Lukas Bubendorf1, Urania Dafni2, Martin Schöbel3, Stephen P Finn4, Verena Tischler5, Aleksandra Sejda6, Antonio Marchetti7, Erik Thunnissen8, Eric K Verbeken9, Arne Warth10, Irene Sansano11, Richard Cheney12, Ernst Jan M Speel13, Daisuke Nonaka14, Kim Monkhorst15, Henrik Hager16, Miguel Martorell17, Spasenija Savic3, Keith M Kerr18, Qiang Tan19, Zoi Tsourti20, Thomas R Geiger21, Roswitha Kammler21, Katja Schulze22, Ashis Das-Gupta23, David Shames22, Solange Peters24, Rolf A Stahel25. 1. Institute of Pathology, University Hospital Basel, Basel, Switzerland. Electronic address: Lukas.Bubendorf@usb.ch. 2. Frontier Science Foundation-Hellas & University of Athens, Athens, Greece. 3. Institute of Pathology, University Hospital Basel, Basel, Switzerland. 4. University of Dublin, Trinity College and St. James's Hospital, Dublin, Ireland. 5. Institute of Clinical Pathology, University Hospital Zurich, Zurich, Switzerland. 6. Department of Pathology, Medical University of Gdansk, Gdansk, Poland. 7. Anatomia Patologica, Ospedale Clinicizzato, Chieti, Italy. 8. Department of Pathology, VU University Medical Center, Amsterdam, Netherlands. 9. Department of Pathology, University Hospital Leuven, Leuven, Belgium. 10. Department of Pathology, University Hospital Heidelberg, Heidelberg, Germany. 11. Hospital Universitari Vall d'Hebron, Barcelona, Spain. 12. Department of Pathology and Laboratory Medicine,Roswell Park Cancer Institute, Buffalo, NY, USA. 13. Department of Pathology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Centre, Maastricht, Netherlands. 14. Christie Hospital NHS Foundation Trust, Manchester, United Kingdom. 15. Department of Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands. 16. Department of Pathology, Aarhus University Hospital, Aarhus, Denmark. 17. Consorcio Hospital General Universitario, Valencia, Spain. 18. Department of Pathology, Aberdeen Royal Infirmary, Aberdeen, United Kingdom. 19. Shanghai Lung Cancer Center, Shanghai, China. 20. Frontier Science Foundation-Hellas, Athens, Greece. 21. Translational Research Coordination, ETOP Coordinating Office, Bern, Switzerland. 22. Oncology Biomarker Development, Genentech Inc, South San Francisco, USA. 23. F. Hoffmann-La Roche Ltd, Basel, Switzerland. 24. Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland. 25. University Hospital Zürich, Zurich, Switzerland.
Abstract
INTRODUCTION: In a well-defined NSCLC cohort of the ETOP Lungscape program, we explored the epidemiology of IHC MET overexpression and amplification, their inter-correlation, and their association to outcome. METHODS: Resected NSCLC were assessed for MET gene copy number (GCN) and expression using silver in-situ hybridization (SISH) and immunohistochemistry (IHC) on TMAs in a multicenter setting. MET amplification was defined as MET/centromere ratio≥2 (with average MET GCN≥4), high MET GCN as CGN≥5 and MET IHC+ as ≥2+ intensity in ≥50% of tumor cells. A total of 182 MET IHC+ and EGFR/KRAS WT tumors were analyzed for METex14 skipping mutation. RESULTS: MET IHC+ was found in 23.8% of 2432 patients, significantly associated with female gender, small tumor size, and adenocarcinoma histology. We observed a high inter-laboratory variability in IHC and SISH analysis. MET amplification prevailed in 4.6% and MET GCN≥5 in 4.1% of 1572 patients. MET amplification and MET GCN≥5 were not significantly associated with any tumor characteristics or stage. Both were significantly associated with IHC MET positivity (p<0.001). METex14 skipping mutation prevailed in 5 of 182 (2.7%) MET IHC+ WT EGFR/KRAS NSCLC, 4 of which within the 88 adenocarcinomas (4.5%). No association of IHC MET overexpression, SISH MET amplification or high MET GCN was found with OS, RFS or TTR. CONCLUSION: MET overexpression is found in 23.8% of surgically resected NSCLC. MET amplification prevails in 4.6% and is associated with MET overexpression. Both have no influence on prognosis. The large inter-laboratory variability in IHC highlights the challenge of MET IHC analysis in routine practice.
INTRODUCTION: In a well-defined NSCLC cohort of the ETOP Lungscape program, we explored the epidemiology of IHC MET overexpression and amplification, their inter-correlation, and their association to outcome. METHODS: Resected NSCLC were assessed for MET gene copy number (GCN) and expression using silver in-situ hybridization (SISH) and immunohistochemistry (IHC) on TMAs in a multicenter setting. MET amplification was defined as MET/centromere ratio≥2 (with average MET GCN≥4), high MET GCN as CGN≥5 and MET IHC+ as ≥2+ intensity in ≥50% of tumor cells. A total of 182 MET IHC+ and EGFR/KRAS WT tumors were analyzed for METex14 skipping mutation. RESULTS: MET IHC+ was found in 23.8% of 2432 patients, significantly associated with female gender, small tumor size, and adenocarcinoma histology. We observed a high inter-laboratory variability in IHC and SISH analysis. MET amplification prevailed in 4.6% and MET GCN≥5 in 4.1% of 1572 patients. MET amplification and MET GCN≥5 were not significantly associated with any tumor characteristics or stage. Both were significantly associated with IHC MET positivity (p<0.001). METex14 skipping mutation prevailed in 5 of 182 (2.7%) MET IHC+ WT EGFR/KRAS NSCLC, 4 of which within the 88 adenocarcinomas (4.5%). No association of IHC MET overexpression, SISH MET amplification or high MET GCN was found with OS, RFS or TTR. CONCLUSION: MET overexpression is found in 23.8% of surgically resected NSCLC. MET amplification prevails in 4.6% and is associated with MET overexpression. Both have no influence on prognosis. The large inter-laboratory variability in IHC highlights the challenge of MET IHC analysis in routine practice.
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