PMID- 27002940 OWN - NLM STAT- MEDLINE DCOM- 20170518 LR - 20181202 IS - 1532-1827 (Electronic) IS - 0007-0920 (Print) IS - 0007-0920 (Linking) VI - 114 IP - 9 DP - 2016 Apr 26 TI - Prognostic role of ERBB2, MET and VEGFA expression in metastatic colorectal cancer patients treated with anti-EGFR antibodies. PG - 1003-11 LID - 10.1038/bjc.2016.74 [doi] AB - BACKGROUND: High amplification of epiregulin (EREG) and amphireglin (AREG) in tumour tissues has been previously reported to be associated with better outcome in metastatic colorectal cancer (mCRC) patients who were treated with anti-EGFR antibodies. Here we investigated associations between the expression of other candidate prognostic biomarkers and outcome in mCRC patients receiving similar treatment. METHODS: The relative mRNA levels of seven genes including ERBB2, MET, VEGFA, EREG, AREG, PTEN and ERCC1 between tumour (T) and non-tumour (NT) tissue sections were analysed by quantitative real-time PCR. Relative mRNA values, that is, T/NT ratios, of target genes were calculated and hazard ratios (HRs) for each gene of interest were adjusted for age, gender, performance status, minor RAS mutations and other clinicopathological variables which exhibited P-values<0.1 on the basis of univariate analysis. RESULTS: Among 108 cases who received anti-EGFR antibodies, there were 96 cases of KRAS exon2 wild-type patients enroled in this study. When the cutoff values for relative mRNA levels were set to the upper 25th percentile of all patients, there were statistically significant differences in overall survival (OS) between the patients with high and low levels of EREG (HR: 0.326, 95% CI: 0.136-0.772, P=0.011), ERBB2 (HR: 1.31, 95% CI: 1.084-1.652, P=0.040), MET (HR: 2.48, 95% CI: 1.356-5.463, P=0.026), and VEGF-A (HR: 1.29, 95% CI: 1.036-1.606, P=0.046). In addition, patients with high ERBB2 had shorter progression-free survival (PFS) compared with low ERBB2 (HR: 1.98, 95% CI: 1.062-3.850). There were no significant differences in PFS and OS with respect to relative expression levels of PTEN and ERCC1. The prognostic role of AREG was evaluated in only T sections, as the mRNA expression level of this gene was mostly (91% cases) undetectable in NT sections. Patients with high AREG had longer OS compared with low AREG (HR: 0.227, 95% CI: 0.095-0.808). CONCLUSIONS: Our study has shown that higher T/NT ratios of ERBB2, MET and VEGFA mRNA were associated with worse OS in mCRC patients treated with anti-EGFR antibodies, with higher EREG and AREG were associated with better prognosis in the same setting. These findings will contribute the further understanding and management of anti-EGFR antibody treatment in mCRC patients. FAU - Takahashi, Naoki AU - Takahashi N AD - Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. FAU - Iwasa, Satoru AU - Iwasa S AD - Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. FAU - Taniguchi, Hirokazu AU - Taniguchi H AD - Pathology and Clinical Laboratory Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. FAU - Sasaki, Yusuke AU - Sasaki Y AD - Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. FAU - Shoji, Hirokazu AU - Shoji H AD - Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. FAU - Honma, Yoshitaka AU - Honma Y AD - Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. FAU - Takashima, Atsuo AU - Takashima A AD - Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. FAU - Okita, Natsuko AU - Okita N AD - Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. FAU - Kato, Ken AU - Kato K AD - Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. FAU - Hamaguchi, Tetsuya AU - Hamaguchi T AD - Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. FAU - Shimada, Yasuhiro AU - Shimada Y AD - Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. FAU - Yamada, Yasuhide AU - Yamada Y AD - Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. LA - eng PT - Journal Article DEP - 20160322 PL - England TA - Br J Cancer JT - British journal of cancer JID - 0370635 RN - 0 (Vascular Endothelial Growth Factor A) RN - EC 2.7.10.1 (ERBB2 protein, human) RN - EC 2.7.10.1 (ErbB Receptors) RN - EC 2.7.10.1 (Receptor, ErbB-2) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Colorectal Neoplasms/pathology MH - ErbB Receptors/*antagonists & inhibitors MH - Female MH - Humans MH - Male MH - Middle Aged MH - Neoplasm Metastasis MH - Prognosis MH - Receptor, ErbB-2/genetics/*metabolism MH - Vascular Endothelial Growth Factor A/genetics/*metabolism PMC - PMC4984915 EDAT- 2016/03/24 06:00 MHDA- 2017/05/19 06:00 PMCR- 2017/04/26 CRDT- 2016/03/23 06:00 PHST- 2016/02/06 00:00 [revised] PHST- 2016/02/17 00:00 [accepted] PHST- 2016/03/23 06:00 [entrez] PHST- 2016/03/24 06:00 [pubmed] PHST- 2017/05/19 06:00 [medline] PHST- 2017/04/26 00:00 [pmc-release] AID - bjc201674 [pii] AID - 10.1038/bjc.2016.74 [doi] PST - ppublish SO - Br J Cancer. 2016 Apr 26;114(9):1003-11. doi: 10.1038/bjc.2016.74. Epub 2016 Mar 22.