Genetic heterogeneity of EGFR and KRAS mutations in primary tumor tissue from non-small cell lung cancer patients

Abstract: Activated epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations characterize molecular subgroups of non-small cell lung cancer (NSCLC) and have a strong predictive value for response to EGFR inhibitor therapy. Recently, EGFR mutation testing was included in the diagnostic algorithm of NSCLC. However, there is a controversy about the clonal stability of the mutation during the progression of the disease. The aim of this study was to analyze NSCLC tumor tissue for the presence of both EGFR and KRAS mutations in morphologically different parts of the primary tumor. Formaldehyd fixed and paraffin embedded lung cancer specimens from primary resected NSCLC patients were selected; five cases harboring EGFR and five with KRAS mutations. From each tumor, three morphologically different tumor sites were manually micro-dissected and analyzed for the presence of EGFR and KRAS mutations. Additionally, normal lung tissue at a distance from the primary tumor as well as in close vicinity was tested.The EGFR and KRAS status were consistent in the three different areas of the primary tumors of all ten cases. EGFR as well as KRAS mutations were as well detectable in close and in some distant normal lung parenchyma in 7 of 10 analyzed patient samples. In conclusion, we found consistent KRAS and EGFR mutation status in primary NSCLC tumors. This finding is of importance for clinical practice, because it indicates that any part of the tumor, independent of intratumoral histological pattern, is representative for EGFR and KRAS mutation testing.