Epidermal growth factor receptor gene amplification and gefitinib sensitivity in patients with recurrent lung cancer

Abstract

To evaluate the epidermal growth factor receptor (EGFR) protein expression, gene mutations and amplification as predictors of clinical outcome in patients with non-small-cell lung cancer (NSCLC) receiving gefitinib, we have performed fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). We investigated the EGFR amplification and EGFR protein expression statuses in 27 surgically treated non-small-cell lung cancer (NSCLC) cases. These patients experienced relapse after surgery and received gefitinib 250 mg/day. The presence or absence of EGFR mutations of kinase domains was analyzed by genotyping analysis and sequences, and already reported. EGFR mutations were found from 15/27 lung cancer patients. EGFR mutation status was significantly correlated with better prognosis (log-rank test P=0.0023). Smoking status (never smoker vs. smoker, P=0.0032), and pathological subtypes (adenocarcinoma vs. non-adenocarcinoma, P=0.0011), but not EGFR amplification (P=0.1278), were correlated with survival of lung cancers. EGFR IHC results were correlated with FISH results (P=0.0125), but not correlated with prognosis (P=0.7921). Thus, the EGFR gene amplification or protein expression is not a predictor of gefitinib efficacy in Japanese patients with NSCLC. We have also evaluated the EGFR mutation status and clinico-pathological features for 27 NSCLC patients who had undergone surgery followed by treatment with gefitinib at the National Hospital Organization, Kinki-chuo Chest Medical Center. The EGFR mutation status, especially exon19 mutation was correlated with good response to gefitinib than exon 21 point mutation.

Fig. 1

FISH analysis for lung cancer tissues. Left high polysomy case (4 copy numbers in cells >40%), right disomy case

Fig. 2

The overall survival of 27 gefitinib untreated lung cancer patients was studied in reference to the EGFR amplification status (left) and EGFR protein expression (right). Prognosis from patients with EGFR amplification (n = 12, 9 were dead) and without EGFR amplification (n = 15, 8 were dead) was not significantly different (log-rank test, P = 0.1278; Breslow–Gehan–Wilcoxon test, P = 0.0528). Prognosis from patients with positive EGFR expression (n = 13, 8 were dead) and without negative EGFR expression (n = 14, 9 were dead) was not significantly different (log-rank test, P = 0.7921; Breslow–Gehan–Wilcoxon test; P = 0.9105)

Fig. 3

EGFR protein expression by immunohistochemistry. Left positive case, right negative case

Fig. 4

The overall survival of 27 gefitinib-treated lung cancer patients was studied in reference to the EGFR mutation status. Prognosis from patients with EGFR mutations (n = 15, 6 were dead) was significantly better than the patients without EGFR mutations (n = 12, 11 were dead) (log-rank test, P = 0.0023, Breslow–Gehan–Wilcoxon test; P = 0.0012)

Fig. 5

The overall survival of 54 gefitinib-treated lung cancer patients was studied in reference to the EGFR mutation status. Left upper prognosis from patients with exon 19 deletion mutations (n = 12, 3 were dead) was significantly better than the patients without EGFR mutations (Log-rank test, P = 0.0032, Breslow–Gehan–Wilcoxon test; P = 0.006). Right upper prognosis from patients with L858R mutation (n = 8, 5 were dead) and patients without EGFR mutation was not significantly different (log-rank test, P = 0.2823, Breslow–Gehan–Wilcoxon test; P = 0.142). Left lower there was a tendency towards better prognosis in the patients with exon 19 deletions than in the patients with the L858R mutation (log-rank test, P = 0.1032, Breslow–Gehan–Wilcoxon test; P = 0.1732)