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J. Ying



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    MA 06 - Lung Cancer Biology I (ID 660)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Biology/Pathology
    • Presentations: 1
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      MA 06.09 - Detection of EGFR T790M Mutations by Four Testing Platforms in ctDNA from Chinese Patients with Advanced NSCLC (ID 8615)

      15:45 - 17:30  |  Author(s): J. Ying

      • Abstract
      • Presentation
      • Slides

      Background:
      Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI) targeting sensitizing mutations and T790M mutation, which causes ~60% of acquired resistance after first-line TKI treatment. T790M testing provides guidance for second-line treatment decisions. This study evaluated four T790M detection platforms using plasma circulating tumor DNA (ctDNA).

      Method:
      ADELOS is a multicentre, open-label, single-arm study (NCT 02997501) of Chinese patients with advanced non-small cell lung cancer (NSCLC) and progression on previous EGFR-TKI treatment. Plasma ctDNA testing for T790M was performed by Cobas[®] real-time polymerase chain reaction (PCR), super amplification refractory mutation system (Super-ARMS) PCR, capture-based next-generation sequencing (NGS, 168 gene panel), and QuantStudio3D digital PCR (3D dPCR). T790M-positive patients detected by these platforms received osimertinib 80 mg/day orally until progression. Matched tissue re-biopsy samples were also tested by Cobas[®] or NGS. The primary objectives were to evaluate concordance between the Cobas[®] test and the other three platforms and to assess the efficacy of osimertinib in ctDNA T790M-positive patients.

      Result:
      Of 256 patients enrolled, 181 were ctDNA T790M-positive, among which 167 received osimertinib monotherapy. T790M plasma positive rate was from 37.4% to 63.5% (Cobas[®]< Super-ARMS90% for all three platforms. Specificity was between 53% (3D dPCR) and 89% (Super-ARMS). Compared with paired tissue testing results (n=73), NGS showed the highest concordance and sensitivity, while Cobas[® ]showed the highest specificity (Table 1). Table 1. Comparison of different platforms for T790M detection

      Cobas[®] PCR n=254 Super-ARMS PCR n=256 NGS n=256 3D dPCR n=255
      T790M detected, n (%) 95 (37.4) 108 (42.2) 138 (53.9) 162 (63.5)
      Comparison vs Cobas plasma test (n=254)
      Concordance %, (95% CI) -- 91.3 (87.2, 94.5) 82.7 (77.5, 87.1) 66.8 (60.6, 72.6)
      Sensitivity %, (95% CI) -- 94.7 (88.1, 98.3) 98.9 (94.3, 100.0) 90.5 (82.8, 95.6)
      Specificity %, (95% CI) -- 89.3 (83.4, 93.6) 73.0 (65.3, 79.7) 52.5 (44.4, 60.5)
      Comparison vs Tissue (n=73)
      Concordance %, (95% CI) 67.1 (55.1, 77.7) 64.4 (52.3, 75.3) 69.9 (58.0, 80.1) 61.6 (49.5, 72.8)
      Sensitivity %, (95% CI) 57.1 (42.2, 71.2) 61.2 (46.2, 74.8) 71.4 (56.7, 83.4) 69.4 (54.6, 81.7)
      Specificity %, (95% CI) 87.5 (67.6, 97.3) 70.8 (48.9, 87.4) 66.7 (44.7, 84.4) 45.8 (25.6, 67.2)


      Conclusion:
      Super-ARMS showed highest concordance and NGS showed highest sensitivity compared with Cobas® plasma T790M testing. Concordance and specificity of 3D dPCR was lower using other ctDNA tests or tissue as reference. Subsequent osimertinib treatment in these patients will justify the effectiveness of T790M testing by different technologies.

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    MA 11 - Emerging Diagnostic/Biomarkers in NSCLC (ID 668)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Advanced NSCLC
    • Presentations: 1
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      MA 11.05 - Targeted DNA- and RNA-Based Next-Generation Sequencing for Identifying MET Exon 14 Alterations in Pulmonary Sarcomatoid Carcinoma (ID 9266)

      11:00 - 12:30  |  Author(s): J. Ying

      • Abstract
      • Presentation
      • Slides

      Background:
      Highly diverse somatic splice site alteration at MET exon 14 (METex14) result in exon skipping, which is supposed to be a therapeutic target in NSCLC. Here we report detection of METex14 alterations using targeted DNA- and RNA-based Next-Generation Sequencing (NGS) in pulmonary sarcomatoid carcinoma (PSC) with a high frequency of METex14 skipping.

      Method:
      Tumor specimens were collected from 77 Chinese PSC patients. DNA and RNA were subject to targeted NGS, allowing the detection of somatic splice site alterations and intragenic METex14 skipping respectively. Then, somatic mutations (mutation allele frequency ≥2%) that lead to METex14 skipping were recognized, and Fisher’s exact test was used to examine the association between METex14 skipping and clinical characteristics or other mutations. Two-sided P-values <0.05 were considered statistically significant. Moreover, RT-PCR and Sanger sequencing was also performed on the METex14-positive specimens.

      Result:
      We have detected genetic aberrations in 77 FFPE samples. For RNA-based NGS, METex14 skipping was identified in 16 (20.78%) of 77 patient cases. And 15 (93.75%) METex14-positive patients were detected somatic mutations by DNA-based NGS, including 12 (80%) cases with splice donor site mutations, 1 (6.67%) cases with splice acceptor site alterations, 1 (6.67%) case with a novel deletion (chr7: 116411868 - 116411883) at MET intron 13 region and 1 (6.67%) case with a novel deletion (chr7: 116412027 - 116412042) at MET exon14 region. In this study, 6 somatic mutations which induce METex14 skipping were firstly discovered. So far, RT-PCR and Sanger sequencing were performed on 3 specimens, including 1 sample with conflicting RNA- and DNA-based NGS results and 2 samples with unreported somatic deletions. According to the results of RT-PCR and Sanger, the unmatched sample was false negative on the basis of DNA-based NGS result. Interestingly, METex14 skipping was mutually exclusive with other recognized genomic alterations (such as mutations in KRAS, BRAF, EGFR, NRAS and PIK3CA), while no significant difference was found between METex14 skipping and single driver gene.

      Conclusion:
      Mutational events of MET leading to exon 14 skipping are frequent occurred in Chinese PSC patients. DNA-based NGS could discover new somatic mutations which results in METex14 skipping. However, RNA-based NGS could provide more accurate results than DNA-based NGS. METex14 skipping was mutually exclusive with other drivers, thus strongly highlighting its potential oncogenic role.

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