Author of

• 18972

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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)

  • 23216

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    P2.02-018 - Genomic Profiling of Driver Gene Mutations in 498 Chinese NSCLC Patients (ID 10433)

    09:30 - 16:00  |  Author(s): Y. Shang
    • Abstract

    Background:
    Identifying genomic alterations of actionable driver genes in non-small cell lung cancer (NSCLC) such as EGFR, ALK, ROS1 has been used as important evidences for firstline treatments. Patients with driver mutations received matched target drugs could have significantly longer progression free and overall survival.
    
    Method:
    FFPE tumor samples of 498 Chinese NSCLC patients including 279 males (56%) and 219 females (44%) with a median age of 60 were collected for next-generation sequencing (NGS)-based multi genes panel assay. Genomic alterations including single base substitution, short and long insertions/deletions, copy number variations, and gene rearrangement and fusions in selected genes were assessed.
    
    Result:
    Different histological subtypes of adenocarcinoma (417/498, 83.7%), squamous carcinoma (68/498, 13.7%), mixed carcinoma (6/498, 1.2%) and large cell carcinoma (7/498, 1.4%) were included in the Chinese NSCLC cohort. The top ranked genomic alterations in driver genes were EGFR (47.8%), KRAS (10.0%), ALK fusions (8.2%), PIK3CA (7.0%), HER2 (6.2 %), PTEN (3.6%), BRAF (2.6%), MET (3.6%), RET fusions (1.6%), and ROS1 fusions (0.8%), which counts up to 86.9% of the 498 patients with at least one driver mutation. In addition to common driver mutations, rare mutation types such as EGFR-KDD, EGFR-RAD51, AMOTL2-NTRK1 and KIF13A-RET were also detected by deep sequencing assay.
    
    Conclusion:
    Our study revealed the landscape of driver gene mutations in 498 Chinese NSCLC patients. Comparing to the largest public NSCLC cohort from Foundation Medicine, mostly Western populations (N=6823, PMID: 27151654), we identified similar frequencies of some driver genes, but more ALK fusions (8.2% vs 3.9%), EGFR mutations (47.8% vs 20.0%) as druggable target genes, and less KRAS mutations (10.0% vs 32.0%) consistent with reported results. Totally 78.7% of the Chinese patietns harbored at least one mutaiton in the 8 core driver genes including EGFR, ALK, BRAF, ERBB2, MET, ROS1, RET, or KRAS (vs. 71% in the FMI cohort). Our findings demonstrated that genomic profiling of driver genes in NSCLC showed significant differences among racial or ethnic groups, which indicated different treatment options between Eastern and Western populations.
    
    

• 20186

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  P3.07 - Immunology and Immunotherapy (ID 723)

  • Event: WCLC 2017
  • Type: Poster Session with Presenters Present
  • Track: Immunology and Immunotherapy
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)

  • 24118

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    P3.07-009 - PI3K/mTOR Pathway Altertions May Mediate PD-1/PD-L1 Blockade Resistance in Non-Small Cell Lung Cancer (ID 10489)

    09:30 - 16:00  |  Author(s): Y. Shang
    • Abstract

    Background:
    Immune checkpoint inhibitors have changed the clinical practice for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) as the first line or second line therapies. Although PD-1/PD-L1 blockade has been demonstrated as a promising anti-tumor therapy with significant clinical benefits, the fact of acquired resistance after a response to PD-1/PD-L1 blockade has become a common concern. The mechanism underlying acquired resistance to immune checkpoint inhibitors have remained unclear.
    
    Method:
    FFPE samples from 127 Chinese NSCLC patients were collected, including 103 (81.1%) adenocarcinoma, 21 (16.5%) squamous cell carcinoma, 2 (1.6%) adenosquamous carcinoma and 1 (0.8%) large cell carcinoma. Comprehensive genomic profiling (CGP) assay with 450 genes whole exon region were performed for the analysis of genomic alterations including single base substitution, short and long insertions/deletions, copy number variations, gene rearrangement in selected genes and also tumor mutation burden (TMB) calculated as total somatic substitutions and indels per megabase. We considered high TMB as over 80% of the 500 patient TMB distrbutions from our inhouse cancer database across solid tumor types.
    
    Result:
    32 patients with higher TMB values were collected from 127 Chinese NSCLC patients. Interestingly, we identified the frequency of PI3K/mTOR pathway genes (AKT1, FBXW7, PIK3CA, PTEN, TSC1/2, STK11 and mTOR) was significantly higher in patients with high TMB value (28.1% vs 10.5%, p=0.033). Moreover, PI3K/mTOR pathway alterations existed in 3 patients who initially responded to PD-1/PD-L1 blockade and then were resistant to immune checkpoint inhibitors. Two patients with PIK3CA K111N and FBXW7 R465H have started to receive mTOR inhibitor everolimus mono therapy after 6 cycle nivolumab or pembrollizumab treatments. So far both showed stable disease or minor shrinkage on tumor. More investments are under way.
    
    Conclusion:
    In our study, PI3K/mTOR pathway alterations occurred more frequently in the NSCLC patients with higher TMB values. Several PD-1/PD-L1 blockade resistance patients harbored PI3K/mTOR mutations showed responses. The activation of PI3K/mTOR pathway might mediate the acquired resistance to immune checkpoint inhibitors. This finding suggested that mTOR inhibitors might be a potential strategy for those who harbored mutations in PI3K/mTOR pathway after the resistance of PD-1/PD-L1 blockade therapies.