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K. Kosco

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    ORAL 38 - Liquid Biopsies (ID 147)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      ORAL38.05 - Dynamic Changes in EGFR Mutation Circulating Tumor DNA in Urine on Anti-EGFR Therapy (ID 2230)

      16:45 - 18:15  |  Author(s): K. Kosco

      • Abstract
      • Slides

      Circulating tumor DNA can be detected in urine efficiently, serially, and completely non-invasively. Utilizing a PCR enriched NGS detection platform, we sought to demonstrate the feasibility of detecting activating and resistance EGFR mutations in urinary ctDNA to understand mechanisms of resistance to targeted therapies in patients with EGFR-mutated lung adenocarcinoma.

      In a biomarker study of 46 patients enrolled, urine was collected every 3-6 weeks from patients on first line anti-EGFR TKI therapy and then daily at progression during the first week of 3rd generation anti-EGFR TKI treatment when available. Urinary ctDNA was extracted by a method that preferentially isolates short, fragmented ctDNA. Quantitative analysis of EGFR activating exon19del, L858R, and T790M resistance mutations was performed utilizing wild type blocker probes, PCR enrichment, and NGS detection (MiSeq). Early pharmacodynamic events within the first hours to days of anti-EGFR therapy were further studied by quantitating ctDNA mutations and comparing with the reponse or lack of response by RECIST on CT scans 6 weeks after initiation of second line therapy.

      Interim analysis was conducted on 34 patients receiving first line anti-EGFR therapy with erlotinib. The average quantity of DNA obtained per patient was 830ng/70ml of urine. The sensitivity between tissue and urine for EGFR Exon19del, L858R, and T790M was 94%, 100%, and 100% respectively, and interim specificity was 94%, 100%, and 96% respectively. Analysis of longitudinal samples from patients on erlotinib revealed that the EGFR T790M mutation was detected in the urine of 17 out of 24 (71%) patients 4-15 weeks before radiographic progression on erlotinib. All 10 patients who were positive for T790M mutation by tissue were also positive by urine. Three patients were T790M tissue negative but urine was positive for T790M. Early peaks in EGFR Exon19del, L858R, and T790M ctDNA on days 1-4 of urine collected daily within the first week on next generation anti-EGFR TKI correlated with CT radiographic response or lack of response 6 weeks after first drug dosing. Figure 1

      We demonstrate that EGFR activating and resistance mutations can be detected in ctDNA in urine months before progression on anti-EGFR TKIs. Urinary ctDNA testing identifies additional patients who are potentially eligible for next generation anti-T790M treatment. The size of the peaks in ctDNA upon second line anti-EGFR inhibitors correlate with tumor lysis and CT radiographic response. The clinical utility of daily kinetic monitoring of ctDNA in urine after drug adminstration is being further validated in an expanded cohort.

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