Department of Medical Oncology, Regina Elena National Cancer Institute, Rome, Italy.
J Thorac Oncol. 2012 Apr;7(4):672-80. doi: 10.1097/JTO.0b013e31824a8bde.
The optimal use of epidermal growth factor receptor (EGFR)-related molecular markers to prospectively identify tyrosine kinase inhibitor (TKI)-sensitive patients, particularly after a previous chemotherapy treatment, is currently under debate.
We designed a prospective phase II study to evaluate the activity of EGFR-TKI in four different patient groups, according to the combination of molecular (EGFR gene mutations, EGFR gene copy number and protein expression, and phosphorylated AKT expression, pAKT) and clinicopathological (histology and smoking habits) factors. Correlations between molecular alterations and clinical outcome were also explored retrospectively for first-line chemotherapy and EGFR-TKI treatment.
Patients who had progressed during or after first-line chemotherapy were prospectively assigned to EGFR-TKI treatment as follows: (G1) EGFR mutation (n = 12); (G2) highly polysomic/amplified EGFR (n = 18); (G3) EGFR and/or pAKT positive (n = 41); (G4) adenocarcinoma/bronchoalveolar carcinoma and no smoking history (n = 15). G1 and G4 had the best and second-best overall response rate (25% and 20%, respectively), whereas the worst outcome was observed in G2 (ORR, 6%; p = 0.05). Disease control was highest in G1 and G4 (>50%) and lowest in G3 (<20%) (p = 0.02). Patients selected by EGFR mutation or clinical parameters (G1 and G4) also had significantly better progression-free survival and overall survival (p = 0.02 and p = 0.01, respectively). Multivariate analysis confirmed the impact of sex, smoking history, EGFR/KRAS mutation, and pAKT on outcomes and allowed us to derive an efficient predictive model. Histology, EGFR mutations, and pAKT were independent predictors of response to first-line chemotherapy at retrospective analysis, whereas pAKT and human epidermal growth factor receptor 2 expression were the only independent predictors of progression-free survival and overall survival.
Selection of patients based on either EGFR mutation or clinical characteristics seems an effective approach to optimize EGFR-TKI treatment in chemotherapy-pretreated non-small-cell lung cancer patients.
目前，关于表皮生长因子受体（EGFR）相关分子标志物的最佳应用，以前瞻性地识别酪氨酸激酶抑制剂（TKI）敏感患者，尤其是在先前化疗治疗后，仍存在争议。
我们设计了一项前瞻性的 II 期研究，根据分子（EGFR 基因突变、EGFR 基因拷贝数和蛋白表达以及磷酸化 AKT 表达，pAKT）和临床病理因素（组织学和吸烟习惯），评估 EGFR-TKI 在 4 个不同患者组中的活性。还回顾性探讨了分子改变与一线化疗和 EGFR-TKI 治疗的临床结局之间的相关性。
在一线化疗期间或之后进展的患者被前瞻性地分配到 EGFR-TKI 治疗中，具体分组如下：（G1）EGFR 突变（n=12）；（G2）高度多倍体/扩增 EGFR（n=18）；（G3）EGFR 和/或 pAKT 阳性（n=41）；（G4）腺癌/细支气管肺泡癌且无吸烟史（n=15）。G1 和 G4 的总缓解率（ORR）最佳，分别为 25%和 20%，而 G2 的 ORR 最差（6%，p=0.05）。G1 和 G4 的疾病控制率最高（均>50%），G3 的疾病控制率最低（<20%）（p=0.02）。通过 EGFR 突变或临床参数（G1 和 G4）选择的患者的无进展生存期和总生存期也明显更长（p=0.02 和 p=0.01）。多变量分析证实了性别、吸烟史、EGFR/KRAS 突变和 pAKT 对结局的影响，并允许我们得出一个有效的预测模型。组织学、EGFR 突变和 pAKT 是回顾性分析中对一线化疗反应的独立预测因素，而 pAKT 和人表皮生长因子受体 2 表达是无进展生存期和总生存期的唯一独立预测因素。
基于 EGFR 突变或临床特征选择患者，似乎是优化化疗预处理非小细胞肺癌患者 EGFR-TKI 治疗的有效方法。
