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L. Brcic
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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)
11:20 - 11:30 | Author(s): L. Brcic
- 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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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-075 - PD-1 Protein Expression Predicts Survival in Resected Adenocarcinomas of the Lung (ID 5641)
14:30 - 14:30 | Author(s): L. Brcic
- Abstract
Background:
Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) have demonstrated clinical activity in patients with advanced non-small cell lung carcinoma (NSCLC). The ability of PD-1 and PD-L1 immunohistochemistry (IHC) to predict benefit of immune checkpoint inhibitors remains controversial. We assessed the prognostic value of PD-1 and PD-L1 IHC in patients with completely resected adenocarcinoma of the lung.
Methods:
We determined protein expression of PD-1 and PD-L1 in formalin-fixed paraffin-embedded surgical specimens of 161 NSCLC patients with adenocarcinoma histology by IHC. We used the EH33 antibody (Cell Signaling) for PD-1 and the E1L3N antibody (Cell Signaling) for PD-L1 IHC. Cut-points of ≥1% PD-1-positive immune cells at any staining intensity and ≥1% PD-L1-positive tumor cells at any staining intensity were correlated with clinicopathological features and patient survival.
Results:
Positive PD-1 immunostaining in immune cells was observed in 71 of 159 (45%) evaluable tumor samples. PD-1 positive staining was not significantly associated with any of the clinicopathological features. Positive PD-1 immunostaining was associated with longer recurrence-free and overall survival of the patients. Multivariate Cox proportional hazards regression analyses identified PD-1 to be an independent prognostic factor for recurrence (adjusted hazard ratio [HR] for recurrence 0.58; 95% confidence interval [CI] 0.36 to 0.94; P = 0.026) and death (adjusted HR for death 0.46; 95% CI 0.26 to 0.82; P = 0.008). PD-L1 positive staining in tumor cells was seen in 59 of 161 (37%) cases. Positive PD-L1 immunostaining correlated with KRAS mutation (P = 0.019) and type of surgery (P = 0.01) but was not significantly associated with any of the other clinicopathological parameters. Positive PD-L1 immunostaining was not associated with survival of the patients (adjusted HR for recurrence 0.92; 95% CI 0.58 to 1.47; P = 0.733; adjusted HR for death 0.61; 95% CI 0.34 to 1.07; P = 0.084).
Conclusion:
Positive PD-1 but not PD-L1 immunostaining is a favorable independent prognostic factor in patients with completely resected adenocarcinoma of the lung.
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P3.01 - Poster Session with Presenters Present (ID 469)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.01-036 - Eukaryotic Translation Initiation Factors impact Non Small Cell Lung Cancer (ID 3923)
14:30 - 14:30 | Author(s): L. Brcic
- Abstract
Background:
Non small cell lung cancer (NSCLC) belongs to the most frequently diagnosed cancer entities and is one of the leading causes of cancer related death worldwide. Deregulation of protein synthesis has received considerable attention as a major step in cancer development and progression. Protein synthesis is regulated at multiple stages, including translation of mRNA into proteins. Studies suggest that ribosomal protein synthesis plays a direct role during tumor-initiation. Crucial for this translation process are eukaryotic initiation factors (eIFs), which ensure the correct 80S ribosome assembly. eIFs are linked to the MAPK and the mTOR signalling pathways, which have become major targets in cancer therapy. Mutations or deregulated expression of eIFs influence cell growth and proliferation, and contribute to carcinogenesis. We hypothesized that eIFs represent crossroads for carcinogenesis in lung cancer and might serve as potential biomarker.
Methods:
Expression profiling of paired NSCLC and non-neoplastic lung tissue (NNLT) from 1.000 individuals were studied by immunohistochemistry on tissue micro arrays (TMAs) with antibodies against the eIF subunits 2α; 3C; 3H; 3M; 4E and 6. eIF expression was evaluated with respect to the staining intensity (intensity score 0-3; 0: no staining, 1: weak, 2: moderate and 3: strong) and percentage of positive tumor cells (proportion score; 0-100%). In addition, the protein and mRNA expression levels of eIFs and mTOR pathway members were determined in 25 patients by Western Blot analysis and qRT-PCR. For the statistical analysis α was set to 5%.
Results:
Western Blot analysis of NSCLC revealed a significant up-regulation of mTOR and the eIF subunits p2α, 2α, 1A, 4A, and eIF6 compared to NNLT (p< 0,05). The mRNA levels of NSCLC also displayed a significant upregulation of the eIF subunits 2α, 4A, and eIF6 compared to NNLT. Immunohistochemistry highlighted a stronger staining in neoplastic cells for eIF2α, eIF4E, eIF3H and eIF6.
Conclusion:
Our data indicated that eIFs are significantly upregulated in NSCLC, suggesting an important contribution of eIFs and mTOR signalling to the development and progression of lung carcinomas. A better understanding of the molecular mechanisms in pulmonary carcinogenesis is necessary for the development of novel treatment strategies.
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P3.02b - Poster Session with Presenters Present (ID 494)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02b-114 - Second Line Treatment of EGFR Positive Lung Adenocarcinoma - Our Experience (ID 6064)
14:30 - 14:30 | Author(s): L. Brcic
- Abstract
Background:
EGFR testing and specific targeted therapy of lung adenocarcinoma is a standard worldwide. In Croatia, tirosin-kinase inhibitors (TKI)are allowed as a second-line therapy for EGFR positive (+) patients. We analysed the median overall survival (mOS) differences between TKI- and.conventional chemotherapy-treated patients as a second-line therapy.
Methods:
Medical records of patients diagnosed with lung adenocarcinoma and tested for specific mutations in Clinical hospital center Zagreb, Department for respiratory diseases Jordanovac, during the year 2013 and 2014, were retrospectively collected and reviewed. Median overall survival (mOS) was measured and analyzed using routine statistic tests.
Results:
A total of 334 patients were tested for EGFR mutations, 47 of whom came positive and 287 negative. There was signifficant difference between the two subgroups regarding some demographic categories: the majority (78,7%) of the EGFR + patients were female, as opposed to the EGFR - group. Also, the EGFR+ patients were older on average ath time of diagnosis.(66,04 vs 63,04 years). After recieving first line platinum based chemotherapy a total of 20 positive EGFR patients recieved second-line therapy. 15 were treated with TKI and 5 recieved pemetrexed. In the EGFR negative group, 100 patients received second-line therapy, 85 of whom recieved pemetrexed and the other 15 were treated with platinum- or gemcitabine- based chemotherapy. If analysing mOS of all the patients, there was statistically significant difference between the TKI-treated patients (mOS not met) compared to the other ones (mOS=20 months) (chi-square= 6,07; p=0,014). Also, if analysing only the EGFR positive patients, the mOS difference reached statistical significance, comparing the TKI-treated patients (mOS =24,3months) with those treated with pemetrexed. (mOS=15,7 months) (chi-square= 7,99; p=0,005)
Conclusion:
Our results showed the significance of molecular testing and specific TKI treatment of patients with EGFR positive lung adenocarcinoma, as they had a significatly better overall survival compared to patients treated with pemetrexed. The results are conclusive with the general experience and treatment recommendations, and should be implemented in every day praxis, i.e. enabling molecular testing and specific treatment for all EGFR+ patients, at least as a second-line therapy option, should be an imperative.
