Predictive value of MMP-7 expression for response to chemotherapy and survival in patients with non-small cell lung cancer

Abstract

Fundamental studies have suggested that matrix metalloproteinases-7 (MMP-7) expression is associated with chemoresistance and constitutes a prognostic factor in several solid tumors. The present study assessed the prognostic and predictive value of MMP-7 in tumors of patients with advanced non-small cell lung cancer (NSCLC) treated with platinum-based chemotherapy. In total, 159 patients with stage III and IV NSCLC were retrospectively enrolled. Immunohistochemistry was performed to evaluate the expression of MMP-7, apoptosis-related proteins Bcl-2, Bax, Fas and FasL and the Ki-67 proliferation marker. The TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling) method was performed to investigate tumor apoptosis. Ninety carcinomas (56.6%) were identified as high expression of MMP-7. Overexpression of MMP-7 was more frequent in adenocarcinomas than in squamous cell carcinomas (P = 0.032). The expression of MMP-7 was positively related with Ki-67 index and Bcl-2, but not apoptosis index. MMP-7 status was correlated inversely with response to chemotherapy in overall patients (response rates, 20.0% and 35.8%, for patients with high-MMP-7 and low-MMP-7 tumors, respectively, P = 0.036), especially in adenocarcinoma (P = 0.021), but not in patients with squamous cell carcinomas (P = 0.373). The overall survival was significantly lower in NSCLC patients with high MMP-7 than in those with low MMP-7 (P < 0.001). A Cox regression analyses also demonstrated MMP-7 status to be a significant prognostic factor (hazard ratio, 5.49 P = 0.001). These findings suggest that the expression level of MMP-7 in tumor cells is predictive of response to chemotherapy and outcome in patients with advanced NSCLC receiving platinum-based chemotherapy.

Figure 1

Representative immunohistochemical staining of non‐small cell lung cancer (×200). A squamous cell carcinoma with (a) high expression of matrix metalloproteinases‐7 (MMP‐7; Grade 4), (b) high Ki‐67 proliferation index and (c) high expression of Bcl‐2 (grade 4). An adenocarcinoma with (d) low expression of MMP‐7 (Grade 1), (e) low Ki‐67 proliferation index and (f) low expression of Bcl‐2 (Grade 1). (g) High expression of Fas in an adenocarcinoma (grade 4). (h) High expression of FasL in an adenocarcinoma (grade 4). (i) High expression of Bax in a squamous cell carcinoma (Grade 3).

Figure 2

Overall survival of 159 patients with advanced non‐small cell lung cancer (NSCLC) according to of matrix metalloproteinases‐7 (MMP‐7) expression status: (a) in 159 NSCLC patients; (b) in 81 patients with adenocarcinomas; and (c) in 67 patients with squamous cell carcinomas.