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W.A. Franklin
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MA 13 - New Insights of Diagnosis and Update of Treatment (ID 674)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:S. Ishikura, H. Nakayama
- Coordinates: 10/17/2017, 15:45 - 17:30, Room 311 + 312
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MA 13.02 - Comprehensive Genetic Analysis Related to PD-L1 Expression in Early-stage Lung Squamous Cell Carcinoma (ID 9077)
15:45 - 17:30 | Author(s): W.A. Franklin
- Abstract
- Presentation
Background:
Recently, anti PD-1/PD-L1 immunotherapies have yielded promising outcomes in advanced squamous NSCLC. Several studies have suggested that tumor PD-L1 protein expression status might correlate with outcome and response to treatment. The aim of this study is to identify mRNA gene signatures and microRNAs associated with tumor PD-L1 expression in early-stage lung squamous cell carcinoma (SCC).
Method:
Early stage (I-II) SCC resected patient tumors were collected from 6 cancer centers as part of the SPECS II program. Gene expression profiling was performed on the specimens. PD-L1 protein expression was evaluated by immunohistochemistry on SCC FFPE tissue using the Dako 22C3 PD-L1 antibody. The tumor proportion score (TPS) for PD-L1 protein expression was compared with comprehensive clinicopathological, mRNA and miRNA data.
Result:
The prevalence of PD-L1 expression in this cohort of 255 Stage I-II SCC patients was 46.7% with a TPS cutoff of ≥ 1%, and 9.8% with a cutoff of ≥ 50%. Among 202 cases with available clinical and expression data, no significant association was observed between PD-L1 expression and clinical outcome. We identified a 12-gene signature from mRNA microarray using the Minimax Concave Penalty (MCP) regression method with an AUC of 0.92 at ≥ 5% TPS cutoff. A subset of 138 miRNAs was shown to be significantly differentially expressed between PD-L1 positive and PD-L1 negative groups at false discovery rate (FDR) of 0.05 with TPS cutoffs of ≥ 1%, ≥ 5% and ≥ 10%. No miRNAs were found to be significantly differentially expressed between the groups using a TPS cutoff of ≥ 50%. Gene Set Enrichment Analysis (GSEA) identified two pathways with gene sets that were significantly enriched (FDR < 0.05) in the PD-L1 negative group. No significant association was found between tumor mutation burden and PD-L1 expression level.
Conclusion:
PD-L1 expression prevalence is lower in early-stage lung SCC than in advanced NSCLC. No significant association was found between PD-L1 expression and prognosis in this cohort. Both mRNA gene signatures and miRNAs were identified to be predictive of PD-L1 expression. Through GSEA, two distinct gene sets were identified with expression correlated to PD-L1, one comprising genes related to ovary and another related to collagens and extracellular matrix (ECM). No significant association was found between tumor mutation burden and PD-L1 expression level. Following validation, these predictive signatures could be used to select patients with positive PD-L1 expression who may benefit from immunotherapy.
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P2.03 - Chemotherapy/Targeted Therapy (ID 704)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.03-019 - Sizing Capillary Electrophoresis with PCR to Detect Various EGFR Exon 19 Deletions in Non-Small Cell Lung Cancer (ID 8614)
09:30 - 16:00 | Author(s): W.A. Franklin
- Abstract
Background:
This study points out an issue of PCR-based methods to detect exon 19 deletions. PCR methods are used for clinical examination, because they are useful, rapid and cost-effective to detect EGFR mutations. Exon 19 deletions are most important among EGFR mutations to dictate EGFR tyrosine kinase inhibitors (EGFR-TKIs) therapy in non-small cell lung cancer (NSCLC), and have various species. The sensitive PCR methods select major exon 19 deletions, but cannot detect unusual variants. We investigated the clinical significance of minority exon 19 deletions.
Method:
A series of 73 NSCLC patients, which were treated with EGFR-TKI for recurrent disease after they had undergone surgery from 1992 to 2004. In all cases, Microdissenction and direct sequence were performed. Scorpion Amplification Refractory Mutation System (ARMS) and cobas version 2.0, as sensitive PCR methods, were performed in 47 patients along with sizing capillary electrophoresis for the exhaustive detection of exon 19 deletions.
Result:
EGFR mutations were detected from 35 patients (47.9%), which were one exon 18 mutation, 23 exon 19 deletions, and 11 exon 21 mutations in all 73 cases. The catalog of somatic mutation in cancer (COSMIC) database included 174 different exon 19 deletions in 4190 submitted cases at December 2014. E746_A750 deletion was most common deletion of exon 19, accounting for 70% of the total exon 19 deletions (2931/4190). Predicted frequency of exon 19 tested by Scorpion-ARMS was 81.6% (3419/4190), and that of cobas version 2.0 had 82.5% (3457/4190) in the detection of various exon 19 deletions. In clinical samples of this study, Scorpion-ARMS and cobas version 2.0 failed to detect four exon 19 deletions, in two squamous cell carcinomas (EGFR-TKI effects were stable disease and no assessable patient) and two papillary adenocarcinomas (EGFR-TKI effects were stable disease and no assessable patient). One of papillary adenocarcinoma had minority deletion ‘T751_I759 deletion and insertion S’, which had long stable disease for 43.4 months in EGFR-TKI therapy. Sizing capillary electrophoresis was able to detect this deletion.
Conclusion:
This study suggests sizing capillary electrophoresis is necessary for the exhaustive detection of exon 19 deletions, and may identify tumors responsive to EGFR-TKIs therapy, especially those with unusual deletions.
