P1.02-040 Heterogeneity of the EGFR / KRAS Gene Mutation in Multifocal Lung Adenocarcinoma and the Clinical Significance

Abstract

Significant advances on EGFR-targeted therapy have allowed increasing availability of therapeutic options for non-small cell lung cancers. For multifocal lung adenocarcinoma patients in clinic, the EGFR gene mutation is generally examined only on the largest tumor or the one containing the most tumor cells, which could omit the tumors harboring the EGFR mutation and thus loss of opportunity for the tyrosine kinase inhibitors therapy. A total of 58 cases of multifocal lung adenocarcinoma, including 129 intrapulmonary tumors resected surgically, was recruited for this study. The genome DNA samples were prepared from formalin-fixed and paraffin-embedded tumor tissues. The EGFR / KRAS mutational status of each tumor was examined by Sanger’s DNA sequencing. The targeted hotspot mutations in EGFR gene included p.G719S/C/A (exon 18), p.T790M (exon 20), p.S768I (exon 20), p.L858R (exon 21), p.L861Q (exon 21) and deletions in exon 19. The hotspot mutations in KRAS gene were within codon 12 including p.G12C/V/S/R/D/A. In this group of 58 patients with multifocal lung adenocarcinoma, 38 patients were found EGFR or KRAS mutations in their tumors. Among them, the EGFR mutations were detected in 59 tumors derived from 34 cases; while the KRAS mutations were detected in 7 tumors from 5 cases. One patient (Case 30) was identified EGFR (exon 18, p.G719A) or KRAS (p.G12A or p.G12C) mutation in her 3 tumors, respectively. It is noteworthy that there were 21 (36.2%) in the 58 cases showing the mutational heterogeneity among the multiple intrapulmonary tumors derived from one individual, and that 6 tumors harbored 2 different types of EGFR mutation. However, none of the specimens investigated contained both EGFR and KRAS mutations within a same tumor. Comparing data from the present study along with the molecular pathological diagnosis records from the Department of Pathology, among the 58 cases enrolled, 30 cases accepted routine molecular pathological examination to check the EGFR / KRAS mutation, and 28 cases did not. However, 37 out of 66 tumors from the 30 cases were tested -- only 5 patients had all their tumors examined; whereas in the rest total 92 tumors unchecked, 42 EGFR sensitive mutations were identified in this study. Current finding suggests that the EGFR and KRAS mutational heterogeneity is widely existed in multifocal lung adenocarcinomas. Therefore, reliable and exhaustive examination for EGFR/KRAS mutation should be executed in the every tumor, to provide more individualized therapy choices for the patients.