Abstract 5618: Correlation between MET gene amplification and TP53 mutation in upregulating PD-L1 expression in EGFR wild-type lung cancer
Authors: Albitar Maher , Sudarsanam Sucha , Ma Wanlong , Jiang Shiping , Chen Wayne , Funari Vincent , Brodie Steven , Agersborg Sally 
Published: July 2017

Abstract
Introduction: MET gene activation has been reported to be associated with resistance to EGFR inhibitors in lung cancer. Resistance to EGFR inhibitors is also reported to be associated with upregulation of PD-L1. We studied PD-L1 expression levels with MET gene amplification and mutation in EGFR, KRAS, or TP53 in a large number of primary untreated lung cancers.
Methods: Tissue samples collected from 397 core biopsies or resections from lung cancers were studied for MET gene amplification by fluorescent in-situ hybridization (FISH) using MET (7q31) probe and centromere 7 as a control. Signals were quantified. PD-L1 expression on the same samples was evaluated using clone SP142 and standard immunohistochemistry (IHC) procedure. Samples were also sequenced using next generation sequencing (NGS) for mutations in TP53, KRAS, and EGFR.
Results: PD-L1 expression was detected in 166 patients (42%). Twenty seven (7%) had expression between 1% and 5%, 61 (15%) between 1% and 20%, 92 (23%) between 1% and 50%, and 105 (26%) had PD-L1 &gt; 50% in tumor cells. Ratio of MET: centromere signals was &gt; 1.5 in 16 (4%) of patients. Patients with MET ratio &gt; 1.5% had significantly higher (P=0.004) percentage of PD-L1 as a continuous variable as well as when cut-off points of 5% (P=0.01), 20% (P=0.0006), and 50% (P=0.01) were used. Patients with EGFR mutation had significantly lower levels of PD-L1 expression (P=0.003). When a cut-off point of 50% is used for PD-L1 expression, the EGFR-mutant cases had significantly less number of positive cases (P=0.0003). There was no correlation between the presence of High MET: Ratio and EGFR mutation. There was no correlation between KRAS mutation and overall PD-L1 expression (P=0.4). There was no correlation between MET ratio and KRAS mutation. Patients with TP53 mutation had significantly higher MET ratio when a cut-off at 1.5 is used (P=0.01). Also there was significant correlation between TP53 mutation and overall PD-L1 expression (P=0.0001). This remained significant when cut-off point of 50% or 5% are used (P=0.0004 and P=0.007, respectively). TP53 mutation was significantly more common in EGFR wild-type cases (P=0.0002).
Conclusions: Extra copies of MET gene as detected by FISH testing in therapy-naïve lung cancer patients is associated with higher expression of PD-L1, while EGFR-mutant lung cancers had significantly lower expression of PD-L1 when clone SP142 is used and NGS is used for detecting EGFR mutations. Patients with TP53 mutation had strikingly high expression of PD-L1 using SP142 clone and higher copy number of MET gene. This data suggests that in lung cancer, both MET and TP53 genes play a direct role in regulating PD-L1 expression opposing the EGFR gene, which appears to suppress PD-L1 expression. KRAS gene may not be involved in PD-L1 expression in lung cancer.
Citation Format: Maher Albitar, Sucha Sudarsanam, Wanlong Ma, Shiping Jiang, Wayne Chen, Vincent Funari, Steven Brodie, Sally Agersborg. Correlation between MET gene amplification and TP53 mutation in upregulating PD-L1 expression in EGFR wild-type lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5618. doi:10.1158/1538-7445.AM2017-5618