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期刊来源：Nat Med

原文链接：https://doi.org/10.1038/s41591-023-02791-w

摘要内容如下：

在转移性结直肠癌（mCRC）中，某些基因改变和右侧原发肿瘤位置与抗表皮生长因子（EGFR）治疗耐药相关。3期范式试验（n=802）显示，与抗血管内皮生长因子（贝伐单抗）联合改良FOLFOX6相比，一线抗EGFR（帕尼单抗）联合改良FOLFOX6治疗伴左侧原发性肿瘤的ras野生型mCRC患者的总生存期更长。这项预先指定的探索性生物标志物分析（n=733）评估了循环肿瘤DNA（ctDNA）基因改变与疗效结果之间的相关性，重点关注与EGFR抑制抵抗相关的一组广泛的基因改变，包括KRAS、NRAS、PTEN和细胞外结构域EGFR突变、HER2和MET扩增以及ALK、RET和NTRK1融合。与贝伐单抗联合改良FOLFOX6相比，帕尼单抗联合改良FOLFOX6延长了ctDNA患者的总生存期，这些患者的ctDNA缺乏基因改变（即阴性超选择；总体人群的中位数:40.7对34.4个月；风险比为0.76；95%置信区间，0.62-0.92），但在组中含有任何基因改变的ctDNA患者中，与帕尼单抗相似或较差（19.2个月对22.2个月；风险比为1.13；95%可信区间为0.83-1.53），不考虑肿瘤的侧别。使用ctDNA的阴性超选择可能指导mCRC患者的最佳治疗选择。ClinicalTrials.gov注册：NCT02394834和NCT02394795。

英文原文如下：

Abstracts

Certain genetic alterations and right-sided primary tumor location are associated with resistance to anti-epidermal growth factor (EGFR) treatment in metastatic colorectal cancer (mCRC). The phase 3 PARADIGM trial (n = 802) demonstrated longer overall survival with first-line anti-EGFR (panitumumab) versus antivascular endothelial growth factor (bevacizumab) plus modified FOLFOX6 in patients with RAS wild-type mCRC with left-sided primary tumors. This prespecified exploratory biomarker analysis of PARADIGM (n = 733) evaluated the association between circulating tumor DNA (ctDNA) gene alterations and efficacy outcomes, focusing on a broad panel of gene alterations associated with resistance to EGFR inhibition, including KRAS, NRAS, PTEN and extracellular domain EGFR mutations, HER2 and MET amplifications, and ALK, RET and NTRK1 fusions. Overall survival was prolonged with panitumumab plus modified FOLFOX6 versus bevacizumab plus modified FOLFOX6 in patients with ctDNA that lacked gene alterations in the panel (that is, negative hyperselected; median in the overall population: 40.7 versus 34.4 months; hazard ratio, 0.76; 95% confidence interval, 0.62-0.92) but was similar or inferior with panitumumab in patients with ctDNA that contained any gene alteration in the panel (19.2 versus 22.2 months; hazard ratio, 1.13; 95% confidence interval, 0.83-1.53), regardless of tumor sidedness. Negative hyperselection using ctDNA may guide optimal treatment selection in patients with mCRC. ClinicalTrials.gov registrations: NCT02394834 and NCT02394795 .

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