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Cancer Immunology, Immunotherapy

, Volume 64, Issue 2, pp 173–180 | Cite as

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

  • Pia Vihinen
  • Taina Tervahartiala
  • Timo Sorsa
  • Johan Hansson
  • Lars Bastholt
  • Steinar Aamdal
  • Ulrika Stierner
  • Seppo Pyrhönen
  • Kari Syrjänen
  • Johan Lundin
  • Micaela Hernberg
Original Article

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.

Keywords

Adjuvant interferon Melanoma MMP Prognosis Serum Survival 

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

Notes

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.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Pia Vihinen
    • 1
  • Taina Tervahartiala
    • 2
    • 3
  • Timo Sorsa
    • 2
    • 4
  • Johan Hansson
    • 5
  • Lars Bastholt
    • 6
  • Steinar Aamdal
    • 7
  • Ulrika Stierner
    • 8
  • Seppo Pyrhönen
    • 1
  • Kari Syrjänen
    • 1
  • Johan Lundin
    • 9
    • 11
  • Micaela Hernberg
    • 10
  1. 1.Department of Oncology and RadiotherapyTurku University HospitalTurkuFinland
  2. 2.Department of Oral and Maxillofacial DiseasesHelsinki University Central HospitalHelsinkiFinland
  3. 3.Institute of DentistryUniversity of HelsinkiHelsinkiFinland
  4. 4.Division of Periodontology, Department of Dental MedicineKarolinska Institutet, Karolinska University HospitalStockholmSweden
  5. 5.Department of Oncology-PathologyKarolinska Institutet, Karolinska University HospitalStockholmSweden
  6. 6.Department of OncologyOdense University HospitalOdenseDenmark
  7. 7.Department of Medical Oncology and RadiotherapyThe Norwegian Radium Hospital, Oslo University HospitalOsloNorway
  8. 8.Department of OncologySahlgrenska University HospitalGothenburgSweden
  9. 9.Institute for Molecular Medicine Finland (FIMM)HelsinkiFinland
  10. 10.Department of Oncology and RadiotherapyHelsinki University Central HospitalHelsinkiFinland
  11. 11.Karolinska Institutet, Karolinska University HospitalStockholmSweden

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