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Tao Wang



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    EP1.14 - Targeted Therapy (ID 204)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.14-26 - Uncommon EGFR Mutations Sensitive to First-Generation EGFR-TKI, Icotinib (Now Available) (ID 2091)

      08:00 - 18:00  |  Author(s): Tao Wang

      • Abstract
      • Slides

      Background

      The first-generation EGFR-TKIs are the standard of care for non-small cell lung cancer patients withEGFR activating mutations. Patients with EGFR L858R (p.L858R) or exon 19 deletions are the most prevalent subgroup sensitive to EGFR-TKIs. Previous reports showed that the minority of lung cancer patients with rare EGFR mutations still achieved clinical benefit with EGFR-TKIs. Here, we profiled the landscape of gene mutations in lung cancer patients who responded to Icotinib (a first- generation EGFR-TKI approved in China) treatment without classic EGFR activating mutations.

      Method

      We performed a comprehensive sequencing study by a NGS-based panel on a cohort of eleven lung adenocarcinoma patients without common EGFR sensitive mutations and receiving Icotinib treatment in a previous clinical trial (ICOGEN, NCT01040780). The pre-treatment FFPE tissues from all eleven patients were sequenced using a 500-gene panel.

      Result

      Six patients responded to Icotinib treatment including three patients with partial response (PR) and three patients with stable disease (SD). The other five patients showed immediate disease progression (PD) after the treatment of Icotinib. Rare EGFR mutations in the EGFR tyrosine kinase domain , including EGFR mutations W731C (exon 19), M793I (exon 20), and V845L (exon 21), were detected in the PR and SD groups but not in the PD group. EGFR somatic mutation M793I has been detected in the lung tissue of a patient according to the COSMIC record (COSM1716335). In the PR and SD groups, ERBB2 I655V and JAK2 R215Q were identified as potential mutations which could relate to Icotinib sensitivity.

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      Conclusion

      This study uncovered potential new biomarkers predicting the clinical benefit to Icotinib. With further validation and evidence, it may expand the current patient populations which benefits from the first-generation EGFR-TKIs.

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    P2.03 - Biology (ID 162)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.03-21 - MUC16 Germline Mutations May Associate with Inherited Lung Cancer (ID 2150)

      10:15 - 18:15  |  Presenting Author(s): Tao Wang

      • Abstract
      • Slides

      Background

      Study of inherited cancer may facilitate the understanding of the molecular mechanism of tumorigenesis. Though sporadic reports have shown that mutations in EGFR or ERBB2 may associate with familial lung cancer, the knowledge of the genetic causes for inherited lung cancer is still limited.

      Method

      Genomic DNA (gDNA) from cancer patients or healthy people were extracted from whole blood samples and analyzed using a 500-gene next generation sequencing (NGS) panel. Variants identified by NGS panel were confirmed by Sanger sequencing.

      Result

      In November 2017, four siblings in a Chinese family were diagnosed with lung adenocarcinomas. Additionally, the 5th sibling in the family had prostate cancer. A questionnaire for the family did not reveal significant environmental or habitual reasons leading to cancer in the family, suggestive of possible genetic causes. NGS analysis for gDNA samples indicated all 4 siblings with lung cancer had 3 heterozygous alleles of SNPs in MUC16, namely rs754254000, rs754856910, and rs746152510. In contrast, the sibling with prostate cancer was wild-type for all of the three alleles (Figure below). The NGS results were then confirmed by Sanger sequencing. The three germline mutations in MUC16 all had very low population minor allele frequency (below 0.1%). We further analyzed the gDNA of the children in the family, and detected the 3 heterozygous SNPs in a child whose parent had lung cancer, whereas both children of the prostate cancer patient were wild-type for the 3 MUC16 alleles. Taken together, these results are consistent with a hypothesis that germline mutation of rs754254000, rs754856910, and rs746152510 may predispose the family members to lung cancer. MUC16, also known as CA125, is a biomarker for ovarian cancer, and also shown to be involved in tumorigenesis and metastasis of lung cancer cells. The child with heterozygous SNPs of MUC16 need be cautious in the future routine check-ups.

      muc16 3 snp.png

      Conclusion

      In this study, we have demonstrated that germline mutations of MUC16 may associate with inherited lung adenocarcinomas, which warrants further mechanistic study of MUC16 gene in lung cancer.

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      P2.03-28 - A 500-Gene Panel to Detect Tumor Mutation Burden of Tissue and Plasma Samples from Lung Cancer Patients (ID 2157)

      10:15 - 18:15  |  Author(s): Tao Wang

      • Abstract
      • Slides

      Background

      Tumor mutation burden (TMB) from cancer tissue is an FDA approved biomarker for selecting appropriate patients for immunotherapy. However, tissue samples are not readily accessible. Though reports have shown correlation between tissue TMB and plasma based TMB (bTMB), no FDA approved bTMB product is available yet. More assay needs to be evaluated for correlation analysis of TMB and bTMB.

      Method

      Matched gDNA, ctDNA, and tumor tissue DNA samples from the same patient with non-small-cell lung cancer (NSCLC) were extracted from blood, plasma, and formalin-fixed paraffin-embedded (FFPE) tissue using Qiagen DNA extraction kits. DNA libraries were prepared using Agilent SureSelectXT HS Reagent Ki and were sequenced by a comprehensive 500-gene NGS cancer panel. After variant calling, non-synonymous variants were included to calculate TMB and bTMB using allele frequency cutoffs at 5% and 0.8%, respectively. An in-house bioinformatics method to get rid of germline mutations were also validated in our dataset.

      Result

      To validate the 500-gene panel for TMB and bTMB analysis, we first retrieved TCGA whole exome sequencing (WES) data including 1144 lung cancer patients and about 15500 pan-cancer patients. We then calculated the correlations between the 500-gene panel and WES data on the two datasets and acquired R-square values of 0.93 and 0.94, respectively. Such data demonstrated that our 500-gene is a suitable panel to substitute WES for TMB analysis. We then used the 500-gene panel to analyze 17 NSCLC patients with matched FFPE, ctDNA, and gDNA samples. Using 5% and 0.8% as the allele frequency cutoffs for the variants called from the tissue DNA and ctDNA samples, we found a 0.84 R-square correlation between TMB and bTMB analysis. These results suggest that the bTMB from plasma samples of cancer patients highly correlates to the TMB of the paired tissues using our 500-gene panel.

      Conclusion

      We have demonstrated in this study that a 500-gene panel is suitable for TMB analysis of cancer tissues. We further show that bTMB analysis using the 500-gene panel is close and highly correlate to the TMB from paired cancer tissues. Upon further clinical studies, the TMB and bTMB analysis using the 500-gene panel may represent a good biomarker for patient selection using either cancer tissue or plasma samples.

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