Expanded Low Allele Frequency RAS and BRAF V600E Testing in Metastatic Colorectal Cancer as Predictive Biomarkers for Cetuximab in the Randomized CO.17 Trial.
Expanded Low Allele Frequency RAS and BRAF V600E Testing in Metastatic Colorectal Cancer as Predictive Biomarkers for Cetuximab in the Randomized CO.17 Trial.
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DOI：
10.1158/1078-0432.ccr-20-2710
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发表时间：
2021-01-01
期刊：
影响因子：
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通讯作者：
Kopetz S
中科院分区：
文献类型：
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作者：
Loree JM;Dowers A;Tu D;Jonker DJ;Edelstein DL;Quinn H;Holtrup F;Price T;Zalcberg JR;Moore MJ;Karapetis CS;O'Callaghan CJ;Waring P;Kennecke HF;Hamilton SR;Kopetz S
扩大的RAS/BRAF突变尚未被评估为转移性结直肠癌（mCRC）单药西妥昔单抗的预测，低突变等位基因频率（MAF）突变的意义尚不清楚。我们的目的是利用高灵敏度的BEAMing，在最佳选择的患者中建立西妥昔单抗的疗效，能够检测低于标准临床分析的改变。CO.17比较西妥昔单抗与最佳支持治疗（BSC）在RAS/BRAF非选择的mCRC。我们使用beam对242例CO.17患者的显微解剖组织进行了KRAS/NRAS（密码子12/13/59/61/117/146）和BRAF V600E的RAS/BRAF分析。患者没有喜气，但先前的Sanger测序检测到突变。KRAS、NRAS和BRAF突变分别存在于53%、4%和3%的肿瘤中。与BSC相比，西妥昔单抗改善了RAS/BRAF野生型患者的总生存期（OS） （HR 0.51, 95% CI 0.32-0.81， P=0.004）和无进展生存期（PFS） （HR 0.25, 95% CI 0.15-0.41， P<0.0001）。西妥昔单抗没有改善KRAS、NRAS或BRAF突变肿瘤的OS/PFS，相互作用试验证实KRAS （P=0.0002）和NRAS （P=0.006）扩大是可预测的，而BRAF突变没有（P=0.089）。与Sanger测序相比，BEAMing鉴定出的RAS突变肿瘤多14%，西妥昔单抗在这些患者中缺乏活性。242例患者中有6例（2%）发现MAF<5%的突变。1例KRAS A59T突变患者（MAF=2%）对西妥昔单抗有反应。低MAF突变的NRAS多于KRAS （OR 20.50, 95% CI 3.88 ~ 96.85， P=0.0038）。我们在最佳选择的患者中建立了单药西妥昔单抗的疗效，并表明亚克隆RAS/BRAF改变并不常见，并且仍然具有不确定的意义。
Expanded RAS/BRAF mutations have not been assessed as predictive for single-agent cetuximab in metastatic colorectal cancer (mCRC) and low mutant allele frequency (MAF) mutations are of unclear significance. We aimed to establish cetuximab efficacy in optimally selected patients using highly sensitive BEAMing, capable of detecting alterations below standard clinical assays. CO.17 compared cetuximab versus best supportive care (BSC) in RAS/BRAF unselected mCRC. We performed RAS/BRAF analysis on micro-dissected tissue of 242 patients in CO.17 using BEAMing for KRAS/NRAS (codons 12/13/59/61/117/146) and BRAF V600E. Patients without BEAMing but with previous Sanger sequencing detected mutations were included. KRAS, NRAS, and BRAF mutations were present in 53%, 4%, and 3% of tumors, respectively. Cetuximab improved overall survival (OS) (HR 0.51, 95% CI 0.32–0.81, P=0.004) and progression free survival (PFS) (HR 0.25, 95% CI 0.15–0.41, P<0.0001) compared to BSC in RAS/BRAF wild type patients. Cetuximab did not improve OS/PFS for KRAS, NRAS, or BRAF mutated tumors and tests of interaction confirmed expanded KRAS (P=0.0002) and NRAS (P=0.006) as predictive, while BRAF mutations were not (P=0.089). BEAMing identified 14% more tumors as RAS mutant than Sanger sequencing and cetuximab lacked activity in these patients. Mutations at MAF<5% were noted in 6/242 patients (2%). One patient with a KRAS A59T mutation (MAF=2%) responded to cetuximab. More NRAS than KRAS mutations were low MAF (OR 20.50, 95% CI 3.88–96.85, P=0.0038). We establish single-agent cetuximab efficacy in optimally selected patients and show that subclonal RAS/BRAF alterations are uncommon and remain of indeterminate significance.