BRAFV600 变异等位基因频率可预测接受 BRAF 和 MEK 抑制剂治疗的转移性黑色素瘤患者的结局。

BRAFV600 variant allele frequency predicts outcome in metastatic melanoma patients treated with BRAF and MEK inhibitors.

机构信息

University of Perugia, Perugia, Italy.

Unit of Medical Oncology, Santa Maria della Misericordia Hospital, Perugia, Italy.

出版信息

J Eur Acad Dermatol Venereol. 2023 Oct;37(10):1991-1998. doi: 10.1111/jdv.19281. Epub 2023 Jun 27.

DOI:10.1111/jdv.19281

PMID:37335879

Abstract

BACKGROUND

The prognostic impact of variant allele frequency (VAF) on clinical outcome in BRAFV600 mutated metastatic melanoma patients (MMPs) receiving BRAF (BRAFi) and MEK inhibitors (MEKi) is unclear.

MATERIALS AND METHODS

A cohort of MMPs receiving first line BRAFi and MEKi was identified by inspecting dedicated databases of three Italian Melanoma Intergroup centres. VAF was determined by next generation sequencing in pre-treatment baseline tissue samples. Correlation between VAF and BRAF copy number variation was analysed in an ancillary study by using a training and a validation cohort of melanoma tissue samples and cell lines.

RESULTS

Overall, 107 MMPs were included in the study. The VAF cut-off determined by ROC curve was 41.3%. At multivariate analysis, progression-free survival (PFS) was significantly shorter in patients with M1c/M1d [HR 2.25 (95% CI 1.41-3.6, p < 0.01)], in those with VAF >41.3% [HR 1.62 (95% CI 1.04-2.54, p < 0.05)] and in those with ECOG PS ≥1 [HR 1.82 (95% CI 1.15-2.88, p < 0.05)]. Overall survival (OS) was significantly shorter in patients with M1c/M1d [HR 2.01 (95% CI 1.25-3.25, p < 0.01)]. Furthermore, OS was shorter in patients with VAF >41.3% [HR 1.46 (95% CI 0.93-2.29, p = 0.06)] and in patients with ECOG PS ≥1 [HR 1.52 (95% CI 0.94-2.87, p = 0.14)]. BRAF gene amplification was found in 11% and 7% of samples in the training and validation cohort, respectively.

CONCLUSIONS

High VAF is an independent poor prognostic factor in MMP receiving BRAFi and MEKi. High VAF and BRAF amplification coexist in 7%-11% of patients.

摘要

背景

在接受 BRAF（BRAFi）和 MEK 抑制剂（MEKi）治疗的 BRAFV600 突变转移性黑色素瘤患者（MMP）中，变异等位基因频率（VAF）对临床结局的预后影响尚不清楚。

材料与方法

通过检查三个意大利黑色素瘤研究组的专用数据库，确定了一线接受 BRAFi 和 MEKi 治疗的 MMP 队列。通过下一代测序在治疗前基线组织样本中确定 VAF。通过使用黑色素瘤组织样本和细胞系的培训和验证队列，在辅助研究中分析 VAF 与 BRAF 拷贝数变异之间的相关性。

结果

总体而言，107 名 MMP 患者纳入研究。ROC 曲线确定的 VAF 截断值为 41.3%。多变量分析显示，无进展生存期（PFS）在 M1c/M1d 患者[HR 2.25（95%CI 1.41-3.6，p<0.01)]、VAF>41.3%患者[HR 1.62（95%CI 1.04-2.54，p<0.05)]和 ECOG PS≥1 患者[HR 1.82（95%CI 1.15-2.88，p<0.05)]较短。M1c/M1d 患者的总生存期（OS）明显缩短[HR 2.01（95%CI 1.25-3.25，p<0.01)]。此外，VAF>41.3%患者的 OS 较短[HR 1.46（95%CI 0.93-2.29，p=0.14)]，ECOG PS≥1 患者的 OS 较短[HR 1.52（95%CI 0.94-2.87，p=0.14)]。在培训和验证队列中，分别有 11%和 7%的样本中发现 BRAF 基因扩增。