Mutational status of epidermal growth factor receptor is the only predictor of clinical response to gefitinib treatment in non-small cell lung cancer

Abstract

The clinical profile of lung cancer in Hong Kong shows distinct characteristics. The incidences in both genders are comparable to those in Western populations with male (M):female (F) ratio of 2.4:1 in 2002. However, the majority of the women have never smoked and the smoker (SM):non-smoker (NS) ratio was 0.3:1, compared to 6.2:1 in male patients. Consistent with findings in various Asian populations, we have previously shown that mutations of the epidermal growth factor receptor (EGFR) in lung cancers are associated with adenocarcinomas, women and non-smokers. The purpose of this study was to examine the clinical correlates and EGFR mutational status (exons 18 to 21) of non-small cell lung cancer (NSCLC) in relation to clinical responses to the tyrosine kinase inhibitor gefitinib (Iressa). All patients who had resistant disease to conventional chemotherapy, had available clinical material (biopsy, fine needle aspiration, lavage or pleural effusion fluid) for mutation analysis, and who received gefitinib treatment in our institution were retrospectively evaluated. There were 27 F (26 NS, 1 SM) and 16 M (9 NS, 7 SM, p=0.002) aged 35-85 (median 64), and included 32 histologically confirmed adenocarcinomas (AD), 2 squamous and 9 NSCLC of advanced stage disease (IIIB and IV). Gefitinib (250mg/day) was given for 0.5 to 21.2 (median 3) months and patients were monitored for 0.5 to 26.4 (median 6.3) months. The median survival was 10.5 months (95% CI, 8.3-12.7) and one-year survival rate was 37.3%. There were 25 mutations (9 substitutions, 17 deletions) that resulted in amino acid changes from 20 F, 5 M (p=0.010), and 23 NS, 2 SM (p=0.052). One case showed both exon 19 deletion and exon 20 substitution. Common changes (exon 19 deletions, L858R) involved 88% of the mutants. 2 other cases showed silent mutations. Clinical response (CR) from gefitinib treatment was observed in 23 (53.5%) patients who showed either reduction of longest tumour diameter by ≥30%, improvement in performance status, and/or reduced serum carcinoembryonic antigen tumour marker. They included 17/27 (63%) female, 6/16 (37.5%) male, 19/35 (54.3%) NS, 4/8 (50%) SM, and 19/32 (59.4%) AD. Clinical response was correlated only with the EGFR mutation status (19/25 mutants, 4/18 wild types, p<0.001) but not patient gender, smoking history or tumor diagnosis. Survival analysis showed that patients with EGFR mutation had significantly better outcome than those without mutation (one-year survival rate 55.5% vs. 10.6%, p=0.013). Within the limits of the small patient number of this study, the data suggested that the EGFR mutational status is the only predictor of clinical response to gefitinib treatment for NSCLC in our population. (Supported by HKU CRCG 200507176201)