Skip to main content

Advertisement

SpringerLink
Log in

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

  • Epidemiology
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Previtali E, Bucciarelli P, Passamonti SM, Martinelli I (2011) Risk factors for venous and arterial thrombosis. Blood Transfus 9(2):120–138

    PubMed  PubMed Central  Google Scholar 

  2. Cushman M (2007) Epidemiology and risk factors for venous thrombosis. Semin Hematol 44(2):62–69

    Article  PubMed  PubMed Central  Google Scholar 

  3. Prandoni P, Falanga A, Piccioli A (2005) Cancer and venous thromboembolism. Lancet Oncol 6(6):401–410

    Article  PubMed  Google Scholar 

  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):321–331

    Article  CAS  PubMed  Google Scholar 

  5. Levine MN (2007) Adjuvant therapy and thrombosis: how to avoid the problem? The Breast 16(Suppl 2):169–174

    Article  Google Scholar 

  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):65–80

    Article  PubMed  Google Scholar 

  7. Deitcher SR, Gomes MPV (2004) The risk of venous thromboembolic disease associated with adjuvant hormone therapy for breast carcinoma. Cancer 101(3):439–449

    Article  PubMed  Google Scholar 

  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):3784–3796

    Article  PubMed  PubMed Central  Google Scholar 

  9. Goss PE, Ingle JN, Pritchard KI et al (2016) Extending aromatase-inhibitor adjuvant therapy to 10 years. N Engl J Med 375(3):209–219

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):3317–3327

    Article  CAS  PubMed  Google Scholar 

  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 26:106–114

    Article  PubMed  Google Scholar 

  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):1802–1810

    Article  CAS  PubMed  Google Scholar 

  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):3337–3346

    CAS  PubMed  Google Scholar 

  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):831–836

    Article  CAS  PubMed  Google Scholar 

  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):1299–1309

    Article  CAS  PubMed  Google Scholar 

  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):849–857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):100–103

    Article  CAS  PubMed  Google Scholar 

  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):2120–2126

    Article  Google Scholar 

  19. Sikka R, Xia F, Aubert RE (2005) Estimating medication persistency using administrative claims data. Am J Manag Care 11(7):449–457

    PubMed  Google Scholar 

  20. Chlebowski RT, Budoff MJ (2016) Changing adjuvant breast-cancer therapy with a signal for prevention. N Engl J Med 375:274–275

    Article  PubMed  Google Scholar 

  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):1081–1092

    Article  CAS  PubMed  Google Scholar 

  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):3758–3767

    Article  CAS  PubMed  Google Scholar 

  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):2747–2757

    Article  Google Scholar 

  24. Singh S, Loke YK (2002) Drug safety assessment in clinical trials: methodological challenges and opportunities. Trials 13(1):138

    Article  Google Scholar 

  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):4442–4449

    Article  CAS  PubMed  Google Scholar 

  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):1687–1717

    Article  CAS  Google Scholar 

  27. National Comprehensive Cancer Network (2018) NCCN clinical practice guidelines in oncology (NCCN Guidelines) Breast Cancer. Version 1.1018. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed 16 November 2018

  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):107–118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Haque R, Shi J, Schottinger JE et al (2016) Cardiovascular disease after aromatase inhibitor use. JAMA Oncol 2(12):1590–1597

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

  1. Department of Research & Evaluation, Kaiser Permanente Southern California, 100 South Los Robles, 2nd Floor, Pasadena, CA, 91101, USA

    Xiaoqing Xu, Jiaxiao Shi & Reina Haque

  2. City of Hope, 1500 E. Duarte Rd., Duarte, CA, 91010, USA

    Rowan T. Chlebowski

  3. Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, 1124 West Carson Street, Torrance, CA, 90502, USA

    Rowan T. Chlebowski

  4. Medstar Heart and Vascular Institute, 110 Irving Street, Washington, DC, 20010, USA

    Ana Barac

  5. Georgetown University, Washington, DC, USA

    Ana Barac

Authors
  1. Xiaoqing Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rowan T. Chlebowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jiaxiao Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ana Barac
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Reina Haque
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Reina Haque.

Ethics declarations

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.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 126 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xu, X., Chlebowski, R.T., Shi, J. et al. Aromatase inhibitor and tamoxifen use and the risk of venous thromboembolism in breast cancer survivors. Breast Cancer Res Treat 174, 785–794 (2019). https://doi.org/10.1007/s10549-018-05086-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-018-05086-8

Keywords

Search

Navigation