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S. Ekman
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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-084 - Profiling of Eph Signaling in Malignant Pleural Effusions- Identification of Therapy Approaches and Associated Biomarkers (ID 4573)
14:30 - 14:30 | Author(s): S. Ekman
- Abstract
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.
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P2.05 - Poster Session with Presenters Present (ID 463)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Radiotherapy
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.05-033 - Predictors of Survival after Whole Brain Radiotherapy for Patients with Brain Metastasized Lung Cancer (ID 4794)
14:30 - 14:30 | Author(s): S. Ekman
- Abstract
Background:
Whole Brain Radiotherapy (WBRT) has been the standard of care for multiple brain metastases, but due to its toxicity and lack of survival benefit, its use in the palliative setting has started to be questioned. New clinical algorithms regarding the correct use of WBRT are needed.
Methods:
This was a retrospective, single institution cohort study, consisting of 280 patients with brain metastasized lung cancer who received WBRT at Karolinska University Hospital between 2010 and 2015. Information about RPA and GPA scores, demographics, histopathological results and received oncological therapy was collected. Predictors of Overall survival (OS) from the time of received WBRT were identified by Cox regression analyses. OS between GPA and RPA classes was compared by pairwise log rank test. A subgroup analysis was performed stratified by RPA class. Separate multivariate analyses were performed for RPA and GPA scoring systems, due to significant collinearity between them.
Results:
Median OS was 324, 130 and 41 days for RPA class 1(n=13), 2(n=165) and 3(n=101), respectively. Median OS for GPA groups 0 (0-1 points, n=168), 1 (1.5-2.5 points, n=98) and 2 (3-4 points, n=13) was 55, 166 and 110 days, respectively. Age>70 years was associated with worse OS. OS differed significantly between RPA class 1 versus 3 and 2 versus 3, GPA groups 0 versus 1 and age (p<0.0001 for all comparisons). Multivariate analyses are shown in table 1.Figure 1
Conclusion:
WBRT should be omitted for RPA class 3 patients. RPA class 1 patients should receive WBRT if clinically indicated. For RPA class 2 subgroup, patients with age≤70 years and GPA≥1.5 points should be treated as RPA 1, whereas patients with age>70 and GPA<1.5 points as RPA 3. WBRT is not recommended in patients older than 70 years and GPA≥1.5 points, and should be considered in younger patients with GPA<1.5 points.
