Huang Zhuohao, Wu Yanxia, Ye Haiyin, Wang Yongcun, Huang Zhong, Chen Yuting, Cheng Zhen, Huang Xiaobi, Xiao Chang, Li Jinmei, Chen Guanghua, Su Wenmei
Department of Pulmonary Oncology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.
Pathological Diagnosis and Research Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.
J Thorac Dis. 2025 Jun 30;17(6):3897-3911. doi: 10.21037/jtd-2025-97. Epub 2025 Jun 25.
Lung cancer, especially non-small cell lung cancer (NSCLC), is a leading cause of cancer mortality. Epidermal growth factor receptor (EGFR) mutations drive NSCLC progression but also sensitize tumors to EGFR-tyrosine kinase inhibitors (TKIs). However, the response rate to targeted therapy is only 70%, and most patients experience disease progression 9 to 14 months after first- or second-generation EGFR-TKI treatment. This study aims to examine the association between super-amplification refractory mutation system (ARMS)-derived ΔCt values [mutant DNA cycle threshold (Ct) value relative to the endogenous reference gene (Ct) value] and EGFR mutation (EGFRm) abundance in predicting the efficacy and prognosis of EGFR-TKIs in NSCLC patients.
The present retrospective research encompassed 139 patients with stage IIIB-IV NSCLC treated with EGFR-TKIs. Patients were categorized based on super-ARMS ΔCt values and Kaplan-Meier, and Cox regression models were used to evaluate the outcomes in survival and independent influencing factors, thus establishing the optimal ΔCt value for EGFR-TKIs response.
High mutation abundance, defined by ΔCt ≤3.76, was correlated with increased objective response rate (ORR) (61.2% 36.8%, P=0.003) and longer median progression-free survival (mPFS) (20.9 15.8 months, log-rank P=0.005) compared to low abundance. The optimal ΔCt cut-off predictive of EGFR-TKIs response was 4.335. Patients with ΔCt ≤4.335 demonstrated superior ORR (64.6% 28.1%, P<0.001) and mPFS (20.9 13.5 months, log-rank P<0.001) compared to those with ΔCt >4.335. Multivariate Cox analysis identified median ΔCt value group (ΔCt ≤3.76 or ΔCt >3.76), the optimal ΔCt cut-off value group (ΔCt ≤4.335 or ΔCt >4.335), brain metastasis, liver metastasis, EGFRm status, performance status (PS) score, and the generation of EGFR-TKIs as independent predictors of PFS in first-line EGFR-TKIs-treated patients.
Stratification based on ΔCt values derived from the super-ARMS system can predict the efficacy and clinical prognosis of first-line EGFR-TKI treatment in NSCLC patients. Additionally, higher mutation abundance may contribute to the superior efficacy and prognosis of EGFR-TKIs in patients with exon 19 deletions compared to those with the 21L858R mutation.
肺癌，尤其是非小细胞肺癌（NSCLC），是癌症死亡的主要原因。表皮生长因子受体（EGFR）突变推动NSCLC进展，但也使肿瘤对EGFR酪氨酸激酶抑制剂（TKIs）敏感。然而，靶向治疗的缓解率仅为70%，大多数患者在第一代或第二代EGFR-TKI治疗后9至14个月出现疾病进展。本研究旨在探讨超扩增难治性突变系统（ARMS）衍生的ΔCt值[突变DNA循环阈值（Ct）值相对于内源性参考基因（Ct）值]与EGFR突变（EGFRm）丰度之间的关联，以预测EGFR-TKIs在NSCLC患者中的疗效和预后。
本回顾性研究纳入了139例接受EGFR-TKIs治疗的IIIB-IV期NSCLC患者。根据超ARMS ΔCt值对患者进行分类，并使用Kaplan-Meier法和Cox回归模型评估生存结局和独立影响因素，从而确定EGFR-TKIs反应的最佳ΔCt值。
与低丰度相比，由ΔCt≤3.76定义的高突变丰度与客观缓解率（ORR）增加（61.2%对36.8%，P = 0.003）和更长的中位无进展生存期（mPFS）（20.9个月对15.8个月，对数秩检验P = 0.005）相关。预测EGFR-TKIs反应的最佳ΔCt截止值为4.335。与ΔCt>4.335的患者相比，ΔCt≤4.335的患者表现出更高的ORR（64.6%对28.1%）和mPFS（20.9个月对13.5个月，对数秩检验P<0.001）。多因素Cox分析确定中位ΔCt值组（ΔCt≤3.76或ΔCt>；3.76）、最佳ΔCt截止值组（ΔCt≤4.335或ΔCt>；4.335）、脑转移、肝转移、EGFRm状态、体能状态（PS）评分以及EGFR-TKIs的代别为一线EGFR-TKIs治疗患者PFS的独立预测因素。
基于超ARMS系统衍生的ΔCt值进行分层可预测NSCLC患者一线EGFR-TKI治疗的疗效和临床预后。此外，与携带21L858R突变的患者相比，更高的突变丰度可能导致携带外显子19缺失的患者中EGFR-TKIs具有更好的疗效和预后。
