Skip to main content

Advertisement

Springer Nature Link
Log in

Breast cancer recurrence, bone metastases, and visceral metastases in women with stage II and III breast cancer in Denmark

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

Abstract

Purpose

We developed and validated algorithms to identify metastases and breast cancer recurrence in Danish medical registries. We computed the incidence rate (IR) and hazard ratios (HRs) to evaluate predictors of these outcomes in stage II/III breast cancer patients.

Methods

We included all women in Denmark diagnosed during 1999–2011 with regional or stage II/III breast cancer. Demographic, tumor, and treatment data were ascertained from population-based health registries. To facilitate diagnostic work-up of the primary cancer, follow-up began 180 days after diagnosis and continued until recurrence/metastases, death, or 31 December 2012, whichever occurred first. We computed the positive predictive values (PPVs) of recurrence, bone metastases, and visceral metastases using medical records as a gold standard. We calculated the cumulative incidence, IR per 10,000 person years, and used Cox regression to compute the HRs and associated 95% confidence intervals (95% CI) for each outcome.

Results

Among 23,478 patients, 7073 had regional stage and 16,405 had stage II/III breast cancer. The PPV for recurrence was 72.6% (95% CI 59.3, 83.3%). The PPVs for bone and visceral metastases were 92.3% (95% CI 69.3–99.2%) and 70.8% (95% CI 51.1, 85.9%), but had low sensitivity. Five-year cumulative incidence of recurrence, bone metastases, and visceral metastases were 18.4, 2.2, and 5.2%, with corresponding 5-year IRs of 540 (95% CI 524, 557), 60 (95% CI 55, 65), and 144 (95% CI 136, 152), respectively. Predictors of recurrence and metastases included age, stage, hormone receptor status, and cancer treatment.

Conclusion

Our algorithms show moderate to high PPVs for recurrence and metastases. The IRs of metastases were lower compared with other registry-based cohort studies, so may be underestimated in Danish registries.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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. Jemal A, Bray F, Center MM et al (2011) Global cancer statistics. CA Cancer J Clin 61:69–90

    Article  PubMed  Google Scholar 

  2. Statens Serum Institute (2013) The Danish cancer registry: numbers and analyses 2012

  3. Peto R, Boreham J, Clarke M et al (2000) UK and USA breast cancer deaths down 25% in year 2000 at ages 20–69 years. Lancet 355:1822

    Article  CAS  PubMed  Google Scholar 

  4. Patnaik JL, Byers T, DiGuiseppi C et al (2011) Cardiovascular disease competes with breast cancer as the leading cause of death for older females diagnosed with breast cancer: a retrospective cohort study. Breast Cancer Res 13:R64

    Article  PubMed  PubMed Central  Google Scholar 

  5. Patnaik JL, Byers T, Diguiseppi C et al (2011) The influence of comorbidities on overall survival among older women diagnosed with breast cancer. J Natl Cancer Inst 103:1101–1111

    Article  PubMed  PubMed Central  Google Scholar 

  6. Hagberg KW, Taylor A, Hernandez RK et al (2013) Incidence of bone metastases in breast cancer patients in the United Kingdom: results of a multi-database linkage study using the general practice research database. Cancer Epidemiol 37:240–246

    Article  PubMed  Google Scholar 

  7. Liede A, Jerzak KJ, Hernandez RK et al (2016) The incidence of bone metastasis after early-stage breast cancer in Canada. Breast Cancer Res Treat 156:587–595

    Article  CAS  PubMed  Google Scholar 

  8. Jensen AO, Norgaard M, Yong M et al (2009) Validity of the recorded International classification of diseases, 10th edition diagnoses codes of bone metastases and skeletal-related events in breast and prostate cancer patients in the Danish National Registry of Patients. Clin Epidemiol 1:101–108

    Article  PubMed  PubMed Central  Google Scholar 

  9. Jensen AO, Jacobsen JB, Norgaard M et al (2011) Incidence of bone metastases and skeletal-related events in breast cancer patients: a population-based cohort study in Denmark. BMC Cancer 11:29

    Article  PubMed  PubMed Central  Google Scholar 

  10. Giacchetti S, Porcher R, Lehmann-Che J et al (2014) Long-term survival of advanced triple-negative breast cancers with a dose-intense cyclophosphamide/anthracycline neoadjuvant regimen. Br J Cancer 110:1413–1419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Harries M, Taylor A, Holmberg L et al (2014) Incidence of bone metastases and survival after a diagnosis of bone metastases in breast cancer patients. Cancer Epidemiol 38:427–434

    Article  CAS  PubMed  Google Scholar 

  12. Pedersen CB, Gotzsche H, Moller JO et al (2006) The Danish civil registration system. A cohort of eight million persons. Dan Med Bull 53:441–449

    PubMed  Google Scholar 

  13. Schmidt M, Pedersen L, Sorensen HT (2014) The Danish civil registration system as a tool in epidemiology. Eur J Epidemiol 29:541–549

    Article  PubMed  Google Scholar 

  14. Storm HH, Michelsen EV, Clemmensen IH et al (1997) The Danish cancer registry—history, content, quality and use. Dan Med Bull 44:535–539

    CAS  PubMed  Google Scholar 

  15. Storm HH (1988) Completeness of cancer registration in Denmark 1943–1966 and efficacy of record linkage procedures. Int J Epidemiol 17:44–49

    Article  CAS  PubMed  Google Scholar 

  16. Lund JL, Froslev T, Deleuran T et al (2013) Validity of the Danish National registry of patients for chemotherapy reporting among colorectal cancer patients is high. Clin Epidemiol 5:327–334

    Article  PubMed  PubMed Central  Google Scholar 

  17. Erichsen R, Lash TL, Hamilton-Dutoit S et al (2010) Existing data sources for clinical epidemiology: the Danish National pathology registry and data bank. Clin Epidemiol 2:51–56

    Article  PubMed  PubMed Central  Google Scholar 

  18. Cronin-Fenton DP, Sondergaard F, Pedersen LA et al (2010) Hospitalisation for venous thromboembolism in cancer patients and the general population: a population-based cohort study in Denmark, 1997–2006. Br J Cancer 103:947–953

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lash TL, Riis AH, Ostenfeld EB et al (2015) A validated algorithm to ascertain colorectal cancer recurrence using registry resources in Denmark. Int J Cancer 136:2210–2215

    Article  CAS  PubMed  Google Scholar 

  20. Suissa S (2008) Immortal time bias in pharmaco-epidemiology. Am J Epidemiol 167:492–499

    Article  PubMed  Google Scholar 

  21. Yerushalmi R, Woods R, Kennecke H et al (2010) Patterns of relapse in breast cancer: changes over time. Breast Cancer Res Treat 120:753–759

    Article  CAS  PubMed  Google Scholar 

  22. Metzger-Filho O, Sun Z, Viale G et al (2013) Patterns of recurrence and outcome according to breast cancer subtypes in lymph node-negative disease: results from international breast cancer study group trials VIII and IX. J Clin Oncol 31:3083–3090

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hasebe T, Imoto S, Yokose T et al (2008) Histopathologic factors significantly associated with initial organ-specific metastasis by invasive ductal carcinoma of the breast: a prospective study. Hum Pathol 39:681–693

    Article  CAS  PubMed  Google Scholar 

  24. Mouridsen HT, Bjerre KD, Christiansen P et al (2008) Improvement of prognosis in breast cancer in Denmark 1977–2006, based on the nationwide reporting to the DBCG registry. Acta Oncol 47:525–536

    Article  PubMed  Google Scholar 

  25. Christiansen P, Al-Suliman N, Bjerre K et al (2008) Recurrence pattern and prognosis in low-risk breast cancer patients—data from the DBCG 89-A programme. Acta Oncol 47:691–703

    Article  PubMed  Google Scholar 

  26. Mikkelsen EM, Njor SH, Vejborg I (2016) Danish quality database for mammography screening. Clin Epidemiol 8:661–666

    Article  PubMed  PubMed Central  Google Scholar 

  27. Eckhoff L, Nielsen M, Moeller S et al (2011) TAXTOX—a retrospective study regarding the side effects of docetaxel given as part of the adjuvant treatment to patients with primary breast cancer in Denmark from 2007 to 2009. Acta Oncol 50:1075–1082

    Article  CAS  PubMed  Google Scholar 

  28. Watanabe T, Kuranami M, Inoue K et al (2017) Comparison of an AC-taxane versus AC-free regimen and paclitaxel versus docetaxel in patients with lymph node-positive breast cancer: final results of the National surgical adjuvant study of breast cancer 02 trial, a randomized comparative phase 3 study. Cancer 123:759–768

    Article  CAS  PubMed  Google Scholar 

  29. Hadji P, Coleman RE, Wilson C et al (2016) Adjuvant bisphosphonates in early breast cancer: consensus guidance for clinical practice from a European panel. Ann Oncol 27:379–390

    Article  CAS  PubMed  Google Scholar 

  30. Wilson C, Coleman R (2016) Adjuvant bone-targeted therapies for postmenopausal breast cancer. JAMA Oncol 2:423–424

    Article  PubMed  Google Scholar 

  31. Gnant M, Pfeiler G, Dubsky PC et al (2015) Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 386:433–443

    Article  CAS  PubMed  Google Scholar 

  32. American Cancer Society (2015) Denosumab improves disease-free survival for postmenopausal patients with HR-positive breast cancer. American Cancer Society, Atlanta

  33. Cancer Research UK (2016) A trial looking at denosumab for early breast cancer (D-CARE). Cancer Research UK, London

  34. Solomayer EF, Diel IJ, Meyberg GC et al (2000) Metastatic breast cancer: clinical course, prognosis and therapy related to the first site of metastasis. Breast Cancer Res Treat 59:271–278

    Article  CAS  PubMed  Google Scholar 

  35. Han HH, Lee SH, Kim BG et al (2016) Estrogen receptor status predicts late-onset skeletal recurrence in breast cancer patients. Medicine 95:e2909

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Pedersen AB, Mikkelsen EM, Cronin-Fenton D et al (2017) Missing data and multiple imputation in clinical epidemiological research. Clin Epidemiol 9:157–166

    Article  PubMed  PubMed Central  Google Scholar 

  37. Ren Y, Black DM, Mittendorf EA et al (2014) Crossover effects of estrogen receptor status on breast cancer-specific hazard rates by age and race. PLoS ONE 9:e110281

    Article  PubMed  PubMed Central  Google Scholar 

  38. Ganz PA (2009) Survivorship: adult cancer survivors. Prim Care Clin Off Pract 36:721–741

    Article  Google Scholar 

Download references

Acknowledgements

The authors thank Henriette Kristoffersen and Hanne M. Madsen for reviewing medical records.

Funding

The study received financial support from Amgen Incorporated.

Author information

Authors and Affiliations

  1. Department of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Alle 43-45, 8200, Aarhus N, Denmark

    Deirdre Cronin-Fenton, Anders Kjærsgaard, Mette Nørgaard & Henrik T. Sørensen

  2. Amgen Incorporated, Thousand Oaks, CA, USA

    Justyna Amelio, Alexander Liede & Rohini K. Hernandez

Authors
  1. Deirdre Cronin-Fenton
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Anders Kjærsgaard
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Mette Nørgaard
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Justyna Amelio
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Alexander Liede
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Rohini K. Hernandez
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Henrik T. Sørensen
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

DCF, AK, and MN have no disclosures. HTS has not received any personal grants; this study was partly supported by a grant to Clinical Institute, Aarhus University Hospital. JA was an employee and stock owner at Amgen at the time of completion of this study, and is currently employed and owns stock at GSK. AL and RKH are employees and own stock at Amgen, Inc.

Corresponding author

Correspondence to Deirdre Cronin-Fenton.

Ethics declarations

Conflict of interest

The authors declare no conflicts of interest.

Ethical approval

This study was approved by the Danish Data Protection Agency (J.nr. 2014-41-3250) and the Danish Health Board (J.nr. 3-3013-670/1/). Under Danish law, informed consent is not required for registry-based research.

Appendix

Appendix

Breast cancer recurrence algorithm:

  1. 1.

    DNRP-registered or DCR-registered metastases code (ICD10: DC76–DC80) 180 or more days after first breast cancer surgery, and without a new primary cancer diagnosis registered in the DNRP or DCR between the date of the first breast cancer surgery and the date of the DNRP or DCR metastases code. Here and below, a new primary cancer was defined as a new cancer that is different from non-melanoma skin cancer (ICD10 C44).

  2. 2.

    Pathology Registry SNOMED combinations recorded 180 or more days after first breast cancer surgery, and without a new primary cancer diagnosis registered in the DNRP or DCR. Combinations were (1) T code (topography/location) in the breast (T04000-T09420) with morphology codes M8 or M9 with ≥3 in the fifth position (e.g., M8XXX3), (2) any T code with morphology codes M8 or M9 with the numbers 4, 6, or 7 in the fifth position.

  3. 3.

    A code specific for local breast cancer recurrence in the DNRP any time after primary diagnosis: DC509X (these codes have only been used in DNRP beginning in 2012). A code for “recurrence operation” (KHAF) in the DNRP any time after diagnosis.

We used the DC509X code to distinguish local from non-local recurrent disease.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cronin-Fenton, D., Kjærsgaard, A., Nørgaard, M. et al. Breast cancer recurrence, bone metastases, and visceral metastases in women with stage II and III breast cancer in Denmark. Breast Cancer Res Treat 167, 517–528 (2018). https://doi.org/10.1007/s10549-017-4510-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-017-4510-3

Keywords