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Hua Bai



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    MA06 - PDL1, TMB and DNA Repair (ID 903)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 206 AC
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      MA06.07 - Genetic and Epigenetic Alterations are Associated with Tumor Mutation Burden in Non-Small Cell Lung Cancer (ID 12822)

      14:10 - 14:15  |  Author(s): Hua Bai

      • Abstract
      • Presentation
      • Slides

      Background

      Although several studies have indicated that tumor mutation burden (TMB) is associated with non-small cell lung cancer (NSCLC) development and clinical efficacy of immune checkpoint inhibitors (CPIs), identification of factors associated with TMB is still a major biological issue. It is well-known that DNA transcription can be regulated through methylation and demethylation, gene silencing caused by DNA hypermethylation is associated with cancer development. However, the relationship between DNA methylation and TMB in NSCLCs remains unclear.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The landscape of DNA sequence in Chinese NSCLCs population were surveyed by using whole-exome sequencing (WES) by profiling 178 lung tissues (89 without any systemic anti-cancer therapy tumors and matched normal lung tissues). According to the 104 median-level of TMB in our cohort, high TMB (n=16, 252-465 range mutations per tumor) and low TMB (n=13, 57-79 range mutations per tumor) groups were divded. The NSCLC methylome between high and low TMB was characterized on a genome-wide scale using Illumina Infinium MethylationEPIC arrays combined with the WES data.

      4c3880bb027f159e801041b1021e88e8 Result

      The results show frequently aberrant DNA methylation, abundant chromosomal amplifications and deletions, and mutational signatures in high TMB lung cancer. Combining with clinical data, cigarette smoking associated with high TMB were observed in our cohort. Cancer-specific epigenetic alterations were observed in 294,141 CpG sites, comprising both tumor hyper- (769,38) and hypo- (217,203) methylation in high TMB lung cancer while none in low. These different methylations sites cover 1232 genes including 25 HOX genes.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Global DNA hypomethylation and TP53 mutation, associated with increased chromosomal instability, were associated with TMB in NSCLCs.The high TMB NSCLCs are characterized by numerous copy number alterations and aberrantly methylated sites and display distinct mutational signatures. 25 hypermethylated HOX genes can be potentially useful as DNA methylation markers for prediction of TMB level. The results provide insights into the epigenetic impact of TMB, which may contribute to improve precison management of NSCLCs.

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    P2.01 - Advanced NSCLC (Not CME Accredited Session) (ID 950)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.01-101 - Dynamic Monitoring of Gene Alterations with ctDNA by NGS for EGFR Mutated Lung Adenocarcinoma Treated with Gefitinib in BENEFIT Study (CTONG 1405) (ID 14347)

      16:45 - 18:00  |  Author(s): Hua Bai

      • Abstract

      Background

      Blood-based cell-free tumor DNA (ctDNA) could be dynamically monitored to provide gene alterations during EGFR-TKI treatment, which might offer critical clue for prognosis and clinical treatment decision. Here we reported the dynamic gene alterations monitoring using next generation sequencing (NGS) in BENEFIT study to explore the mechanisms of different responses and resistances to EGFR-TKI in EGFR-sensitizing-mutated lung-adenocarcinoma (LADC) patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with systemic treatment-naïve, stage IV LADC and EGFR-sensitizing-mutation in ctDNA were enrolled to receive gefitinib. Blood samples were dynamically obtained at baseline, every 8 weeks and at disease progression (PD). The dynamic analysis of quantity of ctDNA, multiple driver genes and tumor suppressors were investigated with NGS (Nextseq500 sequencer, consisting of critical exons/introns of 168 genes), and were correlated with efficacy and resistance.

      4c3880bb027f159e801041b1021e88e8 Result

      Totally 181 LADC patients with EGFR-sensitizing-mutation (exon-19-deletion and exon-21-L858R-point-mutation) provided sufficient blood samples for NGS analysis at baseline, of which 143 patients obtained at least four timepoints of dynamic blood sample collection until PD (baseline, 8 weeks, 8 weeks before PD and PD). At baseline, 180 of patients (99.4%) were confirmed as EGFR-sensitizing-mutation with NGS (92 EGFR-19-deletion and 88 EGFR-L858R-point-mutation) including 44 (24.3%) EGFR-amplification, 116 (64%) TP53-mutation, or other known oncogenic drivers including MET (N=5, 2.8%), ERBB2 (N=7,3.9%), KRAS (N=6, 3.3%), BRAF (N=2, 1.2%), RET (N=1, 0.6%), ROS1 (N=1, 0.6%), or EGFR-T790M (N=4, 2.2%), which was correlated with poor efficacy compared with those with only EGFR-sensitizing-mutation (PFS 4.7 months [m] vs. 13.2m , p=0.002). Additionally, tumor suppressor genes exhibiting cumulative effect to poor prognosis: PFS for 164 patients with TP53&RB1&PTEN-mutation≤1 was 11.1m, while for 16 patients with TP53&RB1&PTEN-mutation>1,PFS was 4.7 m, p<0.0001. To cut-off date, 117 patients had PD, among them, 63 (54%) patients acquired EGFR-T790M-mutation presented as dominant resistance mechanism besides MET-amplification/ERBB2-amplification/ERBB2-S310F (N=16, 14%), RET fusion/splice (N=2, 1.7%), ROS1-C2336F-mutation (N=1, 0.9%), RB1-nonsense-mutation (N=2, 1.7%), TP53-Y205S-mutation (N=1, 0.9%) and TP53-Y205S-mutation accompanied with FGFR1-amplification (N=1, 0.9%). The remaining resistance mechanisms (31%) were unknown. Patients with only T790M-mutation had a significantly longer PFS (11.5m) compared with patients obtaining other acquired resistant mechanisms (3.0m). Interestingly, seventy-five (53.2%) patients had molecular progression before radiographic progression, and the median time difference was 8.7 weeks.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Dynamic alterations of multi-drivers and suppressors together with EGFR-sensitizing-mutation and T790M-mutation could separate LADC into different subgroups with distinguished molecular features, which may play a vital role during EGFR-TKI treatment for resistance-predicting, and initial/subsequent treatment decision-making.

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    P2.04 - Immunooncology (Not CME Accredited Session) (ID 953)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.04-03 - NF-κB and HIF-1α Play Important Roles in Regulating PD-L1 Expression by EGFR or KRAS Mutants in Non-Small Cell Lung Cancer Cells (ID 12672)

      16:45 - 18:00  |  Author(s): Hua Bai

      • Abstract

      Background

      Programmed death ligand 1 (PD-L1) is expressed in various human tumors and is of critical importance for the immune escape of tumor cells. Some driver gene mutations including EGFR and KRAS have been reported to be involved in PD-L1 expression regulation. However, the potential role and precise mechanism of EGFR and KRAS mutants in PD-L1 expression regulation in non-small cell lung cancer (NSCLC) remain obscure.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The expression levels of PD-L1 and key molecules of EGFR and KRAS signaling pathways were examined in 11 NSCLC cells with wild-type or mutant EGFR and KRAS genes. Additionally, ectopic expression or depletion of EGFR or KRAS mutants and pharmacological inhibitors of MEK/ERK, PI3K/AKT, IκBα, and HIF-1α were employed to elucidate the effects of activation or inhibition of EGFR or KRAS pathway on PD-L1 expression regulation in NSCLC cells. The effects of pathway inhibitors on tumorigenesis and PD-L1 expression of EGFR or KRAS-mutated NSCLC cells were also examined using xenograft mouse model, Furthermore, the correlations between EGFR and KRAS status and protein levels of HIF-1α and PD-L1 were analyzed in 97 NSCLC tissues.

      4c3880bb027f159e801041b1021e88e8 Result

      Examination of the EGFR and KRAS signaling cascades in NSCLC cells revealed an apparent association of PD-L1 overexpression with activation of MEK/ERK and PI3K/AKT pathways, especially with increased protein levels of p-IκBα and HIF-1α. Notably, ectopic expression or depletion of EGFR or KRAS mutants and administration of EGFR or KRAS pathway inhibitors showed important interplay and cooperation between NF-κB and HIF-1α in PD-L1 expression regulation in NSCLC cells. Furthermore, administration of EGFR or KRAS pathway inhibitors significantly inhibited xenograft tumor growth and PD-L1 expression of NSCLC cells in nude mice. Moreover, NSCLC tissues with positive HIF-1α staining presented significantly increased positive rate of PD-L1 expression compared with tissues scored HIF-1α negative (49.1% vs. 20.5%, P = 0.003). NSCLC tissues with EGFR or KRAS mutants showed obviously elevated expression levels of HIF-1α and PD-L1 compared with tissues carrying wild-type EGFR and KRAS genes (68.4% vs. 43.4%, P = 0.018 and 50.0% vs. 28.3%, P = 0.035, respectively).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Taken together, both EGFR and KRAS mutants were identified to regulate PD-L1 expression via signaling effectors, NF-κB and HIF-1α, suggesting the correlation between driver gene mutations and tumor immune escape in NSCLC.

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