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R. Langfort
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P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.04-044 - Analysis of the Intra-Tumor Heterogeneity and Consistency between FGFR1 Gene Amplification and Protein Expression in Squamous Cell Lung Cancer (ID 681)
09:30 - 09:30 | Author(s): R. Langfort
- Abstract
Background:
Preclinical data have shown that inhibition of fibroblast growth factor receptor 1 (FGFR1) could be a promising therapy for lung tumors with FGFR1 amplification or expression. The candidate predictive biomarkers FGFR1 amplification and protein overexpression has been reported respectively in 10-20% or 10-41% patients (pts) with squamous cell lung carcinoma (SqCLC). Therefore, there is an urgent need to assess relationship between both, as well as the heterogeneity of their intratumoral distribution as the potential confounding factors for testing reliability.
Methods:
3 to 5 FFPE sections from different regions of each of 20 SqCLC tumors were analyzed. FGFR1 gene copy number was assessed by FISH method using probes specific for the 8p12 locus and the chromosome 8 centromere (CEN8). Criteria of FGFR1 amplification were as follows: FGFR1/CEN8 >2.0 or the average number of FGFR1 signals per cell >6 or >10% of tumor cells containing >15 FGFR1 signals. FGFR1 protein expression was determined by immunohistochemistry (IHC). Expression was defined as staining intensity 2+ or 3+ (graded from 0 to 3+) in >1% of the cancer cells. For the heterogeneity analysis only patients with >4 slides per tumor were taken into account (15/20 pts). Different definition of heterogeneity was considered. Finally, tumor was classified as heterogeneous, when >25% of slides showed different results of FISH or IHC. Statistical calculation of correlation between FISH and IHC results (19/20 pts) was performed using the GraphPad Prism software using Spearman test.
Results:
FGFR1 amplification was observed in 6/20 (30%) SqCLC tumors. The average FGFR1 gene copy number per cell ranged from 1.9 to 10.9 (mean: 4.6) and the mean FGFR1/CEN8 ratio was 2.3 (range: 0.7–3.7). The mean content of tumor cells with >15 FGFR1 copies was 2.2%. In IHC(+) tumors (5/20, 25%) the percentage of stained cancer cells with intensity >2 was low - only 10/78 samples contained more than 10% of them. In total, 62 FFPE samples from 15 SqCLC patients were analyzed for tumor heterogeneity. FGFR1 amplification was homogeneous in all pts (15/15), in contrast to expression, as 1/15 tumor was confirmed heterogeneous. The FISH and IHC results were consistent in 52% SqCC patients (n=19), including 1/19 (5.2%) double-positive and 9/19 (47.3%) double-negative tumors. In 9/19 pts results were discordant: 5/19 (26.3%) IHC(-) FISH(+), while in 4 (21%) pts IHC(+) FISH(-). FGFR1 amplification did not correlate with protein expression (P=0.543; r=-0.149) for 19 SqCLC tumors .
Conclusion:
Our study demonstrated relative SqCLC tumor homogeneity in terms of FGFR1 amplification and expression. However, FGFR1 amplification did not relate to protein expression. Therefore, further more detailed evaluation of both biomarkers FGFR1 amplification and protein expression regarding their predictive diagnostic value towards anti-FGFR therapy is needed.
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P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.04-075 - The Biological and Clinical Significance of Alpha-1 Antitrypsin in Non-Small Cell Lung Cancer (ID 2132)
09:30 - 09:30 | Author(s): R. Langfort
- Abstract
Background:
Lung cancer progression is generally associated with extensive tissue remodeling to provide a suitable environment for tumor growth, invasion and metastasis, and it is known that proteinases expressed by cancer cells and/or host cells play a key role in this process. However, the biological role of alpha-1 antitrypsin (AAT) in lung carcinogenesis is not clear.
Methods:
Serum and FFPE tissue samples from 206 NSCLC patients (stages I-IV) were analyzed for AAT and CRP blood concentration, AAT phenotype and AAT protein expression in tumor cells. Reference groups consisted of 183 PiMM COPD patients and 23 PiMM patients with benign lung nodules (positive chest radiograph).
Results:
Only 10/206 (5%) NSCLC patients carried deficient AAT allele (mean AAT blood concentration 150 mg/dl). In the PiMM NSCLC patients mean AAT serum concentration (195.5 mg/dl) was significantly higher than in the PiMM COPD group (171 mg/dl) and the patients with benign lung nodules (154 mg/dl; p<0.0001). AAT concentration was significantly higher in SQC type (202 mg/dl) than ADC (175 mg/dl; p<0.029) patients, and in advanced (IIIb-IV, 247 mg/dl) versus early stage disease (I-IIIa, 190 mg/dl, p<0.0001). The AAT levels significantly correlated with CRP (R=0.6; p<0.0001), however CRP level did not differentiate NSCLC from COPD. Importantly, the strong AAT expression observed in tumor tissue was positively associated with the higher AAT blood levels, while weak or no AAT expression directly correlated with the lower AAT blood levels.
Conclusion:
Our results evidenced that local production of AAT by tumor cells significantly contribute to high levels of AAT in blood of NSCLC patients reflecting an active role of this anti-protease in lung carcinogenesis. The study is on-going.
