PO.CL01.10 · 临床研究
基线ctDNA分析可识别EML4-ALK阳性NSCLC对第二代ALK抑制剂耐药的分子预测因子
Baseline ctDNA profiling identifies molecular predictors of resistance to second-generation ALK inhibitors in EML4-ALK-positive NSCLC
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
引言：肺癌仍是全球癌症相关死亡的首要原因。尽管酪氨酸激酶抑制剂（TKI）改善了EML4-ALK阳性非小细胞肺癌（NSCLC）的结局，但大多数患者仍会出现疾病进展。理解驱动耐药的临床和分子因素对于指导更有效的治疗策略至关重要。
目的：识别与接受一线alectinib或brigatinib治疗患者的治疗耐药和生存相关的分子特征。
患者与方法：纳入72例接受一线alectinib或brigatinib治疗的EML4-ALK阳性NSCLC患者。在基线、治疗期间和疾病进展时采集血浆样本。使用深度测序癌症个体化分析（CAPP-seq）以及我们实验室近期开发的R/Bioconductor软件包DNAfusion分析循环肿瘤DNA（ctDNA）。将进展时和基线时的ctDNA特征与进展时间（TTP）和总生存期（OS）进行关联分析。
结果：在中位随访27个月期间，54%（39/72）的患者出现疾病进展。进展时的ALK靶点耐药突变仅见于短EML4-ALK变体（40%对长变体的0%，p<0.05）。携带短变体的患者在数值上也有更短的TTP（14对35个月，p=0.12）和OS（38个月对未达到，p=0.16）。分析基线ctDNA谱以评估与临床结局的关联。高血浆突变负荷（>1个突变）的患者与低负荷（0-1个突变）者相比，TTP（13对51个月，p<0.05）和OS（36个月对未达到，p<0.05）显著更短。此外，TP53突变与不良结局强相关（TTP：10对45个月，p<0.05；OS：12个月对未达到，p<0.05）。
结论：进展时ALK靶点耐药突变的出现与短EML4-ALK变体存在显著关联。基线时的高突变负荷和TP53突变可识别在第二代ALK TKI治疗下有早期进展和不良生存风险的患者。这些发现提示，基于ctDNA的分子分析可能有助于指导个体化治疗策略并改善EML4-ALK阳性NSCLC的生存结局。
查看英文原文 English abstract
Introduction: Lung cancer remains the leading cause of cancer-related death worldwide. Although tyrosine kinase inhibitors (TKIs) have improved outcomes for EML4-ALK-positive non-small cell lung cancer (NSCLC), most patients experience disease progression. Understanding the clinical and molecular factors that drive resistance is essential for guiding more effective treatment strategies.
Aim: To identify molecular features associated with treatment resistance and survival in patients receiving first-line alectinib or brigatinib.
Patients and Methods: Seventy-two patients with EML4-ALK-positive NSCLC treated with first-line alectinib or brigatinib were included. Plasma samples were obtained at baseline, during treatment, and at disease progression. Circulating tumor DNA (ctDNA) was analyzed using cancer personalized profiling by deep sequencing (CAPP-seq) and the R/Bioconductor package, DNAfusion , recently developed in our lab. ctDNA features at progression and at baseline were correlated to time to progression (TTP) and overall survival (OS).
Results: During a median follow-up of 27 months, 54% (39/72) of patients developed disease progression. ALK on-target resistance mutations at progression were observed exclusively in short EML4-ALK variants (40% vs 0% in long variants, p<0.05). Patients with short variants also had numerically shorter TTP (14 vs 35 months, p=0.12) and OS (38 months vs NE, p=0.16). Baseline ctDNA profiles were analyzed to assess associations with clinical outcomes. Patients with a high plasma mutation load (>1 mutation) had significantly shorter TTP (13 vs 51 months, p<0.05) and OS (36 months vs NE, p<0.05) compared with those with a low load (0-1 mutation). In addition, TP53 mutations were strongly associated with poor outcomes (TTP: 10 vs 45 months, p<0.05; OS: 12 months vs NE, p<0.05).
Conclusion: Development of ALK on-target resistance mutations at progression demonstrates a significant association with short EML4-ALK variants. A high mutation load and TP53 mutations at baseline identify patients at risk of early progression and poor survival under second-generation ALK TKI treatment. These findings suggest that ctDNA-based molecular profiling may help guide personalized treatment strategies and improve survival outcomes for EML4-ALK-positive NSCLC.
利益披露 Disclosure
E. R. Sønderbek, None..
M. P. Ulhøi, None..
B. S. Sorensen, None.