao Shi
  • Ana Barac
  • Reina HaqueEmail author



Venous thromboembolism (VTE) is the second most common cause of death in hospitalized patients with cancer, and cancer treatments may exacerbate VTE risk. Patients with hormone-receptor-positive breast cancer usually receive adjuvant endocrine therapy for 5 years or longer. The aim of this study is to examine VTE risk following long-term use of aromatase inhibitor (AI) compared with tamoxifen use among breast cancer survivors.


A prospective cohort of 12,904 postmenopausal women who were diagnosed with a first primary hormone-receptor-positive breast cancer and free from previous cardiovascular disease or VTE from 1991 to 2010 were followed through December 2011. Data elements were captured from the comprehensive electronic health records of a large California health plan, Kaiser Permanente. Women who developed deep vein thrombosis (DVT) or pulmonary embolism (PE) were identified as having VTE. We calculated person-year rates of VTE by endocrine therapy groups. Multivariable Cox proportional hazards models were applied to assess the association between time-dependent endocrine therapy and VTE risk.


We identified 623 VTE events during a median follow-up of 5.4 years. The crude rates were 4.6 and 2.8 per 1000 person-years for DVT and PE, respectively. Compared with tamoxifen use, AI use was associated with at least 41% lower VTE risk (adjusted HR 0.59, 95% CI 0.43, 0.81). Greater risk reductions in AI users were seen in women who also underwent adjuvant chemotherapy.


These findings supplement existing evidence to inform treatment decisions that balance cancer control and cardiovascular toxic outcomes.


Aromatase inhibitors Tamoxifen Breast cancer DVT PE 



This study was funded by the California Breast Cancer Research Program (Grant#19OB-0201). The funding program was not involved in study design, data collection, analysis, data interpretation, report writing, nor in the decision to submit the paper for publication.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

Only secondary data analyses were performed. The KPSC Institutional Review Board reviewed and approved this study.

Supplementary material

10549_2018_5086_MOESM1_ESM.pdf (127 kb)
Supplementary material 1 (PDF 126 KB)


  1. 1.
    Previtali E, Bucciarelli P, Passamonti SM, Martinelli I (2011) Risk factors for venous and arterial thrombosis. Blood Transfus 9(2):120–138Google Scholar
  2. 2.
    Cushman M (2007) Epidemiology and risk factors for venous thrombosis. Semin Hematol 44(2):62–69CrossRefGoogle Scholar
  3. 3.
    Prandoni P, Falanga A, Piccioli A (2005) Cancer and venous thromboembolism. Lancet Oncol 6(6):401–410CrossRefGoogle Scholar
  4. 4.
    Van de Velde CJH, Rea D et al (2011) Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trial. Lancet 377(9762):321–331CrossRefGoogle Scholar
  5. 5.
    Levine MN (2007) Adjuvant therapy and thrombosis: how to avoid the problem? The Breast 16(Suppl 2):169–174CrossRefGoogle Scholar
  6. 6.
    Mandalà M, Ferretti G, Cremonesi M, Cazzaniga M, Curigliano G, Barni S (2003) Venous thromboembolism and cancer: new issues for an old topic. Crit Rev Oncol Hematol 48(1):65–80CrossRefGoogle Scholar
  7. 7.
    Deitcher SR, Gomes MPV (2004) The risk of venous thromboembolic disease associated with adjuvant hormone therapy for breast carcinoma. Cancer 101(3):439–449CrossRefGoogle Scholar
  8. 8.
    Burstein HJ, Prestrud AA, Seidenfeld J et al (2010) American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor–positive breast cancer. J Clin Oncol 28(23):3784–3796CrossRefGoogle Scholar
  9. 9.
    Goss PE, Ingle JN, Pritchard KI et al (2016) Extending aromatase-inhibitor adjuvant therapy to 10 years. N Engl J Med 375(3):209–219CrossRefGoogle Scholar
  10. 10.
    Winer EP, Hudis C, Burstein HJ et al (2002) American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for women with hormone receptor–positive breast cancer: status report 2002. J Clin Oncol 20(15):3317–3327CrossRefGoogle Scholar
  11. 11.
    Rydén L, Arnlind MH, Vitols S, Höistad M, Ahlgren J (2016) Aromatase inhibitors alone or sequentially combined with tamoxifen in postmenopausal early breast cancer compared with tamoxifen or placebo–Meta-analyses on efficacy and adverse events based on randomized clinical trials. The Breast 26:106–114CrossRefGoogle Scholar
  12. 12.
    Baum M, Buzdar A, Cuzick J et al (2003) Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: results of the ATAC (arimidex, tamoxifen alone or in combination) trial efficacy and safety update analyses. Cancer 98(9):1802–1810CrossRefGoogle Scholar
  13. 13.
    Melichar B, Kalabova H, KrČMovÁ L et al (2009) Effect of aromatase inhibitors on lipid metabolism, inflammatory response and antioxidant balance in patients with breast carcinoma. Anticancer Res 29(8):3337–3346Google Scholar
  14. 14.
    Bines J, Dienstmann R, Obadia RM et al (2014) Activity of megestrol acetate in postmenopausal women with advanced breast cancer after nonsteroidal aromatase inhibitor failure: a phase II trial. Ann Oncol 25(4):831–836CrossRefGoogle Scholar
  15. 15.
    Amir E, Seruga B, Niraula S, Carlsson L, Ocana A (2011) Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: a systematic review and meta-analysis. J Natl Cancer Inst 103(17):1299–1309CrossRefGoogle Scholar
  16. 16.
    Walker AJ, West J, Card TR, Crooks C, Kirwan CC, Grainge MJ (2016) When are breast cancer patients at highest risk of venous thromboembolism? A cohort study using English health care data. Blood 127(7):849–857CrossRefGoogle Scholar
  17. 17.
    Costa M, Luis A, Kopreski MS et al (1999) Effect of the potent aromatase inhibitor fadrozole hydrochloride (CGS 16949A) in postmenopausal women with breast carcinoma. Cancer 85(1):100–103CrossRefGoogle Scholar
  18. 18.
    Haque R, Yood MU, Geiger AM et al (2011) Long-term safety of radiotherapy and breast cancer laterality in older survivors. Cancer Epidemiol Biomark Prev 20(10):2120–2126CrossRefGoogle Scholar
  19. 19.
    Sikka R, Xia F, Aubert RE (2005) Estimating medication persistency using administrative claims data. Am J Manag Care 11(7):449–457Google Scholar
  20. 20.
    Chlebowski RT, Budoff MJ (2016) Changing adjuvant breast-cancer therapy with a signal for prevention. N Engl J Med 375:274–275CrossRefGoogle Scholar
  21. 21.
    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 Engl J Med 350(11):1081–1092CrossRefGoogle Scholar
  22. 22.
    Nabholtz JM, Buzdar A, Pollak M et al (2000) Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. J Clin Oncol 18(22):3758–3767CrossRefGoogle Scholar
  23. 23.
    Breast International Group (BIG) 1–98 Collaborative Group (2005) A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353(26):2747–2757CrossRefGoogle Scholar
  24. 24.
    Singh S, Loke YK (2002) Drug safety assessment in clinical trials: methodological challenges and opportunities. Trials 13(1):138CrossRefGoogle Scholar
  25. 25.
    Hernandez RK, Sørensen HT, Pedersen L, Jacobsen J, Lash TL (2009) Tamoxifen treatment and risk of deep venous thrombosis and pulmonary embolism. Cancer 115(19):4442–4449CrossRefGoogle Scholar
  26. 26.
    Early Breast Cancer Trialists’ Collaborative G (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
  27. 27.
    National Comprehensive Cancer Network (2018) NCCN clinical practice guidelines in oncology (NCCN Guidelines) Breast Cancer. Version 1.1018. Accessed 16 November 2018
  28. 28.
    Pagani O, Regan MM, Walley BA et al (2014) Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med 371(9471):107–118CrossRefGoogle Scholar
  29. 29.
    Haque R, Shi J, Schottinger JE et al (2016) Cardiovascular disease after aromatase inhibitor use. JAMA Oncol 2(12):1590–1597CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Research & EvaluationKaiser Permanente Southern CaliforniaPasadenaUSA
  2. 2.City of HopeDuarteUSA
  3. 3.Los Angeles Biomedical Research Institute at Harbor-UCLA Medical CenterTorranceUSA
  4. 4.Medstar Heart and Vascular InstituteWashingtonUSA
  5. 5.Georgetown UniversityWashingtonUSA

Personalised recommendations