Lung Cancer with Epidermal Growth Factor Receptor Exon 20 Mutations Is Associated with Poor Gefitinib Treatment Response

Abstract

Purpose: Clinical reports about responsiveness to gefitinib treatment in patients of non-small cell lung cancer (NSCLC) with mutations in exon 20 of epidermal growth factor receptor (EGFR) are limited. To increase understanding of the influence of exon 20 mutations on NSCLC treatment with gefitinib, we investigated the clinical features of lung cancer in patients with exon 20 mutations and analyzed the gefitinib treatment response. Experimental Design: We surveyed the clinical data and mutational studies of NSCLC patients with EGFR exon 20 mutations in the National Taiwan University Hospital and reviewed the literature reports about EGFR exon 20 mutations and the gefitinib treatment response. Results: Twenty-three patients with mutations in exon 20 were identified. Nine (39%) had coexisting mutations in EGFR exons other than exon 20. Sixteen patients received gefitinib treatment, and a response was noted in 4 patients. The gefitinib response rate of NSCLC with exon 20 mutations was 25%, far lower than those with deletions in exon 19 and L858R mutations. Interestingly, different exon 20 mutations and coexisting mutations seemed to have a different influence on gefitinib response. Conclusions: EGFR exon 20 mutations of NSCLC patients result in poorer responsiveness to gefitinib treatment, but variability exists between different individuals.

Molecular pathology of lung cancer: key to personalized medicine

“…15,67 The most important mutation in exon 20 is T790M, which is associated with a small fraction of adenocarcinomas with primary resistance to EGFR TKI and over one-half of the patients with acquired resistance to EGFR TKI ( Figure 2). 12,[67][68][69][70][71] A comprehensive literature review by Yamamoto et al 33 indicated that 569 mutations were found in 2880 lung cancer patients (20%). The distribution of EGFR mutations was as follows: 48% in exon 19, 43% in exon 21, 4% in exon 20, and 3% in exon 18.…”

“…Exons 18-21 in the tyrosine kinase region of the EGFR gene are scaled up; a detailed list of EGFR mutations in these exons associated with sensitivity (green) or resistance (orange) to EGFR TKI. 6,12,[67][68][69][70][71][80][81][82][83][84]195 The frequency of the mutations is labeled to the side of the color-coded bars. The most prevalent EGFR mutations are in-frame deletions of exon 19 (45%), followed by L858R substitution in exon 21 (41%).…”

“…The incidences of mutations were as follows: KRAS 25%, EGFR 23%, ALK rearrangements 6%, BRAF 3%, PIK3CA 3%, MET amplifications 2%, ERBB2 1%, MAP2K1 0.4%, NRAS 0.2%, and AKT1 0% (Figure 3). 12,[67][68][69][70][71] It is noteworthy that 95% of molecular lesions were mutually exclusive. 79 EGFR mutations are responsible for the constitutive activation of the tyrosine kinase receptor.…”

“…85,86 However, upto 25% of patients with TKI resistanceassociated mutations will also respond to the therapy. 67 Pao et al 7 analyzed EGFR mutation of exons 18-24 in tumors from 10 gefitinib-responsive and from 7 erlotinib-responsive patients. The results demonstrated that EGFR mutations were present in 7 of 10 (70%) gefitinib-responsive and in 5 of 7 (71%) erlotinib-responsive tumors.…”

“…70,[179][180][181] Clinically, patients with EGFR exon 20 mutations do not respond to gefitinib. 67 Moreover, the appearance of a secondary mutation in exon 20 (T790M) accounts for B50% of acquired drug resistance. 71,182 Screening for the emergence of such mutations on circulating tumor cells from the blood of patients during the course of treatment may allow earlier identification of acquired resistance.…”