Biomarker analysis of cetuximab plus oxaliplatin/leucovorin/5-fluorouracil in first-line metastatic gastric and oesophago-gastric junction cancer: results from a phase II trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO).
Biomarker analysis of cetuximab plus oxaliplatin/leucovorin/5-fluorouracil in first-line metastatic gastric and oesophago-gastric junction cancer: results from a phase II trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO).
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DOI：
10.1186/1471-2407-11-509
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发表时间：
2011-12-07
期刊：
影响因子：
3.8
通讯作者：
Lordick F
中科院分区：
文献类型：
--
作者：
Luber B;Deplazes J;Keller G;Walch A;Rauser S;Eichmann M;Langer R;Höfler H;Hegewisch-Becker S;Folprecht G;Wöll E;Decker T;Endlicher E;Lorenzen S;Fend F;Peschel C;Lordick F
在一项前瞻性 II 期研究中，评估了表皮生长因子受体 (EGFR) 导向的单克隆抗体西妥昔单抗联合奥沙利铂/亚叶酸/5-氟尿嘧啶 (FUFOX) 在一线转移性胃癌和食管胃交界处 (OGJ) 癌中的活性，显示出 65% 的客观肿瘤缓解率和较低的 KRAS 突变频率 (3%)。相关肿瘤组织研究的目的是探讨西妥昔单抗联合FUFOX治疗的胃癌和OGJ癌患者EGFR基因拷贝数、EGFR通路激活、E-cadherin表达和突变、V600E BRAF突变与临床结局之间的关系。该相关研究中纳入的患者 (n = 39) 是临床 II 期研究的一部分患者。研究了 EGFR 基因拷贝数、EGFR 通路的激活、在这些疾病中起重要作用的 E-钙粘蛋白的丰度和突变、BRAF 突变和患者临床结果之间的关联。通过 FISH 评估 EGFR 基因拷贝数。通过免疫组织化学分析了 EGFR 及其下游效应子 Akt 和 MAPK 以及 E-钙粘蛋白的磷酸化形式的表达。通过等位基因特异性 PCR 评估突变体 V600E BRAF 的频率，并通过 DHPLC 检查 E-钙粘蛋白基因 CDH1 的突变谱，然后进行直接序列分析。评估了与总生存期 (OS)、进展时间 (TTP) 和总缓解率 (ORR) 的相关性。我们的研究表明，胃癌和 OGJ 癌中 EGFR 基因拷贝数增加（≥ 4.0）与 OS 之间存在显着相关性，这表明可以根据遗传基础选择患者进行治疗。此外，激活的 EGFR 与较短的 TTP 和 ORR 之间显示出显着相关性，但激活的 EGFR 与 OS 之间不存在显着相关性。未发现 V600E BRAF 突变。另一方面，观察到高 E-钙粘蛋白表达水平和更好的 OS 之间的有趣趋势，并检测到两个 CDH1 外显子 9 错义突变（A408V 和 D402H）。我们发现增加的 EGFR 基因拷贝数、激活的 EGFR 和 E-钙粘蛋白状态是潜在有趣的生物标志物，需要在更大规模的随机临床试验中得到证实。欧洲临床试验数据库编号 2004-004024-12 的多中心临床研究。
The activity of the epidermal growth factor receptor (EGFR)-directed monoclonal antibody cetuximab combined with oxaliplatin/leucovorin/5-fluorouracil (FUFOX) was assessed in first-line metastatic gastric and oesophago-gastric junction (OGJ) cancer in a prospective phase II study showing a promising objective tumour response rate of 65% and a low mutation frequency of KRAS (3%). The aim of the correlative tumour tissue studies was to investigate the relationship between EGFR gene copy numbers, activation of the EGFR pathway, expression and mutation of E-cadherin, V600E BRAF mutation and clinical outcome of patients with gastric and OGJ cancer treated with cetuximab combined with FUFOX. Patients included in this correlative study (n = 39) were a subset of patients from the clinical phase II study. The association between EGFR gene copy number, activation of the EGFR pathway, abundance and mutation of E-cadherin which plays an important role in these disorders, BRAF mutation and clinical outcome of patients was studied. EGFR gene copy number was assessed by FISH. Expression of the phosphorylated forms of EGFR and its downstream effectors Akt and MAPK, in addition to E-cadherin was analysed by immunohistochemistry. The frequency of mutant V600E BRAF was evaluated by allele-specific PCR and the mutation profile of the E-cadherin gene CDH1 was examined by DHPLC followed by direct sequence analysis. Correlations with overall survival (OS), time to progression (TTP) and overall response rate (ORR) were assessed. Our study showed a significant association between increased EGFR gene copy number (≥ 4.0) and OS in gastric and OGJ cancer, indicating the possibility that patients may be selected for treatment on a genetic basis. Furthermore, a significant correlation was shown between activated EGFR and shorter TTP and ORR, but not between activated EGFR and OS. No V600E BRAF mutations were identified. On the other hand, an interesting trend between high E-cadherin expression levels and better OS was observed and two CDH1 exon 9 missense mutations (A408V and D402H) were detected. Our finding that increased EGFR gene copy numbers, activated EGFR and the E-cadherin status are potentially interesting biomarkers needs to be confirmed in larger randomized clinical trials. Multicentre clinical study with the European Clinical Trials Database number 2004-004024-12.
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影响因子：
158.5
作者：
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