Previously documented mutations in the epidermal growth factor receptor (EGFR) gene in a non-small cell lung cancer (NSCLC) population treated with gefitinib are not associated with response

Abstract

7163 Background: Mutations in the tyrosine kinase domain of EGFR that may correlate with clinical features and response of NSCLC to EGFR tyrosine kinase inhibitors have been described. But, varying methodologies have contributed to an uncertain relationship between EGFR mutational status and response. This study sought to characterize EGFR mutations in microdissected tumour tissue from pts with advanced NSCLC treated with gefitinib and correlate their clinical data. Methods: Biopsy material from pts treated with gefitinib for advanced NSCLC at the British Columbia Cancer Agency was analyzed. Malignant cells (cytology specimens) or tissue (paraffin embedded biopsies) was reviewed and tumour cells isolated by laser- capture microdissection or manual scrape. Genomic DNA was extracted and exons coding for the EGFR tyrosine kinase domain (18 - 24) were amplified by PCR and sequenced. When insufficient, the priority was 18, 19, 21, followed by 20, 23, 22, and 24. EGFR mutational analyses were correlated with response to gefitinib and clinical features. Results: 61 pts were identified, 14 (23%) radiological responders (CR, PR): 10 Asian, 10 female, 8 non-smokers, 8 adenocarcinoma, 2 BAC. Of 51 tumour samples available, 39 had adequate tissue for sequencing analysis. EGFR copy number by FISH is pending. Laser-capture microdissection allowed for high quality DNA to be extracted almost exclusively from tumour. Exons 18, 19, 20, 21, 22, 23 and 24 have been sequenced in 37, 34, 30, 33, 12, 10, and 13 patients, respectively. 4 mutations were identified: 2 in 2 non-smoking Asian pts (exon 19; deletion or substitution of L747-T751) and 2 in Caucasians (exon 20 point mutation resulting in a L798F substitution). None of these pts had a response to gefitinib. Conclusions: As with other series, most responders were female, non-smokers of Asian origin. Our results support the relationship between Asian ethnicity and EGFR mutations but question the role of EGFR mutational status in predicting response. Prospective studies will need to focus the detection of additional genetic features using accurate and reproducible techniques before recommendations for selecting populations to be treated can be made. No significant financial relationships to disclose.