利用下一代测序技术对转移性结直肠癌患者进行超选择，以提高抗 EGFR 治疗的临床疗效。
Ultra-selection of metastatic colorectal cancer patients using next-generation sequencing to improve clinical efficacy of anti-EGFR therapy.
机构信息
Medical Oncology Department, Hospital del Mar-IMIM, CIBERONC Instituto de Salud Carlos III, Barcelona.
Pathology Department, Hospital del Mar, Barcelona.
出版信息
Ann Oncol. 2019 Mar 1;30(3):439-446. doi: 10.1093/annonc/mdz005.
BACKGROUND
Extended RAS analysis is mandatory in metastatic colorectal cancer (mCRC) patients. The optimal threshold of RAS mutated subclones to identify patients most likely to benefit from antiepidermal growth factor receptor (EGFR) therapy is controversial. Our aim was to assess the clinical impact of detecting mutations in RAS, BRAF, PIK3CA and EGFRS492R in basal tissue tumour samples by using a highly sensitive next-generation sequencing (NGS) technology in mCRC patients treated with chemotherapy plus anti-EGFR or anti-vascular endothelial growth factor.
PATIENTS AND METHODS
Five hundred and eighty-one tumour samples from untreated mCRC patients from 7 clinical studies were collected. Mutational analysis was carried out by standard-of-care (therascreen pyro) with a sensitivity detection of 5% mutant allele fraction (MAF), and compared with NGS technology using 454GS Junior platform (Roche Applied Science, Germany) with a sensitivity of 1%. Molecular results were correlated with clinical outcomes.
RESULTS
After quality assessment, 380 samples were evaluable for molecular analysis. Standard-of-care mutational analysis detected RAS, BRAFV600E or PIK3CA mutations in 56.05% of samples compared with 69.21% by NGS (P = 0.00018). NGS identified coexistence of multiple low-frequency mutant alleles in 96 of the 263 mutated cases (36.5%; range 2-7). Response rate (RR), progression-free survival (PFS) and overall survival (OS) were increasingly improved in patients with RAS wild-type, RAS/BRAF wild-type or quadruple (KRAS/NRAS/BRAF/PIK3CA) wild-type tumours treated with anti-EGFR, assessed by standard-of-care. No additional benefit in RR, PFS or OS was observed by increasing the detection threshold to 1% by NGS. An inverse correlation between the MAF of the most prevalent mutation detected by NGS and anti-EGFR response was observed (P = 0.039). EGFRS492Rmutation was not detected in untreated samples.
CONCLUSIONS
No improvement in the selection of patients for anti-EGFR therapy was obtained by adjusting the mutation detection threshold in tissue samples from 5% to 1% MAF. Response to anti-EGFR was significantly better in patients with quadruple wild-type tumours.
背景
在转移性结直肠癌（mCRC）患者中，需要进行扩展 RAS 分析。确定最有可能从抗表皮生长因子受体（EGFR）治疗中获益的患者的 RAS 突变亚克隆的最佳阈值存在争议。我们的目的是通过使用高度敏感的下一代测序（NGS）技术，评估在接受化疗加抗 EGFR 或抗血管内皮生长因子治疗的 mCRC 患者的基础组织肿瘤样本中检测 RAS、BRAF、PIK3CA 和 EGFRS492R 突变的临床影响。
患者和方法
收集了来自 7 项临床研究的 581 个未经治疗的 mCRC 患者的肿瘤样本。通过标准护理（therascreen pyro）进行突变分析，其敏感性检测为 5%的突变等位基因分数（MAF），并与使用 Roche Applied Science（德国）454GS Junior 平台的 NGS 技术进行比较，其敏感性为 1%。分子结果与临床结果相关。
结果
经过质量评估，有 380 个样本可用于分子分析。与 NGS（P=0.00018）相比，标准护理突变分析在 56.05%的样本中检测到 RAS、BRAFV600E 或 PIK3CA 突变。NGS 在 263 例突变病例中的 96 例（36.5%；范围 2-7）中发现了多个低频率突变等位基因的共存。用标准护理评估，在接受抗 EGFR 治疗的 RAS 野生型、RAS/BRAF 野生型或四重（KRAS/NRAS/BRAF/PIK3CA）野生型肿瘤的患者中，RR、无进展生存期（PFS）和总生存期（OS）随着 RAS 野生型、RAS/BRAF 野生型或四重（KRAS/NRAS/BRAF/PIK3CA）野生型肿瘤的患者而逐渐改善。通过将 NGS 检测阈值从 5%提高到 1%，RR、PFS 或 OS 无额外获益。在 NGS 检测到的最常见突变的 MAF 与抗 EGFR 反应之间观察到负相关（P=0.039）。在未经处理的样本中未检测到 EGFRS492R 突变。
结论
在组织样本中，将突变检测阈值从 5%调整至 1% MAF，并未提高患者接受抗 EGFR 治疗的选择。与四重野生型肿瘤患者相比，抗 EGFR 治疗的反应明显更好。
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