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Lesli Ann Kiedrowski

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    MA16 - Novel Mechanisms for Molecular Profiling (ID 917)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 13:30 - 15:00, Room 203 BD
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      MA16.01 - Frequency and Genomic Context of Emerging Markers for Molecular Testing in Lung Adenocarcinoma in Cell-Free DNA NGS Analysis (ID 13465)

      13:30 - 13:35  |  Author(s): Lesli Ann Kiedrowski

      • Abstract
      • Presentation
      • Slides


      The recently updated CAP/IASLC/AMP lung cancer molecular testing guideline (Lindeman et al 2018) recommends several genes be analyzed by next-generation sequencing (NGS) in lung adenocarcinoma (LUAD), including EGFR, ALK, BRAF, KRAS, and others. It also includes a list of 20 emerging markers (EMs) for molecular testing and suggests practitioners remain aware of these and other genes between guideline updates. We investigated the frequency of genomic alterations (GAs) in several of these EMs in a cohort of patients with advanced lung adenocarcinoma who underwent clinical cell-free DNA (cfDNA) NGS analysis and assessed co-occurrence with canonical driver GAs.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Genomic data was reviewed from 6530 patients with at least one GA detected on clinical Guardant360 cfDNA NGS testing (Guardant Health, Inc) with an indicated diagnosis of lung adenocarcinoma from 11/25/16-3/1/18. Synonymous alterations were excluded from further analyses.

      4c3880bb027f159e801041b1021e88e8 Result

      2600 patients (40%) had at least one nonsynonymous alteration in the EM genes assessed; excluding GAs classified as variants of unknown significance (VUS), 1350 patients (21%) had at least one characterized alteration. Table 1 shows number and frequency of GAs observed per patient by gene and alteration type. Of EMs assessed, GAs were observed most commonly in NF1, PIK3CA, PDGFRA, KIT, and FGFR1-2. GAs in multiple EMs, including RIT1, NRAS, FGFR2-3, NTRK1, KIT, and AKT1, were observed co-occurring with established driver alterations, often in a genomic context consistent with resistance to targeted therapy at allelic fractions suggestive of subclonality.

      table 1.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Effective therapies are continually emerging for a growing number of molecular biomarkers in lung cancer. Comprehensive genomic profiling with cfDNA NGS can identify GAs in both recommended and EM genes to guide therapeutic decision-making and catalyze clinical trial enrollment. Further investigation of mutual exclusivity and co-occurrence of established drivers and EMs may reveal novel resistance mechanisms and facilitate identification of rational combination therapeutic strategies.


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