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A. Sidoni
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MA04 - HER2, P53, KRAS and Other Targets in Advanced NSCLC (ID 380)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
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MA04.06 - Signaling Networks in KRAS-Mutant Advanced NSCLC: A Complex Landscape Involving Immunoresponse, Inflammation and DNA Repair (ID 5768)
16:00 - 17:30 | Author(s): A. Sidoni
- Abstract
- Presentation
Background:
KRAS is the most frequently mutated oncogene in Non-Small Cell Lung Cancer (NSCLC) and its role as prognostic and predictive biomarker remains widely debated. Unfortunately, KRAS direct targeting strategies have been unsuccessful and no approved target therapy exists for KRAS-mutant-NSCLC. This pilot study evaluated the activated signaling architecture of advanced NSCLC harbouring a KRAS mutation to better characterize the signaling network driving this subgroup of pulmonary malignancies.
Methods:
Twenty Stage IV Formalin-fixed, paraffin-embedded (FFPE) NSCLCs were collected from chemo-naïve patients at S. Maria della Misericordia Hospital (Perugia, Italy). Ten tumors were KRAS-wild-type (KRAS-WT) and ten were KRAS-Mutant (KRAS-MUT). Whole-tissue lysates were obtained for all samples. Signaling network analysis was performed using the Reverse Phase Protein Array (RPPA) platform to quantitatively evaluate the expression/activation of 148 key proteins and phosphoproteins involved in cellular growth, survival, proliferation, apoptosis, autophagy, inflammation, invasion and cell motility. Wilcoxon Rank-Sum Test was used to compare the signaling architecture of KRAS-MUT and KRAS-WT tumours. All p-values <0.05 were considered significant. Non-parametric correlation analysis was performed to explore the signaling interconnection within each group of patients. Only correlations with p<0.0001 were considered significant.
Results:
This preliminary analysis revealed a statistically significant different activation level of 20 proteins between the KRAS-MUT and KRAS-WT samples. Five of the proteins that were statistically different in the KRAS-MUT group are involved in the inflammatory immunoresponse (ASK1 S83 p<0.01, Axl Y702 p=0.01, Stat2 Y690 p<0.01, Tyk2 Y1054/Y1055 p=0.01 and Twist p<0.01) and six in cell cycle control and DNA repair (ATM S1981 p=0.01; Bcl-xL p=0.03; Cleaved Caspase 3 D175 p=0.02; Histone H3 S10 p<0.01; p53 S15 p<0.01; p27 T187 p=0.04). The analytes that were statistically significant were all lower in the KRAS-MUT group compared to the WT (except for p27 T187 which decreased in the KRAS-MUT group compared to KRAS-WT). Pair-wise correlation analysis of the signaling proteins showed an overall more complex protein-protein interaction network and pathway activation (included AKT/mTOR signaling pathway) in the KRAS-MUT population with high number of statistically significant correlations compared to the KRAS-WT group.
Conclusion:
This pilot study indicated that the effect of KRAS mutation status on protein signaling in NSCLC was an alteration of the immunoresponse axis and DNA repair network. If validated in a larger cohort of patients, these results could have important clinical implications for stratification KRAS-MUT advanced NSCLC patients towards more efficacious targeted treatment and to identify new therapeutic targets based on multi-targets/multi-pathways KRAS inhibitory approach. (AIRC-supported study).
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P1.07 - Poster Session with Presenters Present (ID 459)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.07-018 - Incidence of Brain Recurrence and Survival Outcomes in High-Grade Neuroendocrine Carcinomas of the Lung: Implications for Clinical Practice (ID 3879)
14:30 - 15:45 | Author(s): A. Sidoni
- Abstract
Background:
Among patients with advanced high-grade neuroendocrine carcinoma (HGNEC) of the lung, the optimal therapeutic management is much less established for large cell neuroendocrine carcinomas (LCNECs) than for small cell lung cancers (SCLCs). We evaluated the survival outcomes and incidence of brain recurrence of advanced LCNECs, and compared them with those of a population of SCLCs matched by stage.
Methods:
Forty-eight unresected stage III HGNECs (16 LCNECs and 32 SCLCs) and 113 stage IV HGNECs (37 LCNECs and 76 SCLCs) were eligible for the analysis. The efficacy of platinum-etoposide chemotherapy with or without thoracic radiotherapy (TRT) and/or prophylactic cranial irradiation (PCI) was investigated.
Results:
Overall response was significantly lower for LCNECs compared with SCLCs for both stage III (43.8% vs 90.6% respectively, P=0.004) and stage IV (43.3% vs 64.5%, respectively, P=0.04). Similarly, an inferior outcome was observed in terms of progression-free survival (PFS), and overall survival (OS) for LCNECs compared with SCLCs, which, however, reached significance only for stage III disease (median: 5.6 vs 8.9 months, P=0.06 and 10.4 vs 17.6 months, P=0.03 for PFS and OS, respectively), (Figure 1). Histologic subtype (LCNEC vs SCLC) was an independent prognosticator in multivariate analysis. In the lack of PCI, LCNECs showed a high cumulative incidence of brain metastases, as 58% and 48% of still living stage III and IV patients, respectively, developed brain metastases at 18 moFigure 1
Conclusion:
Patients with advanced LCNECs are at high risk for brain recurrence. Unresected stage III LCNECs treated with platinum-etoposide with or without TRT bear a dismal prognosis, when compared indirectly with SCLC counterparts. Randomized trials should evaluate whether PCI could improve survival of advanced LCNECs.
