- Email: [email protected]
CREB Pathway in Lung Adenocarcinoma Oncogenesis
November 2017 target regions using the Oncomine® Focus Assay on an Ion PGM platform. This panel evaluates 132 hotspot sites of driver mutations in 35 genes, copy number variations in 19 genes and 23 gene fusions. Result: To date 262-lung adenocarcinomas have been included. Genetic alterations were detected in 72% (189 of 262) of all patients. Corroborating previous data from different groups, including ours, the most common actionable alteration detected in this study were EGFR mutation (23%) and ALK rearrangement (7%). Oncogene rare mutations were detected in 68 patients. HER2 mutations were found in 4% and BRAF in 2% of tested patients. ROS were the second most common fusion (3%) followed by RET (2%) and MET exon 14 mutation in 1.5%. PIK3CA was seen 5% of patients. Other rare mutations such as MTOR, CTNNB1, FGFR2, JAK2, SMO, KIT, IDH1, GNA11, ERBB3, PGFRA, FGFR1 and MAP2K1 were detected each with less than 1%. Conclusion: In a representative Brazilian cohort, the percentage of rare mutations detected matches data published elsewhere. An extended cohort and health economics data will be presented during the meeting and will allow a better description of the rare mutations and the potential impact they may have in the landscape of lung adenocarcinoma treatment in Brazil. These data may support drug access decisions in the country. Keywords: Rare mutations, next generation sequencing, Multiplex diagnosis platform
PUB071 Circulating Programmed Death Ligand-1 (PD-L1) in Non-Small Cell Lung Cancer (NSCLC) S. Vecchiarelli,1 A. D’Incecco,2 G. Minuti,1 M. Gallo,3 A. De Luca,3 L. Landi,1 C. Bennati,1 M. Spreafico,4 M. D’Arcangelo,1 L. Attilia,1 V. Mazza,1 N. Normanno,3 F. Cappuzzo1 1Oncohematology Department, Ausl Romagna, Ravenna/IT, 2Center for Immuno-Oncology, University Hospital of Siena, Siena/IT, 3Cell Biology and Biotherapy Unit, Instituto Nazionale Tumori ‘Fondazione Giovanni Pascale, Ircc, Naples/ IT, 4Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo Per Lo Studio E La Cura Dei Tumori (Irst), Ravenna/IT Background: The treatment landscape of Non-Small Cell Lung Cancer (NSCLC) is rapidly changing with the introduction of immunecheckpoint inhibitors. Programmed death 1 (PD-1) is a key immunecheckpoint expressed in activated T cells, which mediates immunosuppression by binding its ligand, PD-L1. The predictive and prognostic value of PD-L1 is currently under investigation. The possibility to assess PD-L1 expression in plasma has been partially investigated and no data exist on the feasibility of such test in clinical setting as well as how levels of PD-L1 expression change during systemic therapy. Aim of the present study was to define feasibility of plasma PD-L1 testing and to assess how PD-L1 expression is modified by standard treatment. Method: PD-L1 expression was evaluated in plasma samples from patients with chemo-naïve NSCLC candidate for systemic first-line therapy, irrespective of histology or any other clinical or biological characteristic. A cohort of healthy volunteers (Healthy control Cohort-HC), individuals who are not affected by oncology, autoimmune, metabolic and infectious diseases, was also analyzed for plasma PD-L1 expression. PD-L1 in plasma samples was evaluated using the Human programmed death ligand-1 (PD-L1/CD274) ELISA kit (CUSABIO, MD, USA). Result: A total of 56 individuals with histologically confirmed stage IV NSCLC and 16 HC were included onto the study. Patients had a median age of 70 years (range 48-85), were predominantly male (67.9%) and former smokers (57.1%), with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (67.8%). The majority of patients received chemotherapy as front line treatment (N¼41, 73.2%), 3 (5.4%) immunotherapy and 12 (21.4%) targeted therapies (N EGFR inhibitors¼ 9, N ALK inhibitors¼ 3). PD-L1 plasma levels was first detected in the HC and then in NSCLC patients. In HCs median PD-L1 basal level was 37.81 pg/ml (range 9.73-90.21), while in NSCLC patients was 42.21 pg/ml (range 12.00-143.49). This difference was not statistically significant (p ¼ 0.78). Interestingly,
Abstracts
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levels of PD-L1 plasma expression significantly increased during the first 3 months of systemic therapy (Wilcoxon test p¼0.04). In addition, the 5 patients with high levels of plasma PD-L1 expression had significantly shorter progression free survival (PFS) and overall survival (OS) than individuals with low or no plasma PD-L1 expression (PFS: 1.2 versus 6.4 months, p¼0.056; OS: 1.2 versus 9.7 months, p¼0.003). Conclusion: Plasma PD-L1 expression is feasible in clinical practice. High levels of expression could correlate with worst prognosis. Additional studies exploring correlation between plasma and tumor tissue PD-L1 expression are needed. Keywords: Immunotherapy, PD-L1, Non-Small Cell Lung Cancer (NSCLC)
PUB072 Significance of PAK1/CREB Pathway in Lung Adenocarcinoma Oncogenesis S. Yoon, J. Chung, L. Kang, H. Ock, H. Seo, Y. Kim Pulmonology, Pusan National University Yangsan Hospital, Yangsan-Si/KR Background: P21-activated kinase 1 (PAK1) is serine/threonine protein kinase that contributes to Ras-driven tumorigenesis in non-small cell lung cancer (NSCLC). Cyclic AMP-response element-binding protein (CREB) is the transcription factor that regulates tumor cell differentiation and proliferation. Several studies have shown that expression level of PAK1 and CREB is elevated in NSCLC, respectively. However, the association between PAK1 and CREB in the regulation of carcinogenesis has not been well known in NSCLC. Here, we identified that overexpression of PAK1 and CREB is more prevalent in lung adenocarcinoma compared to normal tissue and PAK1 expression is significantly associated with CREB expression. Method: Sixteen tumor tissues from patients with lung adenocarcinoma were collected to evaluate PAK1 and CREB expressions by immunostaining and western blot analysis. Knockdown of PAK1 by siRNA was performed to evaluate the association between PAK1 and CREB. Result: PAK1 and CREB expressions, which were evaluated by immunohistochemistry and western blot assay were significantly increased in lung adenocarcinoma compared to normal lung tissues. Kaplan-Meier survival analysis with an online database showed the prognostic significance of PAK1 and CREB in lung adenocarcinoma. Knockdown of PAK1 by siRNA significantly suppressed the expression of CREB. PAK1 expression level was linearly correlated with CREB expression level by regression analysis (p¼0.013). Conclusion: We demonstrated that expression level of both PAK1 and CREB was elevated in lung adenocarcinoma and high expression predicted a poor prognosis. Our results suggest that PAK1 regulates carcinogenesis through CREB in lung adenocarcinoma. Keywords: lung adenocarcinoma, PAK1, CREB
PUB073 Lung Cancer Screening with LDCT e Results of a Small Cohort Continual Monitoring (Pilot Silesian Study) S. Szablowska-Siwik,1 E. Wachula,1 D. Czyzewski,2 S. Nawrocki,3 M. Adamek2 1Department of Oncology, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Katowice/ PL, 2Department of Thoracic Surgery, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Katowice/ PL, 3Department of Radiotherapy, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Katowice/PL Background: Lung cancer still remains the leading cause of cancer deaths worldwide. Screening with low-dose computed tomography (LDCT) has been demonstrated to shift detected lesions towards lower stages, thus reducing lung cancer mortality. The aim of the study was to evaluate the results of a Pilot Silesian Study for Early Lung Cancer Detection with LDCT. Method: In total 602 asymptomatic volunteers over 50 years of age with a smoking history of at least 20 pack-years have been undergoing LDCT screening annually or in shorter intervals, if
PUB071 Circulating Programmed Death Ligand-1 (PD-L1) in Non-Small Cell Lung Cancer (NSCLC) S. Vecchiarelli,1 A. D’Incecco,2 G. Minuti,1 M. Gallo,3 A. De Luca,3 L. Landi,1 C. Bennati,1 M. Spreafico,4 M. D’Arcangelo,1 L. Attilia,1 V. Mazza,1 N. Normanno,3 F. Cappuzzo1 1Oncohematology Department, Ausl Romagna, Ravenna/IT, 2Center for Immuno-Oncology, University Hospital of Siena, Siena/IT, 3Cell Biology and Biotherapy Unit, Instituto Nazionale Tumori ‘Fondazione Giovanni Pascale, Ircc, Naples/ IT, 4Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo Per Lo Studio E La Cura Dei Tumori (Irst), Ravenna/IT Background: The treatment landscape of Non-Small Cell Lung Cancer (NSCLC) is rapidly changing with the introduction of immunecheckpoint inhibitors. Programmed death 1 (PD-1) is a key immunecheckpoint expressed in activated T cells, which mediates immunosuppression by binding its ligand, PD-L1. The predictive and prognostic value of PD-L1 is currently under investigation. The possibility to assess PD-L1 expression in plasma has been partially investigated and no data exist on the feasibility of such test in clinical setting as well as how levels of PD-L1 expression change during systemic therapy. Aim of the present study was to define feasibility of plasma PD-L1 testing and to assess how PD-L1 expression is modified by standard treatment. Method: PD-L1 expression was evaluated in plasma samples from patients with chemo-naïve NSCLC candidate for systemic first-line therapy, irrespective of histology or any other clinical or biological characteristic. A cohort of healthy volunteers (Healthy control Cohort-HC), individuals who are not affected by oncology, autoimmune, metabolic and infectious diseases, was also analyzed for plasma PD-L1 expression. PD-L1 in plasma samples was evaluated using the Human programmed death ligand-1 (PD-L1/CD274) ELISA kit (CUSABIO, MD, USA). Result: A total of 56 individuals with histologically confirmed stage IV NSCLC and 16 HC were included onto the study. Patients had a median age of 70 years (range 48-85), were predominantly male (67.9%) and former smokers (57.1%), with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (67.8%). The majority of patients received chemotherapy as front line treatment (N¼41, 73.2%), 3 (5.4%) immunotherapy and 12 (21.4%) targeted therapies (N EGFR inhibitors¼ 9, N ALK inhibitors¼ 3). PD-L1 plasma levels was first detected in the HC and then in NSCLC patients. In HCs median PD-L1 basal level was 37.81 pg/ml (range 9.73-90.21), while in NSCLC patients was 42.21 pg/ml (range 12.00-143.49). This difference was not statistically significant (p ¼ 0.78). Interestingly,
Abstracts
S2389
levels of PD-L1 plasma expression significantly increased during the first 3 months of systemic therapy (Wilcoxon test p¼0.04). In addition, the 5 patients with high levels of plasma PD-L1 expression had significantly shorter progression free survival (PFS) and overall survival (OS) than individuals with low or no plasma PD-L1 expression (PFS: 1.2 versus 6.4 months, p¼0.056; OS: 1.2 versus 9.7 months, p¼0.003). Conclusion: Plasma PD-L1 expression is feasible in clinical practice. High levels of expression could correlate with worst prognosis. Additional studies exploring correlation between plasma and tumor tissue PD-L1 expression are needed. Keywords: Immunotherapy, PD-L1, Non-Small Cell Lung Cancer (NSCLC)
PUB072 Significance of PAK1/CREB Pathway in Lung Adenocarcinoma Oncogenesis S. Yoon, J. Chung, L. Kang, H. Ock, H. Seo, Y. Kim Pulmonology, Pusan National University Yangsan Hospital, Yangsan-Si/KR Background: P21-activated kinase 1 (PAK1) is serine/threonine protein kinase that contributes to Ras-driven tumorigenesis in non-small cell lung cancer (NSCLC). Cyclic AMP-response element-binding protein (CREB) is the transcription factor that regulates tumor cell differentiation and proliferation. Several studies have shown that expression level of PAK1 and CREB is elevated in NSCLC, respectively. However, the association between PAK1 and CREB in the regulation of carcinogenesis has not been well known in NSCLC. Here, we identified that overexpression of PAK1 and CREB is more prevalent in lung adenocarcinoma compared to normal tissue and PAK1 expression is significantly associated with CREB expression. Method: Sixteen tumor tissues from patients with lung adenocarcinoma were collected to evaluate PAK1 and CREB expressions by immunostaining and western blot analysis. Knockdown of PAK1 by siRNA was performed to evaluate the association between PAK1 and CREB. Result: PAK1 and CREB expressions, which were evaluated by immunohistochemistry and western blot assay were significantly increased in lung adenocarcinoma compared to normal lung tissues. Kaplan-Meier survival analysis with an online database showed the prognostic significance of PAK1 and CREB in lung adenocarcinoma. Knockdown of PAK1 by siRNA significantly suppressed the expression of CREB. PAK1 expression level was linearly correlated with CREB expression level by regression analysis (p¼0.013). Conclusion: We demonstrated that expression level of both PAK1 and CREB was elevated in lung adenocarcinoma and high expression predicted a poor prognosis. Our results suggest that PAK1 regulates carcinogenesis through CREB in lung adenocarcinoma. Keywords: lung adenocarcinoma, PAK1, CREB
PUB073 Lung Cancer Screening with LDCT e Results of a Small Cohort Continual Monitoring (Pilot Silesian Study) S. Szablowska-Siwik,1 E. Wachula,1 D. Czyzewski,2 S. Nawrocki,3 M. Adamek2 1Department of Oncology, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Katowice/ PL, 2Department of Thoracic Surgery, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Katowice/ PL, 3Department of Radiotherapy, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Katowice/PL Background: Lung cancer still remains the leading cause of cancer deaths worldwide. Screening with low-dose computed tomography (LDCT) has been demonstrated to shift detected lesions towards lower stages, thus reducing lung cancer mortality. The aim of the study was to evaluate the results of a Pilot Silesian Study for Early Lung Cancer Detection with LDCT. Method: In total 602 asymptomatic volunteers over 50 years of age with a smoking history of at least 20 pack-years have been undergoing LDCT screening annually or in shorter intervals, if