High mesothelin expression in advanced lung adenocarcinoma is associated withKRASmutations and a poor prognosis

// Anish Thomas 1 , Yuanbin Chen 1 , Seth M. Steinberg 2 , Ji Luo 3 , Svetlana Pack 4 , Mark Raffeld 4 , Zied Abdullaev 4 , Christine Alewine 5 , Arun Rajan 1 , Giuseppe Giaccone 6 , Ira Pastan 5 , Markku Miettinen 4 , Raffit Hassan 1 1 Thoracic and GI Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA 2 Biostatistics and Data Management Section, Center for Cancer Research, National Institutes of Health, Bethesda, MD, USA 3 Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA 4 Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA 5 Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA 6 Lombardi Cancer Center, Georgetown University, Washington DC, USA Correspondence to: Raffit Hassan, e-mail: hassanr@mail.nih.gov Keywords: mesothelin, non-small cell lung cancer, KRAS, EGFR Received: January 12, 2015      Accepted: February 24, 2015      Published: April 13, 2015 ABSTRACT Mesothelin is a cell surface glycoprotein which is highly expressed in several epithelial cancers and may have a role in cell adhesion and metastases. In this study, we used prospectively obtained clinical and pathological data to characterize mesothelin expression in advanced lung adenocarcinoma. Tissue was obtained from patients who underwent molecular profiling of potentially actionable genes on a trial of molecular profiling and targeted therapies in advanced thoracic malignancies. We immunohistochemically evaluated the intensity, and the percentage of cells expressing mesothelin in 93 advanced lung adenocarcinomas. The evaluation was blinded for molecular data and outcome. Mutations of EGFR, KRAS, BRAF, AKT1, PIK3CA and HER2 were assessed by pyrosequencing; HER2 amplification and ALK translocation were assessed by fluorescence in situ hybridization. 53% of advanced lung adenocarcinomas expressed mesothelin to some degree; high mesothelin expression, defined as mesothelin positivity in more than 25% of cells, was found in 24% of patients. High mesothelin expression was associated with inferior survival (median 18.2 months vs. 32.9 months; P = 0.014). High mesothelin expression was strongly associated with mutant KRAS ( P < 0.0001) and wild-type EGFR ( P = 0.002). Our results provide strong rationale to explore anti-mesothelin targeted therapies in advanced lung adenocarcinoma especially in the KRAS -mutant subgroup.