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H..J. Achenbach



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    OA 10 - Liquid Biopsy for Genomic Alterations (ID 678)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Advanced NSCLC
    • Presentations: 1
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      OA 10.06 - Longitudinal Mutation Monitoring in Plasma by Deep Sequencing as a Potential Predictor of Disease Progression in NSCLC (ID 9595)

      11:55 - 12:05  |  Author(s): H..J. Achenbach

      • Abstract
      • Presentation
      • Slides

      Background:
      Circulating tumor DNA (ctDNA) sequencing and analysis has the potential to transform clinical management of patients with advanced NSCLC. Non-invasive sampling of blood draws at different time points during treatment could potentially be used for routine monitoring of disease progression and detection of therapy resistant mutations by using next generation sequencing (NGS).

      Method:
      448 longitudinal plasma samples (mean 6.3 per subject) collected from 71 subjects with advanced NSCLC during 1[st] line treatment were analyzed by NGS. Of these 71 subjects, 47 also had matched baseline tumor tissue samples. The AVENIO ctDNA Surveillance kit and AVENIO FFPET Analysis kit (RUO, Roche, Pleasanton, CA, USA) were used for sequencing analysis. The Surveillance kit contains 17 cancer driver genes and additional 180 frequently mutated genes mainly selected for NSCLC and colorectal cancer. This kit is capable of detecting four mutation classes: SNVs, fusions, CNVs and InDels. CT images were reviewed centrally using RECIST v1.1.

      Result:
      Somatic, disease-associated mutations were detected with allele frequency (AF) of >5% in 94% of baseline tumor samples (44/47), and in 100% of plasma samples with AF in ctDNA ranging from ≥0.5% to ≤30%. The most commonly mutated genes in tumors were TP53 (22/47 subjects), KRAS (14/47), BRAF (7/47), STK11 (5/47), and ERBB2 (5/47). Tracking the AF’s of key tumor mutations by the Surveillance panel in the paired longitudinal plasma samples allowed the monitoring of treatment response at the molecular level. We identified a number of subjects in which the AF of cfDNA mutations increased three to four months before clinical evidence of progression of disease detected by CT scans that were centrally reviewed according to RECIST v1.1. Cases were also observed where the AF’s of key mutations decreased in 1[st] line chemotherapy to nearly zero which correlated with clinical partial response and stable disease. . Additionally, first post treatment plasma samples collected during first line treatment showed a difference of 96 days in median survival times of ctDNA- vs ctDNA+ groups (logrank p value =0.0371).

      Conclusion:
      ctDNA testing with molecular bar coded duplex sequencing and digital background error suppression of a large 197 gene panel offers high sensitivity for tumor variant detection. The study demonstrated that the presence of tumor variants detected in blood at the beginning and end of 1[st] line treatment is a risk factor for early disease progression. Longitudinal mutation monitoring has the potential to predict disease progression earlier than regular CT imaging.

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