Hepatocyte Growth Factor is Associated With Liver Dysfunction and Survival: Biomarker Results of a Phase 2 Study of Proton Beam Therapy in Patients with Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma

Abstract

HGF is the ligand to c-MET, a receptor tyrosine kinase upstream of multiple oncogenic pathways. In a prior study from the University of Michigan, high circulating HGF levels after liver SBRT were correlated with increased risk of worsening of liver function. The purpose of this study is to explore the association of plasma HGF with outcomes of patients treated with H-PBT for HCC and ICC. Using ELISA, we measured plasma HGF at baseline and weekly during H-PBT in pts with localized HCC or ICC enrolled in a phase II study (NCT00976898) at MGH. Pts received 15 fraction PBT to a dose of 67.5 Gy, with dose de-escalation based on mean liver dose. HGF levels at day 1, 8 and 15 were analyzed for correlations with overall survival (OS) and worsening of liver function defined as an increase in Childs-Turcotte-Pugh (CTP) score of 2 or greater at any time point. Forty-one pts were evaluated: 20 pts had HCC, 20 pts had ICC, 1 patient had both (analyzed as ICC). Thirteen (32%) pts were female. Twelve (60%) HCC pts and 4 (19%) ICC pts had history of hepatitis C. Fifteen (75%) HCC pts and 17 (81%) ICC pts were CTP A, and the remainder of patients had CTP B at baseline, except 2 HCC and 1 ICC pts with no cirrhosis. Median tumor size was 6.3 cm (HCC 6.7 cm, ICC 5.4 cm). Median dose was 58.0 Gy for both HCC and ICC pts. The median of mean liver-GTV dose was 19.8 Gy for HCC pts and 15.8 Gy for ICC pts. 2 yr OS and PFS were 49% and 30% for HCC pts and 32% and 17% for ICC pts. A CTP increase ≥2 points occurred in 10/41 patients. No increase in CTP occurred in pts with an HGF level below the median (P = 0.001). The median baseline level of HGF was 2,284 pg/mL, when stratified by the median HGF, pts with HGF above the median had a 2 yr OS of 29%, vs. 86% if HGF was below the median (log rank P = 0.001). The outcomes of H-PBT in both HCC and ICC were associated with baseline HGF. High HGF was associated with worsening liver function and worse OS. HGF will be used as an integral biomarker in NRG GI-003, a randomized trial of protons vs. photons in HCC.