Serum VEGF-A and CCL5 levels as candidate biomarkers for efficacy and toxicity of regorafenib in patients with metastatic colorectal cancer

// Mitsukuni Suenaga 1 , Tetsuo Mashima 2 , Naomi Kawata 1, 2 , Takeru Wakatsuki 1 , Yuki Horiike 1 , Satoshi Matsusaka 1 , Shingo Dan 3 , Eiji Shinozaki 1 , Hiroyuki Seimiya 2 , Nobuyuki Mizunuma 1 , Kensei Yamaguchi 1 , Toshiharu Yamaguchi 4 1 Department of Gastroenterological and Chemotherapy Cancer Institute Hospital of Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135–8550, Japan 2 Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135–8550, Japan 3 Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135–8550, Japan 4 Department of Gastroenterological and Surgery Cancer Institute Hospital of Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135–8550, Japan Correspondence to: Mitsukuni Suenaga, email: m.suenaga@jfcr.or.jp Keywords: regorafenib, metastatic colorectal cancer, VEGF-A, CCL5, prognostic marker Received: December 27, 2015 Accepted: April 16, 2016 Published: May 05, 2016 ABSTRACT Regorafenib is an oral multi-kinase inhibitor used as salvage therapy for metastatic colorectal cancer (mCRC). We tested whether serum cytokine levels are associated with clinical outcome in the mCRC patients receiving regorafenib. Serum samples were collected before treatment start, day 21, and progressive disease, and eleven angiogenic and inflammatory cytokine serum levels were examined. Fifty-four patients of a total of 62 enrolled patients were eligible for the analyses. The chemokine ligand 5 (CCL5) levels ≤ cut-off value (59959 pg/ml) at baseline was associated with relative tumor shrinkage ( P = 0.021), better progression-free survival (PFS) ( P = 0.036) and overall survival (OS) ( P = 0.019). Vascular endothelial growth factor A (VEGF-A) levels showing a decrease on day 21 were significantly associated with a better PFS ( P = 0.021). CCL5 levels ≤ cut-off was associated with any grade hand-foot skin reaction (HFSR) ( P = 0.025) and thrombocytopenia ( P = 0.013). Low chemokine ligand 2 levels at baseline were associated with grade 2 ≤ HFSR. High angiopoietin-2 and basic fibroblast growth factor (bFGF) levels at baseline were associated with grade 3 ≤ total bilirubin increase and transaminases increase, respectively. Low bFGF levels at baseline were associated with grade 3 ≤ hypertension. No correlation with severe events was observed. Baseline serum CCL5 levels and decrease of the serum VEGF-A levels may serve as potential predictive markers for survival or treatment-specific toxicities in mCRC patients receiving regorafenib.