Although V600E accounts for the majority of theBRAFmutations in metastatic colorectal cancer (mCRC), non-V600BRAFvariants have been shown in recent years to represent a distinct molecular subtype. This study provides a comprehensive profile ofBRAFvariants 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)BRAFvariants (aBRAF; class II, class III, unclassified). Overall, 1733 out of 14,742 mCRC patients in the ctDNA cohort had at least oneBRAFvariant. Patients with atypicalBRAFvariants tended to be younger and male. In contrast toBRAFV600E,BRAFclass II and III variants and their co-occurrence withKRAS/NRASmutations were increased at baseline and especially with those patients predicted to have prior anti-EGFR exposure. Our clinical cohort included 38 patients with atypicalBRAFmCRC treated at a large academic referral center. While there were no survival differences between atypicalBRAFclasses, concurrentRASmutations 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-frequencyKRAS/NRASco-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 atypicalBRAFvariants, utilizing both ctDNA and clinical cohorts.
尽管V600E突变在转移性结直肠癌（mCRC）的BRAF突变中占主导地位，但近年研究表明非V600 BRAF变异代表了一种独特的分子亚型。本研究通过大型循环肿瘤DNA（ctDNA）基因组数据库，对mCRC中的BRAF变异进行全面分析，并在一组非典型（非V600）BRAF变异（aBRAF；II类、III类及未分类）患者中评估临床结局。在ctDNA队列的14,742例mCRC患者中，共有1733例携带至少一种BRAF变异。非典型BRAF变异患者呈现年轻化及男性为主的趋势。与BRAF V600E相比，II类和III类BRAF变异及其与KRAS/NRAS突变的共存现象在基线时更为常见，尤其在预测曾接受抗EGFR治疗的患者中尤为显著。我们的临床队列纳入了38例在大型学术转诊中心接受治疗的非典型BRAF mCRC患者。虽然不同非典型BRAF类别间生存期无显著差异，但并发RAS突变或肝脏转移与不良预后相关。值得注意的是，50岁以下患者生存期极短。这些患者高频出现的KRAS/NRAS共突变及其与不良预后的相关性，凸显了开发新型治疗策略的迫切需求。本研究通过整合ctDNA与临床队列数据，迄今对非典型BRAF变异进行了最全面的特征描述。
肿瘤(癌症)患者之家