Mutations of KRAS/NRAS/BRAF predict cetuximab resistance in metastatic colorectal cancer patients.
Mutations of KRAS/NRAS/BRAF predict cetuximab resistance in metastatic colorectal cancer patients.
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DOI：
10.18632/oncotarget.8076
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发表时间：
2016-04-19
期刊：
影响因子：
--
通讯作者：
Yang TS
中科院分区：
文献类型：
--
作者：
Hsu HC;Thiam TK;Lu YJ;Yeh CY;Tsai WS;You JF;Hung HY;Tsai CN;Hsu A;Chen HC;Chen SJ;Yang TS
大约45%具有野生型KRAS外显子2的转移性结直肠癌(MCRC)患者对西妥昔单抗治疗耐药。我们开始寻找其他可能预测西妥昔单抗治疗反应的遗传标记。53例野生型KRAS外显子2 mCRC患者接受西妥昔单抗/伊立替康为主的化疗作为一线或三线治疗。采用下一代测序技术分析10个EGFR通路基因在原发肿瘤中的突变状态。BRAF、PIK3CA、KRAS(外显子3和4)、NRAS、PTEN和AKT1突变分别为6、6、5、4、1和1例。其中四个BRAF突变是非V600变种。四种肿瘤存在多种共存(复杂)突变。所有具有BRAF突变或复杂突变模式的患者均为西妥昔单抗无效。除一名携带KRAS、NRAS或BRAF突变的患者外，所有患者均为无应答。与野生型患者(74.4%和11.6个月)相比，这三个基因中的任何一个突变都与较差的应答率(7.1%)和较低的生存期(PFS=8.0个月)相关。我们的数据表明，KRAS、NRAS和BRAF突变可以预测mCRC患者对西妥昔单抗治疗的反应。
Approximately 45% of metastatic colorectal cancer (mCRC) patients with wild-type KRAS exon 2 are resistant to cetuximab treatment. We set out to identify additional genetic markers that might predict the response to cetuximab treatment. Fifty-three wild-type KRAS exon 2 mCRC patients were treated with cetuximab/irinotecan-based chemotherapy as a first- or third-line therapy. The mutational statuses of 10 EGFR pathway genes were analyzed in primary tumors using next-generation sequencing. BRAF, PIK3CA, KRAS (exons 3 and 4), NRAS, PTEN, and AKT1 mutations were detected in 6, 6, 5, 4, 1, and 1 patient, respectively. Four of the BRAF mutations were non-V600 variants. Four tumors harbored multiple co-existing (complex) mutations. All patients with BRAF mutations or complex mutation patterns were cetuximab non-responders. All patients but one harboring KRAS, NRAS, or BRAF mutations were non-responders. Mutations in any one of these three genes were associated with a poor response rate (7.1%) and reduced survival (PFS = 8.0 months) compared to wild-type patients (74.4% and 11.6 months). Our data suggest that KRAS, NRAS, and BRAF mutations predict response to cetuximab treatment in mCRC patients.
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