Abstract 396: Analysis of MET-amplified solid tumors using chromogenic in situ hybridization (CISH)
Authors: Arguello David , Gatalica Zoran , Vranic Semir , Reddy Sandeep , VanderWalde Ari 
Published: July 2016

Abstract
MET amplification has been implicated in signaling pathways that promote cell proliferation, invasion, and survival. It has been identified as an oncogenic driver in various malignancies and is currently being investigated as a potential therapeutic target. To date, MET exon 14 skipping by sequencing and MET amplification by FISH have been found to have potential clinical utility in predicting those patients who may derive benefit from MET-targeted therapy. However, little research has been conducted on alternative technologies to FISH such as CISH, which does not require a dark room and can be interpreted by a board-certified pathologist. The purpose of this study is to report our experience with MET amplification across solid tumors using CISH.
A retrospective analysis was done on 26,619 specimens analyzed for MET amplification by CISH at a CLIA-certified lab (Caris Life Sciences). The validated CISH assay, previously validated against a FISH assay, utilized a gene copy number &gt; 5 to assess amplification. Concordance and correlative studies were done in MET-amplified, non-small cell lung cancer (NSCLC) specimens analyzed using a cMET IHC (SP44, 2+ or 3+ staining intensity in 50% or more tumor cell membrane) analyzing protein expression. Correlative studies involving co-existing aberrations, including PD-L1 (SP142, any intensity in at least 50% of tumor cells), in this MET-amplified, NSCLC cohort were also performed.
MET amplification utilizing CISH was 0.7% (188/26,619) overall. MET-amplified solid tumors included carcinomas such as NSCLC (3.1%, 87/2767), gastric adenocarcinoma (3.8%, 11/293), esophageal and esophagogastric junction adenocarcinoma (3.3%, 11/338), and endometrial carcinoma (0.4%, 9/2020) along with non-carcinomas, including glioblastoma multiforme (1.0%, 5/510), uterine sarcoma (1.3%, 5/400), melanoma (0.4%, 2/538), and rare tumors such as placental-site trophoblastic tumor (100%, 1/1) and prostatic neuroendocrine tumor (100%, 1/1). A sub-analysis of MET-amplified, NSCLC specimens demonstrated co-occurring protein overexpression in 92.6% (75/81) of cases. These same MET-amplified, NSCLC specimens were found to have EGFR pathogenic/presumed pathogenic mutations (19.7%, 15/76), ALK rearrangements (2.5%, 2/80), and PD-L1 overexpression (27.5%, 14/51). ROS1 rearrangements were not detected in this NSCLC cohort (0%, 0/76).
Our data suggest MET amplification detection utilizing CISH is a viable option for identifying MET-driven cancers. The presence of MET across various solid tumors contrasts with biomarkers like HER2, which are exclusive to carcinomas. A sub-analysis of our NSCLC population shows MET-amplified tumors contains a similar molecular distribution to the general NSCLC population. Future studies should incorporate MET CISH in clinical trials utilizing MET-targeted agents to determine its potential as a predictive test for evaluating who may derive the most benefit.
Citation Format: David Arguello, Zoran Gatalica, Semir Vranic, Sandeep Reddy, Ari VanderWalde. Analysis of MET-amplified solid tumors using chromogenic in situ hybridization (CISH). [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 396.