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ihab Eldessouki
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EP1.01 - Advanced NSCLC (ID 150)
- Event: WCLC 2019
- Type: E-Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 2
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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EP1.01-23 - SRC Inhibition with Bosutinib as a Potential Approach for Restoring Pemetrexed Responsiveness (Now Available) (ID 2843)
08:00 - 18:00 | Author(s): ihab Eldessouki
- Abstract
Background
One of the principle approaches in malignant mesothelioma andnon-squamousnon-smallcelllung cancer management is cellular folate-dependentpathways inhibition with pemetrexed(PEM) combined with platinum-basedchemotherapy. Despite the promising activity of PEM, drug resistance demands new approaches allowing for abolishing resistance and better outcomes. In lung cancer, there is an association betweenin vitroPEMresistance, SRC over-expression, and thymidylatesynthase(TS) overexpression.
Method
We treated lung cancer cell line (A549) and mesothelioma cell line (MSTO) with PEM and bosutinib (a small molecule tyrosine kinase inhibitor (TKI)) which is also an SCR inhibitor. Increasing dose regimen was adopted with these drugs. Then we conducted cellviability assays (MTT tetrazolium), detection of SRC andTS expression by western blot and apoptotic assays (AnnexinV) for drug effect evaluation.
Result
Data showed that sequential treatment with bosutinib then PEM lowered the IC50 of PEM of both cell lines as indicated by cellviability and apoptosis assays. There was a 9% increase in apoptosis with combination regimen compared to PEM only regimen. Nevertheless, a decrease in TS expression was found, with correlation to the decrease in SRC expression.
Conclusion
Combining bosutinib’s SCR inhibition to PEM activity may improve the latter’s therapeutic response due to synergism. Further in vivo evaluation for these results are needed to better understand these effects on tumor response
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EP1.01-67 - Molecular Profiling of K-Ras and Its Subtypes in NSCLC Patients with Liver Metastasis (Now Available) (ID 2802)
08:00 - 18:00 | Author(s): ihab Eldessouki
- Abstract
Background
Non-small cell lung cancer (NSCLC) tend to have a poor prognosis in the presence of liver metastasis. Molecular profiling of NSCLC has played a major role in identifying a number of oncogenic targets that have led to novel targeted therapies. KRAS is a frequently mutated gene in NSCLC, occurring in approximately 30% of lung adenocarcinomas and most commonly manifesting as the transversion mutations G12C, G12V, G12A. there are presently no targeted therapies approved for KRAS-mutant NSCLC. Immunotherapy has emerged as a standard of care for first-line treatment of advanced NSCLC, specifically through targeting the programmed cell death protein-1 (PD-1/PD-L1). Given the aggressive nature of KRAS-mutant NSCLC with liver metastases and the lack of approved therapies targeting the KRAS pathway, checkpoint blockade immunotherapy may represent an impactful primary therapeutic option for these patients.
Method
The CARIS database from 2016 - 2018 was queried and patients with NSCLC were identified. PD-L1 antibody 22c3 ≥1% was considered positive. PD-L1 expression as well as k-ras and TP53 mutation status were analyzed and correlation between different variables were identified using ANOVA
Result
We identified 361 patients with NSCLC having Liver metastasis. Median age was 67. Gender distribution was equal (51.4% males, 49.7% females). Of the 361 patients, we identified 74 patients with mutated K-ras. Thirty nine out of the 74 patients had PD-L1 expression (52.7%). Twenty one patients had the G12C sub-type (28%) with 14 patients (66%) having positive PD-L1 expression.Of the 287 patients with wild type K-ras, 115 patients had PD-L1 positive expression (40%) with no statistical significance (P=0.134) in comparison to the k-ras mutant population.We also studied 2237 K-ras mutant patients without liver metastases where 882 patients had the G12C subtype (39.4%). On the other hand, only 21 patients were positive for G12C k-ras subtype out of the 74 k-ras mutant patients with liver metastases.Among patients with liver metastases, adenocarcinoma was the most common histological subtype (223 patients), Carcinoma NOS was the second common histological subtype (61 patients).Patients with no liver metastasis had median age of 68. Gender distribution was equivocal.
Conclusion
Patients with k-ras mutant G12C subtype were associated with more frequent PD-L1 expression and less occurrence of liver metastases.
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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-64 - Predictive Value of K-Ras Subset Mutations and PD-L1 in Pulmonary Sarcomatoid Carcinoma (PSC) (Now Available) (ID 2824)
09:45 - 18:00 | Author(s): ihab Eldessouki
- Abstract
Background
Pulmonary sarcomatoid carcinoma (PSC) is a rare malignant neoplasm that accounts for a 0.4% of non-small- cell lung carcinomas (NSCLC). It is associated with poor response to therapy. We studied clinical, genetic and molecular criteria of PSC by analyzing their KRAS, TMB, TP53 and PD-L1 status.
Method
This is a retrospective study that included 8,469 NSCLC patients with equivalent number of samples collected prospectively. Next generation sequencing (NGS) was performed for molecular and genetic analysis of the samples.Categorical variables were reported as counts and percentages, and we used Fisher’s exact test and Chi (X2) test for comparisons as appropriate.
Result
Among the 8,469 patients there were 53 patients with pulmonary sarcomatoid carcinoma (PSC). PSC was more prevalent in males (64.2%) vs other NSCLC histopathological subtypes (49.8%) (P=0.039). PD-L1 analysis revealed 79.2% positive expression (>1%) in PCS vs 51.0% in other NSCLC histopathological subtypes (P<0.001). KRAS analysis showed that G12V was the most common mutatedKRAS codon in PSC (31.3%). Of the 53 patients with pulmonary sarcomatoid carcinoma, sixteen patients were k-ras mutant (31%). Of the 16 patients with mutant k-ras, fifteen had PD-L1 positive status (Table 1). PDL-1 was positive in 64.3% (n=27) of PSC cases with wild-type KRAS and 35.7% in mutant KRAS, P=0.087. (Table 2). KRAS MAF was higher in PSC (median 51.00 [34.50, 57.25]) vs 29.00 [19.00, 42.00] in other NSCLC histopathological subtypes (P=0.003). Using NGS, TP53 was found to be mutated in 58.8% of all NSCLC cases compared to 27.3% of the mutant k-ras where G12C was the most common subtype (39.1%). Our analysis revealed no difference in TP53 NGS, TP53 exon, TP53 MAF, KRAS NGS, KRAS codons or specimen site (P>0.05). We correlated the clinical and genetic profiles of 53 PSC patients and it was significant in the younger age population (r=-0.29, p=0.037).
Conclusion
PSC was significant in males, younger age group with more common G12V k-ras sub-type (31.3%) compared to the G12c subtype (25%). PD-L1 expression was significantly higher in PSC (79.2%) compared to other NSCLC subtypes (51%).
Table 1:showing the results for mutant KRAS subpopulation in relation to PDL122c3 expression. It also illustrates the percentage expression within each subtype of KRAS pathologic mutation:
KRAS mutation
PDL122c3 expression (n, %)
Total
(n, %)
Negative
Positive
G12V
0
0.0
5
33.3
5
31.3
G12D
0
0.0
2
13.3
2
12.5
G12A
0
0.0
2
13.3
2
12.5
G12C
1
100.0
3
20.0
4
25.0
G12S
0
0.0
2
13.3
2
12.5
9.0
0
0.0
1
6.7
1
6.3
Total (n, %)
1
100.0
15
100.0
16
100.0
N= number
