title: Serum VEGF-A and CCL5 levels as candidate biomarkers for efficacy and toxicity of regorafenib in patients with metastatic colorectal cancer.
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.
authors.affiliation: Department of Gastroenterological and Chemotherapy Cancer Institute Hospital of Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Mitsukuni
authors.initials: M
authors.lastname: Suenaga
authors.affiliation: Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Mashima
authors.affiliation: Department of Gastroenterological and Chemotherapy Cancer Institute Hospital of Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.|Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Naomi
authors.initials: N
authors.lastname: Kawata
authors.affiliation: Department of Gastroenterological and Chemotherapy Cancer Institute Hospital of Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Takeru
authors.initials: T
authors.lastname: Wakatsuki
authors.affiliation: Department of Gastroenterological and Chemotherapy Cancer Institute Hospital of Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Horiike
authors.affiliation: Department of Gastroenterological and Chemotherapy Cancer Institute Hospital of Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Matsusaka
authors.affiliation: Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Dan
authors.affiliation: Department of Gastroenterological and Chemotherapy Cancer Institute Hospital of Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Shinozaki
authors.affiliation: Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Seimiya
authors.affiliation: Department of Gastroenterological and Chemotherapy Cancer Institute Hospital of Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Mizunuma
authors.affiliation: Department of Gastroenterological and Chemotherapy Cancer Institute Hospital of Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Kensei
authors.initials: K
authors.lastname: Yamaguchi
authors.affiliation: Department of Gastroenterological and Surgery Cancer Institute Hospital of Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Yamaguchi
mesh_terms: D000328:Adult; D000368:Aged; D042702:Angiopoietin-2 / Q000097:blood; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood; D018946:Chemokine CCL5 / Q000097:blood*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D018572:Disease-Free Survival; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000097:blood; D006801:Humans; D008297:Male; D008875:Middle Aged; D010671:Phenylurea Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011725:Pyridines / Q000009:adverse effects / Q000627:therapeutic use*; D016879:Salvage Therapy; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000097:blood*
chemical_list: D042702:Angiopoietin-2; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C483024:CCL5 protein, human; D018946:Chemokine CCL5; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; C559147:regorafenib
keywords: CCL5; VEGF-A; metastatic colorectal cancer; prognostic marker; regorafenib