West Cancer Center and Research Institute, OneOncology, Germantown, USA.
Department of Medical Oncology, City of Hope National Medical Center, Duarte, USA.
Ann Oncol. 2021 Aug;32(8):959-967. doi: 10.1016/j.annonc.2021.03.206. Epub 2021 Apr 7.
Colorectal cancer (CRC) is still a leading cause of cancer-related deaths in the United States and worldwide, despite recent improvements in cancer management. CRC, like many malignancies, is a heterogeneous disease, with subtypes characterized by genetic alterations. One common mutation in CRC is in the BRAF gene (most commonly V600E substitution). This occurs in ∼10% of patients with metastatic CRC (mCRC) and is a marker of poor prognosis.
Herein, we review the clinical and translational literature on the role of the BRAF V600E mutation in the pathogenesis of mCRC, its mechanisms as a prognostic marker, and its potential utility as a predictive marker of treatment response. We then summarize the current evidence-based recommendations for management of BRAF V600E-mutated mCRC, with a focus on recent clinical research advances in this setting.
The current standard therapies for first-line treatment of BRAF-mutated mCRC are chemotherapy with bevacizumab as well as 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab in patients with a good performance status. Combination strategies involving mitogen-activated protein kinase (MAPK) pathway blockade have shown promising results for the treatment of patients with BRAF V600E-mutated mCRC. The Binimetinib, Encorafenib, And Cetuximab cOmbiNed to treat BRAF-mutant ColoRectal Cancer (BEACON CRC) study represents the largest study in this population to date and has given strong clinical evidence to support BRAF and epidermal growth factor receptor inhibition with the combination of encorafenib plus cetuximab.
The treatment of BRAF-mutated mCRC has evolved rapidly over the last several years. Recently, combination strategies involving MAPK pathway blockade have shown promising results in BRAF V600E-mutated mCRC, and other potential targets continue to be explored. In addition, a greater understanding of the role of BRAF V600E mutation in the pathogenesis of CRC should also continue to fuel advances in the management of patients with mCRC harboring this genetic aberration.
尽管癌症管理方面取得了一些进展，但结直肠癌（CRC）仍然是美国和全球癌症相关死亡的主要原因。CRC 与许多恶性肿瘤一样，是一种异质性疾病，其亚型的特征是遗传改变。CRC 中一种常见的突变是 BRAF 基因（最常见的 V600E 取代）。这种情况发生在约 10%的转移性 CRC（mCRC）患者中，是预后不良的标志。
本文回顾了 BRAF V600E 突变在 mCRC 发病机制、作为预后标志物的机制及其作为治疗反应预测标志物的潜在效用方面的临床和转化文献。然后，我们总结了目前基于循证的 BRAF V600E 突变型 mCRC 管理建议，重点介绍了该领域最近的临床研究进展。
目前，BRAF 突变型 mCRC 一线治疗的标准疗法是贝伐单抗联合化疗，以及体能状况良好的患者用氟尿嘧啶、亚叶酸、奥沙利铂和伊立替康（FOLFOXIRI）联合贝伐单抗。涉及丝裂原活化蛋白激酶（MAPK）通路阻断的联合策略已显示出对治疗 BRAF V600E 突变型 mCRC 患者有希望的结果。Binimetinib、Encorafenib 和 Cetuximab cOmbiNed to treat BRAF-mutant ColoRectal Cancer（BEACON CRC）研究是迄今为止该人群中最大的研究，为支持 BRAF 和表皮生长因子受体抑制与 encorafenib 加 cetuximab 联合使用提供了强有力的临床证据。
近年来，BRAF 突变型 mCRC 的治疗迅速发展。最近，涉及 MAPK 通路阻断的联合策略在 BRAF V600E 突变型 mCRC 中显示出有希望的结果，其他潜在靶点也在继续探索。此外，对 BRAF V600E 突变在 CRC 发病机制中的作用的进一步了解也应继续推动携带这种遗传异常的 mCRC 患者管理方面的进展。
