Cancer Therapeutics Program, Ottawa Hospital Research Institute, Box 926, 3rd Floor TOHRCC, 501 Smyth Rd, Ottawa, Ontario, Canada K1H 8L6.
J Clin Oncol. 2010 Dec 20;28(36):5247-56. doi: 10.1200/JCO.2010.31.0805. Epub 2010 Nov 15.
To evaluate the prognostic and predictive significance of plasma levels of the epidermal growth factor receptor (EGFR) ligands, transforming growth factor α (TGF-α) and amphiregulin, in patients with non-small-cell lung cancer (NSCLC) enrolled in NCIC Clinical Trials Group BR.21 comparing erlotinib with placebo.
TGF-α and amphiregulin were assessed retrospectively by enzyme-linked immunosorbent assay from available prospectively collected baseline plasma samples in 565 of 731 BR.21 patients. Cutoff points were determined for both amphiregulin (low, <10 pg/mL; high, ≥10 pg/mL) and TGF-α (low, ≤12 pg/mL; high, >12 pg/mL) using a graphical method. Cox regression models were used to correlate biomarker data and baseline characteristics with outcomes including overall (OS) and progression-free survival (PFS).
High TGF-α and amphiregulin were associated with poorer performance status (P=.06 and P<.0001, respectively) and no prior platinum therapy (P=.06 and P=.02, respectively). High amphiregulin was also associated with anemia (P=.001), increased lactate dehydrogenase (P=.03), ever-smokers (P=.04), and non-Asian ethnicity (P=.001). Patients on the placebo arm with high amphiregulin had poorer OS than patients with low amphiregulin (hazard ratio [HR]=1.88; 95% CI, 1.34 to 2.64; P=.0002), which remained significant in multivariate analysis. Amphiregulin levels did not predict for benefit from erlotinib (interaction P=.87). Conversely, TGF-α levels did not have prognostic significance, but high TGF-α predicted lack of benefit from erlotinib compared with low TGF-α (TGF-α low, OS HR=0.66; 95% CI, 0.54 to 0.81; P<.0001; high, OS HR=1.32; 95% CI, 0.73 to 2.39; P=.36; interaction P=.04).
High baseline amphiregulin is a poor prognostic factor, whereas high baseline TGF-α predicts for lack of benefit from erlotinib in advanced NSCLC.
评估非小细胞肺癌（NSCLC）患者血浆表皮生长因子受体（EGFR）配体转化生长因子-α（TGF-α）和 Amphiregulin 的水平对预后和预测的意义，这些患者来自于 NCIC 临床试验组 BR.21，接受厄洛替尼与安慰剂的比较。
BR.21 研究中，对 731 例患者的前瞻性采集的基线血浆样本进行了回顾性酶联免疫吸附试验，检测 TGF-α和 Amphiregulin 的水平。使用图形法确定 Amphiregulin（低，<10 pg/mL；高，≥10 pg/mL）和 TGF-α（低，≤12 pg/mL；高，>12 pg/mL）的截断点。Cox 回归模型用于将生物标志物数据和基线特征与总生存期（OS）和无进展生存期（PFS）等结果相关联。
高 TGF-α和 Amphiregulin 与较差的表现状态（P=.06 和 P<.0001）和没有铂类治疗史（P=.06 和 P=.02）相关。高 Amphiregulin 还与贫血（P=.001）、乳酸脱氢酶升高（P=.03）、曾经吸烟（P=.04）和非亚洲人种（P=.001）相关。在安慰剂组中，高 Amphiregulin 患者的 OS 不如低 Amphiregulin 患者（HR=1.88；95%CI，1.34 至 2.64；P=.0002），在多变量分析中仍然具有显著意义。Amphiregulin 水平不能预测厄洛替尼的获益（交互 P=.87）。相反，TGF-α 水平没有预后意义，但高 TGF-α与厄洛替尼相比预测缺乏获益（TGF-α 低，OS HR=0.66；95%CI，0.54 至 0.81；P<.0001；高，OS HR=1.32；95%CI，0.73 至 2.39；P=.36；交互 P=.04）。
高基线 Amphiregulin 是预后不良的因素，而高基线 TGF-α 预测厄洛替尼在晚期 NSCLC 中缺乏获益。
