2nd Department of Pathology, Semmelweis University, Budapest, H-1091, Hungary.
Curr Cancer Drug Targets. 2010 Dec;10(8):813-23. doi: 10.2174/156800910793357989.
KRAS mutation testing opened up a new era in routine pathological diagnostics of colorectal cancer similar to the introduction of HER-2 testing in breast cancer with the significant difference that mutational analysis exclusively relies on molecular methodologies. In order to critically analyze the current rational of KRAS mutation testing in colorectal carcinoma we have performed evaluation of related articles available in PubMed/Medline, Society recommendations, anti-EGFR antibody registration documents and NCCN guidelines. KRAS mutation is frequent in colorectal cancer and data suggest a negative prognostic, but neutral predictive significance, with the exception of its strong negative predictive value in case of anti-EGFR antibody therapies. However, there is only scattered information on the significance of rare mutations and copy number changes of KRAS. Furthermore, other mutations in EGFR signaling pathway may also have predictive value such as BRAF, PIK3CA or PTEN. It also seems to be a critical issue whether the K-RAS testing must be done on primary, regional or distant metastatic tissues: data already suggest a small but significant chance of alteration during tumor progression. Technically KRAS mutation testing can be performed by various methods characterized by different sensitivities and specificities, although the clinical significance of these parameters are unknown at the present. The consensus strongly suggests the need for an effective quality control program for these methods. KRAS mutation testing in colorectal cancer raised fundamental biological, clinical and molecular pathological questions as it has become a standard application for predicting sensitivity for anti-EGFR antibody therapies. However, these questions can only be answered by rigorous, dogma-free preclinical and clinical studies.
KRAS 基因突变检测在结直肠癌的常规病理诊断中开创了一个新时代，与乳腺癌中 HER-2 检测的引入类似，但有一个重要的区别，即突变分析完全依赖于分子方法。为了批判性地分析 KRAS 基因突变检测在结直肠癌中的当前合理性，我们对 PubMed/Medline 中可用的相关文章、协会建议、抗 EGFR 抗体注册文件和 NCCN 指南进行了评估。KRAS 基因突变在结直肠癌中很常见，数据表明其具有负面的预后意义，但具有中性的预测意义，除了在抗 EGFR 抗体治疗中具有强烈的负面预测价值。然而，关于 KRAS 罕见突变和拷贝数变化的意义，只有零散的信息。此外，EGFR 信号通路中的其他突变，如 BRAF、PIK3CA 或 PTEN，也可能具有预测价值。另外，K-RAS 检测必须在原发、区域或远处转移组织上进行，这似乎也是一个关键问题：已有数据表明，在肿瘤进展过程中，突变发生的可能性虽然很小，但却具有统计学意义。从技术上讲，KRAS 基因突变检测可以通过各种方法进行，这些方法的特点是敏感性和特异性不同，尽管目前尚不清楚这些参数的临床意义。目前的共识强烈建议需要为这些方法制定有效的质量控制计划。KRAS 基因突变检测在结直肠癌中的应用引发了一些基本的生物学、临床和分子病理学问题，因为它已成为预测抗 EGFR 抗体治疗敏感性的标准应用。然而，这些问题只能通过严格的、无教条的临床前和临床研究来回答。
