Breast Cancer Research and Treatment

, Volume 138, Issue 3, pp 839–850 | Cite as

Health economic impact of risk group selection according to ASCO-recommended biomarkers uPA/PAI-1 in node-negative primary breast cancer

  • Volker R. Jacobs
  • Ronald E. Kates
  • Eva Kantelhardt
  • Martina Vetter
  • Rachel Wuerstlein
  • Thorsten Fischer
  • Manfred Schmitt
  • Fritz Jaenicke
  • Michael Untch
  • Christoph Thomssen
  • Nadia Harbeck
Clinical Trial

Abstract

Invasion factors uPA/PAI-1 are guideline-recommended (ASCO, AGO) biomarkers for decision support regarding adjuvant chemotherapy (CTX) in women with primary breast cancer. They define a high-risk group with strong benefit from adjuvant CTX and a low-risk group with uncertain benefit and excellent survival without CTX. In a target population (age > 35/N0/G2/HR+/HER2−), administration of adjuvant CTX is not mandatory in Germany and other countries. Based on existing data, this economic model was developed to determine for the first time health economic impact of uPA/PAI-1 testing. Incremental cost-effectiveness ratio (ICER) resulting from uPA/PAI-1 testing was estimated for the target population by Markov modeling and sensitivity analysis. Survival data, CTX–uPA/PAI-1 interactions, and uPA/PAI-1 hazard ratios were derived from the Chemo N0 trial and other evidence. Incremental costs were computed from a payer’s perspective appropriate to the German setting. Incremental effectiveness in life years (ly) was estimated taking into account age-adjusted life expectancy, disease-free survival (with/without CTX), and 2 years post-relapse survival. Sensitivity analysis was performed by varying residual adjuvant CTX benefit in the low-risk group, denoted HR_CTX(LR), in range 0.8–0.99. All patients receive adjuvant endocrine therapy. Test is restricted to patients willing to forgo CTX if both markers are below specific cut-off values and to undergo CTX otherwise. For a typical 55-year-old patient, comparing to an “all-CTX” strategy without the test, ICER (all-CTX vs. test) > €50,000 if HR_CTX(LR) > 0.85, with savings of €18,500 per low-risk patient attributable to the test. The cost-effectiveness of forgoing CTX is very high as HR_CTX(LR) approaches one. Conversely, comparing to a “no-CTX” strategy (e.g., patients who initially refuse CTX) without the test, the test is very cost-effective at all ages in the target group if high-risk patients are willing to undergo CTX: ICER (test vs. no-CTX) < €6,000 at age 55 and even better at younger ages, remaining < €25,000 up to age 75. The main determinants of cost utility are age and residual CTX benefit in low-uPA/PAI-1 patients. The uPA/PAI-1 test is cost-effective in the target group compared to either an “all-CTX” or a “no-CTX” scenario. This model thus lends health economic support to current guideline recommendations that uPA/PAI-1 testing is beneficial for BC patients with no lymph node involvement.

Keywords

Economics Biomarker Cost model Markov model Cost-effectiveness analysis Prevention of chemotherapy Costs 

References

  1. 1.
    Sullivan R, Peppercorn J, Sikora K, Zalcberg J, Meropol NJ, Amir E, Khayat D, Boyle P, Autier P, Tannock IF, Fojo T, Siderov J, Williamson S, Camporesi S, McVie JG, Purushotham AD, Naredi P, Eggermont A, Brennan MF, Steinberg ML, De Ridder M, McCloskey SA, Verellen D, Roberts T, Storme G, Hicks RJ, Ell PJ, Hirsch BR, Carbone DP, Schulman KA, Catchpole P, Taylor D, Geissler J, Brinker NG, Meltzer D, Kerr D, Aapro M (2011) Delivering affordable cancer care in high-income countries. Lancet Oncol 12(10):933–980PubMedCrossRefGoogle Scholar
  2. 2.
    Campbell HE, Epstein D, Bloomfield D, Griffin S, Manca A, Yarnold J, Bliss J, Johnson L, Earl H, Poole C, Hiller L, Dunn J, Hopwood P, Barrett-Lee P, Ellis P, Cameron D, Harris AL, Gray AM, Sculpher MJ (2011) The cost-effectiveness of adjuvant chemotherapy for early breast cancer: a comparison of no chemotherapy and first, second, and third generation regimens for patients with differing prognoses. Eur J Cancer 47(17):2517–2530PubMedCrossRefGoogle Scholar
  3. 3.
    Hershman DL, Wilde ET, Wright JD, Buono DL, Kalinsky K, Malin JL, Neugut AI (2012) Uptake and economic impact of first-cycle colony-stimulating factor use during adjuvant treatment of breast cancer. J Clin Oncol 30(8):806–812PubMedCrossRefGoogle Scholar
  4. 4.
    Lux MP, Hartmann M, Jackisch C, Raab G, Schneeweiss A, Possinger K, Oyee J, Harbeck N (2009) Cost-utility analysis for advanced breast cancer therapy in Germany: results of the fulvestrant sequencing model. Breast Cancer Res Treat 117(2):305–317PubMedCrossRefGoogle Scholar
  5. 5.
    Williams C, Brunskill S, Altman D, Briggs A, Campbell H, Clarke M, Glanville J, Gray A, Harris A, Johnston K, Lodge M (2006) Cost-effectiveness of using prognostic information to select women with breast cancer for adjuvant systemic therapy. Health Technology Assess 10(34):1–204Google Scholar
  6. 6.
    Retèl VP, Joore MA, Knauer M, Linn SC, Hauptmann M, Harten WH (2010) Cost-effectiveness of the 70-gene signature versus St. Gallen guidelines and Adjuvant Online for early breast cancer. Eur J Cancer 46(8):1382–1391PubMedCrossRefGoogle Scholar
  7. 7.
    Retèl VP, Joore MA, van Harten WH (2012) Head-to-head comparison of the 70-gene signature versus the 21-gene assay: cost-effectiveness and the effect of compliance. Breast Cancer Res Treat 131(2):627–636PubMedCrossRefGoogle Scholar
  8. 8.
    Yang M, Rajan S, Issa AM (2012) Cost effectiveness of gene expression profiling for early stage breast cancer: a decision-analytic model. Cancer 118(20):5163–5170PubMedCrossRefGoogle Scholar
  9. 9.
    Lippman ME, Ethier S, Hayes DF (2009) Cost-effective analyses in breast cancer research and treatment. Breast Cancer Res Treat 115(2):221–222PubMedCrossRefGoogle Scholar
  10. 10.
  11. 11.
    Harris L, Fritsche H, Mennel R, Norton L, Ravdin P, Taube S, Somerfield MR, Hayes DF, Bast RC Jr (2007) American Society of Clinical Oncology 2007 Update of Recommendations for the Use of Tumor Markers in Breast Cancer. J Clin Oncol 25(33):5287–5312Google Scholar
  12. 12.
    Duffy MJ, Reilley D, O’Sullivan C, O’Higgins N, Fennelly JJ, Andreasen P (1990) Urokinase-plasminogen activator, a new and independent prognostic marker in breast cancer. Cancer Res 50(21):6827–6829PubMedGoogle Scholar
  13. 13.
    Jänicke F, Schmitt M, Hafter R, Hollrieder A, Babic R, Ulm K, Gössner W, Graeff H (1990) Urokinase-type plasminogen activator (uPA) antigen is a predictor of early relapse in breast cancer. Fibrinolysis 4(2):69–78Google Scholar
  14. 14.
    Jänicke F, Schmitt M, Graeff H (1991) Clinical relevance of the urokinase-type and tissue type plasminogen activators and of their type 1 inhibitor in breast cancer. Sem Thromb Hemostasis 17:303–312CrossRefGoogle Scholar
  15. 15.
    Jänicke F, Schmitt M, Pache L, Ulm K, Harbeck N, Höfler H, Graeff H (1993) Urokinase (uPA) and its inhibitor PAI-1 are strong, independent prognostic factors in node-negative breast cancer. Breast Cancer Res Treat 24:195–208PubMedCrossRefGoogle Scholar
  16. 16.
    Foekens JA, Schmitt M, van Putten WLJ, Peters HA, Kramer MD, Jänicke F, Klijn JG (1994) Plasminogen activator inhibitor-1 and prognosis in primary breast cancer. J Clin Oncol 12(8):1648–1658PubMedGoogle Scholar
  17. 17.
    Stephens RW, Brünner N, Jänicke F, Schmitt M (1998) The urokinase plasminogen activator system as a target for prognostic studies in breast cancer. Breast Cancer Res Treat 52(1–3):99–111PubMedCrossRefGoogle Scholar
  18. 18.
    Harbeck N, Thomssen C (2011) A new look at node-negative breast cancer. Oncologist 16(Suppl 1):51–60PubMedCrossRefGoogle Scholar
  19. 19.
    Jacobs VR, Kates R, Kantelhardt EJ, Vetter M, Schmitt M, Jaenicke F, Untch M, Thomssen C, Harbeck N (2010) Health economic impact of risk group selection according to ASCO-recommended biomarkers uPA/PAI-1 in node-negative primary breast cancer. 33rd Annual San Antonio Breast Cancer Symposium, San Antonio, TX, USA, December 7–12, 2010. Cancer Res 70(24 Suppl):196–197Google Scholar
  20. 20.
    World Health Organization (WHO). World Health Statistics 2010. WHO, Geneva, Switzerland 2010Google Scholar
  21. 21.
    Harbeck N, Schmitt M, Meisner C, Friedel C, Untch M, Schmid M, Sweep CGJ, Lisboa BW, Lux MP, Beck T, Hasmüller S, Kiechle M, Jänicke F, Thomssen C, for the Chemo-N0 Study Group (2013) Ten-year analysis of the prospective multicenter Chemo-N0 trial validates ASCO-recommended biomarkers uPA and PAI-1 for therapy decision making in node-negative breast cancer patients. Eur J Cancer 2013 (in print). 10.1016/j.ejca.2013.01.007
  22. 22.
    Harbeck N, Schmitt M, Vetter M, Krol J, Paepke D, Uhlig M, Paepke S, Jänicke F, Geurts-Moespot A, von Minckwitz G, Sweep F, Thomssen C (2008) Prospective biomarker trials Chemo N0 and NNBC-3 Europe validate the clinical utility of invasion markers uPA and PAI-1 in node-negative breast cancer. Breast Care (Basel) 3(s2):11–15Google Scholar
  23. 23.
    Schmidt M, Victor A, Bratzel D, Boehm D, Cotarelo C, Lebrecht A, Siggelkow W, Hengstler JG, Elsässer A, Gehrmann M, Lehr HA, Koelbl H, von Minckwitz G, Harbeck N, Thomssen C (2009) Long-term outcome prediction by clinicopathological risk classification algorithms in node-negative breast cancer—comparison between Adjuvant!, St Gallen, and a novel risk algorithm used in the prospective randomized Node-Negative-Breast Cancer-3 (NNBC-3) trial. Ann Oncol 20(2):258–264PubMedCrossRefGoogle Scholar
  24. 24.
    Look MP, van Putten WL, Duffy MJ, Harbeck N, Christensen IJ, Thomssen C, Kates R, Spyratos F, Fernö M, Eppenberger-Castori S, Sweep CG, Ulm K, Peyrat JP, Martin PM, Magdelenat H, Brünner N, Duggan C, Lisboa BW, Bendahl PO, Quillien V, Daver A, Ricolleau G, Meijer-van Gelder M, Manders P, Fiets WE, Blankenstein MA, Broët P, Romain S, Daxenbichler G, Windbichler G, Cufer T, Borstnar S, Kueng W, Beex LV, Klijn JG, O’Higgins N, Eppenberger U, Jänicke F, Schmitt M, Foekens JA (2002) Pooled analysis of prognostic impact of urokinase-type plasminogen activator and its inhibitor PAI-1 in 8377 breast cancer patients. J Natl Cancer Inst 94(2):116–128PubMedCrossRefGoogle Scholar
  25. 25.
    Look M, van Putten W, Duffy M, Harbeck N, Christensen IJ, Thomssen C, Kates R, Spyratos F, Fernö M, Eppenberger-Castori S, Fred Sweep CG, Ulm K, Peyrat JP, Martin PM, Magdelenat H, Brünner N, Duggan C, Lisboa BW, Bendahl PO, Quillien V, Daver A, Ricolleau G, Meijer-van Gelder M, Manders P, Edward Fiets W, Blankenstein M, Broët P, Romain S, Daxenbichler G, Windbichler G, Cufer T, Borstnar S, Kueng W, Beex L, Klijn J, O’Higgins N, Eppenberger U, Jänicke F, Schmitt M, Foekens J (2003) Pooled analysis of prognostic impact of uPA and PAI-1 in breast cancer patients. Thromb Haemost 90(3):538–548PubMedGoogle Scholar
  26. 26.
    Harbeck N, Kates RE, Look MP, Meijer-Van Gelder ME, Klijn JG, Krüger A, Kiechle M, Jänicke F, Schmitt M, Foekens JA (2002) Enhanced benefit from adjuvant chemotherapy in breast cancer patients classified high-risk according to urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (n = 3424). Cancer Res 62(16):4617–4622PubMedGoogle Scholar
  27. 27.
    Jänicke F, Prechtl A, Thomssen C, Harbeck N, Meisner C, Untch M, Sweep CG, Selbmann HK, Graeff H, Schmitt M, German N0 Study Group (2001) Randomized adjuvant chemotherapy trial in high-risk, lymph node-negative breast cancer patients identified by urokinase-type plasminogen activator and plasminogen activator inhibitor type 1. J Natl Cancer Inst 93(12):913–920PubMedCrossRefGoogle Scholar
  28. 28.
    Kim SJ, Shiba E, Kobayashi T, Yayoi E, Furukawa J, Takatsuka Y, Shin E, Koyama H, Inaji H, Takai S (1998) Prognostic impact of urokinase-type plasminogen activator (PA), PA inhibitor type-1 and tissue-type PA antigen levels in node-negative breast cancer: a prospective study on multicenter basis. Clin Cancer Res 4(1):177–182PubMedGoogle Scholar
  29. 29.
    Schmitt M, Harbeck N, Brünner N, Jänicke F, Meisner C, Mühlenweg B, Jansen H, Dorn J, Nitz U, Kantelhardt EJ, Thomssen C (2011) Cancer therapy trials employing level-of-evidence-1 disease forecast cancer biomarkers uPA and its inhibitor PAI-1. Expert Rev Mol Diagn 11(6):617–634PubMedCrossRefGoogle Scholar
  30. 30.
    Rote Liste (German pharmaceutical price list). www.rote-liste.de
  31. 31.
    Aapro MS, Bohlius J, Cameron DA, Dal Lago L, Donnelly JP, Kearney N, Lyman GH, Pettengell R, Tjan-Heijnen VC, Walewski J, Weber DC, Zielinski C, European Organisation for Research and Treatment of Cancer (2011) 2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. Eur J Cancer 47(1):8–32PubMedCrossRefGoogle Scholar
  32. 32.
    German Medical Fee Schedule (Gebührenordnung für Ärzte/GOÄ). www.gesetze-im-internet.de/go__1982/
  33. 33.
    Hanseatische Krankenkasse (HKK) Erste Krankenkasse zahlt Brustkrebs-Test [First health care fund reimburses breast cancer test]. Press Release, November 10th 2010. www.hkk.de/top/presse/pressearchiv/mitteilung_einzelansicht/?tx_ttnews%5Btt_news%5D=147&tx_ttnews%5BbackPid%5D=554%cHash=89636c6086Google Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Volker R. Jacobs
    • 1
  • Ronald E. Kates
    • 2
  • Eva Kantelhardt
    • 3
  • Martina Vetter
    • 3
  • Rachel Wuerstlein
    • 2
    • 4
  • Thorsten Fischer
    • 1
  • Manfred Schmitt
    • 5
  • Fritz Jaenicke
    • 6
  • Michael Untch
    • 7
  • Christoph Thomssen
    • 3
  • Nadia Harbeck
    • 2
    • 4
    • 8
  1. 1.Frauenklinik (OB/GYN)Paracelsus Medical University (PMU)SalzburgAustria
  2. 2.Breast Center, Frauenklinik MaistrasseUniversity of Munich (LMU)MunichGermany
  3. 3.Frauenklinik (OB/GYN)University Clinic of Halle/SaaleHalle (Saale)Germany
  4. 4.Comprehensive Cancer Center (CCC)University of Munich (LMU)MunichGermany
  5. 5.Frauenklinik (OB/GYN)Technical University Munich (TUM)MunichGermany
  6. 6.Frauenklinik (OB/GYN)University Clinic of Hamburg-EppendorfHamburgGermany
  7. 7.Frauenklinik (OB/GYN)Helios-Klinikum Berlin-BuchBerlinGermany
  8. 8.Breast Center, Frauenklinik GroßhadernUniversity of Munich (LMU)MunichGermany

Personalised recommendations