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A. Morey

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    P1.06 - Poster Session 1 - Prognostic and Predictive Biomarkers (ID 161)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.06-034 - MET expression, copy number and oncogenic mutations in early stage NSCLC (ID 2424)

      09:30 - 16:30  |  Author(s): A. Morey

      • Abstract

      The MET receptor tyrosine kinase and its ligand are associated with the malignant phenotype. In non-small cell lung cancer (NSCLC) MET expression increases with disease stage and is involved in de novo and acquired resistance to tyrosine kinase inhibitors. Despite this, in early stage NSCLC, conflicting data series have reported MET expression and copy number to be prognostic in some studies but not others[1,2]. We investigated a large cohort of patients who underwent curative surgical resection at our institution to determine whether MET receptor or gene amplification was prognostic.

      Tissue Microarrays (TMAs) were constructed using 1mm cores of FFPE primary NSCLC tissues in triplicate. TMAs were stained with the MET SP44 clone and a H-score calculated based on % cells stained and intensity; (%cellsx1)+(%cellsx2)+(%cellsx3) with a minimum of 0 and maximum of 300. The mean of triplicate values was calculated. MET gene amplification was detected using Ventana’s MET DNP probe with ultraView SISH DNP silver detection, performed on Ventana’s XT autostainer. DNA was isolated and subjected to mutational profiling using Sequenom’s LungCarta panel.

      Data for 508 patients, 352 (69%) male, were available for analysis including 329 pathological node negative (pN0), 67 pN1, 104 pN2 and 8 patients with resected primaries and solitary brain metastases (M1). Most patients were smokers with only 33 (6%) non-smokers. The median MET H-score was 100 and consistent across N0, N1 and N2 patients, although was higher in M1 patients. Median H-scores were significantly higher in adenocarcinoma compared to squamous cell carcinoma (140 vs 91.5, p<0.0001). Increased MET expression (H-score>100) was seen in 227 (45%) patients. High quality DNA was isolated in 443/508 (87%) of samples. The commonest mutations were in KRAS (21%), TP53 (10%), EGFR (5%), PIK3CA (4%) MET (3%) and NRF2 (3%). No mutation was found in 44% of samples. EGFR and KRAS mutations were associated with significantly higher MET expression, whereas TP53 was associated with significantly lower expression (Chi square p=0.0005). These differences may reflect the higher rates of adenocarcinoma in both EGFR and KRAS mutated tumours. Increased MET copy number by SISH was only observed in 6 samples. MET expression was not associated with cancer specific survival across all stages. In tumours harbouring mutations and in wild type tumours, there were no significant differences in survival according to MET expression.

      Although increased MET expression was associated with both KRAS and EGFR mutations, it was not prognostic in this large cohort of resected NSCLC. MET expression may be both predictive and prognostic in advanced NSCLC, but its role in early stage NSCLC is unclear. References: 1. Dziadziuszko R, et al. Correlation between MET Gene Copy Number by Silver In Situ Hybridization and Protein Expression by Immunohistochemistry in Non-small Cell Lung Cancer. Journal of Thoracic Oncology. 2012 Feb;7(2):340–7. 2. Cappuzzo F, et al. Increased MET gene copy number negatively affects survival of surgically resected non-small-cell lung cancer patients. Journal of Clinical Oncology. 2009 Apr 1;27(10):1667–74.