Skip to main content

Advertisement

SpringerLink
Log in

Pre-diagnostic high-sensitive C-reactive protein and breast cancer risk, recurrence, and survival

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

Abstract

Inflammation may initiate and promote breast cancer development, and be associated with elevated circulating levels of inflammation markers. A total of eight 130 initially healthy women, participated in the population-based Tromsø study (1994–2008). Pre-diagnostic high-sensitivity C-reactive protein (hs-CRP) was assessed. During 14.6 years of follow-up, a total of 192 women developed invasive breast cancer. These cases were followed for additional 7.2 years. Detailed medical records were obtained. We observed an overall positive dose–response relationship between pre-diagnostic hs-CRP and breast cancer risk (hazard ratio (HR) = 1.06, 95 % CI 1.01–1.11). Postmenopausal women with above median levels of hs-CRP (>1.2 mg/l) had a 1.42 (95 % CI 1.01–2.00) higher breast cancer risk compared to postmenopausal women with hs-CRP below median. Postmenopausal women, who were hormone replacement therapy non-users, and were in the middle tertile (0.8–1.9 mg/l), or highest tertile of hs-CRP (>1.9 mg/l), had a 2.31 (95 % CI 1.31–4.03) and 2.08 (95 % CI 1.16–3.76) higher breast cancer risk, respectively, compared with women in the lowest tertile. For each unit increase in pre-diagnostic hs-CRP levels (mg/l), we observed an 18 % increase in disease-free interval (95 % CI 0.70–0.97), and a 22 % reduction in overall mortality (95 % CI 0.62–0.98). Our study supports a positive association between pre-diagnostic hs-CRP and breast cancer risk. In contrast, increased pre-diagnostic hs-CRP was associated with improved overall mortality, but our findings are based on a small sample size, and should be interpreted with caution.

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

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Pages F, Galon J, Dieu-Nosjean MC, Tartour E, Sautes-Fridman C, Fridman WH (2010) Immune infiltration in human tumors: a prognostic factor that should not be ignored. Oncogene 29(8):1093–1102. doi:10.1038/onc.2009.416

    Article  CAS  PubMed  Google Scholar 

  2. Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454(7203):436–444. doi:10.1038/nature07205

    Article  CAS  PubMed  Google Scholar 

  3. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674. doi:10.1016/j.cell.2011.02.013

    Article  CAS  PubMed  Google Scholar 

  4. Allin KH, Nordestgaard BG, Flyger H, Bojesen SE (2011) Elevated pre-treatment levels of plasma C-reactive protein are associated with poor prognosis after breast cancer: a cohort study. Breast Cancer Res 13(3):R55. doi:10.1186/bcr2891

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Chan DS, Bandera EV, Greenwood DC, Norat T (2015) Circulating C-reactive protein and breast cancer risk—systematic literature review and meta-analysis of prospective cohort studies. Cancer Epidemiol Biomark Prev. doi:10.1158/1055-9965.epi-15-0324

    Google Scholar 

  6. Visser M, Bouter LM, McQuillan GM, Wener MH, Harris TB (1999) Elevated C-reactive protein levels in overweight and obese adults. JAMA J Am Med Assoc 282(22):2131–2135

    Article  CAS  Google Scholar 

  7. Gunter MJ, Wang T, Cushman M, Xue X, Wassertheil-Smoller S, Strickler HD, Rohan TE, Manson JE, McTiernan A, Kaplan RC, Scherer PE, Chlebowski RT, Snetselaar L, Wang D, Ho GY (2015) Circulating adipokines and inflammatory markers and postmenopausal breast cancer risk. J Natl Cancer Inst. doi:10.1093/jnci/djv169

    Google Scholar 

  8. Macinnis RJ, English DR, Gertig DM, Hopper JL, Giles GG (2004) Body size and composition and risk of postmenopausal breast cancer. Cancer Epidemiol Biomark Prev 13(12):2117–2125

    CAS  Google Scholar 

  9. Suzuki S, Kojima M, Tokudome S, Mori M, Sakauchi F, Wakai K, Fujino Y, Lin Y, Kikuchi S, Tamakoshi K, Tamakoshi A (2013) Obesity/weight gain and breast cancer risk: findings from the Japan collaborative cohort study for the evaluation of cancer risk. J Epidemiol Japan Epidemiol Assoc 23(2):139–145

    Article  Google Scholar 

  10. Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M (2008) Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 371(9612):569–578. doi:10.1016/s0140-6736(08)60269-x

    Article  PubMed  Google Scholar 

  11. Harvey AE, Lashinger LM, Hursting SD (2011) The growing challenge of obesity and cancer: an inflammatory issue. Ann N Y Acad Sci 1229:45–52. doi:10.1111/j.1749-6632.2011.06096.x

    Article  CAS  PubMed  Google Scholar 

  12. Sicking I, Edlund K, Wesbuer E, Weyer V, Battista MJ, Lebrecht A, Solbach C, Grinberg M, Lotz J, Hoffmann G, Rahnenfuhrer J, Hengstler JG, Schmidt M (2014) Prognostic influence of pre-operative C-reactive protein in node-negative breast cancer patients. PLoS ONE 9(10):e111306. doi:10.1371/journal.pone.0111306

    Article  PubMed Central  PubMed  Google Scholar 

  13. Pierce BL, Ballard-Barbash R, Bernstein L, Baumgartner RN, Neuhouser ML, Wener MH, Baumgartner KB, Gilliland FD, Sorensen BE, McTiernan A, Ulrich CM (2009) Elevated biomarkers of inflammation are associated with reduced survival among breast cancer patients. J Clin Oncol 27(21):3437–3444. doi:10.1200/jco.2008.18.9068

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Nyrnes A, Njolstad I, Mathiesen EB, Wilsgaard T, Hansen JB, Skjelbakken T, Jorgensen L, Lochen ML (2012) Inflammatory biomarkers as risk factors for future atrial fibrillation. An eleven-year follow-up of 6315 men and women: the Tromso study. Gender Med 9(6):536–547.e532. doi:10.1016/j.genm.2012.09.001

  15. Kaptoge S, Di Angelantonio E, Lowe G, Pepys MB, Thompson SG, Collins R, Danesh J (2010) C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet 375(9709):132–140. doi:10.1016/s0140-6736(09)61717-7

    Article  PubMed  Google Scholar 

  16. Koh CH, Bhoo-Pathy N, Ng KL, Jabir RS, Tan GH, See MH, Jamaris S, Taib NA (2015) Utility of pre-treatment neutrophil-lymphocyte ratio and platelet-lymphocyte ratio as prognostic factors in breast cancer. Br J Cancer 113(1):150–158. doi:10.1038/bjc.2015.183

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Dirican A, Kucukzeybek BB, Alacacioglu A, Kucukzeybek Y, Erten C, Varol U, Somali I, Demir L, Bayoglu IV, Yildiz Y, Akyol M, Koyuncu B, Coban E, Ulger E, Unay FC, Tarhan MO (2015) Do the derived neutrophil to lymphocyte ratio and the neutrophil to lymphocyte ratio predict prognosis in breast cancer? Int J Clin Oncol 20(1):70–81. doi:10.1007/s10147-014-0672-8

    Article  CAS  PubMed  Google Scholar 

  18. Eggen AE, Mathiesen EB, Wilsgaard T, Jacobsen BK, Njolstad I (2013) The sixth survey of the Tromso Study (Tromso 6) in 2007–2008: collaborative research in the interface between clinical medicine and epidemiology: study objectives, design, data collection procedures, and attendance in a multipurpose population-based health survey. Scand J Public Health 41(1):65–80. doi:10.1177/1403494812469851

    Article  PubMed  Google Scholar 

  19. Jacobsen BK, Eggen AE, Mathiesen EB, Wilsgaard T, Njolstad I (2012) Cohort profile: the Tromso Study. Int J Epidemiol 41(4):961–967. doi:10.1093/ije/dyr049

    Article  PubMed Central  PubMed  Google Scholar 

  20. Wulaningsih W, Holmberg L, Garmo H, Malmstrom H, Lambe M, Hammar N, Walldius G, Jungner I, Van Hemelrijck M (2015) Prediagnostic serum inflammatory markers in relation to breast cancer risk, severity at diagnosis and survival in breast cancer patients. Carcinogenesis. doi:10.1093/carcin/bgv096

    PubMed  Google Scholar 

  21. Heikkila K, Harris R, Lowe G, Rumley A, Yarnell J, Gallacher J, Ben-Shlomo Y, Ebrahim S, Lawlor DA (2009) Associations of circulating C-reactive protein and interleukin-6 with cancer risk: findings from two prospective cohorts and a meta-analysis. Cancer Causes Control 20(1):15–26. doi:10.1007/s10552-008-9212-z

    Article  PubMed  Google Scholar 

  22. Zhang SM, Lin J, Cook NR, Lee IM, Manson JE, Buring JE, Ridker PM (2007) C-reactive protein and risk of breast cancer. J Natl Cancer Inst 99(11):890–894. doi:10.1093/jnci/djk202

    Article  CAS  PubMed  Google Scholar 

  23. Dossus L, Jimenez-Corona A, Romieu I, Boutron-Ruault MC, Boutten A, Dupre T, Fagherazzi G, Clavel-Chapelon F, Mesrine S (2014) C-reactive protein and postmenopausal breast cancer risk: results from the E3 N cohort study. Cancer Causes Control 25(4):533–539. doi:10.1007/s10552-014-0355-9

    Article  PubMed  Google Scholar 

  24. Wang G, Li N, Chang S, Bassig BA, Guo L, Ren J, Su K, Li F, Chen S, Wu S, Zou Y, Dai M, Zheng T, He J (2015) A prospective follow-up study of the relationship between C-reactive protein and human cancer risk in the Chinese Kailuan Female Cohort. Cancer Epidemiol Biomark Prev 24(2):459–465. doi:10.1158/1055-9965.epi-14-1112

    Article  CAS  Google Scholar 

  25. Ahmadi-Abhari S, Luben RN, Wareham NJ, Khaw KT (2013) Distribution and determinants of C-reactive protein in the older adult population: European Prospective Investigation into Cancer-Norfolk study. Eur J Clin Invest 43(9):899–911. doi:10.1111/eci.12116

    Article  CAS  PubMed  Google Scholar 

  26. Silvestri A, Gebara O, Vitale C, Wajngarten M, Leonardo F, Ramires JA, Fini M, Mercuro G, Rosano GM (2003) Increased levels of C-reactive protein after oral hormone replacement therapy may not be related to an increased inflammatory response. Circulation 107(25):3165–3169. doi:10.1161/01.cir.0000074208.02226.5e

    Article  CAS  PubMed  Google Scholar 

  27. Margolis KL, Rodabough RJ, Thomson CA, Lopez AM, McTiernan A (2007) Prospective study of leukocyte count as a predictor of incident breast, colorectal, endometrial, and lung cancer and mortality in postmenopausal women. Arch Intern Med 167(17):1837–1844. doi:10.1001/archinte.167.17.1837

    Article  PubMed  Google Scholar 

  28. Han Y, Mao F, Wu Y, Fu X, Zhu X, Zhou S, Zhang W, Sun Q, Zhao Y (2011) Prognostic role of C-reactive protein in breast cancer: a systematic review and meta-analysis. Int J Biol Mark 26(4):209–215. doi:10.5301/jbm.2011.8872

    CAS  Google Scholar 

  29. Tibau A, Ennis M, Goodwin PJ (2013) Post-surgical highly sensitive C-reactive protein and prognosis in early-stage breast cancer. Breast Cancer Res Treat 141(3):485–493. doi:10.1007/s10549-013-2694-8

    Article  CAS  PubMed  Google Scholar 

  30. O’Hanlon DM, Lynch J, Cormican M, Given HF (2002) The acute phase response in breast carcinoma. Anticancer Res 22(2b):1289–1293

    PubMed  Google Scholar 

  31. Larsen IK, Smastuen M, Johannesen TB, Langmark F, Parkin DM, Bray F, Moller B (2009) Data quality at the Cancer Registry of Norway: an overview of comparability, completeness, validity and timeliness. Eur J Cancer (Oxford, England: 1990) 45 (7):1218–1231. doi:10.1016/j.ejca.2008.10.037

  32. Imayama I, Alfano CM, Neuhouser ML, George SM, Wilder Smith A, Baumgartner RN, Baumgartner KB, Bernstein L, Wang CY, Duggan C, Ballard-Barbash R, McTiernan A (2013) Weight, inflammation, cancer-related symptoms and health related quality of life among breast cancer survivors. Breast Cancer Res Treat 140(1):159–176. doi:10.1007/s10549-013-2594-y

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to acknowledge the participants in the municipality of Tromsø Northern Norway, and Anna-Kirsti Kvitnes, and the Department of Oncology, University Hospital of Northern Norway (UNN).

Funding

Our research is funded by the Research Council of Norway (Grant Number 213997/H10). The study was initially funded by the UiT The Arctic University of Norway, and has been so for the entire period since 1974, but there have also been substantial contributions, directly and indirectly from, for example, the National Screening Services, the Research Council of Norway, The Norwegian Cancer Society, Northern Norway Regional Health Authority, Norwegian Council on Cardiovascular Diseases, and Norwegian Foundation for Health and Rehabilitation.

Author information

Authors and Affiliations

  1. Department of Oncology, The Cancer Centre, Ullevål, Oslo University Hospital HF, 0424, Oslo, Norway

    H. Frydenberg, I. Thune, T. Lofterød, E. A. Wist & V. G. Flote

  2. Institute of Clinical Medicine, Faculty of Health Sciences, UiT, The Arctic University of Norway, Tromsø, Norway

    I. Thune

  3. Molecular Pathology Research Group, Department of Medical Biology, Faculty of Health Sciences, UiT, The Arctic University of Norway, Tromsø, Norway

    E. S. Mortensen

  4. Department of Community Medicine, Faculty of Health Sciences, UiT, The Arctic University of Norway, Tromsø, Norway

    A. E. Eggen, A-S Furberg & T. Wilsgaard

  5. Department of Oncology, University Hospital of Northern Norway, Tromsø, Norway

    T. Risberg

  6. Department of Microbiology and Infection Control, University Hospital of North Norway, Tromsø, Norway

    A-S Furberg

  7. Department of Clinical Medicine, Centre for Cancer Biomarkers CCBIO, University of Bergen, Bergen, Norway

    L. A. Akslen

  8. Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    A. McTiernan

Authors
  1. H. Frydenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. I. Thune
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T. Lofterød
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E. S. Mortensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A. E. Eggen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. T. Risberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. E. A. Wist
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. V. G. Flote
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A-S Furberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. T. Wilsgaard
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. L. A. Akslen
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. A. McTiernan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H. Frydenberg.

Ethics declarations

Ethical Considerations

This study has been approved by the Regional Committee for Medical and Health Research Ethics, North Norway (2015/599), and was performed in accordance with the 1964 Helsinki declaration and its later amendments. Informed consent was obtained from all individual participants included in the study.

Conflict of interests

The authors declare that they have no conflict of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 22 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Frydenberg, H., Thune, I., Lofterød, T. et al. Pre-diagnostic high-sensitive C-reactive protein and breast cancer risk, recurrence, and survival. Breast Cancer Res Treat 155, 345–354 (2016). https://doi.org/10.1007/s10549-015-3671-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-015-3671-1

Keywords

Search

Navigation