Comparison of EGFR and K-RAS gene status between primary tumours and corresponding metastases in NSCLC

Abstract

In non-small-cell lung cancer (NSCLC), epidermal growth factor receptor (EGFR) and K-RAS mutations of the primary tumour are associated with responsiveness and resistance to tyrosine kinase inhibitors (TKIs), respectively. However, the EGFR and K-RAS mutation status in metastases is not well studied. We compared the mutation status of these genes between the primary tumours and the corresponding metastases of 25 patients. Epidermal growth factor receptor and K-RAS mutation status was different between primary tumours and corresponding metastases in 7 (28%) and 6 (24%) of the 25 patients, respectively. Among the 25 primary tumours, three 'hotspot' and two non-classical EGFR mutations were found; none of the corresponding metastases had the same mutation pattern. Among the five (20%) K-RAS mutations detected in the primary tumours, two were maintained in the corresponding metastasis. Epidermal growth factor receptor and K-RAS mutations were detected in the metastatic tumours of three (12%) and five (20%) patients, respectively. The expressions of EGFR and phosphorylated EGFR showed 10 and 50% discordance, in that order. We conclude that there is substantial discordance in EGFR and K-RAS mutational status between the primary tumours and corresponding metastases in patients with NSCLC and this might have therapeutic implications when treatment with TKIs is considered.

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

“…This is similar to the previously published studies regardless of methodological approaches. 2,6,7,10,[23][24][25] The presence of discordant mutations most likely can be used as an indicator of a different clone. 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.…”

“…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.…”

“…2,[4][5][6][7][8][9][10] The data from published reports indicate a highly variable percentage of multifocal tumors identified as clonally related (up to 70%) and all reports agree that multifocal tumors may arise either as metastases from a single tumor or as independent tumors. Discrepancy between clinical and molecular classification of originally presumed cases of multiple primary lung cancers ranged in different series from 18 to 30%.…”

Cancer Stem Cells in Tumor Heterogeneity

“…Intriguingly, although many reports at least partially support the prediction of the clonal evolution theory (Fujii et al, 1996;Kuukasjarvi et al, 1997;Jones et al, 2008), several of the studies performed to date report remarkably diverging patterns of genetic alterations in primary tumors as compared to metastases from the same patient (Albanese et al, 2004;Katona et al, 2007;Artale et al, 2008;Kalikaki et al, 2008).…”

Esophagitis resulting from treatment with crizotinib for anaplastic lymphoma kinase rearrangement-positive lung adenocarcinoma: A case report

“…Furthermore, in the present case, the FFPE tissue specimen used for determining ALK-positivity was obtained from a metastatic tumor of the ovary. However, it has been previously reported that there may be a difference in EGFR and KRAS gene status between primary and metastatic tumor samples of NSCLC (12). Further studies are required in order to evaluate the adequacy of pathological samples obtained from metastatic tumors for the diagnosis of ALK-positivity of NSCLC.…”