Prognostic role of ERBB2, MET and VEGFA expression in metastatic colorectal cancer patients treated with anti-EGFR antibodies.
Prognostic role of ERBB2, MET and VEGFA expression in metastatic colorectal cancer patients treated with anti-EGFR antibodies.
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DOI：
10.1038/bjc.2016.74
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发表时间：
2016-04-26
影响因子：
8.8
通讯作者：
Yamada Y
中科院分区：
文献类型：
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作者：
Takahashi N;Iwasa S;Taniguchi H;Sasaki Y;Shoji H;Honma Y;Takashima A;Okita N;Kato K;Hamaguchi T;Shimada Y;Yamada Y
先前已报道肿瘤组织中表皮调节蛋白（EREG）和双调蛋白（AREG）的高扩增与用抗EGFR抗体治疗的转移性结直肠癌（mCRC）患者的更好结局相关。在这里，我们研究了其他候选预后生物标志物的表达与接受类似治疗的mCRC患者的结局之间的关系。采用实时荧光定量PCR技术检测ERBB 2、MET、VEGFA、EREG、AREG、PTEN和ERCC 1等7个基因在肿瘤组织和非肿瘤组织中的相对表达水平。计算靶基因的相对mRNA值，即T/NT比，并根据年龄、性别、体能状态、轻微RAS突变和其他临床病理变量调整每个目标基因的风险比（HR），这些变量基于单变量分析显示P值<0.1。在接受抗EGFR抗体治疗的108例患者中，有96例KRAS外显子2野生型患者入组本研究。当相对mRNA水平的截止值设定为所有患者的第25百分位数时，EREG水平高和低的患者之间的总生存期（OS）存在统计学显著差异（HR：0.326，95% CI：0.136-0.772，P=0.011），ERBB 2（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）和VEGF-A（HR：1.29，95%CI：1.036-1.606，P=0.046）。此外，与低ERBB 2患者相比，高ERBB 2患者的无进展生存期（PFS）较短（HR：1.98，95% CI：1.062-3.850）。就PTEN和ERCC 1的相对表达水平而言，PFS和OS没有显著差异。仅在T切片中评估AREG的预后作用，因为该基因的mRNA表达水平在NT切片中大多数（91%病例）检测不到。与低AREG患者相比，高AREG患者的OS更长（HR：0.227，95% CI：0.095-0.808）。我们的研究表明，在接受抗EGFR抗体治疗的mCRC患者中，ERBB 2、MET和VEGFA mRNA的T/NT比值较高与OS较差相关，在相同情况下，EREG和AREG较高与预后较好相关。这些发现将有助于进一步了解和管理抗EGFR抗体治疗mCRC患者。
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. 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. 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). 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.