COX-2 expression predicts worse breast cancer prognosis and does not modify the association with aspirin

  • Michelle D. Holmes
  • Wendy Y. Chen
  • Stuart J. Schnitt
  • Laura Collins
  • Graham A. Colditz
  • Susan E. Hankinson
  • Rulla M. Tamimi
Epidemiology

Abstract

Some previous studies have found worse prognosis among cyclooxygenase-2 (COX-2)-expressing breast cancers. Aspirin and NSAIDs inhibit COX-2. Three studies, including ours, have reported a survival advantage among women with breast cancer who take either aspirin or NSAIDs. Through this study we hypothesized that in the Nurses’ Health Study (NHS), COX-2 expression would be associated with worse prognosis, and aspirin use would be associated with better survival particularly among women with COX-2 positive tumors. In this study we investigated 2,001 women presenting with invasive breast cancers stained for COX-2 by immunohistochemistry. Tumor prognostic factors were from medical records. Aspirin use was assessed at least 12 months after diagnosis and updated. Cause of death was identified from death certificates. Statistical analyses included logistic regression of prognostic factors with COX-2 status as the outcome, and proportional hazards regression with breast cancer death as the outcome. Tumor COX-2 expression was associated with higher diagnostic stage. Compared with stage I, the RR(95% CI) for stages II–IV were 1.16 (0.93–1.45), 1.68 (1.27–2.22), and 1.76 (0.93–3.32). COX-2 expression was associated with lobular compared with ductal histology (1.40 [1.02–1.92]), and estrogen receptor positive compared with negative (2.22 [1.66–2.95]). The RR(95% CI) of breast cancer death for current aspirin use was similar for women with COX-2-positive and COX-2-negative tumors; 0.64 (0.43–0.96) and 0.57 (0.44–0.74), respectively. In the NHS, COX-2 breast cancer expression was associated with higher stage at diagnosis. The survival benefit associated with aspirin use did not differ by COX-2 status. COX-2 breast cancer expression is associated with worse prognosis. If aspirin truly impacts breast cancer survival, then it is not solely via COX-2.

Keywords

Breast neoplasms Cyclooxygenase-2 Tumor markers Prognosis Survival Aspirin 

References

  1. 1.
    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
  2. 2.
    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
  3. 3.
    Holmes MD, Chen WY, Li L, Hertzmark E, Spiegelman D, Hankinson SE (2010) Aspirin intake and survival after breast cancer. J Clin Oncol 28:1467–1472. doi:10.1200/JCO.2009.22.7918 PubMedCrossRefGoogle Scholar
  4. 4.
    Egan KM, Stampfer MJ, Giovannucci E, Rosner BA, Colditz GA (1996) Prospective study of regular aspirin use and the risk of breast cancer. J Natl Cancer Inst 88(14):988–993PubMedCrossRefGoogle Scholar
  5. 5.
    Takkouche B, Regueira-Mendez C, Etminan M (2008) Breast cancer and use of nonsteroidal anti-inflammatory drugs: a meta-analysis. J Natl Cancer Inst 100(20):1439–1447. doi:10.1093/jnci/djn324 PubMedCrossRefGoogle Scholar
  6. 6.
    Chan AT, Ogino S, Fuchs CS (2009) Aspirin use and survival after diagnosis of colorectal cancer. JAMA 302(6):649–658. doi:10.1001/jama.2009.1112 PubMedCrossRefGoogle Scholar
  7. 7.
    Ristimaki A, Sivula A, Lundin J, Lundin M, Salminen T, Haglund C, Joensuu H, Isola J (2002) Prognostic significance of elevated cyclooxygenase-2 expression in breast cancer. Cancer Res 62(3):632–635PubMedGoogle Scholar
  8. 8.
    Zeeneldin AA, Mohamed AM, Abdel HA, Taha FM, Goda IA, Abodeef WT (2009) Survival effects of cyclooxygenase-2 and 12-lipooxygenase in Egyptian women with operable breast cancer. Indian J Cancer 46(1):54–60PubMedCrossRefGoogle Scholar
  9. 9.
    Zhang SM, Cook NR, Manson JE, Lee IM, Buring JE (2008) Low-dose aspirin and breast cancer risk: results by tumour characteristics from a randomised trial. Br J Cancer 98(5):989–991. doi:10.1038/sj.bjc.6604240 PubMedCrossRefGoogle Scholar
  10. 10.
    Nassar A, Radhakrishnan A, Cabrero IA, Cotsonis G, Cohen C (2007) COX-2 expression in invasive breast cancer: correlation with prognostic parameters and outcome. Appl Immunohistochem Mol Morphol 15(3):255–259. doi:10.1097/01.pai.0000213130.63417.b3 PubMedCrossRefGoogle Scholar
  11. 11.
    Park K, Han S, Shin E, Kim HJ, Kim JY (2006) Cox-2 expression on tissue microarray of breast cancer. Eur J Surg Oncol 32(10):1093–1096. doi:10.1016/j.ejso.2006.05.010 PubMedCrossRefGoogle Scholar
  12. 12.
    Surowiak P, Materna V, Matkowski R, Szczuraszek K, Kornafel J, Wojnar A, Pudelko M, Dietel M, Denkert C, Zabel M, Lage H (2005) Relationship between the expression of cyclooxygenase 2 and MDR1/P-glycoprotein in invasive breast cancers and their prognostic significance. Breast Cancer Res 7(5):R862–R870. doi:10.1186/bcr1313 PubMedCrossRefGoogle Scholar
  13. 13.
    Kim JH, Bossuyt V, Ponn T, Lannin D, Haffty BG (2005) Cyclooxygenase-2 expression in postmastectomy chest wall relapse. Clin Cancer Res 11(14):5199–5205. doi:10.1158/1078-0432.CCR-05-0524 PubMedCrossRefGoogle Scholar
  14. 14.
    Denkert C, Winzer KJ, Muller BM, Weichert W, Pest S, Kobel M, Kristiansen G, Reles A, Siegert A, Guski H, Hauptmann S (2003) Elevated expression of cyclooxygenase-2 is a negative prognostic factor for disease free survival and overall survival in patients with breast carcinoma. Cancer 97(12):2978–2987PubMedCrossRefGoogle Scholar
  15. 15.
    Wulfing P, Diallo R, Muller C, Wulfing C, Poremba C, Heinecke A, Rody A, Greb RR, Bocker W, Kiesel L (2003) Analysis of cyclooxygenase-2 expression in human breast cancer: high throughput tissue microarray analysis. J Cancer Res Clin Oncol 129(7):375–382PubMedCrossRefGoogle Scholar
  16. 16.
    Costa C, Soares R, Reis-Filho JS, Leitao D, Amendoeira I, Schmitt FC (2002) Cyclo-oxygenase 2 expression is associated with angiogenesis and lymph node metastasis in human breast cancer. J Clin Pathol 55(6):429–434PubMedCrossRefGoogle Scholar
  17. 17.
    Witton CJ, Hawe SJ, Cooke TG, Bartlett JM (2004) Cyclooxygenase 2 (COX2) expression is associated with poor outcome in ER-negative, but not ER-positive, breast cancer. Histopathology 45(1):47–54PubMedCrossRefGoogle Scholar
  18. 18.
    Nakopoulou L, Mylona E, Papadaki I, Kapranou A, Giannopoulou I, Markaki S, Keramopoulos A (2005) Overexpression of cyclooxygenase-2 is associated with a favorable prognostic phenotype in breast carcinoma. Pathobiology 72(5):241–249. doi:10.1159/000089418 PubMedCrossRefGoogle Scholar
  19. 19.
    Spizzo G, Gastl G, Wolf D, Gunsilius E, Steurer M, Fong D, Amberger A, Margreiter R, Obrist P (2003) Correlation of COX-2 and Ep-CAM overexpression in human invasive breast cancer and its impact on survival. Br J Cancer 88(4):574–578PubMedCrossRefGoogle Scholar
  20. 20.
    Tamimi RM, Baer HJ, Marotti J, Galan M, Galaburda L, Fu Y, Deitz AC, Connolly JL, Schnitt SJ, Colditz GA, Collins LC (2008) Comparison of molecular phenotypes of ductal carcinoma in situ and invasive breast cancer. Breast Cancer Res 10(4):R67. doi:10.1186/bcr2128 PubMedCrossRefGoogle Scholar
  21. 21.
    Howe LR, Lippman SM (2008) Modulation of breast cancer risk by nonsteroidal anti-inflammatory drugs. J Natl Cancer Inst 100(20):1420–1423. doi:10.1093/jnci/djn347 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Michelle D. Holmes
    • 1
    • 3
  • Wendy Y. Chen
    • 1
    • 2
  • Stuart J. Schnitt
    • 4
  • Laura Collins
    • 4
  • Graham A. Colditz
    • 5
    • 3
  • Susan E. Hankinson
    • 1
    • 3
  • Rulla M. Tamimi
    • 1
    • 3
  1. 1.Channing Laboratory, Department of MedicineBrigham and Women’s Hospital and Harvard Medical SchoolBostonUSA
  2. 2.Department of Medical OncologyDana Farber Cancer InstituteBostonUSA
  3. 3.Department of EpidemiologyHarvard School of Public HealthBostonUSA
  4. 4.Department of PathologyBeth Israel Deaconess Medical CenterBostonUSA
  5. 5.Department of SurgeryWashington University School of MedicineSt. LouisUSA

Personalised recommendations