High levels of tissue inhibitor of metalloproteinase-1 (TIMP-1) in the serum are associated with poor prognosis in HPV-negative squamous cell oropharyngeal cancer

Abstract

Background: An emerging subset of oropharyngeal squamous cell carcinomas (OPSCC) is caused by HPV. HPV-positive OPSCC has a better prognosis than HPV-negative OPSCC, but other prognostic markers for these two different diseases are scarce. Our aim was to evaluate serum levels and tumor expression of matrix metalloproteinase-8 (MMP-8) and tissue inhibitor of metalloproteinase-1 (TIMP-1) and to assess their prognostic role in HPV-positive and HPV-negative OPSCC. Materials and methods: A total of 90 consecutive OPSCC patients diagnosed and treated with curative intent at the Helsinki University Hospital between 2012 and 2016 were included. Serum samples were prospectively collected. An immunofluorometric assay and an enzyme-linked immunosorbent assay were used to determine MMP-8 and TIMP-1 serum concentrations, respectively. HPV status of the tumors was determined using a combination of HPV-DNA genotyping and p16-INK4a immunohistochemistry. The endpoints were overall survival (OS) and disease-free survival (DFS). Results: High TIMP-1 serum levels were strongly and independently associated with poorer OS (adjusted HR 14.7, 95% CI 1.8–117.4, p = 0.011) and DFS (adjusted HR 8.7, 95% CI 1.3–57.1, p = 0.024) among HPV-negative patients; this association was not observed in HPV-positive OPSCC. Although TIMP-1 was immunoexpressed in the majority of the tumor tissue samples, the level of immunoexpression was not associated with prognosis, nor did MMP-8 serum levels. Conclusion: Our results indicate that serum TIMP-1 levels may serve as an independent prognostic marker for HPV-negative OPSCC patients.