研究显示，表皮生长因子受体（EGFR）靶向抗体对转移性结直肠癌（mCRC）具有疗效。RAS扩展分析进一步明确了EGFR依赖性肿瘤对EGFR抑制剂更敏感。除了RAS基因突变以外，EGFR配体（双调蛋白（AREG）和表皮调节素（EREG））的表达已经显示具有预测价值。
将这些生物标志物应用到临床所面临的挑战是肿瘤内标准化定量检测。如果AREG和/或EREG中生殖细胞单核苷酸多态性（SNPs）能预测，那么将可以很容易的应用于临床实践。我们先前的研究显示，rs1615111与胃癌复发时间相关。本研究旨在分析rs1615111对西妥昔单抗治疗转移性结直肠癌患者的预测价值。
研究方法
对FIRE-3试验（NCT00433927）中采用FOLFIRI加西妥昔单抗（139例）或FOLFIRI加贝伐单抗（160例）进行一线治疗的299例患者（中位年龄为64岁，男性67.2％）组织样品进行基因组DNA分离。174份样本中，对肿瘤细胞进行微解剖以提取mRNA。使用LightCycler技术进行rT-PCR。所有患者均为KRAS / NRAS野生型。贝伐单抗组作为阴性对照组。
研究结果
rs1615111次要等位基因A与FOLFIRI加西妥昔单抗治疗患者肿瘤应答下降（37％：78.4％，双侧Fisher p值= 0.02），无进展生存期较短（5.9个月：10.6个月logrank P = 0.001 HR 3.46）和OS较短（11.4个月vs33.1个月，logrank P = 0.001，HR 3.87）相关。低AREG mRNA表达与OS较短（3.2个月：33.1个月，logrank P <0.001，HR 0.08）相关，但与rs1615111无关。FOLFIRI加贝伐单抗治疗患者的rs1615111并无任何预测价值。
结论
AREG SNP rs1615111可预测西妥昔单抗疗效。rs1615111的生物学功能尚不清楚，因为与mRNA表达无关。除了RAS基因突变和EGFR配体表达外，AREG SNPs是EGFR抑制剂的一种新型有价值预测指标，但有必要进行前瞻性研究来验证和确认这些数据。
医脉通整理报道，转载请注明出处。
会议专题》》》2014年ASCO年会专题报道
阅读原文摘要
Amphiregulin (AREG) SNP rs161511 to predict cetuximab efficacy independent of AREG mRNA levels: Data from FIRE3 (AIO KRK-0306).（Abstract Number:3521）
Authors: Sebastian Stintzing, Stefan Stremitzer, Volker Heinemann,et al.
Session Type: Poster Highlights Session
Background: Anti-bodies targeting the epidermal growth factor receptor (EGFR) have shown efficacy in metastatic colorectal cancer (mCRC). The extended RAS analysis has further defined EGFR dependent tumors that are more sensitive to EGFR inhibition. Beyond RAS mutations, expression of EGFR ligands (amphiregulin (AREG) and epiregulin (EREG)) have shown predictive values. The challenge to move these biomarkers into clinic are the standardization of quantitative intra-tumor measurements. If germline single nucleotide polymorphisms (SNPs) in AREG and/or EREG would be predictive this could easily used in clinical practice. We have previously shown that rs1615111 associated with time-to-recurrence in gastric cancer. Aim of this study was to test the predictive value of rs1615111 in cetuximab treated mCRC patients.
Methods: Genomic DNA was isolated from tissue samples of 299 patients (median age 64 years, male 67.2%) treated in first-line with either FOLFIRI cetuximab (n=139) or FOLFIRI bevacizumab (n=160) from the FIRE-3 trial (NCT00433927). In 174 samples, tumor cells were micro-dissected for mRNA extraction. rtPCR was carried out using LightCycler technology. All patients were KRAS/NRAS wild-type. The bevacizumab arm served as negative control arm.
Results: The minor allele A of rs1615111 was associated with decreased tumor response (37% vs. 78.4%, two-sided Fisher’s p=0.02) shorter progression free survival (5.9 months vs. 10.6 months, logrank p=0.001 HR 3.46) and OS (11.4 months vs. 33.1 months, logrank p=0.001, HR 3.87) in FOLFIRI plus cetuximab treated patients. Low AREG mRNA expression was associated with short OS (3.2 months vs. 33.1 months logrank p<0.001, HR 0.08) but no association with rs1615111 could be established. In FOLFIRI plus bevacizumab treated patients rs1615111 did not have any predictive value.
Conclusions: AREG SNP rs1615111 is predictive for cetuximab treatment. No prognostic value could be established. Biological function of rs1615111 remains unknown as it was not associated with mRNA expression. Beyond RAS mutations and EGFR ligand expression SNPs in AREG are new promising predictive marker for EGFR inhibitors. Prospective studies to validate and confirm these data are warranted.
