Abstract 2242: cMET in non-small cell lung cancer: pieces of the puzzle

Abstract

Abstract A rapidly growing domain in present-day oncology is the development of targeted therapies, including several cMET inhibitors against non-small cell lung cancer (NSCLC). Nowadays, cMET amplification is used as a standard biomarker for patient selection, however there is no clear cut-off value to determine amplification, nor is there a real consensus about the way to test this. More recently, splicing variants of cMET, which skip exon 14, are gaining importance since it has been shown that patients harboring this mutation can respond to cMET directed targeted therapy. In this study, we explored the occurrence of cMET aberrations and their correlation with cMET expression in a population of 155 primary EGFR-TKI naive NSCLC tumors. Since cMET is considered as important in metastatic behavior, we also investigated the correlation of cMET expression and amplification between the primary tumor and metastases. Finally, given the link between the EGFR and cMET pathways, the EGFR status was also studied. Samples were collected at the Antwerp University Hospital and the Onze-Lieve-Vrouw Hospital Aalst. The expression of EGFR and cMET was determined by immunohistochemistry (Ventana, clones 3C6 and SP66 respectively), while cMET amplification was examined by in situ hybridization (Ventana, MET DNP and CEN7 DIG probes). EGFR mutations and cMET splice site mutations were detected by Sanger sequencing. Significant correlations were tested using the Chi2 and kappa test (SPSS 23). In 146/155 tumors cMET expression could be determined; 73/146 samples showed high (2+ or 3+ score) cMET expression and 4/118 samples showed amplification (ratio ≥ 2). No significant correlations could be determined between cMET expression and histological subtype of NSCLC (p = 0.065), differentiation degree (p = 0.468) and cMET amplification (p = 0.214). However, a significant correlation was found between cMET expression, EGFR expression (p = 0.015) and EGFR mutations (p = 0.029). Splice site mutation regions were sequenced in 87/155 samples, all of which were wild-type. When comparing cMET amplification between the primary tumor and the corresponding metastases (n = 40), only one sample showed amplification in the metastases and not in the primary tumor. Hence, cMET expression showed a significant correlation between primary tumors and their metastases (kappa = 0.003). The overall results of our study are in agreement with earlier data. Moreover, we showed that overall expression levels of cMET in primary tumors and metastases are very similar despite large intratumor heterogeneity. In conclusion, this study shows that high cMET expression in most NSCLC samples does not originate from presently known genetic cMET aberrations. High cMET expression is likely to be caused by temporary changes in transcription and translation, influenced by EGFR-signaling, miRNAs or other regulatory mechanisms. Citation Format: Nele Van Der Steen, Vanessa Deschoolmeester, Filip Lardon, Christian Rolfo, Elisa Giovannetti, Godefridus J. Peters, Patrick Pauwels. cMET in non-small cell lung cancer: pieces of the puzzle. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2242.