KRAS mutation status in primary nonsmall cell lung cancer and matched metastases

Abstract

BACKGROUND:The objective of this study was to determine whether the mutation status of the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and epidermal growth factor receptor (EGFR) differed between primary tumors and matched distant metastases in nonsmall cell lung cancer (NSCLC). METHODS: Patients who underwent resection for both primary NSCLC and matched distant metastases were included in the study. KRAS and EGFR mutation status were assessed by polymerase chain reaction (PCR) amplification and direct sequencing on both primary tumors and metastases. For KRAS analysis, mutant-enriched PCR (ME-PCR) was performed in case of discordance between a primary tumor and its matched metastasis. RESULTS: Twenty-one patients were included. No EGFR mutations were detected. KRAS mutations were detected in 6 patients (28%). In all patients, the mutations identified by direct sequencing were discordant between the primary tumor and the matched metastasis. The use of ME-PCR allowed a resolution of the discordance in 3 of the 6 cases by demonstrating the presence of low levels of mutant KRAS in lesions that were negative by direct sequencing. CONCLUSIONS: Highly sensitive tools are required to identify biomarkers. The KRAS mutation status mostly was concordant between primary tumors and matched distant metastases. In a few patients, KRAS mutation status differed between different tumor sites. Cancer 2010;116:2682-7.

Morphological and molecular approach to synchronous non-small cell lung carcinomas: impact on staging

“…Earlier studies indicated a broad range of discordance (25-49%) in driver mutations (EGFR, KRAS) between primary and metastatic lung tumors that in part can be explained by different methodological approaches, although authors mostly suggested intratumoral heterogeneity. 7,24,26 Yatabe et al 27 showed that the co-founding factors in the interpretation of targeted PCR-based mutation assays are related to the coexistence of gene amplification, contamination with normal tissue, tumor cell content and assay sensitivity rather than heterogeneity of somatic mutations. More recently, Vignot et al 28 demonstrated a high concordance rate (94%) for driver somatic alterations between primary lung tumors and matched metastases using next-generation sequencing approach.…”

Clonality of multifocal nonsmall cell lung cancer: implications for staging and therapy

“…A different prevalence of the main driving mutations in the KRAS and EGFR genes between primary NSCLC and associated lymph node or distant metastases has been reported with discordance rates of up to 33% [22][23][24][25][26][27][28][29][30], thus challenging the concept of a tumor-specific therapy. However, a 100% concordance was reported in a series of 6 NSCLCs and their corresponding brain metastases [23], possibly indicating that different metastatic sites may influence clonal selection and thus the rate of EGFR mutations.…”

Heterogeneity in Lung Cancer

“…Several authors (Badalian et al [89], Cortot et al [90], Kalikaki et al [91], Schmid et al [92], and Sun et al [93]) identified ITH for KRAS mutation status in adenocarcinomas, ranging from 69 to 86%. However, Alsdorf et al [94] reported that intra-tumour KRAS heterogeneity is a rare event, without discordance between primary tumour and metastasis.…”