new prognostic biomarkers and therapeutic effect of bevacizumab for patients with non-small-cell lung cancer

Maiko Niki, Takashi Yokoi, Takayasu Kurata, Shosaku Nomura First Department of Internal Medicine, Kansai Medical University, Hirakata, Osaka, Japan Background: Several biomarkers have emerged as potential prognostic and predictive markers for non-small-cell lung cancer (NSCLC). Successful inhibition of angiogenesis with the anti-vascular endothelial growth factor antibody, bevacizumab, has improved the efficacy seen with standard cytotoxic therapy of NSCLC. However, despite such enhanced treatment strategies, the prognosis for patients with advanced NSCLC remains poor. Patients and methods: We assessed potential biomarkers in 161 NSCLC patients and 42 control patients. Enzyme-linked immunosorbent assay methods were used to evaluate three biomarkers: platelet-derived microparticle (PDMP), high-mobility group box-1 (HMGB1), and plasminogen activator inhibitor-1 (PAI-1). We studied the effects of bevacizumab on the expression of these markers. We also analyzed the relationship of the newly designed risk factor (NDRF) to overall survival and disease-free survival. The NDRF classification of patients was determined from the levels of PDMP, HMGB1, and PAI-1. To determine the individual prognostic power of PDMP, HMGB1, and PAI-1, we evaluated associations between their levels and patient outcomes by Kaplan–Meier survival analysis in a derivation cohort. Results: PDMP, HMGB1, and PAI-1 levels were higher in NSCLC patients compared with control patients. Notably, the difference in PDMP levels exhibited the strongest statistical significance (p<0.001). Multivariate analysis showed that HMGB1 and PAI-1 levels were significantly correlated with PDMP levels. Patients who received standard chemotherapy with bevacizumab exhibited significantly reduced levels of all three markers compared with patients who received standard chemotherapy. NDRF3 status (high levels of all three markers) was significantly correlated with a poor prognosis (p<0.05 for overall survival and disease-free survival). Conclusion: Our results demonstrate that abnormal levels of PDMP, HMGB1, and PAI-1 are related to each other in NSCLC. Moreover, our findings suggest that the vascular complications associated with these markers may contribute to a poor prognosis for NSCLC patients. Keywords: non-small-cell lung cancer, platelet-derived microparticle, HMGB1, PAI-1, bevacizumab