Author of

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  P3.06 - Poster Session 3 - Prognostic and Predictive Biomarkers (ID 178)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/30/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 12447

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    P3.06-006 - Integrated genomic analysis of EGFR-mutant non-small cell lung cancer immediately following erlotinib initiation in patients (ID 1003)

    09:30 - 09:30  |  Author(s): T.G. Bivona
    • Abstract

    Background
    Major obstacles limiting the clinical success of EGFR TKI therapy in EGFR mutant non-small cell lung cancer (NSCLC) patients are heterogeneity and variability in the initial anti-tumor response to treatment. The underlying molecular basis for this heterogeneity has not been explored in patients immediately after initiation of therapy.

    Methods
    We conducted CT-guided core needle biopsies immediately prior to erlotinib treatment initiation and at 6 days and 60 days post erlotinib initiation in a patient with histologically confirmed NSCLC harboring an established activating mutation in EGFR. DNA and RNA from each of the frozen biopsies were analyzed by whole exome sequencing and whole transcriptome sequencing, respectively. High-resolution CT images were also obtained at the time of each biopsy to assess the degree of molecular and radiographic responses observed.

    Results
    Two established activating somatic mutations were identified in EGFR (p.G719A and p. R776H). Gene expression analysis revealed that several proapoptotic genes including BID, CASP3 and several growth inhibitory genes including GADD45B, GADD45G were upregulated at 6 days post erlotinib treatment, while at 60 days their expression levels decreased to below pretreatment levels. Other proapoptotic genes such as BAD and BAX and were noted to be upregulated most significantly 60 days, as was growth inhibitory gene CDKN1A. In contrast, the growth-promoting genes CCNB1 and CCND3 exhibited a progressive decrease in expression across time points. Whole exome sequencing demonstrated the progressive evolution of global copy number abnormalities. High-resolution CT scans revealed no interval radiographic change in tumor size after 6 days of erlotinib treatment, and a decrease in tumor size 60 days into therapy. No clinical complications were encountered.

    Conclusion
    This study is the first reported longitudinal integrated genomic analysis of EGFR-mutant NSCLC in a patient treated with an EGFR TKI. We documented the feasibility, safety and utility of this strategy to establish initial drug efficacy at the molecular level prior to any radiographic evidence of response (6 days), as well as evidence that acquired resistance can emerge early in the course of TKI therapy. Serial integrated genomic analysis is ongoing in other TKI treated patients to enhance the management of NSCLC patients on targeted therapy.