BRAF突变转移性结直肠癌临床分子特征及治疗进展

Advances in the treatment of V-raf murine sarcoma viral oncogene homolog mutant metastatic colorectal cancer

结直肠癌(colorectal cancer,CRC)是世界上发病率和死亡率高的肿瘤之一。它是一种异质性疾病,可以分为不同的亚型,以特定的分子和形态学改变为特征。约10%的转移性结直肠癌(metastatic colorectal cancer,mCRC)患者存在V-raf鼠肉瘤病毒癌基因同源体B(V-raf murine sarcoma viral oncogene homolog,BRAF^V600E)基因突变,预后不良,这类患者的治疗一直是临床治疗的难点。对于BRAF^V600E突变mCRC一线治疗的选择目前尚无标准方案,根据既往研究结果,对于体能状态好的患者,推荐三药化疗±贝伐珠单抗,对于难以耐受三药化疗的患者,可应用两药化疗±贝伐珠单抗;对于一线治疗失败后的治疗,BRAF抑制剂单药治疗效果不好,通过对BRAF基因mCRC耐药分子机制的研究,开展了一系列临床试验,包括双靶向药、三靶向药的联合治疗。最终,BEACON CRC研究结果的公布,为临床BRAF^V600E突变mCRC患者二线及后续治疗提供了疗效更优的三靶向药物联合治疗方案。本文就BRAF^V600E突变mCRC的标准治疗耐药的分子基础及治疗进展进行综述。

Colorectal cancer(CRC)is one of the tumors with high morbidity and mortality in the world.It is a heterogeneous disease that can be divided into different subtypes,characterized by specific molecular and morphological changes.V-raf murine sarcoma viral oncogene homolog(BRAF^V600E)mutations are present in about 10%of patients with metastatic colorectal cancer(mCRC)and associated with poor prognosis in these patients.The treatment of these patients has always been difficult.Currently,there is no standard treatment options for the first-line treatment of BRAF^V600E mutant mCRC patients.According to previous studies,three drugs chemotherapy±bevacizumab is recommended for patients with good physical condition,and two drugs chemotherapy±bevacizumab is recommended for patients with poor endurance of three-drug chemotherapy.For the treatment after first-line treatment failure,single BRAF inhibitor treatment is not effective.Based on the study about the molecular mechanism of drug resistance in BRAF gene mCRC,a series of clinical trials,including the combination of double or three drugs targeted therapy,have been carried out.Ultimately,the BEACON CRC study provides a better effect after three targeted drugs combination,and this review expounded the molecular basis of standard treatment resistance and advances in clinical diagnosis and treatment for BRAF^V600E mutant mCRC patients.