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T. Forshew

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    MINI 26 - Circulating Tumor Markers (ID 148)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI26.12 - Circulating Tumor DNA for Noninvasive Monitoring of Non-Small Cell Lung Cancer Patients Receiving EGFR-Targeted Therapies (ID 372)

      16:45 - 18:15  |  Author(s): T. Forshew

      • Abstract
      • Slides

      Analysis of circulating tumor DNA (ctDNA) in plasma offers an opportunity to noninvasively monitor tumor burden and identify alternative drivers of disease progression in real-time. However, cancer progression during targeted therapy, such as EGFR-targeted therapies in non-small cell lung cancer (NSCLC), is driven by clonal evolution, and how this impacts the levels of targeted mutations in circulating tumor DNA (ctDNA) for monitoring disease burden is unclear.

      We collected serial plasma samples from 47 NSCLC patients receiving EGFR-targeted therapy (gefitinib) and hydroxychloroquine, and analysed mutations in EGFR, TP53, PTEN and PIK3CA in plasma by digital PCR and tagged-amplicon deep sequencing (TAm-Seq) of ctDNA.

      We identified the same EGFR mutations in tumor and plasma samples in over 97% of patients, and found that patients with high pre-treatment levels of ctDNA are associated with worse progression-free survival and overall survival. Serial plasma analysis of 32 patients reveals clonal dynamics in ctDNA in response to treatment. In >72% of patients (23/32), EGFR mutations levels increased preceding clinical progression, with the resistant mutation T790M detected in around 50% of these patients (13/23) a median of 6 months before progression became clinically evident. In the remaining 9 of the 32 patients, EGFR-mutant ctDNA levels became uninformative during treatment, and in two patients we identified alternative driver mutations in ctDNA that correlated with progression. In one patient we also showed that the analysis of relative representations of resistant and sensitizing mutations may provide insight to the response to sequential treatment.

      Our results demonstrate the potential of ctDNA for noninvasive stratification and monitoring disease progression in NSCLC patients, and highlight that targeted therapy may drive the selection of alterative mutations. This may impact the representation of the targeted mutations in plasma for assessing disease burden. We therefore propose that effective ctDNA-based monitoring of targeted therapies in oncogene-addicted cancers requires tracking of multiple mutations beyond the targeted genes.

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