Breast Cancer Research and Treatment

, Volume 139, Issue 2, pp 507–513 | Cite as

Beta blockers and angiotensin-converting enzyme inhibitors’ purported benefit on breast cancer survival may be explained by aspirin use

  • Michelle D. Holmes
  • Susan E. Hankinson
  • Diane Feskanich
  • Wendy Y. Chen


Preclinical and epidemiologic evidence supports a possible role for beta-adrenergic blocking drugs (beta-blockers), and angiotensin-converting enzyme inhibitors (ACEIs) in promoting survival after breast cancer. However, these drugs are often used concurrently with aspirin, and there is a growing body of evidence indicating a survival benefit for aspirin. Therefore, we analyzed the use of beta-blockers and ACEIs after a breast cancer diagnosis and their association with breast cancer mortality, both individually, combined with each other, and in combination with aspirin use in the Nurses’ Health Study, using updated measures of medication use and Cox proportional hazards models. There were 4,661 women with stages I–III breast cancer included; 292 breast cancer deaths occurred during median follow-up time of 10.5 years. Modeled individually, the multivariable relative risk and 95 % confidence intervals (RR, 95 % CI) for breast cancer death were (0.76, 0.54–1.05) for beta blockers, (0.89, 0.60–1.32) for ACEIs, and (0.46, 0.35–0.60) for aspirin. Modeled simultaneously, the multivariable (RR, 95 % CI) for breast cancer death were (0.83, 0.60–1.16) for beta blockers, (1.00, 0.68–1.46) for ACEIs, and (0.46, 0.35–0.61) for aspirin. We did not see a significant association with beta blockers and survival, but there was a suggestion. Our study was limited in that we could not assess type of beta blocker and the number of events among users was still quite low. We found no evidence of a protective effect for ACEIs. The strong protective association with aspirin use confounds the associations with these other drugs and underscores the importance of considering aspirin use in analyses of breast cancer survival.


Adrenergic beta-antagonists Angiotensin-converting enzyme inhibitors Aspirin Breast neoplasms Survival 



We wish to thank Gideon Aweh for his computer programing assistance. In addition, we would like to thank the participants and staff of the Nurses’ Health Study, for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. This work was supported by the National Institutes of Health grant CA87969. The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. The authors have no further financial relationship with the funder, and no conflicts of interest to declare, with the exception of Dr. Holmes, who has received remuneration from The authors have full control of all primary data and the Journal may review the data if requested.


This work was approved by the Institutional Review Board of the Brigham and Women’s Hospital, Boston MA, and complies with all U.S. laws regarding human subjects.


  1. 1.
    Holmes MD, Chen WY (2012) Hiding in plain view: the potential for commonly used drugs to reduce breast cancer mortality. Breast Cancer Res 14(2):216. doi: 10.1186/bcr3336 PubMedCrossRefGoogle Scholar
  2. 2.
    Antoni MH, Lutgendorf SK, Cole SW, Dhabhar FS, Sephton SE, McDonald PG, Stefanek M, Sood AK (2006) The influence of bio-behavioural factors on tumour biology: pathways and mechanisms. Nat Rev Cancer 6(3):240–248. doi: 10.1038/nrc1820 PubMedCrossRefGoogle Scholar
  3. 3.
    Vaklavas C, Chatzizisis YS, Tsimberidou AM (2011) Common cardiovascular medications in cancer therapeutics. Pharmacol Ther 130(2):177–190. doi: 10.1016/j.pharmthera.2011.01.009 PubMedCrossRefGoogle Scholar
  4. 4.
    Sloan EK, Priceman SJ, Cox BF, Yu S, Pimentel MA, Tangkanangnukul V, Arevalo JM, Morizono K, Karanikolas BD, Wu L, Sood AK, Cole SW (2010) The sympathetic nervous system induces a metastatic switch in primary breast cancer. Cancer Res 70(18):7042–7052. doi: 10.1158/0008-5472.CAN-10-0522 PubMedCrossRefGoogle Scholar
  5. 5.
    Vandewalle B, Revillion F, Lefebvre J (1990) Functional beta-adrenergic receptors in breast cancer cells. J Cancer Res Clin Oncol 116(3):303–306PubMedCrossRefGoogle Scholar
  6. 6.
    Powe DG, Voss MJ, Zanker KS, Habashy HO, Green AR, Ellis IO, Entschladen F (2010) Beta-blocker drug therapy reduces secondary cancer formation in breast cancer and improves cancer specific survival. Oncotarget 1(7):628–638PubMedGoogle Scholar
  7. 7.
    Melhem-Bertrandt A, Chavez-Macgregor M, Lei X, Brown EN, Lee RT, Meric-Bernstam F, Sood AK, Conzen SD, Hortobagyi GN, Gonzalez-Angulo AM (2011) Beta-blocker use is associated with improved relapse-free survival in patients with triple-negative breast cancer. J Clin Oncol 29(19):2645–2652. doi: 10.1200/JCO.2010.33.4441 PubMedCrossRefGoogle Scholar
  8. 8.
    Ganz PA, Habel LA, Weltzien EK, Caan BJ, Cole SW (2011) Examining the influence of beta blockers and ACE inhibitors on the risk for breast cancer recurrence: results from the LACE cohort. Breast Cancer Res Treat. doi: 10.1007/s10549-011-1505-3
  9. 9.
    Barron TI, Connolly RM, Sharp L, Bennett K, Visvanathan K (2011) Beta blockers and breast cancer mortality: a population-based study. J Clin Oncol 29(19):2635–2644. doi: 10.1200/JCO.2010.33.5422 PubMedCrossRefGoogle Scholar
  10. 10.
    Herr D, Rodewald M, Fraser HM, Hack G, Konrad R, Kreienberg R, Wulff C (2008) Potential role of renin–angiotensin-system for tumor angiogenesis in receptor negative breast cancer. Gynecol Oncol 109(3):418–425. doi: 10.1016/j.ygyno.2008.02.019 PubMedCrossRefGoogle Scholar
  11. 11.
    Koh WP, Yuan JM, Sun CL, van den Berg D, Seow A, Lee HP, Yu MC (2003) Angiotensin I-converting enzyme (ACE) gene polymorphism and breast cancer risk among Chinese women in Singapore. Cancer Res 63(3):573–578PubMedGoogle Scholar
  12. 12.
    Koh WP, Yuan JM, Van Den Berg D, Lee HP, Yu MC (2005) Polymorphisms in angiotensin II type 1 receptor and angiotensin I-converting enzyme genes and breast cancer risk among Chinese women in Singapore. Carcinogenesis 26(2):459–464. doi: 10.1093/carcin/bgh309 PubMedCrossRefGoogle Scholar
  13. 13.
    Greco S, Muscella A, Elia MG, Salvatore P, Storelli C, Mazzotta A, Manca C, Marsigliante S (2003) Angiotensin II activates extracellular signal regulated kinases via protein kinase C and epidermal growth factor receptor in breast cancer cells. J Cell Physiol 196(2):370–377. doi: 10.1002/jcp.10313 PubMedCrossRefGoogle Scholar
  14. 14.
    Zhao Y, Chen X, Cai L, Yang Y, Sui G, Fu S (2010) Angiotensin II/angiotensin II type I receptor (AT1R) signaling promotes MCF-7 breast cancer cells survival via PI3-kinase/Akt pathway. J Cell Physiol 225(1):168–173. doi: 10.1002/jcp.22209 PubMedCrossRefGoogle Scholar
  15. 15.
    Chae YK, Valsecchi ME, Kim J, Bianchi AL, Khemasuwan D, Desai A, Tester W (2011) Reduced risk of breast cancer recurrence in patients using ACE inhibitors, ARBs, and/or statins. Cancer Investig 29(9):585–593. doi: 10.3109/07357907.2011.616252 CrossRefGoogle Scholar
  16. 16.
    Holmes MD, Chen WY, Li L, Hertzmark E, Spiegelman D, Hankinson SE (2010) Aspirin intake and survival after breast cancer. J Clin Oncol. doi: 10.1200/JCO.2009.22.7918
  17. 17.
    Holmes MD, Chen WY, Schnitt SJ, Collins L, Colditz GA, Hankinson SE, Tamimi RM (2011) COX-2 expression predicts worse breast cancer prognosis and does not modify the association with aspirin. Breast Cancer Res Treat 130(2):657–662. doi: 10.1007/s10549-011-1651-7 PubMedCrossRefGoogle Scholar
  18. 18.
    Kwan ML, Habel LA, Slattery ML, Caan B (2007) NSAIDs and breast cancer recurrence in a prospective cohort study. Cancer Causes Control 18(6):613–620. doi: 10.1007/s10552-007-9003-y PubMedCrossRefGoogle Scholar
  19. 19.
    Blair CK, Sweeney C, Anderson KE, Folsom AR (2007) NSAID use and survival after breast cancer diagnosis in post-menopausal women. Breast Cancer Res Treat 101(2):191–197. doi: 10.1007/s10549-006-9277-x PubMedCrossRefGoogle Scholar
  20. 20.
    Algra AM, Rothwell PM (2012) Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparison of evidence from observational studies versus randomised trials. Lancet Oncol. doi: 10.1016/S1470-2045(12)70112-2
  21. 21.
    Rothwell PM, Wilson M, Price JF, Belch JF, Meade TW, Mehta Z (2012) Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet 379(9826):1591–1601. doi: 10.1016/S0140-6736(12)60209-8 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Michelle D. Holmes
    • 1
    • 2
  • Susan E. Hankinson
    • 1
    • 2
    • 3
  • Diane Feskanich
    • 1
  • Wendy Y. Chen
    • 1
    • 4
  1. 1.The Channing Division of Network Medicine, Department of MedicineBrigham and Women’s Hospital and Harvard Medical SchoolBostonUSA
  2. 2.Department of EpidemiologyHarvard School of Public HealthBostonUSA
  3. 3.Division of Biostatistics and EpidemiologyUniversity of MassachusettsAmherstUSA
  4. 4.Department of Medical OncologyDana Farber Cancer InstituteBostonUSA

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