Serum proteinase-3 levels as a predictor of progression-free survival of first-line chemotherapy in metastatic colorectal cancer

Abstract

Background: To improve the prognosis of patients with metastatic colorectal cancer (mCRC), investigating predictive biomarkers for prognosis and chemotherapeutic responsiveness is necessary. Therefore, this study aimed to analyze the clinical significance of serum proteinase-3 (PRTN3) as a predictor for prognosis and chemosensitivity, especially to bevacizumab, in mCRC. Methods: This single-center retrospective observational study enrolled 79 patients with mCRC in our hospital and 353 patients with colorectal cancer from the TCGA database. Preoperative serum PRTN3 levels were measured using enzyme-linked immunosorbent assay. The clinicopathological characteristics and prognosis according to serum PRTN3 levels were then evaluated. PRTN3 expression in tumor and stromal cells was evaluated immunohistochemically. The impact of PRTN3 levels on angiogenesis and bevacizumab sensitivity was evaluated using the tube formation assay. Results: Serum PRTN3 level was an independent poor prognostic factor for progression-free survival (PFS) (hazard ratio: 2.082; 95% confidence interval: 1.118–3.647; P=0.010) in patients with mCRC. Similarly, prognostic analysis with TCGA data set showed poorer overall survival in patients with PRTN3 expression compared to those without PRTN3 expression, especially in patients with stage IV. Immunohistochemical analysis of resected specimens revealed that stromal neutrophils expressed PRTN3, and their expression level was significantly correlated with serum PRTN3 levels. Interestingly, the effectiveness of first line chemotherapy was significantly poorer in the high serum PRTN3 level group. High serum PRTN3 was significantly associated with poorer PFS (hazard ratio, 3.027; 95% confidence interval, 1.175–7.793; P=0.0161) in patients treated with bevacizumab, an anti-angiogenic inhibitor. Tube formation assay revealed that PRTN3 administration notably augmented angiogenesis while simultaneously attenuating the anti-angiogenic influence exerted by bevacizumab. Conclusions: Serum PRTN3 levels could be a novel predictive biomarker of PFS of first-line chemotherapy especially for bevacizumab in patients with mCRC; however, future studies are warranted to confirm our results.