Skip to main content

Advertisement

Log in

Comparative safety of cardiovascular medication use and breast cancer outcomes among women with early stage breast cancer

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

Abstract

Breast cancer tends to occur in an older age group of women also burdened with comorbidities such as cardiovascular disease (CVD). Numerous medications used to manage CVD (e.g., statins and antihypertensives) are hypothesized to alter breast cancer risk, but there are few studies on breast cancer outcomes. The COmmonly used Medications and Breast Cancer Outcomes (COMBO) cohort was developed to study how medications and co-morbidities influence breast cancer prognosis. Cohort study among adult women, diagnosed with incident early stage breast cancer, and enrolled in an integrated health plan. Data sources included health plan administrative databases, Surveillance, Epidemiology, and End Results tumor registry, and medical records. Statins, angiotensin-converting enzyme inhibitors (ACEI), beta blockers (BB), calcium blockers, and diuretics were the exposures of interest. The outcome was second breast cancer events (SBCE) defined as recurrence or second primary breast cancer. We used multivariable Cox proportional hazards models to estimate hazard ratios (HR) and 95 % confidence intervals (CI) for SBCE, and components of SBCE. 4,216 women were followed for a median of 6.3 years, and 13.2 % experienced a SBCE (first of: n = 415 recurrences and n = 143 s primary breast cancers). Compared to non-users, we observed an increased risk of second primary breast cancer with ACEI use (HR = 1.66; 95 % CI, 1.06–2.58) and an increased risk of recurrence with BB use (HR = 1.29; 95 % CI, 1.01–1.64). There was suggestion of a reduced risk of SBCE with statin use (HR = 0.82; 95 % CI, 0.62–1.08) and second primary breast cancer with BB use (HR = 0.77; 95 % CI, 0.50–1.19). No differences in outcomes were observed by duration of medication use. A majority of CVD medications evaluated in this study appear safe with respect to SBCE, but ACEI and BB use warrant further evaluation. The study presented is one example of the questions that can be addressed using the COMBO cohort.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. SEER Cancer Statistics Review, 1975–2009. http://seer.cancer.gov/csr/1975_2009_pops09/

  2. Newman L (2001) IOM Report sets policy priorities for improving breast cancer screening. J Natl Cancer Inst 93(8):574–575

    Article  CAS  PubMed  Google Scholar 

  3. Ritchie CS, Kvale E, Fisch MJ (2011) Multimorbidity: an issue of growing importance for oncologists. J Oncol Pract 7(6):371–374

    Article  PubMed Central  PubMed  Google Scholar 

  4. Boudreau DM, Yu O, Johnson J (2010) Statin use and cancer risk: a comprehensive review. Expert Opin Drug Saf 9(4):603–621

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Bonovas S, Filioussi K, Tsavaris N, Sitaras NM (2005) Use of statins and breast cancer: a meta-analysis of seven randomized clinical trials and nine observational studies. J Clin Oncol 23(34):8606–8612

    Article  PubMed  Google Scholar 

  6. Undela K, Srikanth V, Bansal D (2012) Statin use and risk of breast cancer: a meta-analysis of observational studies. Breast Cancer Res Treat 135(1):261–269

    Article  CAS  PubMed  Google Scholar 

  7. 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 Invest 29(9):585–593

    Article  CAS  PubMed  Google Scholar 

  8. Ahern TP, Pedersen L, Tarp M, Cronin-Fenton DP, Garne JP, Silliman RA, Sorensen HT, Lash TL (2011) Statin prescriptions and breast cancer recurrence risk: a Danish nationwide prospective cohort study. J Natl Cancer Inst 103(19):1461–1468

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Kwan ML, Habel LA, Flick ED, Quesenberry CP, Caan B (2008) Post-diagnosis statin use and breast cancer recurrence in a prospective cohort study of early stage breast cancer survivors. Breast Cancer Res Treat 109(3):573–579

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Grossman E, Messerli FH, Goldbourt U (2002) Carcinogenicity of antihypertensive therapy. Curr Hypertens Rep 4(3):195–201

    Article  PubMed  Google Scholar 

  11. Felmeden DC, Lip GY (2001) Antihypertensive therapy and cancer risk. Drug Saf 24(10):727–739

    Article  CAS  PubMed  Google Scholar 

  12. 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):628–638

    PubMed Central  PubMed  Google Scholar 

  13. 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

    Article  CAS  PubMed  Google Scholar 

  14. 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 129(2):549–556

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Nickels S, Vrieling A, Seibold P, Heinz J, Obi N, Flesch-Janys D, Chang-Claude J (2013) Mortality and recurrence risk in relation to the use of lipid-lowering drugs in a prospective breast cancer patient cohort. PLoS ONE 8(9):e75088

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Chae YK, Brown EN, Lei X, Melhem-Bertrandt A, Giordano SH, Litton JK, Hortobagyi GN, Gonzalez-Angulo AM, Chavez-Macgregor M (2013) Use of ACE inhibitors and angiotensin receptor blockers and primary breast cancer outcomes. J Cancer 4(7):549–556

    Article  PubMed Central  PubMed  Google Scholar 

  17. Sorensen GV, Ganz PA, Cole SW, Pedersen LA, Sorensen HT, Cronin-Fenton DP, Garne JP, Christiansen PM, Lash TL, Ahern TP (2013) Use of beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin ii receptor blockers, and risk of breast cancer recurrence: a danish nationwide prospective cohort study. J Clin Oncol 31(18):2265–2272

    Article  PubMed  Google Scholar 

  18. McDougall JA, Malone KE, Daling JR, Cushing-Haugen KL, Porter PL, Li CI (2013) Long-term statin use and risk of ductal and lobular breast cancer among women 55–74 years of age. Cancer Epidemiol Biomarkers Prev 22(9):1529–1537

    Article  PubMed  Google Scholar 

  19. Li CI, Daling JR, Tang MT, Haugen KL, Porter PL, Malone KE (2013) Use of antihypertensive medications and breast cancer risk among women aged 55 to 74 years. JAMA Int Med 173(17):1629–1637

    Article  Google Scholar 

  20. Wong WW, Dimitroulakos J, Minden MD, Penn LZ (2002) HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis. Leukemia 16(4):508–519

    Article  CAS  PubMed  Google Scholar 

  21. Chan KK, Oza AM, Siu LL (2003) The statins as anticancer agents. Clin Cancer Res 9(1):10–19

    CAS  PubMed  Google Scholar 

  22. Demierre MF, Higgins PD, Gruber SB, Hawk E, Lippman SM (2005) Statins and cancer prevention. Nat Rev Cancer 5(12):930–942

    Article  CAS  PubMed  Google Scholar 

  23. Denoyelle C, Vasse M, Korner M, Mishal Z, Ganne F, Vannier JP, Soria J, Soria C (2001) Cerivastatin, an inhibitor of HMG-CoA reductase, inhibits the signaling pathways involved in the invasiveness and metastatic properties of highly invasive breast cancer cell lines: an in vitro study. Carcinogenesis 22(8):1139–1148

    Article  CAS  PubMed  Google Scholar 

  24. Kusama T, Mukai M, Iwasaki T, Tatsuta M, Matsumoto Y, Akedo H, Nakamura H (2001) Inhibition of epidermal growth factor-induced RhoA translocation and invasion of human pancreatic cancer cells by 3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibitors. Cancer Res 61(12):4885–4891

    CAS  PubMed  Google Scholar 

  25. Wong WW, Tan MM, Xia Z, Dimitroulakos J, Minden MD, Penn LZ (2001) Cerivastatin triggers tumor-specific apoptosis with higher efficacy than lovastatin. Clin Cancer Res 7(7):2067–2075

    CAS  PubMed  Google Scholar 

  26. Nelson ER, Wardell SE, Jasper JS, Park S, Suchindran S, Howe MK, Carver NJ, Pillai RV, Sullivan PM, Sondhi V et al (2013) 27-Hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology. Science 342(6162):1094–1098

    Article  CAS  PubMed  Google Scholar 

  27. Paquet JL, Baudouin-Legros M, Brunelle G, Meyer P (1990) Angiotensin II-induced proliferation of aortic myocytes in spontaneously hypertensive rats. J Hypertens 8(6):565–572

    Article  CAS  PubMed  Google Scholar 

  28. Rosenthal T, Gavras I (2009) Angiotensin inhibition and malignancies: a review. J Hum Hypertens 23(10):623–635

    Article  CAS  PubMed  Google Scholar 

  29. Molteni A, Ward WF, Ts’ao CH, Taylor J, Small W Jr, Brizio-Molteni L, Veno PA (2003) Cytostatic properties of some angiotensin I converting enzyme inhibitors and of angiotensin II type I receptor antagonists. Curr Pharm Des 9(9):751–761

    Article  CAS  PubMed  Google Scholar 

  30. Fitzgerald PJ (2010) Testing whether drugs that weaken norepinephrine signaling prevent or treat various types of cancer. Clin Epidemiol 2:1–3

    PubMed Central  PubMed  Google Scholar 

  31. Fitzgerald PJ (2009) Is norepinephrine an etiological factor in some types of cancer? Int J Cancer 124(2):257–263

    Article  CAS  PubMed  Google Scholar 

  32. Drell TLt, Joseph J, Lang K, Niggemann B, Zaenker KS, Entschladen F (2003) Effects of neurotransmitters on the chemokinesis and chemotaxis of MDA-MB-468 human breast carcinoma cells. Breast Cancer Res Treat 80(1):63–70

    Article  CAS  PubMed  Google Scholar 

  33. Lang K, Drell TLt, Lindecke A, Niggemann B, Kaltschmidt C, Zaenker KS, Entschladen F (2004) Induction of a metastatogenic tumor cell type by neurotransmitters and its pharmacological inhibition by established drugs. Int J Cancer 112(2):231–238

    Article  CAS  PubMed  Google Scholar 

  34. Masur K, Niggemann B, Zanker KS, Entschladen F (2001) Norepinephrine-induced migration of SW 480 colon carcinoma cells is inhibited by beta-blockers. Cancer Res 61(7):2866–2869

    CAS  PubMed  Google Scholar 

  35. Sloan EK, Priceman SJ, Cox BF, Yu S, Pimentel MA, Tangkanangnukul V, Arevalo JM, Morizono K, Karanikolas BD, Wu L et al (2010) The sympathetic nervous system induces a metastatic switch in primary breast cancer. Cancer Res 70(18):7042–7052

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Daling JR (1996) Calcium channel blockers and cancer: is an association biologically plausible? Am J Hypertens 9(7):713–714

    Article  CAS  PubMed  Google Scholar 

  37. Howes LG, Edwards CT (1998) Calcium antagonists and cancer. Is there really a link? Drug Saf 18(1):1–7

    Article  CAS  PubMed  Google Scholar 

  38. Mason RP (1999) Effects of calcium channel blockers on cellular apoptosis: implications for carcinogenic potential. Cancer 85(10):2093–2102

    Article  CAS  PubMed  Google Scholar 

  39. Sarafidis PA, McFarlane SI, Bakris GL (2007) Antihypertensive agents, insulin sensitivity, and new-onset diabetes. Curr DiabRep 7(3):191–199

    Article  CAS  Google Scholar 

  40. ALLHAT, Officers and Coordinators for the ALLHAT Collaborative Research Group, The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (2002) Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA 288(23):2998–3007

    Google Scholar 

  41. Wolf I, Sadetzki S, Catane R, Karasik A, Kaufman B (2005) Diabetes mellitus and breast cancer. Lancet Oncol 6(2):103–111

    Article  CAS  PubMed  Google Scholar 

  42. Boyd DB (2003) Insulin and cancer. Integr Cancer Ther 2(4):315–329

    Article  CAS  PubMed  Google Scholar 

  43. Wirtz HS, Buist DS, Gralow JR, Barlow WE, Gray S, Chubak J, Yu O, Bowles EJ, Fujii M, Boudreau DM (2013) Frequent antibiotic use and second breast cancer events. Cancer Epidemiol Biomarkers Prev 22(9):1588–1599

    Article  PubMed  Google Scholar 

  44. Calip GS, Boudreau DM, Loggers ET (2013) Changes in adherence to statins and subsequent lipid profiles during and following breast cancer treatment. Breast Cancer Res Treat 138(1):225–233

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Cancer Surveillance System. http://www.fhcrc.org/en/labs/phs/projects/cancer-surveillance-system.html

  46. Overview of the SEER Program. http://seer.cancer.gov/

  47. Greene FL (2002) The American Joint Committee on Cancer: updating the strategies in cancer staging. Bulletin of the American College of Surgeons 87(7):13–15

    PubMed  Google Scholar 

  48. Buist DS, Ichikawa L, Prout MN, Yood MU, Field TS, Owusu C, Geiger AM, Quinn VP, Wei F, Silliman RA (2007) Receipt of appropriate primary breast cancer therapy and adjuvant therapy are not associated with obesity in older women with access to health care. J Clin Oncol 25(23):3428–3436

    Article  PubMed  Google Scholar 

  49. Enger SM, Thwin SS, Buist DS, Field T, Frost F, Geiger AM, Lash TL, Prout M, Yood MU, Wei F et al (2006) Breast cancer treatment of older women in integrated health care settings. J Clin Oncol 24(27):4377–4383

    Article  PubMed Central  PubMed  Google Scholar 

  50. Geiger AM, Thwin SS, Lash TL, Buist DS, Prout MN, Wei F, Field TS, Ulcickas Yood M, Frost FJ, Enger SM et al (2007) Recurrences and second primary breast cancers in older women with initial early-stage disease. Cancer 109(5):966–974

    Google Scholar 

  51. Group Health: Breast Cancer Surveillance. http://www.grouphealthresearch.org/surveillanceproject/screening/history.html

  52. Saunders KW, Davis RL, Stergachis A (2005) Group Health Cooperative. In: Strom BL (ed) Pharmacoepidemiology, 4th edn. Wiley, West Sussex, pp 223–239

    Google Scholar 

  53. Boudreau DM, Doescher MP, Jackson JE, Fishman PA, Saver BG (2004) Impact of healthcare delivery system on where HMO-enrolled seniors purchase medications. Ann Pharmacother 38(7–8):1317–1318

    Article  PubMed  Google Scholar 

  54. Buist DS, LaCroix AZ, Brenneman SK, Abbott T (2004) A population-based osteoporosis screening program: who does not participate, and what are the consequences? J Am Geriatr Soc 52(7):1130–1137

    Article  PubMed  Google Scholar 

  55. Death Data. http://www.doh.wa.gov/ehsphl/CHS/chs-data/death/deatmain.htm

  56. Thwin SS, Clough-Gorr KM, McCarty MC, Lash TL, Alford SH, Buist DS, Enger SM, Field TS, Frost F, Wei F et al (2007) Automated inter-rater reliability assessment and electronic data collection in a multi-center breast cancer study. BMC Med Res Methodol 7:23

    Article  PubMed Central  PubMed  Google Scholar 

  57. McKenney JM (2003) Pharmacologic characteristics of statins. Clin Cardiol 26(4 Suppl 3):III32–III38

    Google Scholar 

  58. Psaty BM, Heckbert SR, Koepsell TD, Siscovick DS, Raghunathan TE, Weiss NS, Rosendaal FR, Lemaitre RN, Smith NL, Wahl PW et al (1995) The risk of myocardial infarction associated with antihypertensive drug therapies. JAMA 274(8):620–625

    Article  CAS  PubMed  Google Scholar 

  59. Hudis CA, Barlow WE, Costantino JP, Gray RJ, Pritchard KI, Chapman JA, Sparano JA, Hunsberger S, Enos RA, Gelber RD et al (2007) Proposal for standardized definitions for efficacy end points in adjuvant breast cancer trials: the STEEP system. J Clin Oncol 25(15):2127–2132

    Article  PubMed  Google Scholar 

  60. Varadhan R, Weiss CO, Segal JB, Wu AW, Scharfstein D, Boyd C (2010) Evaluating health outcomes in the presence of competing risks: a review of statistical methods and clinical applications. Med Care 48(6 Suppl):S96–S105

    Article  PubMed  Google Scholar 

  61. Deyo RA, Cherkin DC, Ciol MA (1992) Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol 45(6):613–619

    Article  CAS  PubMed  Google Scholar 

  62. Newton KM, Wagner EH, Ramsey SD, McCulloch D, Evans R, Sandhu N, Davis C (1999) The use of automated data to identify complications and comorbidities of diabetes: a validation study. J Clin Epidemiol 52(3):199–207

    Article  CAS  PubMed  Google Scholar 

  63. Boudreau DM, Malone DC, Raebel MA, Fishman PA, Nichols GA, Feldstein AC, Boscoe AN, Ben-Joseph RH, Magid DJ, Okamoto LJ (2009) Health care utilization and costs by metabolic syndrome risk factors. Metab Syndr Relat Disord 7(4):305–314

    Article  CAS  PubMed  Google Scholar 

  64. Malone DC, Boudreau DM, Nichols GA, Raebel MA, Fishman PA, Feldstein AC, Ben-Joseph RH, Okamoto LJ, Boscoe AN, Magid DJ (2009) Association of cardiometabolic risk factors and prevalent cardiovascular events. Metab Syndr Relat Disord 7(6):585–593

    Article  PubMed  Google Scholar 

  65. U.S. Census Bureau (2011) Statistical abstract of the United States: 2012, 131st edn. Washington, DC

  66. HMO Research Network. http://hmoresearchnetwork.org

  67. Holmes MD, Hankinson SE, Feskanich D, Chen WY (2013) Beta blockers and angiotensin-converting enzyme inhibitors’ purported benefit on breast cancer survival may be explained by aspirin use. Breast Cancer Res Treat 139(2):507–513

    Article  CAS  PubMed  Google Scholar 

  68. George AJ, Thomas WG, Hannan RD (2010) The renin-angiotensin system and cancer: old dog, new tricks. Nat Rev Cancer 10(11):745–759

    Article  CAS  PubMed  Google Scholar 

  69. Phipps AI, Ichikawa L, Bowles EJ, Carney PA, Kerlikowske K, Miglioretti DL, Buist DS (2010) Defining menopausal status in epidemiologic studies: a comparison of multiple approaches and their effects on breast cancer rates. Maturitas 67(1):60–66

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgements

This manuscript was supported by grant numbers CA120562 (Boudreau), CRTG-03-024-01 (Buist), and CA093772 (Silliman). The collection of cancer incidence data used in this study was supported by the Cancer Surveillance System of the Fred Hutchinson Cancer Research Center (Contract No. N01-CN-67009 and N01-PC-35142) from the Surveillance, Epidemiology and End Results Program of the National Cancer Institute with additional support from the Fred Hutchinson Cancer Research Center and the State of Washington.

Conflict of interest

The authors declare that they have no conflicts of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Denise M. Boudreau.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 28 kb)

Supplementary material 2 (DOC 76 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Boudreau, D.M., Yu, O., Chubak, J. et al. Comparative safety of cardiovascular medication use and breast cancer outcomes among women with early stage breast cancer. Breast Cancer Res Treat 144, 405–416 (2014). https://doi.org/10.1007/s10549-014-2870-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-014-2870-5

Keywords

Navigation