PDF(Pubmed)
Abstract：
Although V600E accounts for the majority of the BRAF mutations in metastatic colorectal cancer (mCRC), non-V600 BRAF variants have been shown in recent years to represent a distinct molecular subtype. This study provides a comprehensive profile of BRAF variants in mCRC using a large genomic database of circulating tumor DNA (ctDNA) and analyzing clinical outcomes in a cohort of patients with atypical (non-V600) BRAF variants (aBRAF; class II, class III, unclassified). Overall, 1733 out of 14,742 mCRC patients in the ctDNA cohort had at least one BRAF variant. Patients with atypical BRAF variants tended to be younger and male. In contrast to BRAFV600E, BRAF class II and III variants and their co-occurrence with KRAS/NRAS mutations were increased at baseline and especially with those patients predicted to have prior anti-EGFR exposure. Our clinical cohort included 38 patients with atypical BRAF mCRC treated at a large academic referral center. While there were no survival differences between atypical BRAF classes, concurrent RAS mutations or liver involvement was associated with poorer prognosis. Notably, patients younger than 50 years of age had extremely poor survival. In these patients, the high-frequency KRAS/NRAS co-mutation and its correlation with poorer prognosis underlines the urgent need for novel therapeutic strategies. This study represents one of the most comprehensive characterizations to date of atypical BRAF variants, utilizing both ctDNA and clinical cohorts.
摘要：
尽管V600E在转移性结直肠癌（mCRC）中占BRAF突变的大多数，近年来,non-V600BRAF变异体被证明代表一种独特的分子亚型.本研究使用循环肿瘤DNA（ctDNA）的大型基因组数据库提供了mCRC中BRAF变体的全面概况，并分析了非典型（非V600）BRAF变体（aBRAF；II类，第三类,未分类)。总的来说,在ctDNA队列中的14742例mCRC患者中有1733例具有至少一个BRAF变异。具有非典型BRAF变异的患者倾向于年轻和男性。与BRAFV600E相比，BRAFII类和III类变体及其与KRAS/NRAS突变的共同出现在基线时增加，尤其是那些预测先前有抗EGFR暴露的患者。我们的临床队列包括在大型学术转诊中心治疗的38例非典型BRAFmCRC患者。虽然非典型BRAF类之间没有生存差异，RAS突变或肝脏受累与预后较差相关.值得注意的是,50岁以下患者的生存率极差.在这些患者中,KRAS/NRAS的高频率共突变及其与不良预后的相关性凸显了对新治疗策略的迫切需要.这项研究代表了迄今为止非典型BRAF变体最全面的特征之一，利用ctDNA和临床队列。
