title: Association between serum ligands and the skin toxicity of anti-epidermal growth factor receptor antibody in metastatic colorectal cancer.
abstract: Skin toxicity is a known clinical signature used to predict the prognosis of anti-epidermal growth factor receptor (EGFR) antibody treatment in metastatic colorectal cancer (mCRC). There are no biological markers to predict skin toxicity before anti-EGFR antibody treatment in mCRC patients. Between August 2008 and August 2011, pretreatment serum samples were obtained from KRAS wild-type (WT) patients who received anti-EGFR antibody treatment. Serum levels of ligands were measured by ELISA. A total of 103 KRAS WT patients were enrolled in the study. Progression-free survival and overall survival of patients with a high grade (grade 2-3) of skin toxicity were significantly longer than those with a low grade (grade 0-1) of skin toxicity (median progression-free survival, 6.4 months vs 2.4 months, P < 0.001; median overall survival, 14.6 months vs 7.1 months, P = 0.006). There were significant differences in distribution of serum levels of epiregulin (EREG), amphiregulin (AREG), and hepatocyte growth factor (HGF) between groups of low/high grade of skin toxicity (P < 0.048, P < 0.012, P < 0.012, respectively). In addition, serum levels of HGF, EREG, and AREG were inversely proportional to grades of skin toxicity as determined by the Cochran-Armitage test (P = 0.019, P = 0.047, P = 0.021, respectively). Our study indicated that serum levels such as HGF, EREG, and AREG may be significant markers to predict the grade of skin toxicity and the prognosis of anti-EGFR antibody treatment, which contribute to improvement of the management of skin toxicity and survival time in mCRC patients.
authors.affiliation: Division of Gastrointestinal Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: Division of Gastrointestinal Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: Division of Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Koh
authors.initials: K
authors.lastname: Furuta
authors.affiliation: Clinical Research Center, Chiba University Hospital, Chiba, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Nagashima
authors.affiliation: Division of Pharmacy, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Kubo
authors.affiliation: Division of Gastrointestinal Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sasaki
authors.affiliation: Division of Gastrointestinal Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Shoji
authors.affiliation: Division of Gastrointestinal Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Honma
authors.affiliation: Division of Gastrointestinal Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Iwasa
authors.affiliation: Division of Gastrointestinal Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Natsuko
authors.initials: N
authors.lastname: Okita
authors.affiliation: Division of Gastrointestinal Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Atsuo
authors.initials: A
authors.lastname: Takashima
authors.affiliation: Division of Gastrointestinal Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Kato
authors.affiliation: Division of Gastrointestinal Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hamaguchi
authors.affiliation: Division of Gastrointestinal Oncology, National Cancer Center Hospital, Tokyo, Japan.|Division of Medical Oncology, Kochi Health Sciences Center, Kouch, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Shimada
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D066258:Amphiregulin; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D054316:Biomarkers, Pharmacological / Q000097:blood*; D000068818:Cetuximab; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D066255:EGF Family of Proteins / Q000097:blood; D066260:Epiregulin / Q000097:blood; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D017228:Hepatocyte Growth Factor / Q000097:blood; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D000077544:Panitumumab; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D012867:Skin / Q000187:drug effects* / Q000473:pathology; D016211:Transforming Growth Factor alpha / Q000097:blood; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D054316:Biomarkers, Pharmacological; D066255:EGF Family of Proteins; C587880:EREG protein, human; D066260:Epiregulin; C066855:HGF protein, human; C117307:KRAS protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D016211:Transforming Growth Factor alpha; D017228:Hepatocyte Growth Factor; D007334:Insulin-Like Growth Factor I; D000077544:Panitumumab; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab
keywords: Colorectal cancer; EGFR; KRAS; ligands; skin toxicity