Journal Thoracic Oncology

Abstracts Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017
vs. 88.1 pg/ml; p=0.0017). Median PFS was 3.7 months. Both in the univariate
and multivariate analyses, a higher percentage change reduction in PDGF
after treatment was associated with a longer PFS (6.37 vs. 3.58 months,
p=0.059; Hazard ratio (HR): 3.15, p=0.024). OS of patients was 8.8 months.
Both in the univariate and mutivariate analysis a higher percentage change in
FGF was associated with a longer OS (13.8 vs. 7.16 months, p=0.006; HR: 3.63,
p=0.033]. Conclusion: A higher reduction of plasma levels of FGF and PDGF
was associated with better clinical outcomes.
Keywords: vascular endothelial growth factor, fibroblast growth factor,
platelet-derived growth factor, angiokinase inhibitor
POSTER SESSION 2 – P2.03B: ADVANCED NSCLC & CHEMOTHERAPY/TARGETED THERAPY/
IMMUNOTHERAPY
BIOMARKERS –
TUESDAY, DECEMBER 6, 2016
P2.03B-084 PROFILING OF EPH SIGNALING IN MALIGNANT
PLEURAL EFFUSIONS- IDENTIFICATION OF THERAPY APPROACHES
AND ASSOCIATED BIOMARKERS
Metka Novak 1 , Petra Hååg 1 , Katarzyna Zielinska Chomej 1 , Xiaoyan Qian 2 ,
Luigi De Petris 1 , Simon Ekman 1 , Per Hydbring 1 , Caroline Kamali 1 , Lena Kanter 1 ,
Magnus Löfdahl 3 , Mats Nilsson 2 , Kristina Viktorsson 1 , Rolf Lewensohn 1
1 Oncology-Pathology, Karolinska Institutet, Stockholm/Sweden, 2 Department of
Biochemistry and Biophysics, Stockholm University, Solna/Sweden, 3 Respiratory
Medicine and Allergology, Karolinska University Hospital, Stockholm/Sweden
Background: For late stage lung cancer (LC) patients few treatment options
are at hand and the survival time is very limited, hence novel therapies and
associated biomarkers are urgently needed. Erythropoietin-Producing
Hepatocellular carcinoma receptor (Eph) tyrosine kinase family and their
ligands, Ephrins, drive multiple hallmarks of cancer e.g. proliferation/invasion.
The Eph signaling pathways are attractive drug targets due to their dual role in
oncogenesis and tumor progression. We analyzed Ephs/Ephrins signaling in LC
cells from pleural effusions (PE) to reveal altered kinase pathways and putative
BMs. We also assessed cytotoxicity and kinome alterations in PE tumor cells
exposed to targeted agents and chemotherapy in vitro. Methods: Tumor
cells purified from PE, assessed for histology, mutation and translocation
status (EGFR, KRAS, BRAF and Alk), were grown in vitro. Toxicity of tyrosine
kinase inhibitors (TKIs (e.g. erlotinib, crizotinib, AG1024, AZD9291, dasatinib),
EGFR blocker (cetuximab) and/or chemotherapy (e.g. cisplatin, gemcitabine,
etoposide) were analyzed after 72 h with the Tox8 assay. Ephs/Ephrins
signaling components were studied using western blot, immunoprecipitation
and by proximity ligation assay. Mutations and signaling heterogeneity were
visualized using padlock probe method. For kinome profiling PathScan RTK
signalling antibody array was used. Results: PE isolated tumor cells were
identified as adenocarcinoma, squamous cell carcinoma and SCLC and their
EGFR, KRAS, BRAF and Alk mutational status determined. High levels of Ephrin
B3 and phosphorylated EphA2 ser897, previously shown to be instrumental
in driving NSCLC proliferation and invasion in vitro, were confirmed and also
shown to directly interact, indicating the importance of this signaling event.
The G391R mutation in EphA2, which is reported to cause a constitutive
activation of EphA2 and to be linked to metastasis, but also mutations in EGFR
(G719A, G719S, T790M and L858R) were detected. The PE derived tumor cells
were hetereogenous in their survival response to TKIs and chemotherapy.
However, cells with ALK translocation were sensitive to crizotinib and EGFR
mutated cells showed response to erlotinib, cetuximab, AG1024, AZD9291 and
dasatinib. Kinome analysis revealed selective signaling pathways that could
also be targeted in combinational drug treatment. Conclusion: Screening of
PE samples from LC patients for targeted agents alongside aberrant Ephs and
kinome signaling, can be used to identify novel drug candidates. Together
with frontline kinome profiling of NSCLC clinical specimens upon treatment it
provides an opportunity to explore/identify new therapeutics for LC.
Keywords: drug targets, new therapeutics, pleural effusions, Ephs
3 Department of Thoracic Surgery, Respiratory Center, Toranomon Hospital, Tokyo/
Japan
Background: Programmed cell death ligand 1 (PD-L1) expression could be used
as a predictive marker for anti PD-1/PD-L1 therapy, especially for
adenocarcinomas. However, the correlation between PD-L1 expression and
the epidermal growth factor receptor (EGFR) mutational status has not been
adequately studied. Additionally, whether PD-L1 positive expression is a
prognostic factor or not is still debatable. We aimed to compare the
clinicopathological findings including EGFR mutation and prognosis of stage
II and III adenocarcinomas with positive or negative PD-L1 expression.
Methods: Sixty-eight surgically resected stage II and III adenocarcinomas
were included in this study. PD-L1 (clone SP142) expression was quantitatively
assessed and considered to be positive when membranous staining of the
tumor cells was >5%. Various clinicopathological parameters including
pathologic findings were examined. Results: PD-L1 expression was positive in
11 of 68 (16.2%) adenocarcinomas. In the univariate analysis, PD-L1 positive
expression was associated with abundant CD8+ lymphocytes (p