Effusion Immunocytochemistry as an Alternative Approach for the Selection of First-Line Targeted Therapy in Advanced Lung Adenocarcinoma

Introduction: Tumor tissue is often not obtainable or suitable for molecular-based epidermal growth factor receptor (EGFR) mutational analysis in advanced non-small-cell lung cancer (NSCLC). This retrospective and single-institution study was conducted to evaluate the role of effusion immunocytochemistry using two EGFR mutant-specific antibodies for the detection of relevant EGFR mutations in NSCLC, along with the selection of candidates for first-line therapy with EGFR tyrosine kinase inhibitors (TKIs). Methods: Immunocytochemistry using two antibodies binding specifically to the major forms of mutant EGFR, L858R, and E746-A750 deletion (delE746-A750), was performed on cell blocks of malignant pleural effusion (MPE) from 78 patients with lung adenocarcinoma, who received first-line EGFR TKIs. The yield of EGFR-mutation detection and prediction of response rate and progression-free survival to TKI treatment by immunocytochemistry were compared with those by clinical characteristics and EGFR sequencing using cell-derived RNA from MPEs. Results: Of the 78 MPE samples, direct sequencing using cell-derived RNA identified L858R mutation in 42 cases, deletions in exon 19 in 12 cases (delE746-A750 in eight cases), other types of mutations in three cases, and wild-type EGFR in 21 cases. Effusion immunocytochemistry with these two mutant-specific antibodies exhibited a sensitivity of 71% and 88% and a specificity of 86% and 96% for identifying predefined L858R and delE746-A750 mutations, respectively. Effusion immunocytochemistry provided a superior prediction of tumor response and progression-free survival to first-line EGFR TKIs than did clinical characteristics like sex and smoking status. Patients whose effusion immunocytochemistry showed a reaction to either of the two antibodies had a comparable TKI response rate (67% versus 72%) to those with EGFR mutations assessed by direct sequencing from cell-derived RNA. Conclusions: Effusion immunocytochemistry could be introduced into clinical practice to identify more NSCLC patients likely to have benefit from first-line TKI treatment, especially for those without adequate tissue for molecular-based EGFR analysis

High co-expression of PD-L1 and HIF-1 alpha correlates with tumour necrosis in pulmonary pleomorphic carcinoma

Background: Pulmonary pleomorphic carcinomas (PPCs) are uncommon malignant tumours characterised by an aggressive clinical course and poor survival. These neoplasms frequently exhibit marked confluent necrosis, in which hypoxia levels are extremely high, causing low responsiveness to chemotherapy and conferring basic resistance to anti-cancer drugs. Programmed death ligand 1 (PD-L1) emediated immune escape may be an underlying source of resistance and a suitable target for specific therapy, but its role in PPCs is unclear. Materials and methods: In total, 122 PPCs were investigated. Paraffin-embedded tumour sections were stained with PD-L1 and hypoxia-inducible factor-1 alpha (HIF-1 alpha) antibodies. Overexpression was denoted by moderate-to-strong PD-L1 membrane staining in >= 5% of tumour cells and HIF-1 alpha nuclear staining in >= 10% of tumour cells. The presence of driver mutations in the epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), v-raf murine sarcoma viral oncogene homolog B (BRAF), telomerase reverse harscriptase gene (TERT), phosphoinositide 3-kinase catalytic alpha (PIK3CA), anaplastic lymphoma kinase (ALK), and ROS1 (ROS1 proto-oncogene receptor tyrosine kinase) genes were examined. Results: The overall frequencies of PD-L1 and HIF-1 alpha overexpression and EGFR mutation were 70.5, 75.4, and 22.1%, respectively. High PD-L1 expression was significantly correlated with that of HIF-1 alpha (p < 0.001) and tumour necrosis (p < 0.001). HIF-1 alpha expression was associated with EGFR mutation (p = 0.015). Advanced stage and high PD-L1 expression were two independent risks for poor overall survival. Conclusions: High PD-L1 and HIF-1 alpha co-expression was observed in PPCs compared with their expression in conventional non-small-cell lung carcinoma. The aggressive behaviour of PPC could be partially related to PD-L1-mediated immune escape and intratumoural hypoxia. High PD-L1 expression correlates with poor prognosis and may provide a rationale for the use of targeted immunotherapy in this subtype of high-grade PPC. (C) 2016 Elsevier Ltd. All rights reserved