Placental growth factor is a predictive biomarker for ramucirumab treatment in advanced gastric cancer

Ramucirumab (RAM) has been used as the second-line standard chemotherapy for advanced gastric cancer (AGC) either alone or combination with paclitaxel (PTX). However, no predictive biomarkers have been identified for RAM treatment in AGC.

We retrospectively identified 26 patients who received either RAM monotherapy or RAM + PTX therapy for AGC refractory to fluoropyrimidine and platinum agents from 2015 to 2018 at Nagoya City University Hospital. First, we extracted RNA using gastric cancer (GC) tissues from two responders and two non-responders, and then analyzed 24 VEGFR-related angiogenic genes. Subsequently, we examined the relationship between the expression of each angiogenic gene and RAM clinical activity in the entire cohort. Finally, we validated using in vitro angiogenesis assays using GC cells and microvascular endothelial cells.

We identified five angiogenic genes with aberrant expression between RAM responders and non-responders and placental growth factor (PlGF) was the most significant gene among them. Overall survival (P = 0.046) and progression-free survival (P = 0.016) were significantly shorter in the PlGF-high group than in the PlGF-low group. Overall response rates were 50% in the PlGF-low group and 0% in the PlGF-high group. In GC cells co-cultured with endothelial cells, PlGF gene silencing from GC cells significantly reinforced the inhibitory effect of RAM in the in vitro angiogenesis assay (tube formation assay and endothelial migration) through the inactivation of ERK, in comparison to the control GC cells.

PlGF gene expression in gastric cancer tissues could be a predictive indicator of AGC treatment by RAM.