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Benefit of adjuvant interferon alfa-2b (IFN-α) therapy in melanoma patients with high serum MMP-8 levels

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Abstract

Matrix metalloproteinases (MMPs) are important enzymes in tissue turnover and various inflammatory processes. In this study, it was evaluated whether serum MMP-8 can predict the response to adjuvant interferon alfa-2b (IFN-α) therapy in patients with operated high-risk cutaneous melanoma. Pre-treatment sera from 460 patients with stage IIB–IIIC melanoma were analyzed for MMP-8. The patients were randomized after surgery to adjuvant IFN-α for 12 or 24 months (n = 313) or observation only (n = 147). The median serum MMP-8 level was used to classify the patients into a low MMP-8 (n = 232) and a high MMP-8 (n = 228) group. In the high MMP-8 subgroup, IFN-α therapy significantly improved relapse-free survival (RFS). RFS was 36.8 months in patients with high MMP-8 levels receiving IFN-α therapy, whereas RFS for those with high MMP-8 levels with observation only was 10.6 months (P = 0.027). Median overall survival for patients with high MMP-8 and observation only was 36.7 versus 71.7 months in those receiving IFN-α (P = 0.13). In a multivariate model, IFN-α therapy was a significant predictor of favorable RFS (HR 0.74; 95 % CI 0.55–0.99; P = 0.048), after adjustment for pre-treatment MMP-8 (HR 1.17; 95 % CI 0.88–1.55; P = 0.28), gender (HR 1.16; 95 % CI 0.86–1.56; P = 0.32), age (HR 1.00; 95 % CI 1.00–1.02; P = 0.12), ulceration (HR 1.09; 95 % CI 0.81–1.46; P = 0.58), and the presence of node metastases (HR 1.36; 95 % CI 1.17–1.58; P < 0.0001). In conclusion, patients with high serum MMP-8 levels may benefit from adjuvant IFN-α therapy, but this observation should be further investigated.

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Abbreviations

AJCC:

American Joint Committee on Cancer

ANOVA:

Analysis of variance

BRAF:

v-Raf murine sarcoma viral oncogene homolog B1

CI:

Confidence interval

CV:

Coefficent of variation

ECOG:

Eastern cooperative oncology group

HNSCC:

Head and neck squamous cell carcinomas

HR:

Hazard ratio

IFMA:

Immunofluorometric assay

IFN:

Interferon

ISG:

Interferon stimulated gene

KRAS:

Kirsten rat sarcoma viral oncogene homolog

LDH:

Lactate dehydrogenase

MIA:

Melanoma-inhibiting activity

MMP:

Matrix metalloproteinase

NRAS:

Neuroblastoma RAS viral oncogene homolog

OS:

Overall survival

RFS:

Relapse-free survival

References

  1. Van Lint P, Libert C (2006) Matrix metalloproteinase-8: cleavage can be decisive. Cytokine Growth Factor Rev 17(4):217–223

    Article  PubMed  Google Scholar 

  2. Gueders MM, Foidart JM, Noel A, Cataldo DD (2006) Matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs in the respiratory tract: potential implications in asthma and other lung diseases. Eur J Pharmacol 533(1–3):133–144

    Article  CAS  PubMed  Google Scholar 

  3. Hanemaaijer R, Sorsa T, Konttinen YT et al (1997) Matrix metalloproteinase-8 is expressed in rheumatoid synovial fibroblasts and endothelial cells. Regulation by tumor necrosis factor-alpha and doxycycline. J Biol Chem 272(50):31504–31509

    Article  CAS  PubMed  Google Scholar 

  4. Herman MP, Sukhova GK, Libby P et al (2001) Expression of neutrophil collagenase (matrix metalloproteinase-8) in human atheroma: a novel collagenolytic pathway suggested by transcriptional profiling. Circulation 104(16):1899–1904

    Article  CAS  PubMed  Google Scholar 

  5. Wahlgren J, Maisi P, Sorsa T et al (2001) Expression and induction of collagenases (MMP-8 and -13) in plasma cells associated with bone-destructive lesions. J Pathol 194(2):217–224

    Article  CAS  PubMed  Google Scholar 

  6. Moilanen M, Pirilä E, Grenman R et al (2002) Expression and regulation of collagenase-2 (MMP-8) in head and neck squamous cell carcinomas. J Pathol 197(1):72–81

    Article  CAS  PubMed  Google Scholar 

  7. Shah SA, Spinale FG, Ikonomidis JS et al (2010) Differential matrix metalloproteinase levels in adenocarcinoma and squamous cell carcinoma of the lung. J Thorac Cardiovasc Surg 139(4):984–990

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Stadlmann S, Pollheimer J, Moser PL et al (2003) Cytokine-regulated expression of collagenase-2 (MMP-8) is involved in the progression of ovarian cancer. Eur J Cancer 39(17):2499–2505

    Article  CAS  PubMed  Google Scholar 

  9. Köhrmann A, Kammerer U, Kapp M et al (2009) Expression of matrix metalloproteinases (MMPs) in primary human breast cancer and breast cancer cell lines: new findings and review of the literature. BMC Cancer 9:188. doi:10.1186/1471-2407-9-188

    Article  PubMed Central  PubMed  Google Scholar 

  10. Palavalli LH, Prickett TD, Wunderlich JR et al (2009) Analysis of the matrix metalloproteinase family reveals that MMP-8 is often mutated in melanoma. Nat Genet 41(5):518–520

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Gogas H, Eggermont AM, Hauschild A et al (2009) Biomarkers in melanoma. Ann Oncol 20(Suppl 6):vi8–vi13

    Article  PubMed Central  PubMed  Google Scholar 

  12. Díaz-Lagares A, Alegre E, Arroyo A et al (2011) Evaluation of multiple serum markers in advanced melanoma. Tumour Biol 32(6):1155–1161

    Article  PubMed  Google Scholar 

  13. Nikkola J, Vihinen P, Vuoristo M-S et al (2005) High serum levels of matrix metalloproteinase-9 and matrix metalloproteinase-1 are associated with rapid progression in patients with metastatic melanoma. Clin Cancer Res 11(14):5158–5166

    Article  CAS  PubMed  Google Scholar 

  14. Tarhini AA, Gogas H, Kirkwood JM (2012) IFN-α in the treatment of melanoma. J Immunol 189(8):3789–3793

    Article  CAS  PubMed  Google Scholar 

  15. Kirkwood JM, Strawderman MH, Ernstoff MS et al (1996) Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 14(1):7–17

    CAS  PubMed  Google Scholar 

  16. Garbe C, Radny P, Linse R et al (2008) Adjuvant low-dose interferon alpha 2a with or without dacarbazine compared with surgery alone: a prospective-randomized phase III DeCOG troal in melanoma patients with regional lymph node metastasis. Ann Oncol 19(6):1195–1201

    Article  CAS  PubMed  Google Scholar 

  17. Mocellin S, Pasquali S, Rossi CR, Nitti D (2010) Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis. J Natl Cancer Inst 102(7):493–501

    Article  CAS  PubMed  Google Scholar 

  18. Mocellin S, Lens MB, Pasquali S et al (2013) Interferon alpha for the adjuvant treatment of cutaneous melanoma. Cochrane Database Syst Rev 6:CD008955

  19. Eggermont AM, Suciu S, Testori A et al (2012) Long-term results of the randomized phase III trial EORTC 18991 of adjuvant therapy with pegylated interferon alfa-2b versus observation in resected stage III melanoma. J Clin Oncol 30(31):3810–3818

    Article  CAS  PubMed  Google Scholar 

  20. Ascierto PA, Napolitano M, Celentano E et al (2010) Regulatory T cell frequency in patients with melanoma with different disease stage and course, and modulating effects of high-dose interferon-alpha 2b treatment. J Transl Med 8:76

    Article  PubMed Central  PubMed  Google Scholar 

  21. Bouwhuis MG, Collette S, Suciu S et al (2011) Changes of ferritin and CRP levels in melanoma patients treated with adjuvant interferon-α (EORTC 18952) and prognostic value on treatment outcome. Melanoma Res 21(4):344–351

    Article  CAS  PubMed  Google Scholar 

  22. Yurkovetsky ZR, Kirkwood JM, Edington HD et al (2007) Multiplex analysis of serum cytokines in melanoma patients treated with interferon-alpha2b. Clin Cancer Res 13(8):2422–2428

    Article  CAS  PubMed  Google Scholar 

  23. Tarhini AA, Stuckert J, Lee S et al (2009) Prognostic significance of serum S100B protein in high-risk surgically resected melanoma patients participating in Intergroup Trial ECOG 1694. J Clin Oncol 27(1):38–44

    Article  PubMed Central  PubMed  Google Scholar 

  24. Bouwhuis MG, Suciu S, Kruit W et al (2011) Prognostic value of serial blood S100B determinations in stage IIB-III melanoma patients: a corollary study to EORTC trial 18952. Eur J Cancer 47(3):361–368

    Article  CAS  PubMed  Google Scholar 

  25. Hansson J, Aamdal S, Bastholt L et al (2011) Two different durations of adjuvant therapy with intermediate-dose interferon alfa-2b in patients with high-risk melanoma (Nordic IFN trial): a randomized phase 3 trial. Lancet Oncol 12(2):144–152

    Article  CAS  PubMed  Google Scholar 

  26. Balch CM, Gershenwald JE, Soong SJ et al (2009) Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 27(36):6199–6206

    Article  PubMed Central  PubMed  Google Scholar 

  27. Utikal J, Schadendorf D, Ugurel S (2007) Serologic and immunohistochemical prognostic biomarkers of cutaneous malignancies. Arch Dermatol Res 298(10):469–477

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Busse A, Rapion J, Fusi A et al (2013) Analysis of surrogate gene expression markers in peripheral blood of melanoma patients to predict treatment outcome of adjuvant pegulated interferon alpha 2b (EORTC 18991 side study). Cancer Immunol Immunother 62(7):1223–1233

    Article  CAS  PubMed  Google Scholar 

  29. Tuomainen AM, Nyyssönen K, Laukkanen JA et al (2007) Serum matrix metalloproteinase-8 concentrations are associated with cardiovascular outcome in men. Arterioscler Tromb Vasc Biol 27(12):2722–2728

    Article  CAS  Google Scholar 

  30. Oka S, Furukawa H, Shimada K (2013) Serum biomarker analysis of collagen disease patients with acute-onset diffuse interstitial collagen disease. BMC Immunol 14:9

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Gutiérrez-Fernández A, Inada M, Balbín M et al (2007) Increased inflammation delays wound healing in mice deficient in collagenase-2 (MMP-8). FASEB J 21(10):2580–2591

    Article  PubMed Central  PubMed  Google Scholar 

  32. Chernov AV, Baranovskaya S, Golobkov VS et al (2010) Microarray-based transcriptional and epigenetic profiling of matrix metalloproteinases, collagens, and related genes in cancer. J Biol Chem 285(25):19647–19659

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Vihinen P, Koskivuo I, Syrjänen K et al (2008) Serum matrix metalloproteinase-8 is associated with ulceration and vascular invasion of malignant melanoma. Melanoma Res 18(4):268–273

    Article  CAS  PubMed  Google Scholar 

  34. Väyrynen JP, Vornanen J, Tervahartiala T et al (2012) Serum MMP-8 levels increase in colorectal cancer and correlate with disease course and inflammatory properties of primary tumors. Int J Cancer 131(4):E463–E474

    Article  PubMed  Google Scholar 

  35. Gutiérrez-Fernández A, Fueyo A, Folgueras AR et al (2008) Matrix metalloproteinase-8 functions as a metastasis suppressor through modulation of tumour cell adhesion and invasion. Cancer Res 68(8):2755–2763

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The Nordic Adjuvant IFN-α study was supported by a research Grant from Schering-Plough (now Merck), the Radiumhemmet Research Funds, and the Stockholm City Council (Drs Hansson, Bastholt, Aamdal, Stierner, Hernberg). The current serum analyses were supported by a research Grant from Schering-Plough (now Merck), the Southwest Funds of the Finnish Cancer Research Society, the Turku University Hospital EVO grant (projects 13040 and 13041) (Drs Vihinen, Pyrhönen, Syrjänen, Hernberg), and the Helsinki University Hospital EVO Grant (project TYH 2012210 and 2013353) (Dr Sorsa). The invaluable input of all investigators participating in the Nordic Adjuvant Trial is gratefully acknowledged.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Department of Oncology and Radiotherapy, Turku University Hospital, POB 52, 20521, Turku, Finland

    Pia Vihinen, Seppo Pyrhönen & Kari Syrjänen

  2. Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, Helsinki, Finland

    Taina Tervahartiala & Timo Sorsa

  3. Institute of Dentistry, University of Helsinki, Helsinki, Finland

    Taina Tervahartiala

  4. Division of Periodontology, Department of Dental Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

    Timo Sorsa

  5. Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

    Johan Hansson

  6. Department of Oncology, Odense University Hospital, Odense, Denmark

    Lars Bastholt

  7. Department of Medical Oncology and Radiotherapy, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway

    Steinar Aamdal

  8. Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden

    Ulrika Stierner

  9. Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland

    Johan Lundin

  10. Department of Oncology and Radiotherapy, Helsinki University Central Hospital, Helsinki, Finland

    Micaela Hernberg

  11. Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

    Johan Lundin

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  1. Pia Vihinen
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  2. Taina Tervahartiala
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  3. Timo Sorsa
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  4. Johan Hansson
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  5. Lars Bastholt
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  6. Steinar Aamdal
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  8. Seppo Pyrhönen
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  9. Kari Syrjänen
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  10. Johan Lundin
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  11. Micaela Hernberg
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Correspondence to Pia Vihinen.

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Vihinen, P., Tervahartiala, T., Sorsa, T. et al. Benefit of adjuvant interferon alfa-2b (IFN-α) therapy in melanoma patients with high serum MMP-8 levels. Cancer Immunol Immunother 64, 173–180 (2015). https://doi.org/10.1007/s00262-014-1620-1

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  • DOI: https://doi.org/10.1007/s00262-014-1620-1

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