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Association between tumor tissue TIMP-1 levels and objective response to first-line chemotherapy in metastatic breast cancer

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Abstract

In a previous study from our laboratory, high tumor levels of tissue inhibitor of metalloproteinases-1 (TIMP-1) have been associated with an adverse response to chemotherapy in metastatic breast cancer suggesting that TIMP-1, which is known to inhibit apoptosis, may be a new predictive marker in this disease. The purpose of this study was to investigate the association between TIMP-1 and objective response to chemotherapy in an independent patient population consisting of patients with metastatic breast cancer from Sweden and Denmark. TIMP-1 was measured using ELISA in 162 primary tumor extracts from patients who later developed metastatic breast cancer and these levels were related to the objective response to first-line chemotherapy. Increasing levels of TIMP-1 were associated with a decreasing probability of response to treatment, reaching borderline significance (OR = 1.59, 95% CI: 0.97–2.62, P = 0.07). This OR is very similar to the result from our previous study. Increasing levels of TIMP-1 were also associated with a shorter disease-free survival and overall survival, however, not statistically significant. The results from the present study support previous data that TIMP-1 is associated with objective response to chemotherapy for metastatic breast cancer.

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References

  1. Goldhirsch A, Ingle JN, Gelber RD et al (2009) Thresholds for therapies: highlights of the St Gallen international expert consensus on the primary therapy of early breast cancer. Ann Oncol 16:1569–1583

    Article  Google Scholar 

  2. Thomssen C, Janicke F (2000) Do we need better prognostic factors in node-negative breast cancer? Eur J Cancer 36:293–298

    Article  CAS  PubMed  Google Scholar 

  3. Goldhirsch A, Coates AS, Gelber RD et al (2006) First–select the target: better choice of adjuvant treatments for breast cancer patients. Ann Oncol 17:1772–1776

    Article  CAS  PubMed  Google Scholar 

  4. Knoop AS, Knudsen H, Balslev E et al (2005) Retrospective analysis of topoisomerase IIα amplifications and deletions as predictive markers in primary breast cancer patients randomly assigned to cyclophosphamide, methotrexate, and fluorouracil or cyclophosphamide, epirubicin, and fluorouracil: Danish Breast Cancer Cooperative Group. J Clin Oncol 23:7483–7490

    Article  CAS  PubMed  Google Scholar 

  5. Nielsen KV, Ejlertsen B, Jørgensen JT, Knoop A et al (2008) The value of TOP2A gene copy number variation as a biomarker in breast cancer: Update of DBCG trial 89D. Acta Oncol 47:725–734

    Article  CAS  PubMed  Google Scholar 

  6. Arriola E, Rodriguez-Pinilla SM, Lambros MBK et al (2007) Topoisomerase II alpha amplification may predict benefit from adjuvant anthracyclines in HER2 positive early breast cancer. Breast Cancer Res Treat 106:181–189

    Article  CAS  PubMed  Google Scholar 

  7. Ree AH, Florenes VA, Berg JP et al (1997) High levels of messenger RNAs for tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) in primary breast carcinomas are associated with development of distant metastases. Clin Cancer Res 3:1623–1628

    CAS  PubMed  Google Scholar 

  8. McCarthy K, Maguire T, McGreal G et al (1999) High levels of tissue inhibitor of metalloproteinase-1 predict poor outcome in patients with breast cancer. Int J Cancer 84:44–48

    Article  CAS  PubMed  Google Scholar 

  9. Schrohl AS, Christensen IJ, Pedersen AN et al (2003) Tumor tissue concentrations of the proteinase inhibitors tissue inhibitor of metalloproteinases-1 (TIMP-1) and plasminogen activator inhibitor type 1 (PAI-1) are complementary in determining prognosis in primary breast cancer. Mol Cell Proteomics 2:164–172

    Article  CAS  PubMed  Google Scholar 

  10. Schrohl AS, Holten-Andersen MN, Peters HA et al (2004) Tumor tissue levels of tissue inhibitor of metalloproteinase-1 as a prognostic marker in primary breast cancer. Clin Cancer Res 10:2289–2298

    Article  CAS  PubMed  Google Scholar 

  11. Würtz SØ, Møller S, Mouridsen H et al (2008) Plasma and serum levels of tissue inhibitor of metalloprrteinases-1 are associated with prognosis in node-negative breast cancer—a prospective study. Mol Cell Proteomics 7:424–430

    PubMed  Google Scholar 

  12. Lipton A, Suhail MA, Leitzel K et al (2007) Elevated plasma tissue inhibitor of metalloproteinase-1 level predicts decreased response and survival in metastatic breast cancer. Cancer 109:1933–1939

    Article  CAS  PubMed  Google Scholar 

  13. Lipton A, Leitzel K, Chaudri-Ross HA et al (2008) Serum TIMP-1 and response to the aromatase inhibitor letrozole versus tamoxifen in metastatic breast cancer. J Clin Oncol 26(16):2653–2658

    Article  CAS  PubMed  Google Scholar 

  14. Schrohl AS, Meijer-van Gelder ME, Holten-Andersen MN et al (2006) Primary tumor levels of tissue inhibitor of metalloproteinases-1 are predictive of resistance to chemotherapy in patients with metastatic breast cancer. Clin Cancer Res 12:7054–7058

    Article  CAS  PubMed  Google Scholar 

  15. Willemoe GL, Hertel PB, Bartels A et al (2009) Lack of TIMP-1 tumor cell immunoreactivity predicts effect of adjuvant anthracycline based chemotherapy in patients (n = 647) with primary breast cancer. A Danish Breast Cancer Cooperative Group Study. Eur J Cancer. doi:10.1016/j.ejca.2009.05.029

    PubMed  Google Scholar 

  16. Davidsen ML, Würtz SO, Romer MU et al (2006) TIMP-1 gene deficiency increases tumour cell sensitivity to chemotherapy-induced apoptosis. Br J Cancer 95:1114–1120

    Article  CAS  PubMed  Google Scholar 

  17. Li G, Fridman R, Kim HR (1999) Tissue inhibitor of metalloproteinase-1 inhibits apoptosis of human breast epithelial cells. Cancer Res 59:6267–6275

    CAS  PubMed  Google Scholar 

  18. McShane LM, Altman DG, Sauerbrei W et al (2005) Reporting recommendations for tumor marker prognostic studies (REMARK). J Clin Oncol 23:9067–9072

    Article  PubMed  Google Scholar 

  19. Pedersen AN, Christensen IJ, Stephens RW (2000) The complex between urokinase and its inhibitor in primary breast cancer, relation to survival. Cancer Res 60:6927–6934

    CAS  PubMed  Google Scholar 

  20. Ejlertsen B, Mouridsen HT, Langkjer ST et al (2004) Phase III study of intravenous vinorelbine in combination with epirubicin versus epirubicin alone in patients with advanced breast cancer: a Scandinavian Breast Group Trial (SBG9403). J Clin Oncol 22:2313–2320

    Article  CAS  PubMed  Google Scholar 

  21. World Health Organization (1979) WHO handbook for reporting results for cancer treatment. World Health Organization Offset Publications No. 48, Geneva

    Google Scholar 

  22. Holten-Andersen MN, Murphy G, Nielsen HJ et al (1999) Quantitation of TIMP-1 in plasma of healthy blood donors and patients with advanced cancer. Br J Cancer 80:495–503

    Article  CAS  PubMed  Google Scholar 

  23. Sørensen NM, Byström P, Christensen IJ et al (2007) TIMP-1 is significantly associated with objective response and survival in metastatic colorectal cancer patients receiving combination of irinotecan, 5-fluorouracil, and folinic acid. Clin Cancer Res 13:4117–4122

    Article  PubMed  Google Scholar 

  24. Würtz SO, Schrohl A, Brünner N, Lademann U (2009) Tissue inhibitor of metalloproteinases-1 protects the human breast carcinoma cell line MCF-7 S1 against anthracycline-induced cell death by activation of the akt survival pathway [abstract]. Cancer Res 69(Suppl):161s

    Google Scholar 

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Acknowledgments

The present study was supported financially by The Swedish Cancer Society, The Swedish Research Council, The Gunnar, Arvid, and Elisabeth Nilsson Foundation, The Mrs Berta Kamprad Foundation, The University Hospital of Lund Research Foundation, Governmental Funding of Clinical Research within the National Health Service, The Danish Cancer Society, Danish Center for Translational Breast Cancer Research, A Race Against Breast Cancer, The Ministry for Health and Prevention, and The Danish Strategic Research Council for Food and Health and the Sino-Danish Breast Cancer Research Centre.

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Authors and Affiliations

  1. Department of Oncology, Clinical Sciences, Barngatan 2B, Lund University, 221 85, Lund, Sweden

    Marie Klintman, Mårten Fernö, Martin Malmberg & Per Malmström

  2. Faculty of Life Sciences, Department of Disease Biology, University of Copenhagen, Ridebanevej 9, 1870, Frederiksberg C, Denmark

    Sidse Ørnbjerg Würtz, Pernille Bræmer Hertel, Anne-Sofie Schrohl & Nils Brünner

  3. Finsen Laboratory, Copenhagen Biocenter, Rigshospitalet, Ole Maaløes vej 5, 2200, Copenhagen, Denmark

    Ib Jarle Christensen

  4. Department of Oncology, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark

    Henning Mouridsen

  5. Department of Oncology R, Odense University Hospital, Sdr. Boulevard 29, 5000, Odense C, Denmark

    Frederik Cold

  6. Department of Medical Oncology, Josephine Nefkens Institute, Erasmus MC Rotterdam, Dr. Molewaterplein 50, 3015 GE, Rotterdam, The Netherlands

    John A. Foekens

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  1. Marie Klintman
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  2. Sidse Ørnbjerg Würtz
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  3. Ib Jarle Christensen
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  4. Pernille Bræmer Hertel
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  6. Martin Malmberg
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  7. Henning Mouridsen
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  8. Frederik Cold
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  9. Anne-Sofie Schrohl
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  10. John A. Foekens
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  11. Per Malmström
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  12. Nils Brünner
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Corresponding author

Correspondence to Marie Klintman.

Additional information

The authors Marie Klintman and Sidse Ørnbjerg Würtz contributed equally to this work.

Per Malmström and Nils Brünner shared senior authorship.

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Klintman, M., Ørnbjerg Würtz, S., Christensen, I.J. et al. Association between tumor tissue TIMP-1 levels and objective response to first-line chemotherapy in metastatic breast cancer. Breast Cancer Res Treat 121, 365–371 (2010). https://doi.org/10.1007/s10549-009-0483-1

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  • DOI: https://doi.org/10.1007/s10549-009-0483-1

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