Plasma hPG(80) (Circulating Progastrin) as a Novel Prognostic Biomarker for Hepatocellular Carcinoma

SIMPLE SUMMARY: Liver cancer is the sixth most common cancer world-wide and hepatocellular carcinoma (HCC), the most common form of primary liver cancer, accounts for 90% of the cases. The diagnosis of HCC is usually based on non-invasive criteria using detection of a liver nodule in abdominal ultrasonography or high serum alpha-fetoprotein (AFP) levels. However, as it is only elevated in 60% of patients with HCC, AFP has limited accuracy, especially in early stages, as both a diagnostic and prognostic test. We investigated hPG80 (circulating progastrin), which is associated with liver cancer biology, and found that hPG80 levels is both an independent prognostic marker in HCC and used in combination with AFP, it improves the stratification of the patients in good and poor prognosis, especially for those patients at early-stage. This will help stratify HCC patients more accurately in the future and improve the management of these patients. ABSTRACT: Alpha-fetoprotein (AFP) is the most widely used biomarker for hepatocellular carcinoma (HCC) prognosis. However, AFP is not useful in establishing a prognosis for patients with a tumor in the early stages. hPG(80) (circulating progastrin) is a tumor promoting peptide present in the blood of patients with various cancers, including HCC. In this study, we evaluated the prognostic value of plasma hPG(80) in patients with HCC, alone or in combination with AFP. A total of 168 HCC patients were tested prospectively for hPG(80) and analyzed retrospectively. The prognostic impact of hPG(80) and AFP levels on patient survival was assessed using Kaplan-Meier curves and log-rank tests. hPG(80) was detected in 84% of HCC patients. There was no correlation between hPG(80) and AFP levels in the training and validation cohorts. Both cohorts showed higher sensitivity of hPG(80) compared to AFP, especially at early stages. Patients with high hPG(80) (hPG(80)+) levels (optimal cutoff value 4.5 pM) had significantly lower median overall survival (OS) compared to patients with low hPG(80) (hPG(80)−) levels (12.4 months versus not reached respectively, p < 0.0001). Further stratification by combining hPG(80) and AFP levels (cutoff 100 ng/mL) improved prognosis in particular for those patients with low AFP level (hPG(80)−/AFP+ and hPG(80)−/AFP−, 13.4 months versus not reached respectively, p < 0.0001 and hPG(80)+/AFP+ and hPG(80)+/AFP−, 5.7 versus 26 months respectively, p < 0.0001). This was corroborated when analyses were performed using the BCLC staging especially at early stages. Our findings show that hPG(80) could serve as a new prognostic biomarker in HCC. Used in combination with AFP, it improves the stratification of the patients in good and poor prognosis, especially for those patients with negative AFP and early-stage HCC.