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Hui Yu
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MA 05 - Immuno-Oncology: Novel Biomarker Candidates (ID 658)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:Yoichi Nakanishi, P. Mitchell
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 303 + 304
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MA 05.14 - Differential Expression of IFN-Stimulating DNA Sensors STING and cGAS in Lung Cancer Subtypes (ID 9578)
17:10 - 17:15 | Author(s): Hui Yu
- Abstract
- Presentation
Background:
STING is a protein that promotes type I IFN production (IFNα/β) essential for activation of dendritic cells and antigen presentation and priming of T-cells. The cytoplasmic DNA sensor cGAS (cGAMP Synthase) is able to detect tumor DNA, and in response will synthesize cGAMP. cGAMP binds STING specifically, resulting in production of type I IFN. STING is therefore referred to as an adaptor protein essential for immune signaling following detection of tumor DNA. Analysis of the TCGA database indicates decreased survival in lung adenocarcinoma patients lacking STING expression. STING expression is decreased in tumor tissues and can be lost as the tumor progresses. One reported mechanism of loss of STING or cGAS in tumors is due to hypermethylation, a common occurrence in lung cancer. Agonists of STING show potent immune response and are currently in clinical trials. Importantly, recent studies show that expression of STING and cGAS proteins are essential for response to PD-1:PD-L1 blockade.
Method:
Section not applicable
Result:
We analyzed 55 NSCLC and 39 SCLC cell lines, and 317 NSCLC and 78 SCLC tissues for STING and cGAS expression using immunohistochemistry. 14/55 (25.45%) NSCLC cell lines and 25/39 (64.10%) SCLC cell lines showed no STING expression. Separated in to adenocarcinoma (AC) and squamous cell carcinoma (SCC) subsets, STING expression in AC shows loss of STING as tumor stage increases (Positive: 70% Stage I, 65% Stage II, 52% Stage III, 40% Stage IV, 71% total; n=156) while STING expression is low at all stages of SCC (Positive: 29% Stage I, 18% Stage II, 36% Stage III, 13% Stage IV, 27% total; n=161). SCLC tissues stained showed widespread loss of STING (Positive: 40% Stage I, 27% Stage II, 31% Stage III, 100% Stage IV, 37.18% total, n=78). Expression of cGAS was higher in AC (94%) than SCC (75%) and showed no correlation with stage. TCGA analysis of STING methylation shows hypermethylation in AC (0.15- ± 0.13 tumor vs 0.05 ± 0.02 normal, n=422) and SCC (0.23 ± 0.16 tumor vs 0.04 ± 0.03 normal, n=359). cGAS shows slight methylation in AC (0.05 ± 0.07 tumor vs 0.05 ± 0.01 normal, n=422) but a large increase in SCC (0.19 ± 0.24 tumor vs 0.04 ± 0.01 normal, n=359).
Conclusion:
This study indicates drastic differences in STING and cGAS expression in AC, SCC, and SCLC. Differential expression of these proteins could impact the efficacy of STING agonists, radiation therapy, and immunotherapy in lung cancer.
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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)
15:50 - 15:55 | Presenting Author(s): Hui Yu
- 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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P2.02 - Biology/Pathology (ID 616)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.02-011 - Clinical and Molecular Features of Lung Cancers with Increased FGFR1 mRNA and/or Gene Copy Number (ID 8825)
09:30 - 09:30 | Author(s): Hui Yu
- Abstract
Background:
Lung cancer cell line data suggest FGFR1 status defined by FGFR1 mRNA levels and FGFR1 gene copy number can predict sensitivity to FGFR tyrosine kinase inhibitors (TKIs).
Method:
A phase II biomarker preselected trial of ponatinib, an FGFR1, FGFR2, and FGFR4 targeted TKI was designed. Patients with metastatic EGFR- and ALK-negative lung cancers (both NSCLC and SCLC) were pre-screened for FGFR1 mRNA levels by in-situ hybridization (ISH) and FGFR1 gene copy number by silver in-situ hybridization (SISH). Positivity criteria for ISH were defined as a score of 3 (Dot clusters seen in 1 to <10% tumor cells; otherwise >10 dots/cell in ≥ 10% tumor cells), or 4 (Dot clusters seen in ≥ 10% of tumor cells). Positivity for SISH was defined as an average of ≥ 4 FGFR1 signal clusters/nucleus or FGFR1/CEN8 ratio ≥ 2.0. Clinical factors including sex, histology, age and sites of metastases at diagnosis of stage IV disease, smoking status, status of other known molecular drivers, and response to initial platinum-doublet therapy for stage IV disease were collected.
Result:
From 11/2013 to 05/2017, the study has pre-screened 163 patient samples for FGFR1 ISH and SISH. Thirty-eight (23.3%) had insufficient tissue; four had incomplete clinical or FGFR1 information. Clinical variables according to FGFR1 ISH/SISH status (n=121) are summarized in Table 1. Impact of alternate positivity cut-points, outcomes of patients treated with ponatinib and survival analysis according to ISH/SISH subgroups will be presented. Figure 1
Conclusion:
Although the numbers were small, the FGFR1 ISH+/SISH+ subgroup had a greater percentage small cell histology, liver metastases at diagnosis and male sex compared to other FGFR1 subgroups. FGFR1 ISH and/or SISH positivity can overlap with other known oncogenic drivers suggesting that the initial cut-points for FGFR1 positivity used may be too low to identify a true FGFR1 addicted state.
