Content area
Full Text
1.
Introduction
Lung cancer is the leading cause of death among all cancer deaths (1). It has the highest morbidity and mortality among all malignancies worldwide (1,2). NSCLC accounts for 70–85% of all lung cancers, and most cases are of advanced stage or metastatic condition when diagnosed (3,4). As a targeted therapy, EGFR tyrosine kinase inhibitors (EGFR-TKIs) have been approved by the FDA for the treatment of advanced NSCLC since 2003 (5). EGFR-TKIs have produced encouraging results by postponing tumor progression and prolonging the progression-free survival (PFS) of advanced NSCLC patients for approximately 5 months compared to platinum-based doublet chemotherapy (6,7).
However, only 15% of NSCLC patients responded to TKI (8), and clinical trials on gefitinib or erlotinib failed in unselected patient populations, as they were not able to significantly prolong patient overall survival (OS) compared to traditional chemotherapy (9–11). Based on known EGFR mutations, researchers eventually discovered the association between TKI sensitivity and EGFR mutations (12). Moreover, they also observed considerable ethnic differences in the frequencies of EGFR mutations in NSCLC patients. EGFR mutations were detected in approximately 50% of Asian patients with NSCLC, but only in 10% of patients in the western world (13–15) (Fig. 1). Two types of EGFR mutations, in-frame deletions in exon 19 (Del19) and point mutations in exon 21 causing a leucine-to-arginine substitution at codon 858 (L858R), which are established to be definitely sensitive to TKIs, comprise approximately 90% of all EGFR mutations (15–18). The remaining 10% of EGFR mutations are defined as uncommon mutations (Fig. 1). Therefore, for NSCLC patients with uncommon EGFR mutations of unknown clinical significance, it is dubious whether they can benefit from TKI targeted therapy.
To answer this important question, there is an urgent need to determine the clinical significance of uncommon mutations in EGFR, particularly their sensitivity to TKIs. Although they only account for a small proportion of patients with EGFR mutations, they are still a large population due to the high incidence of NSCLC.
It seems apparent that we could try to pattern the methodologies of the Del19 and L858R mutations, which have been proven to be sensitive, mostly by means of clinical randomized controlled trials (RCTs) with large sample sizes. However, this is not a practical approach for uncommon mutations, as...