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B. Dome
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MA12 - Miscellaneous Biology/Pathology (ID 476)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Biology/Pathology
- Presentations: 11
- Moderators:B. Dome, W.D. Travis
- Coordinates: 12/06/2016, 14:20 - 15:50, Schubert 1
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MA12.01 - Next Generation Sequencing Based Clinical Framework for Analyses of Treatment Predictive Mutations and Gene Fusions in Lung Cancer (ID 4108)
14:20 - 15:50 | Author(s): K. Ericson Lindquist, A. Karlsson, P. Levéen, H. Brunnström, C. Reuterswärd, K. Holm, M. Jönsson, K. Annersten, F. Rosengren, K. Jirström, J. Kosieradzki, L. Ek, Å. Borg, M. Planck, G. Jönsson, J. Staaf
- Abstract
- Presentation
Background:
The use of new, emerging techniques in the search of tailored patient therapies is rapidly becoming a reality. Here we describe the optimization and implementation of next generation sequencing for treatment predictive mutation screening in parallel with gene fusion status of ALK, RET and ROS1 in non-small cell lung cancer (NSCLC) patients.
Methods:
The Illumina TruSight tumor 26-gene NGS panel was validated in 81 clinical routine FFPE or cytology specimens and implemented in 533 diagnostic NSCLCs during one year of clinical analysis. In parallel, a RNA-based NanoString method was evaluated in 169 cases for gene fusion status of ALK, RET and ROS1.
Results:
We have successfully established a streamlined workflow with a 5-day turnaround time from specimen arrival to mutation report. The concordance in the validation cohort was 99% for comparable variants. In the 533 diagnostic samples, 1-2 variants were detected in 79% of the cases. Most frequently mutated genes included TP53, KRAS, EGFR, STK11, and BRAF, all with differences in mutational patterns between histological subgroups. The RNA-based NanoString assay was successfully established and validated. The success rate in the 169 cases was 80% and 10 gene fusions were found (five ALK fusions, three RET fusions and two ROS1 fusions) all in adenocarcinomas. Integration of mutation and gene fusion status revealed that 68% of adenocarcinomas, 13% of SqCCs and 56% of NSCLC-NOS harbored ≥1 actionable alteration ALK, RET, ROS1, EGFR, KRAS, PIK3CA, BRAF, NRAS, MAP2K1, ERBB2 or AKT1. Specifically, in 13.2% of the adenocarcinomas where no EGFR or ALK alteration was detected emerging targeted therapy may be considered in addition to the 15.3% of patients that was eligible for EGFR or ALK inhibitors. The corresponding proportions for SqCCs were 5.5% in addition to the 2.2%, and for NSCLC-NOS 2.5% in addition to the 11.2% eligible for EGFR or ALK inhibitors.
Conclusion:
Next generation sequencing in combination with the NanoString technology is time- and cost efficient in the diagnostic routine for treatment predictive mutation screening and gene fusion status detection. The techniques represent valuable tools for pinpointing patients eligible to standard targeted therapies in addition to new emerging therapies.
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MA12.02 - MMP12 and LMO7, Two Key Players on opposite Sides of Early Lung Squamous Cell Carcinoma Development (ID 5882)
14:20 - 15:50 | Author(s): A. Barrett, S. Lourenco, K. Kolluri, B. Carroll, M. Falzon, E. Borg, J. George, S.M. Janes, V.H. Teixeira
- Abstract
- Presentation
Background:
Our laboratory has a unique cohort of patients with pre-invasive lung squamous cell carcinoma (SqCC) lesions, within which there is a clear discrepancy between the prevalence of pre-invasive lesions and the incidence of lung cancer, suggesting that not all pre-invasive lesions progress to cancer. Using gene expression microarrays we identified 1846 genes significantly differentially expressed between progressive and regressive pre-invasive SqCC lesions. The macrophage metalloelastase MMP12 gene was found to be highly expressed in progressive lesions, and we hypothesised that it plays a role in epithelial-to-mesenchymal transition (EMT). Conversely, the actin binding protein LIM-domain only 7 (LMO7) gene was highly expressed in regressive lesions, and we postulated that it may be protective against EMT due to its role in the maintenance of epithelial architecture. Initial studies using three SqCC cell lines (A431, H357 and H376) with MMP12-shRNA knockdown showed a significant decrease in migration and invasion compared to non-silencing shRNA controls. LMO7-shRNA knockdown in HBECs was found to significantly increase migration. The aim of this study is to further characterise the function and signalling of MMP12 and LMO7 in lung SqCC development.
Methods:
Eight-week-old NOD/SCID mice were used for tumorigenesis experiments. A431 and H357 MMP12-shRNA knockdown and non-silencing shRNA cells were injected in a suspension of one million cells in a total of 200μl, subcutaneously in the right and left flank, respectively. Tumours were measured every 2–5 days. Adhesion assays were carried out to assess the roles of MMP12 knockdown or LMO7 overexpression on cell adhesion. Cell signalling mechanisms were assessed using western blotting, qPCR and immunostaining.
Results:
We observed that MMP12 knockdown decreases tumorigenicity in an immunocompromised mouse model. Both A431 and H357 MMP12 knockdown cells produced significantly smaller tumours compared with non-silencing shRNA cells. We found that MMP12 knockdown decreases cell adhesion, which is currently being further investigated along with effects on integrin signalling pathways. Levels of EMT markers were assessed in MMP12 knockdown and LMO7 overexpressing cells using qPCR, western blotting and immunostaining. Results indicate that higher MMP12 expression is associated with a mesenchymal phenotype, whereas higher LMO7 expression is associated with an epithelial phenotype.
Conclusion:
Our results suggest that MMP12 is a key driver of migration and invasion in SqCC and its high expression may contribute to EMT, whereas LMO7 is a putative tumour suppressor with a crucial role in maintaining epithelial cell architecture. MMP12 and LMO7 may be potential therapeutic markers for lung cancer at an early stage.
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MA12.03 - Discussant for MA12.01, MA12.02 (ID 7010)
14:20 - 15:50 | Author(s): E. Brambilla
- Abstract
- Presentation
Abstract not provided
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MA12.04 - Mitochondrial-Related Proteins, PGAM5 and FUNDC1, in COPD-Associated Non-Small Cell Lung Carcinoma (ID 5646)
14:20 - 15:50 | Author(s): F. Kwong, A. Nicholson, I. Adcock, F. Chung
- Abstract
- Presentation
Background:
Patients with COPD and/or emphysema have an increased risk of non-small cell lung cancer (NSCLC). COPD and lung cancer are both characterised by increased oxidative stress associated with mitochondrial dysfunction. We hypothesise that mitochondrial dysfunction is a driving mechanism for the increased risk of NSCLC in COPD. We determined whether there is dysregulated expression of mitochondrial-related proteins in NSCLC arising in COPD, and if so, their clinical significance.
Methods:
To determine the clinical relevance of mitochondrial related gene expression, we examined a database containing transcriptomic data of more than 1, 000 human NSCLC samples and with survival outcomes (https://precog.stanford.edu/). Immunohistochemistry for PGAM5 and FUNDC1 was performed on cancer and background (‘normal’) tissue from lung cancer resections from non-smokers, healthy smokers (without COPD) and COPD/ emphysema patients. Protein expression was assessed using a semi-quantitative immunohistochemical scoring system (H score). Specific gene expression was further correlated with outcome in dataset GSE 72194, containing transcriptomic data of NSCLC cases and patient survival.
Results:
25 mitochondrial-related genes were linked to survival in NSCLC. Of those 25, we chose to study further the expression of PGAM5 and FUNDC1, which are regulators of mitochondrial degradation (mitophagy). In background lung tissue, PGAM5 and FUNDC1, only expressed in alveolar macrophages, were most highly expressed in COPD (H score: 180 ± 58 and 23 ± 9, respectively) compared to healthy smokers (146 ± 58 and 20 ± 8) and non-smokers (68 ± 48 and 3.3 ± 1.4) (p<0.05). In cancerous tissue, only the malignant epithelial cells and associated macrophages, at the periphery of the cancer, expressed PGAM5 and FUNDC1. PGAM5 was also expressed in pre-neoplastic epithelium (squamous dysplasia and carcinoma in situ). There was no difference in expression across the 3 groups, although the macrophages, at the edge of cancer, from COPD patients tended to show higher expression of PGAM5 and FUNDC1, compared to those from the other groups. When the expression of PGAM5 was compared with that of 50 known macrophage transcriptomic signatures within NSCLC samples, there was a positive correlation between PGAM5 and 9 macrophage signatures (r= 0.27 - 0.44, p<0.05), with one a determinant of patient survival.
Conclusion:
PGAM5 expression in pre-neoplastic tissue and NSCLC, but not in normal epithelium, suggests it plays a role in the transformation of malignant epithelial cells. PGAM5 and FUNDC1 may contribute to the pathogenesis of both COPD and NSCLC, possibly through mitophagic processes.
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MA12.05 - Can Tumor Spread through Air Spaces (STAS) in Lung Adenocarcinomas Be Predicted Pre- and Intraoperatively? (ID 6026)
14:20 - 15:50 | Author(s): K. Kameda, S. Lu, T. Eguchi, N. Rekhtman, J.C. Chang, J. Montecalvo, D. Jones, W.D. Travis, P.S. Adusumilli
- Abstract
- Presentation
Background:
We and others have reported the prognostic impact of tumor spread through air spaces (STAS) in lung adenocarcinomas. The goal of this study is to investigate preoperative predicting factors for STAS and to determine whether STAS can be detected by intraoperative frozen section analysis.
Methods:
In a cohort of 874 patients with small (≤2cm) stage I adenocarcinoma (1995-2012), we reviewed preoperative computed tomography (CT) and positron emission tomography (PET) scans. According to the 2016 Fleischner Society’s criteria, radiological whole tumor size, consolidation size, as well as C/T ratio (consolidation/whole tumor diameter) were determined using thin slice (<3mm) CT scans where available (n=174). Clinico-radiological prediction of STAS was evaluated by logistic regression model. Using the frozen section slides with adequate adjacent lung parenchyma surrounding tumor without artifact (n=48), the presence of STAS was evaluated by five pathologists who are unaware of the radiological findings or the pathological information on permanent slides. The kappa statistic was calculated to measure the agreement between two pathologists.
Results:
In univariable model for predicting STAS, current smoker, larger consolidation tumor size, C/T ratio, and SUVmax were significant variables. In multivariable model, current smoker and C/T ratio were independent risk factors for the presence of STAS (p=0.027 and p<0.001, respectively; Table 1a). The sensitivity and the specificity of frozen section for prediction of STAS were 71% (95% confidence interval: 52-91%), 92.4% (81-100%) respectively, and the accuracy was 80% (71-89%). The kappa statistics were 0.40-0.74 (Table 1b) with 8/10 being moderate or substantial agreement.
Conclusion:
Smoking status and C/T ratio were independent predictors for the presence of STAS in patients with small lung adenocarcinomas. Frozen section prepared with adequate surrounding normal lung tissue may help identify STAS intraoperatively. Figure 1
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MA12.06 - Tumor Spread through Air Spaces (STAS) in Lung Squamous Cell Cancer is an Independent Risk Factor: A Competing Risk Analysis (ID 6051)
14:20 - 15:50 | Author(s): S. Lu, T. Eguchi, K.S. Tan, S. Bains, K. Kadota, N. Rekhtman, P.S. Adusumilli, W.D. Travis
- Abstract
- Presentation
Background:
Tumor spread through air spaces (STAS) is a recently recognized pattern of invasion in lung adenocarcinoma, however, the incidence of and prognostic importance of STAS have not yet been defined in squamous cell carcinoma (SCC).
Methods:
In a cohort of 445 patients with p-stage I-III lung SCC, cumulative incidence of recurrence and lung cancer-specific death (LCSD) was evaluated by competing risks analysis and overall survival (OS) by Cox models.
Results:
76% of patients were >65 years of age. 273 patients died during follow up, one third (91, 33.3%) died of lung cancer whereas two thirds died of competing events or unknown cause. STAS was present in 132 (30%). The cumulative incidence of any, distant, and locoregional recurrence as well as LCSD were significantly higher in patients with STAS compared to those without STAS (Figure), whereas there was no statistically significant difference in OS. STAS was an independent predictor for both recurrence and LCSD in multivariable analysis (p=0.034 and 0.016, respectively, Table).
Conclusion:
STAS was present in one third of resected lung SCC and it was an independent predictor of recurrence and LCSD, supporting our proposal that STAS is a clinically important pattern of invasion and not an artifact. Figure 1 Figure 2
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MA12.07 - Discussant for MA12.04, MA12.05, MA12.06 (ID 7106)
14:20 - 15:50 | Author(s): E. Thunnissen
- Abstract
- Presentation
Abstract not provided
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MA12.08 - Clinicopathological Significance of Increasing Percentage of High-Grade Histological Subtypes in Lung Adenocarcinomas (ID 6023)
14:20 - 15:50 | Author(s): S. Lu, T. Eguchi, K.S. Tan, J.M. Isbell, D. Jones, W.D. Travis, P.S. Adusumilli
- Abstract
- Presentation
Background:
In early-stage lung adenocarcinomas, high-grade micropapillary (MIP) and solid (SOL) predominant pathology is known to be associated with worse prognosis. The aim of this study is, in addition to predominant patterns, to investigate clinical impact of the presence of small amounts (≥5%) as well as increasing percentage of high-grade patterns.
Methods:
Invasive tumors from early-stage lung adenocarcinoma patients who underwent curative-intent resection with no induction therapy were investigated (N=2017; 1995-2012) (8[th] edition TNM pStage I=1390, II=357, III=270). In 388 cases, synchronous lymph node (LN) metastases were available. Histological subtype (lepidic [LEP], acinar [ACI], papillary [PAP], MIP, or SOL) percentages were stratified into 4 groups; 0-4%, 5-24%, 25-49%, and 50-100%. The association between increasing percentage of patterns of primary tumor and the incidence of lymphatic/vascular invasion, necrosis, tumor spread through air spaces (STAS) as well as estimated 5-year cumulative incidence of recurrence (CIR) were analyzed. The differences in distribution of each pathological variable between 4 groups was analyzed by Chi-square test. The percentages of histological pattern were compared between primary tumor and LN metastasis.
Results:
Increasing percentage of MIP pattern is associated with increasing incidence of lymphatic/vascular invasion, STAS, as well as 5-year CIR (Figure 1a, p<0.001). Increasing percentage of SOL pattern is associated with increasing incidence of necrosis and 5-year CIR (p<0.001). Presence (≥5%) of SOL pattern is associated with higher incidence of lymphatic/vascular invasion and STAS (p<0.001) compared to the absence (<5%) of SOL pattern, but no significant relationship between lymphatic/vascular invasion and proportion of SOL pattern. The percentage of SOL pattern in LN metastasis is higher than that in synchronous primary tumors (Figure 1b).
Conclusion:
In early-stage lung adenocarcinomas, presence (≥5%) of MIP or SOL patterns as well as increasing percentages is associated with poor prognostic clinicopathological variables and incidence of recurrence. Figure 1
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MA12.09 - Comparative Histological Subtype Analysis of Lung Adenocarcinoma Tumor and Metastatic Lymph Nodes and the Prognostic Impact (ID 6036)
14:20 - 15:50 | Author(s): S. Lu, T. Eguchi, Z. Tano, D. Molena, D. Jones, W.D. Travis, P.S. Adusumilli
- Abstract
- Presentation
Background:
The goal of this study is to investigate comprehensive comparative pathological analyses of both primary tumor and metastatic lymph node (LN) and correlate with lung cancer-specific death (LC-death) in patients with LN-positive lung adenocarcinoma.
Methods:
PN1/2 lung adenocarcinoma patients who underwent R0 resection without induction therapy (n=402, 2000-2012) were included in the study. In primary tumor, lymphatic/vascular/pleural invasion, necrosis, tumor spread through air spaces (STAS), as well as histologic subtypes according to 2015 WHO classification were evaluated. In metastatic LN, metastatic tumor size, extracapsular invasion, histologic subtypes were evaluated. Recurrence and LC-death were analyzed by Cox model.
Results:
Micropapillary and solid predominant subtypes were more frequent in LN metastases than in primary tumors (Figure). In multivariable analyses, adjuvant chemotherapy, pleural invasion, extracapsular invasion of LN metastasis, micropapillary predominant subtype in LN metastasis were independent factors for recurrence; adjuvant chemotherapy, pleural invasion, tumor STAS, and extracapsular invasion were for LC-death (Table).
Conclusion:
In lung adenocarcinoma lymph node metastases, predominant micropapillary pattern and extracapsular invasion indicate high risk for recurrence and lung cancer-specific death. Figure 1 Figure 2
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MA12.10 - Histological Subtyping of Matched Primary and Metastases Sites in Lung Adenocarcinoma: Significance of Solid Predominance (ID 5767)
14:20 - 15:50 | Author(s): Y. Takahashi, T. Eguchi, S. Lu, R.J. Downey, D. Jones, W.D. Travis, P.S. Adusumilli
- Abstract
- Presentation
Background:
Clinical significance of 2015 WHO classification histological subtype of early-stage lung adenocarcinoma (LADC) has been well documented; the incidence and significance of histological subtypes in autologous metastatic tumors is unknown.
Methods:
Histological subtyping was performed on paired primary and metastatic LADC tumor samples from patients who underwent resection of metastases (N=203, 1996-2012). 57 cases with inadequate tumor specimen and 4 cases diagnosed as local recurrence were excluded.
Results:
Location of metastatic sites were – brain 51 (35.9%), lung 48 (33.8%), lymph node 14 (9.9%), pleura 10 (7.0%), and adrenal gland 5 (3.5%). Metastatic tumors demonstrated more frequent solid histological pattern than primary tumors (first predominance: 51% vs. 24%; second predominance 29% vs. 17%, Figure 1). Among all histological subtypes, solid subtype showed the highest concordance between primary and metastatic tumors (Figure 2). In addition, analysis of all available clinicopathological factors showed significantly higher percentage of solid subtype in both primary and metastatic tumors was observed in patients with smoking history (p=0.003 and p=0.004, respectively).
Conclusion:
Analysis of a large cohort of primary and autologous metastatic LADC tumors demonstrated a higher percentage of solid histological pattern metastases, even in cancers with a low solid component in the primary site of disease. Figure 1Figure 2
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MA12.11 - Discussant for MA12.08, MA12.09, MA12.10 (ID 6951)
14:20 - 15:50 | Author(s): W.A. Cooper
- Abstract
- Presentation
Abstract not provided
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Author of
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MTE12 - Clinically Relevant Signal Transduction Pathways (Ticketed Session) (ID 306)
- Event: WCLC 2016
- Type: Meet the Expert Session (Ticketed Session)
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 07:30 - 08:30, Schubert 4
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MTE12.01 - Clinically Relevant Signal Transduction Pathways (ID 6561)
07:30 - 08:30 | Author(s): B. Dome
- Abstract
- Presentation
Abstract:
Up to a decade ago, the main non-surgical treatment modalities in oncology have been cytotoxic chemotherapy and/or radiation therapy. These therapies are aimed at inducing DNA damage, thus selectively killing the highly proliferative cancer cells. More recently, new therapies are targeting signaling pathways that are critical to support cancer cell proliferation and/or survival, including micro-environmental factors that sustain tumor. The first part of our presentation will review pathways operating mainly in the tumor cells, and how they constitute targets for lung cancer therapies. The second part will focus on the vascularization mechanisms in primary and metastatic lung tumors, antivascular drugs, potential biomarkers and on mechanisms through which tumors can become resistant to antivascular drugs. DNA Repair Pathway: Genomic DNA encodes all biochemical processes that drive cellular function and biology. Extensive damage to DNA encoding proteins/enzymes involved in cell proliferation will result in cell cycle arrest and cell death. DNA damage may also induce replicative errors and mutations, which leads to constitutive activation of oncogenes, or inactivation of tumor suppressor genes. DNA repair mechanisms are crucial for mitigating catastrophic chromosomal damage during DNA synthesis and replication, thus allowing tumor cells to survive chemotherapy or radiotherapy. New targeted anti-cancer agents being developed include those that inhibit the activity of critical molecules involved in DNA repair, or inhibit cell cycle checkpoint proteins that allow DNA repair mechanisms to occur. EGFR and downstream pathways: The proliferation of epithelial cells depends on growth stimuli arising from either factors produced by the tumor cells themselves (autocrine), factors produced by cells from distant organs (endocrine), or factors from neighboring tumor or non-tumor cells in the tumor microenvironment (paracrine). For lung epithelial cells, a major growth stimulating pathway involve the epidermal growth factor receptor (EGFR) family members. EGFR (HER1) is highly expressed in >90% of squamous cell carcinoma and in 60-80% of adenocarcinoma. EGFR has many ligands, including EGF, TGF-a, amphiregulin, HB-EGF, etc. Binding of the ligands to the EGFR induces homo or hetero dimerization of EGFR and its family members, activates the cytoplasmic tyrosine kinase of the receptor, and promotes auto-phosphorylation. This sequentially leads to binding of SOS1, activation of downstream RAS, RAF, MEK and ERK/MAPK. Targeting EGFR by monoclonal antibodies and small molecule kinase inhibitors have demonstrated clinical efficacy in subpopulation of NSCLC patients. Targeted agents against KRAS, BRAF and MEK are in clinical trials. MET, ALK, and ROS1 pathways: Other tyrosine kinase receptors (RTKs) that may play important role in lung cancers include hepatocyte growth factor (HGF) receptor MET and fibroblast growth factor receptor (FGFR) family members. In contrast to EGFR, the ligands for MET and FGFRs appear to be produced by the tumor stromal fibroblasts. While attempts to inhibit MET signaling pathway by neutralizing antibody have not been successful, more recent data suggest that MET kinase inhibitors may be highly effective in patients with MET exon 14 splice site mutations. Such mutations cause the loss of exon 14, which encode the Cbl binding site of the receptor, a crucial domain required for the degradation of MET receptor. The RTKs with close homology to MET are ALK and ROS1. Constitutive activation of ALK and ROS1 occurs by formation of new chimeric protein through translocation involving these genes. Inhibitors to ALK and ROS1 are now clinically approved for treatment of lung cancers that express fusion proteins resulting from the rearrangement of the ALK and ROS1 genes. PI3K/AKT/mTOR pathway: Aside from activating the MAPK pathway, tyrosine kinase receptors may also activate the PI3K/AKT/mTOR pathway, which plays a crucial role in the survival of lung cancer cells. This pathway is commonly activated in NSCLC through amplification or activating mutation of the PIK3CA gene, or inactivation of PTEN by gene deletion, mutation or methylation. While there is intense research to develop targeted therapies that inhibit this important survival pathway, the efforts have so far met little success, revealing the complexity of this pathway. There is also evidence that alternative RTK and PI3K signaling play an important role as bypass mechanisms for the development of resistance to kinase inhibitor therapies. Angiogenesis pathways: Because an adequate blood supply is regarded as essential for tumor development, there had been overwhelming optimism initially that blocking angiogenic pathways would represent an effective treatment strategy in solid malignancies, including primary and metastatic lung tumors. However, clinical trials investigating antivascular drugs have been both encouraging and disappointing. Success with antivascular strategies therefore requires a deeper knowledge of the clinical significance of the different angiogenic machineries that control lung tumors. VEGF (vascular endothelial growth factor) is the key molecular regulator of new tumor blood capillary formation (i.e. angiogenesis) and its high expression is associated with poorer survival in NSCLC. Bevacizumab, a humanized monoclonal anti-VEGF antibody, is currently approved for the first-line treatment of advanced stage non-squamous NSCLC in combination with chemotherapy. Ramucirumab (a fully human monoclonal antibody against VEGFR2) has been approved for use in combination with docetaxel for the treatment of metastatic NSCLC patients who progressed after platinum-based chemotherapy. Nintedanib (an oral RTK inhibitor against VEGFRs, platelet-derived growth factor receptors (PDGFR) and FGFRs in combination with chemotherapy has been approved by the EMEA in NSCLC patients with locally advanced, metastatic or locally recurrent lung adenocarcinoma after first-line chemotherapy. Additional anti-vascular strategies including vascular disrupting agents (VDAs) to destroy the established tumor vasculature and other investigational antiangiogenic antibodies and small molecule RTK inhibitors are also under clinical testing for NSCLC therapy, though enthusiasm is tempered by short disease control and modest overall survival benefit. Angiogenesis Resistance Mechanisms and Biomarkers: Unfortunately, resistance against antivascular therapies is poorly understood. The possible resistance mechanisms include increased intratumoral hypoxia, the activation of compensatory angiogenic machineries, the release of myeloid or endothelial progenitor cell populations, the downregulation of target receptors in endothelial and/or tumor cells, limited tumor tissue drug penetration, and also a switch to an alternative vascularization mechanism such as intussusceptive angiogenesis or vessel-cooption. Reliable biomarkers for the prediction of response to antivascular drugs are also yet to be identified and clinically validated.
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OA02 - Novel Targets and Biomarkers in Malignant Pleural Mesothelioma (ID 369)
- Event: WCLC 2016
- Type: Oral Session
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:L.E. Raez, M. Jakopovic
- Coordinates: 12/05/2016, 11:00 - 12:30, Stolz 2
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OA02.03 - Circulating Fibroblast Growth Factor 18 is Elevated in Malignant Pleural Mesothelioma Patients - A Multi-Institutional Study (ID 5988)
11:00 - 12:30 | Author(s): B. Dome
- Abstract
- Presentation
Background:
Malignant pleural mesothelioma (MPM) is a rare but devastating malignancy. Despite the search for new promising treatment approaches, the outcome for most MPM patients remains dismal. Therefore, the identification of novel biomarkers is urgently needed in order to identify patients with a better prognosis and to support personalized therapeutic decisions. In our previously published study, we were able to show that fibroblast growth factor 18 (FGF18) is overexpressed in MPM tissue specimens and cell models. The objective of this study was the evaluation of FGF18 as a circulating biomarker in MPM.
Methods:
Plasma was collected from 107 MPM patients at the time of diagnosis or before surgical resection. Samples were included from the Medical University of Vienna, University Hospital Center in Zagreb and from The Concord Repatriation General Hospital and Strathfield Private Hospital in Sydney. Samples from 49 healthy volunteers and from 8 patients with non-malignant pleural diseases served as controls. Circulating FGF18 was measured by enzyme-linked immunosorbent assay and correlated to clinical, pathologic and radiologic parameters.
Results:
Plasma FGF18 level was significantly elevated in MPM patients vs. healthy controls (P<0.0001). A slight increase of circulating FGF18 level was also detected in patients with pleuritis or fibrosis (vs. control, P=0.0067). Sarcomatoid (n=7) morphology was associated with high FGF18 levels when compared to the epithelioid (n=77) histology (P=0.0064). Importantly, MPM patients presenting with FGF18 levels below the median had a significantly longer overall survival when compared to those with high FGF18 levels (median survival 625 versus 382 d, P=0.0038). Data on multivariate analysis, disease-free survival, correlation with other biomarkers and tumor volume will be presented at the conference.
Conclusion:
Our findings reveal that FGF18 is a promising blood-derived candidate biomarker in MPM. Furthermore FGF18 may support the histological classification of MPM and the identification of MPM patients with poor prognosis. .
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OA07 - Lymph Node Metastases and Other Prognostic Factors for Local Spread (ID 376)
- Event: WCLC 2016
- Type: Oral Session
- Track: Surgery
- Presentations: 1
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OA07.01 - Incidence, Local Distribution and Impact of pN2 Skip Metastasis in Patients Undergoing Curative Resection for NSCLC (ID 4177)
14:20 - 15:50 | Author(s): B. Dome
- Abstract
- Presentation
Background:
Background: The presence of N2 lymph node (LN) involvement has strong impact on therapy and prognosis in non-small cell lung cancer (NSCLC). N2 LN metastasis may occur by skipping N1 LN stations (N2skip-met). We aim to analyze incidence, local distribution and impact of N2skip-mets in a large cohort of patients undergoing curative resection for NSCLC.
Methods:
Methods: A retrospective non-interventional singe-center cohort study was conducted, assessing all patients undergoing curative resection for NSCLC between 2006 and 2013 at our institution by reviewing medical charts. Incidence of N2skip-mets among these patients was the primary endpoint. Subsequent secondary correlation of clinical parameters was performed using uni- and multivariate logistic and cox regression models.
Results:
Results: In total, 1110 patients were enrolled, with the following pathological LN status: 789 (71%) pN0, 211 (19%) pN1, 105 (9.5%) pN2, 5 (0.5%) pN3. Histological subtype was: adenocarcinoma, n=675 (61%); squamous cell carcinoma, n=309 (28%); other, n=126 (11%). Incidence of N2skip was 55% (47/105). N2skip-mets occurred more frequently in right sided tumors (odds ratio (OR) 2.14, p=0.058) and patients with adenocarcinoma (vs. other, OR 1.54, p=0.19). Presence of N2skip-mets did not correlate with tumor size (ROC, area under curve (AUC) 0.44, p=0.32). Strikingly, presence of N2skip-mets was significantly increased in smokers (OR 3.5, 95% CI 1.38-8.83, p=0.006). Moreover, patients with N2skip-mets were more likely to develop subsequent brain mets (OR 4.13, p=0.06). Overall- and recurrence free survival will be presented at the conference.
Conclusion:
Conclusion: N2skip-mets occur in a high number of patients with N2 disease, with distinct differences in clinicopathologic features. Considering the results of this study, subclassification of N2 disease as recently proposed by the IASLC may have clinical impact in patients with resectable NSCLC.
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OA19 - Translational Research in Early Stage NSCLC (ID 402)
- Event: WCLC 2016
- Type: Oral Session
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:G. Heller, G. Goss
- Coordinates: 12/07/2016, 11:00 - 12:30, Schubert 3
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OA19.05 - High Oncofetal Chondroitin Sulfate Expression is an Independent Prognostic Factor of Poor Survival in Early-Stage NSCLC (ID 5601)
11:00 - 12:30 | Author(s): B. Dome
- Abstract
- Presentation
Background:
Most human cancers express proteoglycans modified with distinct oncofetal chondroitin sulfate (CS) chains that are normally restricted to placental tissue. Oncofetal CS chains can be conveniently detected and targeted by recombinant VAR2CSA (rVAR2) proteins derived from the malaria parasite Plasmodium falciparum. In the present study, we have analyzed the expression landscape of oncofetal CS modifications in early-stage non-small cell lung cancer (NSCLC).
Methods:
Tissue microarrays from four separate patient cohorts representing a total of 493 clinically annotated stage I-II NSCLC cases were stained for oncofetal CS using rVAR2. Data were analyzed for correlation between low and high oncofetal CS presentation by immunohistochemical (IHC) staining of tumor and stroma compartments in respect to EGFR and KRAS mutations, as well as to clinical characteristics including relapse-free survival (RFS) and overall survival (OS).
Results:
There were 351 patients with low (IHC score 0-1) and 142 with high (IHC score 2-3) expressing tumors. We identified 331 adenocarcinomas, 145 squamous cell carcinomas, and 12 cases with other NSCLC subtypes. There were 314 stage I and 179 stage II cases by AJCC 7[th] edition. High oncofetal CS expression was significantly associated with shorter RFS (vs. high expressiors; 58 vs. 39 months, respectively, p=0.034) and OS (vs. high expressors; 69 vs. 51 months, respectively, p=0.044). High oncofetal CS expression was significantly associated with shorter RFS vs. low expression in men (p=0.024), smokers (p=0.011), and in patients with squamous cell tumors (p=0.012). High oncofetal CS was also significantly associated with shorter OS in men (p=0.005) and smokers (p=0.028). There were no significant RFS or OS differences in oncofetal CS expressions when stratifying the patients according to their EGFR or KRAS statuses. In multivariate survival analyses, histology, stage, and high oncofetal CS expression was significantly associated with shorter RFS vs. high expression (HR, 1.8; 95% CI, 1.32–2.48; p < 0.001).
Conclusion:
This is the first study showing that high oncofetal CS expression is an independent prognostic factor of poor RFS in NSCLC and validates high oncofetal CS expression as a prognostic factor of poor OS. In contrast to non-smoker females, oncofetal CS appears to be a prognostic for OS in males and smokers. Our work promotes oncofetal CS as a candidate target for rVAR2-based therapeutic intervention in NSCLC patients with poor RFS/OS.
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P1.06 - Poster Session with Presenters Present (ID 458)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.06-012 - Central and Peripheral Lung Adenocarcinomas Exhibit Different Timing and Predilection for Distant Metastasis (ID 5649)
14:30 - 15:45 | Author(s): B. Dome
- Abstract
Background:
Although distant metastases are major factors for unfavorable prognosis in lung adenocarcinoma (ADC), metastatic patterns have not been widely analyzed in this malignancy.
Methods:
Clinicopathological data of 1126 ADC patients (541 men, 585 women, mean age: 62.1 ± 9.4 years, 32-88 years) were studied retrospectively, focusing on the localization of primary tumor and distant metastases. Metastases diagnosed at the time of primary tumor diagnosis were defined as early metastases. For statistical analyses, Fisher's exact test and a chi-squared independence test were performed.
Results:
At time of diagnosis, 621 patients had stage IV disease. 435 of them had a solitary organ metastasis, mainly in the contralateral lung (n=187), in the brain (n=66), or in the bone (n=59). During the follow up period another 242 patients developed distant metastasis. 39% of all patients had central (i.e. endobronchially visible) tumor. In cases with early-, late-, and non-metastatic disease, the proportions of central tumors were 43%, 35% and 31%, respectively. Central primary tumors were significantly more likely to give rise to early metastases than peripheral ones (p=0.021). When comparing central and peripheral lung cancers according to their metastatic sites, in central tumors lung metastases appeared significantly earlier (p=0.017), while in peripheral ones bone metastases appeared significantly later (p=0.015). There were significant differences in the metastatic organ distributions of central vs. peripheral primary tumors for early (p=0.025) and late (p=0.009) metastases. There was no significant difference in the metastatic organ distributions of right vs. left lung primaries both for early and late metastases. In right lung tumors brain metastases appeared later (p=0.047). No significant difference was observed in the metastatic organ distributions of primary tumors of the upper vs. lower lobes for early (p=0.051), and late (p=0.528) metastases. Early appearance was characteristic for lung, pleural, and adrenal involvement (p<0.001 in all comparisons), while late development was typical for brain metastasis (p=0.002). Bone, liver, subcutaneous, and pericardial metastases showed no such tendencies.
Conclusion:
There are significant differences in metastatic organ distributions of central vs. peripheral lung cancers both for early and late metastases. Central primary tumors are more likely to give rise to early metastases than peripheral ones. Results of molecular subgroup analyses will be presented during the Conference.
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P1.07 - Poster Session with Presenters Present (ID 459)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 3
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.07-023 - NGS May Discriminate Extreme Long-Term versus Short-Term Survival in Patients with Stage IV Small-Cell Lung Cancer (SCLC) (ID 5660)
14:30 - 15:45 | Author(s): B. Dome
- Abstract
Background:
Molecular underpinnings that may prognosticate survival and could increase our understanding of tumor progression are far less understood processes in highly aggressive malignancies such as SCLC. We aimed to describe the clinocopathological characteristics and biomarker profiling of short versus long-term SCLC survivors using the latest, most clinically actionable genomic and immunohistochemical (IHC) alterations.
Methods:
Consecutive 876 metastatic SCLC patients receiving standard of care therapy were evaluated between 2000 and 2013 at the National Koranyi Institute of Pulmonology. Long-term (LT) (overall survival (OS) > 24 months) and short-term (ST) survivors (OS range 2-9 weeks) with histologically confirmed stage IV SCLC were included in this retrospective analysis. DNA and RNA were isolated from FFPE tissues. A comprehensive next-generation sequencing test (NGS) was performed to analyze gene mutations, copy number variations (CNV), mRNA expression, and protein expression by IHC (PCDx, Paradigm). Multiplex sequencing analysis had coverage >5,000x. We then evaluated the associations amongst these various biomarkers and clinicopathological characteristics.
Results:
Four LT and 11 ST were identified for NGS. There were five mutually exclusive gene mutations, previously not described in SCLC (EP300: c.650A>G p.N217S; c.4561G>A p.E152K; ERBB4: c.949G>A p.E317K; BRCA1: c.4981G>A p.E1661N; and EGFR (ERBB1): c.2225T>C p.V742A). Mismatch repair (MMR) deficiency, CNV and PD-L1 in tumor-infiltrating lymphocytes (TIL)/tumor cells were not found in any of the samples. TOP1 was highly elevated in both groups, supporting campothecins as effective drugs in SCLC. Certain mRNA genes appeared to be linked in a similar or overlapping pathway. HENT1 (SLC29A1) with 50-79% protein concordance and survivin (BIRC5) mRNAs were high in most of the ST vs. LT. All LT survivors, but none of the ST survivors, received consolidation thoracic radiation therapy (RT) along with standard of care chemotherapy. SSTR2 mRNA expressions were higher in LT survivors (vs. ST survivors) treated with first-line platinum-etoposide. Molecular testing revealed that ST survivors treated with cyclophosphamide, epirubicin, and vincristine were not predicted to be sensitive to doxorubicin or epirubicin. LT survivors proved to be sensitive to irinotecan/topotecan and lanreotide/octreotide but not to platinum (BRCA1 and/or survivin mRNA was not present).
Conclusion:
Consolidation RT and certain linked pathways may discriminate between LT and ST survivors in SCLC. NGS profiling of extreme survivors may improve classification of SCLC and possibly identify clinically-relevant new targets.
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P1.07-026 - Activin A is Associated with Poor Prognosis and Promotes Metastatic Growth in Small Cell Lung Cancer (ID 5888)
14:30 - 15:45 | Author(s): B. Dome
- Abstract
Background:
Small cell lung cancer (SCLC) is a devastating malignancy characterized by resistance to therapy and poor clinical outcome. Therefore, identification of novel therapeutic strategies and non-invasive biomarkers that facilitate early detection and predict prognosis is urgently needed. Expression of the growth factor activin A (ActA), a member of the TGF beta superfamily, is deregulated in a number of malignancies. However, to date there is no data on the role of ActA in SCLC.
Methods:
In a cohort of SCLC patients (n=79) and in sex- and age-matched controls (n=66), plasma levels of ActA were measured by ELISA. The diagnostic value of plasma ActA was evaluated by ROC curve analysis. The mRNA and protein expression levels of ActA were analyzed in SCLC cell lines by qRT-PCR and by ELISA, respectively, and one of the cell lines with low baseline ActA expression was transfected with ActA and a control vector. The effect of ActA overexpression on the in vivo growth of SCLC cells was investigated in an orthotopic xenograft model.
Results:
Increased plasma ActA levels were found in patients with SCLC (vs. controls) and ActA levels were elevated in a TNM stage-dependent manner. Moreover, high ActA levels were associated with significantly shorter overall survival and multivariate analysis revealed that plasma ActA concentration is an independent negative prognostic factor in this patient cohort. With an area under the curve of 0.81 (95% CI: 0.74-0-0.88), circulating ActA was identified as a useful biomarker for the diagnosis of SCLC. Expression of ActA in SCLC cell lines was detected in vitro. Furthermore, ActA overexpression increased the metastatic capacity of SCLC cells in our xenograft model.
Conclusion:
Our findings suggest that the measurement of circulating ActA can support the diagnosis and staging of SCLC and, moreover, that it can help to predict the clinical outcome. We also conclude that ActA has a role in the aggressive behavior of this tumor type and that its potential therapeutic relevance needs to be further investigated.
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P1.07-042 - Neutrophil-Lymphocyte and Platelet-Lymphocyte Ratios Predict Prognosis in Early-Stage Resected Small-Cell Lung Cancer Patients (ID 5657)
14:30 - 15:45 | Author(s): B. Dome
- Abstract
Background:
Surgical resection is rarely possible in small-cell lung cancer (SCLC), a highly aggressive malignancy with limited treatment options. However, although in the past decades, for selected early-stage cases, a curative intent surgery is often performed, there is no biomarker to help the selection of patients eligible for surgery. Because previous studies - predominantly from East Asia - showed that high neutrophil to lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) correlate with poor prognosis in several types of tumors including SCLC, the aim of our study was to investigate the prognostic value of NLR and PLR in Caucasian patients with resected SCLC.
Methods:
Consecutive patients with histologically confirmed and surgically resected SCLC evaluated between 2000 and 2013 at the National Koranyi Institute of Pulmonology were analyzed in this retrospective analysis. Patients were divided into "high" and "low" groups according to their NLR and PLR at diagnosis. The cut-off NLR and PLR values were 3 and 110, respectively. Next, we evaluated the associations of preoperative NLR or PLR with vascular involvement, tumor necrosis, peritumoral inflammation, tumor grade, clinicopathological characteristics (including age, gender, stage) and overall survival (OS) in univariate and multivariate analyses.
Results:
There were a total of 65 patients (39 men and 26 women) with a median age of 57.7 years (range, 40-79). The pathological stages were 1, 2 and 3A in 23, 23 and 14 cases by AJCC 7[th] edition (in five patients no pTNM was available). PLR was high (HPLR) in 41 (63%) and low (LPNR) in 24 (37%) patients. NLR was high (HNLR) in 35 (66%) and low (LLNR) in 17 (33%) patients. PLR significantly correlated with pathologic lymph node status (p<0.001) and NLR (p=0.007). HPLR was associated with shorter OS (vs. LPLR, HR, 2.2; 95% CI, 1.13–4.29; p=0.02). There was a non-significant trend towards longer OS in patients with LNLR (vs. HNLR, p=0.078). There were no significant associations between NLR or PLR and age, gender, stage, vascular involvement, tumor necrosis, peritumoral inflammation and tumor grade.
Conclusion:
This is the first study in Caucasian patients with resected SCLC which shows that LPLR (<110) before surgical resection may be a favorable prognostic factor for longer OS. We also conclude that preoperative HPLR may predict lymph node involvement. PLR but not NLR may help in selecting patients for surgery in the future. Further prospective studies are needed to confirm these observations.
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P2.01 - Poster Session with Presenters Present (ID 461)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 2
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.01-039 - Prognostic Significance of Claudin Protein Expression in Histological Subtypes of Non-Small Cell Lung Cancer (ID 5947)
14:30 - 15:45 | Author(s): B. Dome
- Abstract
Background:
We have investigated the correlation between claudin (CLDN) protein expression and clinicopathological parameters as well as survival in histological subtypes of non-small cell lung cancer.
Methods:
137 pathologic stage I primary bronchial cancers including 49 adenocarcinomas of non-lepidic variants (ADC), 46 adenocarcinomas of lepidic variants (L-ADC), and 42 squamous cell carcinomas (SCC) were examined. Immunohistochemistry (IHC) using antibodies against CLDN1,-2,-3,-4,-7 proteins as well as semiquantitative estimation (IHC scores 0-5) were performed on archived surgical resection specimens.
Results:
Claudin IHC scores of L-ADC differed significantly from ADC (CLDN1: p=0.009, CLDN2: p=0.005, CLDN3: p=0.004, CLDN4: p=0.001, CLDN7: p<0.001, respectively) and SCC (CLDN1: p<0.001, CLDN3: p<0.001, CLDN7: p<0.001, respectively). Highly significant CLDN3-CLDN4 parallel expression could be demonstrated in ADC and L-ADC (p<0.001 in both), which was not observed in SCC (p=0.131). ADC and SCC showed no correlation with smoking, whereas in case of L-ADC heavier smoking correlated with higher CLDN3 expression (p=0.020). Regarding claudin expression and survival, in SCC significant correlation could be demonstrated between CLDN1 IHC positivity and better survival (p=0.038). In NSCLC as a whole, high CLDN2 expression proved to be a better prognostic factor when compared with cases where CLDN2 IHC score was 0-1 vs. 2-5 (p=0.009), however, when analyzed separately, none of the histological subgroups showed correlation between CLDN2 expression and overall survival.
Conclusion:
Our results demonstrated significant claudin expression differences not only between the SCC–ADC and SCC–L-ADC but also between the L-ADC and ADC histological subgroups, which strongly underlines that L-ADC represents a distinct entity within the ADC group. CLDN1 overexpression is a good prognostic factor in NSCLC, but only in the SCC subgroup.
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P2.01-088 - Prenylation Inhibitors in Lung Adenocarcinoma: Comparison of Zoledronic Acid and a Novel Lipophilic Bisphosphonate (ID 5640)
14:30 - 15:45 | Author(s): B. Dome
- Abstract
Background:
The prenylation inhibitor zoledronic acid is a standard-of-care therapeutic option in bone metastasis. Recent studies suggest that prenylation inhibition using novel lipophilic bisphosphonates might be active against various malignancies outside the bone metastatic setting. Since prenylation is an important posttranslational modification in RAS protein function we explored the sensitivity of a panel of lung adenocarcinoma cells representing various oncogenic driver mutations.
Methods:
8 human lung adenocarcinoma cell lines were investigated in vitro to assess the short-term viability and long-term clonogenic potential following zoledronic acid and BPH-1222 treatments. The eight lung cancer cell lines represented wild type (HCC78, CALU3), EGFR- (H1650, H1975) KRAS- (A549, H358), BRAF- (CRL5885) and BRAF + NRAS double mutant (CRL5922) molecular subtypes. Effect on short and long term proliferation were measured with a SRB based photometric assay.
Results:
Neither short-term nor long-term treatment showed significant differences between the proliferation inhibitory effect of the hydrophilic zoledronic acid and novel lipophilic bisphosphonate BPH-1222. Interestingly, we found that the two KRAS mutant lung adenocarcinoma cell lines were more sensitive in the long-term bisphosphonate treatment assays than non-KRAS mutant cell lines. BRAF or EGFR mutations did not show a differential response against these inhibitors.
Conclusion:
In vitro proliferation inhibitory efficacies of hydrophilic and lipophilic bisphosphonates were not different in lung adenocarcinoma cells. Nevertheless, due to the different bone accumulation properties of zoledronic acid and lipophilic bisphosphonates further in vivo preclinical studies are warranted to evaluate the inhibitory effect in a more physiological setting.
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P2.03b - Poster Session with Presenters Present (ID 465)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03b-005 - Correlation between Primary Tumor Location and Brain Metastasis Development or Peritumoral Brain Edema in Lung Cancer (ID 5913)
14:30 - 15:45 | Author(s): B. Dome
- Abstract
Background:
In lung cancer overall survival and quality of life are affected adversely by brain metastases, while peritumoral brain edema is responsible for life-threatening complications.
Methods:
The clinicopathological and cerebral radiological data of 575 consecutive lung cancer patients with brain metastases were analyzed retrospectively.
Results:
In squamous cell carcinoma (SCC) and adenocarcinoma (ADC) peritumoral brain edema was more pronounced as compared with small cell lung cancer (SCLC) (p<0.001, p˂0.001, respectively). There was positive correlation between size of metastasis and thickness of peritumoral brain edema (p<0.001). It was thicker in supratentorial tumors (p=0.019), in younger patients (≤50 years) (p=0.042), and in females (p=0.016). The interval time to brain metastasis was shorter in case of central as compared with peripheral lung cancer (5.3 vs. 9.0 months, p=0.035). Early brain metastasis was characteristic for ADCs. A total of 135 patients had brain only metastases (N0 disease) characterized by peripheral lung cancer predominance (p<0.001), and longer time-to-metastasis interval (9.2 vs. 4.4 months, p<0.001). Overall survival was longer in the brain only subgroup than in patients with N1-3 diseases (p˂0.001).
Conclusion:
According to our results, clinicopathological characteristics of lung cancer are related to the development and radiographic features of brain metastases, and these findings might be helpful in selecting patients who could benefit from prophylactic cranial irradiation.
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P3.03 - Poster Session with Presenters Present (ID 473)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.03-046 - Prognostic Fibrinogen/Leucocyte Score at Diagnosis Predicts Survival and Benefit from Multimodality Treatment in MPM (ID 4179)
14:30 - 15:45 | Author(s): B. Dome
- Abstract
Background:
The aim of this study was to identify and validate prognostic and predictive biomarkers in a large cohort of patients with malignant pleural mesothelioma (MPM).
Methods:
We performed a retrospective chart review, including all patients with histologically confirmed MPM, treated at two specialized centers between 1994 and 2014. The effect of different clinical and pathological characteristics and laboratory values on outcome was investigated by using uni- and multivariate logistic and cox regression models.
Results:
Two-hundred ninety-one patients were enrolled (222 males and 69 females). Main histological subtype was epitheloid (n=199, 68%). Multimodality treatment, defined as macroscopic complete resection combined with chemotherapy and/or radiation therapy and/or intracavitary treatment, was performed in 134 (46%) patients. Median overall survival (OS) was 17.7 months from diagnosis. In the multivariate cox regression model, leucocyte count at diagnosis (continuous, hazard ratio (HR) 1.087, p=0.04), fibrinogen at diagnosis (continuous, HR 1.002, p=0.002), histological subtype (epitheloid vs. non-epitheloid, HR 0.064, p=0.006) and age (continuous, HR 1.035, p=0.001) remained as independently significant co-factors influencing OS. ROC curve analyses for predicting 1-year survival revealed an area under the curve (AUC) of 0.72 (p=0.001) for fibrinogen and 0.65 (p=0.001) for leucocytes. Dichotomizing fibrinogen and leucocytes at the median values (550 mg/dl and 8 G/l) revealed a sensitivity of 0.65 and 0.55 and a specificity of 0.69 and 0.61 for predicting 1-year survival, respectively. Combining dichotomized fibrinogen/leucocytes to an inflammation based prognostic score (none, one or both elevated) significantly influenced 1-year survival (p<0.001) and OS (score 0 vs. I, p=0.005; I vs. II, p=0.03). When introducing to the multivariate cox regression model, the fibrinogen/leucocytes score remained as independently prognostic for OS (I vs. O, HR 1.48, p=0.02; II vs. 0, HR 2.26, p<0.001). Strikingly, a significant predictive interaction between the fibrinogen/leucocytes score and treatment modality was observed (p<0.001).
Conclusion:
The inflammation based fibrinogen/leucocytes score predicts OS independently from sex, age, stage, subtype and treatment modality. Multimodality treatment including surgery increases survival selectively in patients with low fibrinogen/leucocytes score.
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P3.04 - Poster Session with Presenters Present (ID 474)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Surgery
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.04-003 - Incidence and Outcome of Female Patients with Previous Breast Cancer Undergoing Curative Resection for Lung Cancer (ID 4178)
14:30 - 15:45 | Author(s): B. Dome
- Abstract
Background:
Due to recent improvements in breast cancer (BC) therapy and outcome, female patients with BC may be at higher risk of developing secondary malignancies such as lung cancer (LC). The aim of this study is to evaluate the incidence and outcome of previous BC in female patients with resectable lung cancer.
Methods:
A retrospective non-interventional singe-center cohort study was conducted, assessing all female patients undergoing curative resection for LC between 2006 and 2013 at our institution by reviewing medical charts. Follow-up will be completed in September 2016. Incidence of previous BC among these patients was the primary endpoint. Subsequent secondary correlation of clinical parameters was performed using uni- and multivariate logistic and cox regression models.
Results:
Allover, 463 female patients with LC were identified. The incidence of previous BC was 8.6% (40/463). Mean age was 64.1 years (SD ± 11.5) and was not different between patients with LC and LC/BC. Main histological LC subtype was adeno-carcinoma (64%; squamous cell, 23%; other, 13%). Stage (TNM-7) distribution was: I, 64.5%; II, 22%; III, 12.5%. Lobectomy was the preferred anatomical resection and mean hospital stay was 8.3 days. Complication rate was 7.6%. Recurrence free and overall survival will be presented at the conference. There were no statistical differences between patients with LC/BC and LC with regard to main clinical parameters and short term outcome.
Conclusion:
Due to improvements in breast cancer therapy, a reasonably number of patients developing subsequent lung cancer is observed. Short-term outcome of patients with LC/BC is similar to those with LC.
