Plasma Transforming Growth Factor α and Amphiregulin Protein Levels in NCIC Clinical Trials Group BR.21

Abstract

Purpose 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. Patients and Methods 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). Results 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). Conclusion High baseline amphiregulin is a poor prognostic factor, whereas high baseline TGF-α predicts for lack of benefit from erlotinib in advanced NSCLC.