RESUMO
BACKGROUND: The impact of primary tumor size on the therapeutic outcomes of EGFR-tyrosine kinase inhibitors (TKIs) in advanced non-small cell lung cancer (NSCLC) with EGFR mutation remains unclear. METHODS: A total of 291 consecutive patients with advanced EGFR-mutant NSCLC administered first-line EGFR-TKIs were enrolled. Computed tomography was used to assess primary tumor diameter. The amplification refractory mutation system plus was used to quantitatively evaluate the abundance of EGFR mutations. Associations between depth of response, abundance of EGFR mutations, and tumor size was investigated. RESULTS: Patients were divided into three groups according to T classification: ≤ 3 cm (n = 109), 3-5 cm (n = 121), and > 5 cm (n = 61). Median progression-free survival (PFS) was significantly longer in the ≤ 3 cm and 3-5 cm groups compared to the > 5 cm group (10.8 vs. 10.5 vs. 7.1 months; P < 0.001). Subgroup analysis revealed a consistent result in patients with exon 19 deletion and 21 L858R mutation. Multivariate analysis revealed that tumor size was an independent predictive factor for PFS (hazard ratio 1.528, 95% confidence interval 1.104-2.115; P = 0.010). Larger tumors (> 5 cm) were marginally significantly less EGFR-mutant abundant than smaller tumors (≤ 5 cm) (mean ± standard deviation 30.5 ± 29.5% vs. 45.8 ± 43.1%; P = 0.08). CONCLUSION: Larger tumors (> 5 cm) were associated with inferior PFS of first-line EGFR-TKI therapy in advanced NSCLC patients with activating EGFR mutations. A potential explaination might be that EGFR mutations are less abundant in larger tumors.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Intervalo Livre de Progressão , Estudos Retrospectivos , Deleção de Sequência , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Carga TumoralRESUMO
BACKGROUND: Herpes Virus Entry Mediator (HVEM) is an important immune checkpoint in cancer recognition. HVEM expressed on tumor cell membranes activates immune cell signaling pathways leading to either inhibition of activity (B- and T-lymphocyte attenuator, BTLA) or activation of immune activity (LIGHT). The aim of this study is to investigate the prevalence of HVEM expression and its association with PDL1 expression in NSCLC. METHODS: A TMA of 527 resected NSCLC samples and 56 NSCLC cell lines were evaluated for HVEM and PD-L1 expression. The IHC assay for HVEM was optimized on the Dako Link48 autostainer using a polyclonal antibody from R&D Systems(AF356). PD-L1 IHC was performed on the Dako Link48 autostainer using the PD-L1 28-8 pharmDx kit. Scoring HVEM employed the H-score system while for PD-L1 the tumor proportion score (TPS) was used. RESULTS: HVEM expression in the NSCLC resected samples and cell lines revealed a positive H-score more than 1 was 18.6% (77/415) and 48.2% (27/56) respectively. HVEM expression was significantly higher in patients with lymph node N2 metastasis (25.5% vs 7.9% vs 17.5%, p = 0.046) when comparing with N1 or no lymph node metastasis, and was marginally significantly higher in patients with stage III/IV disease (24.5% vs 16.4%, p = 0.059). Subgroup analysis showed that HVEM (median 45 vs 36 months, p = 0.706) and PD-L1 expression (median 45 vs 48 months, p = 0.178) status was not predictive of overall survival. HVEM was found to have a significant negative correlation with PD-L1 expression (r=-0.274, p < 0.001) in patients with NSCLC and also a weak negative correlation in NSCLC cell lines (r=-0.162, p = 0.352). CONCLUSION: HVEM was found to be overexpressed in NSCLC patients of N2 lymph node metastasis or later stage and has a negative co-relationship with PD-L1 expression. HVEM was not prognostic for NSCLC patients.
Assuntos
Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/imunologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Linfonodos/imunologia , Linfonodos/metabolismo , Linfonodos/patologia , Metástase Linfática/imunologia , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Membro 14 de Receptores do Fator de Necrose Tumoral/imunologiaRESUMO
INTRODUCTION: Programmed death-ligand 1 (PD-L1) expression using immunohistochemistry is approved by the US Food and Drug Administration to guide treatment with anti-programmed death-1/PD-L1 monoantibodies. However, intratumoral heterogeneity of PD-L1 expression and the accordance between primary and metastatic lesions remains unresolved. MATERIALS AND METHODS: PD-L1 expression was evaluated in tumor cells and tumor-infiltrating lymphocytes (TILs) of surgically resected lung adenosquamous carcinoma. Discrepancy of PD-L1 expression and cluster of differentiation 8-positive TILs of different histologic components was investigated. PD-L1 expression was also compared between primary tumor and nodal metastases. RESULTS: The study included a total of 72 lung adenosquamous carcinomas. Fifteen patients (20.8%) and 25 patients (34.7%) were positive for PD-L1 expression in adenomatous and squamous components respectively, with a cutoff value of 5%. We found that 57.8% of cases showed consistent PD-L1 expression in tumor cells in the different histological components at a cutoff of 1%, and 48.1% of cases were likewise consistent at a cutoff of 5%. In paired squamous components of metastatic nodes and primary lesions, 90% and 80% of cases of PD-L1 expression were consistent, at cutoffs of 1% and 5%, respectively. For the adenomatous component of tumor/metastasis pairs, 77.8% of cases at the 1% cutoff and 74.1% of cases at the 5% cutoff were consistent, partially attributed to the difference of predominant histologic patterns. CONCLUSION: PD-L1 expression showed discrepancy in different histological components within a tumor and consistency in paired histological type between tumor and metastases. Different pathological features might contribute to the heterogeneous PD-L1 expression in patients with non-small-cell lung cancer.