Clinically Relevant Biomarkers to Select Patients for Targeted Inhibitor Therapy after Resection of Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a vascular tumor that proliferates through angiogenic pathways mediated, in part, by vascular endothelial growth factor receptor 2 (VEGFR2), and platelet-derived growth factor receptor (PDGFR) α and β. We hypothesized that overexpression of these proteins is associated with decreased survival after resection. A total of 57 patients, with available tissue for analysis, who underwent liver resection for HCC between August 2000 and March 2008 at a single institution were identified from a prospectively maintained database. Tumor specimens were assessed with immunohistochemistry for VEGFR2, PDGFR-α, and PDGFR-β expression and were graded by an experienced pathologist. Primary outcome was overall survival (OS). Median patient age was 64 years; 65% (n=37) were male. Median follow-up was 24.5 months, and median OS was 25.5 months. Median tumor size and number were 7 cm and 1, respectively. Macro and microvascular invasion was present in 9% (n=5) and 42% (n=24) of patients, respectively. Seventy-five percent of patients had tumors exceeding Milan criteria. 9% had positive resection margins. Thirty-five percent of patients had cirrhosis and the median nonadjusted Model for End-Stage Liver Disease (MELD) score was 7.5. Tumors exhibited differential expression of VEGFR2 (low: 79%, high: 21%), PDGFR-α (low: 93%, high: 7%), and PDGFR-β (low: 96%, high: 4%). After excluding all 30-day deaths (n=7), high PDGFR-α and PDGFR-β expression were independently associated with decreased OS (8.7 vs 29.1 months, P=0.01; 2.8 vs 28.8 months, P<0.001; respectively). High VEGFR2 expression displayed a trend toward decreased OS (20.8 vs 27.5 months, P=0.2). When adjusted for tumor burden, vascular invasion, margin status, and MELD score on independent multivariate analyses, both PDGFR-α and -β high expression were independently associated with decreased survival. High expression of PDGFR-α and PDGFR-β may be independently associated with decreased OS irrespective of margin status, MELD score, and tumor extent. This finding may help to select patients who would benefit from targeted inhibitor therapy in the adjuvant setting.