Met Activation Is Associated with Unique Clinicopathologic and Molecular Features in Lung Adenocarcinoma
Lynette M Sholl, Anthony J Iafrate, Ming-Tsang Wu, Azra Ligon, Pasi A Janne, David C Christiani, Massimo Loda, Lucian R Chirieac. Brigham and Women's Hospital, Boston; Massachusetts General Hospital, Boston; Kaohsiung Medical University, Kaohsiung, Taiwan; Dana Farber Cancer Institute, Boston
Background: MET oncogene activation by gene amplification and/or autocrine HGF-Met signaling is associated with an invasive and metastatic phenotype in numerous tumor types. In EGFR-mutated lung adenocarcinoma (ACA), Met activation is associated with treatment failure in patients receiving tyrosine kinase inhibitors. Identification of Met-activated tumors has important therapeutic implications, however the clinicopathologic features of Met activation in lung tumors are not well established. We examined a cohort of lung ACA enriched for EGFR mutations and correlated Met phosphorylation and MET copy number (CN) with other clinicopathologic and molecular features.
Design: Met activation in 44 lung ACA resected from East Asian, never-smoking women was assayed by immunohistochemistry (IHC) using a Met Y1234/35 phospho-antibody (Cell Signaling Technology) (pMet). Tumors with ≥5% cells with moderate membrane staining were scored as positive. MET CN as assessed by FISH was defined as: relative gain (MET:CEP7 1-3) or amplified (MET:CEP7 >3). pMet and MET CN were correlated with each other and with EGFR mutation, EGFR CN, and clinicopathologic characteristics.
Results: pMet was expressed in 13 of 44 (30%) tumors, commonly at the tumor edge and in foci of pleural invasion. 68% of tumors had MET CN gain; one case was amplified. As compared to pMet negative tumors, pMet positivity correlated with MET CN gain (Fisher's exact, p=0.008), micropapillary features (62% v 23%, p=0.02), and younger age (mean 53 v 62 years; p=0.02). 92% of pMet-expressing tumors had EGFR mutations. Both pMet positive tumors and those with MET CN gain were more likely to present with distant metastases. MET CN gain failed to correlate with other clinical, histologic, or molecular features.
Conclusions: In a cohort of lung ACA enriched for EGFR mutations, pMet expression is seen in a third of cases and defines a clinically, pathologically, and molecularly distinct tumor subtype. In contrast, MET copy number gain is found in a heterogeneous group of tumors, less than half of which show pMet expression. These findings suggest that pMet IHC is better than MET copy number as a marker of Met activation and have important implications for selection of patients who may benefit from Met inhibitor therapy.
Monday, March 19, 2012 1:45 PM
Platform Session: Section D, Monday Afternoon