T790M may not be a rare event before or after TKI therapy in patients with NSCLC with EGFR-activating mutations. The pretreatment T790M mutation was associated with shorter PFS with EGFR TKI therapy in patients with NSCLC.

Purpose: Clinical features of epidermal growth factor receptor (EGFR) mutations, L858R, deletions in exon 19, T790M, and insertions in exon 20, in non-small cell lung cancer (NSCLC) are well known. The clinical significance of other uncommon EGFR mutations, such as their association with the effectiveness of EGFR tyrosine kinase inhibitors (TKI), is not well understood. This study aimed to improve the understanding of these uncommon EGFR mutations of unknown clinical significance.Patients and Methods: Specimens from 1,261 patients were tested for EGFR mutations. We surveyed the clinical data and the effectiveness of gefitinib and erlotinib in NSCLC patients with uncommon EGFR mutations.Results: Of the 1,261 patients, 627 (49.8%) had EGFR mutations. This included 258 patients with deletions in exon 19, 260 patients with L858R, 25 patients with insertions or duplications in exon 20, 6 patients with de novo T790M, and 78 (12.4%) patients with uncommon mutations. Of the 78 patients, 62 received either gefitinib or erlotinib treatment. The response rate of TKIs treatment was 48.4%, and the median progression-free survival (PFS) was 5.0 months. Mutations on G719 and L861 composed a major part (28 of 62) of uncommon mutations, and were associated with a favorable effectiveness of EGFR TKIs (response rate, 57.1%; median PFS, 6.0 months). Mutations other than G719 and L861 led to a worse response to EGFR TKIs (response rate, 20.0%; median PFS, 1.6 months).Conclusions: Uncommon EGFR mutations constituted a distinct part of the whole group of EGFR mutations. Their composition was heterogeneous, and their associations with EGFR TKIs differed. Clin Cancer Res; 17(11); 3812-21. Ó2011 AACR.

Background: Although cigarette smoking is the major risk factor for lung cancer, only 7% of female lung cancer patients in Taiwan have a history of smoking. The genetic mechanisms of carcinogenesis in nonsmokers are unclear, but semaphorins have been suggested to play a role as lung tumor suppressors. This report is a comprehensive analysis of the molecular signature of nonsmoking female lung cancer patients in Taiwan, with a particular focus on the semaphorin gene family.Methods: Sixty pairs of tumor and adjacent normal lung tissue specimens were analyzed by using Affymetrix U133plus2.0 expression arrays. Differentially expressed genes in tumor tissues were identified by a paired t test and validated by reverse transcriptase-PCR and immunohistochemistry. Functional analysis was conducted by using Ingenuity Pathway Analysis as well as gene set enrichment analysis and sigPathway algorithms. Kaplan-Meier survival analyses were used to evaluate the association of SEMA5A expression and clinical outcome.Results: We identified 687 differentially expressed genes in non-small cell lung carcinoma (NSCLC). Many of these genes, most notably the semaphorin family, were participants in the axon guidance signaling pathway. The downregulation of SEMA5A in tumor tissue, both at the transcriptional and translational levels, was associated with poor survival among nonsmoking women with NSCLC.Conclusions: In summary, several semaphorin gene family members were identified as potential therapeutic targets, and SEMA5A may be useful as a prognostic biomarker for NSCLC, which may also be gender specific in Taiwanese patients.Impact: A novel biomarker for NSCLC is identified. Cancer Epidemiol Biomarkers Prev; 19(10); 2590-7. ©2010 AACR.

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.