The importance of KRAS mutations and EGF61A>G polymorphism to the effect of cetuximab and irinotecan in metastatic colorectal cancer
The importance of KRAS mutations and EGF61A>G polymorphism to the effect of cetuximab and irinotecan in metastatic colorectal cancer
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DOI：
10.1093/annonc/mdn712
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发表时间：
2009-05-01
影响因子：
50.5
通讯作者：
Jakobsen, A.
中科院分区：
文献类型：
--
作者：
Spindler, K. -L. Garm;Pallisgaard, N.;Jakobsen, A.
背景：抗表皮生长因子受体（EGFR）抗体（mAb）在转移性结直肠癌中的作用似乎仅限于KRAS野生型（wt）肿瘤，但仍有很大一部分KRASwt患者无反应，需要补充选择标准。我们研究了KRAS检测的方法学方面，以及KRAS状态结合三种egfr相关基因多态性[单核苷酸多态性（snp）]在接受西妥昔单抗和伊立替康治疗的患者中的预测和预后价值。患者和方法：该研究包括71例使用西妥昔单抗-伊立替康三线治疗的患者。对血液样本进行snp分析。通过测序分析和定量PCR （DxS kit）对原发肿瘤和远处转移瘤进行KRAS分析。结果：KRAS在原发肿瘤中的状态与转移有明显的相关性。DxS试剂盒的灵敏度最高。应答仅限于KRASwt患者（40%应答率vs 0%， P < 0.1(-3)），这意味着PFS有显著差异。EGF61A >g多态性与临床预后相关。联合生物标志物分析显示，KRASwt-EGF61纯合子患者的进展率为19%，EGF61A/G患者的进展率为60% (P = 0.006)，总生存期显著增加（17.1个月对5.9个月，log-rank, P = 0.002）。结论：联合生物标志物分析可能是选择包括抗egfr单克隆抗体在内的三线治疗患者的一种有吸引力的方法。
Background: The effect of anti-epidermal growth factor receptor (EGFR) antibodies (mAb) in metastatic colorectal cancer seems limited to KRAS wild-type (wt) tumours, but still a major fraction of KRASwt patients are nonresponders and supplementary selection criteria are needed. We investigated methodological aspects of KRAS testing and the predictive and prognostic value of KRAS status combined with three EGFR-related gene polymorphisms [single-nucleotide polymorphisms (SNPs)] in patients treated with cetuximab and irinotecan.Patients and methods: The study included 71 patients referred to third-line cetuximab-irinotecan. Blood samples were analysed for SNPs. KRAS analysis was carried out by sequencing analysis and quantitative PCR (DxS kit) in primary tumour and distant metastases.Results: There was a clear correlation between KRAS status in primary tumours and metastasis. The DxS kit presented the highest sensitivity. Response was confined to KRASwt patients (40% response rate versus 0%, P < 0.1(-3)), which translated into a significant difference in PFS. The EGF61A > G polymorphism showed relation to clinical outcome. A combined biomarker analysis showed a 19% progression rate in KRASwt-EGF61 homozygote patients and 60% in the EGF61A/G patients (P = 0.006) and a significant increase in overall survival (17.1 versus 5.9 months, log-rank, P = 0.002).Conclusion: The combined biomarker analysis maybe an attractive approach to selection of patients for third-line treatment including anti-EGFR mAbs.