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K. Huberman



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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 10.05 - Non-Invasive Molecular Profiling in NSCLC by Targeted and Whole Exome Analysis of Plasma cfDNA (ID 10422)

      11:45 - 11:55  |  Author(s): K. Huberman

      • Abstract
      • Presentation
      • Slides

      Background:
      Molecular characterization of tumor can guide the choice of therapy for NSCLC patients. However, tumors are complicated by spatial heterogeneity and sometimes may not be of sufficient quality and quantity for analysis. NGS using plasma cell-free DNA (cfDNA) input may capture temporal and spatial heterogeneity, and enable genomic profiling in patients without adequate available tumor tissue. Targeted gene panels allow for robust detection of known oncogenic drivers, but may not be comprehensive enough to screen for novel biomarkers or mechanisms of acquired resistance. Whole exome sequencing (WES) allows for hypothesis-free biomarker discovery, but may be technically challenging in the setting of limited tumor-derived DNA content in plasma cfDNA. In this study, we aim to develop a workflow to guide the selection of samples for targeted and whole exome sequencing for noninvasive molecular profiling.

      Method:
      Plasma samples were collected from 20 NSCLC patients receiving a variety of treatment (chemotherapy, targeted therapy, or immunotherapy). Most patients (>70%) had stage III or IV disease at the time of plasma collection. CfDNA was extracted from 3 mL of plasma, and analyzed using low-pass shallow whole genome sequencing (sWGS) and MSK-IMPACT, a hybridization capture-based assay targeting over 400 cancer-related genes. Analysis of matched normal was performed for somatic variant calling.

      Result:
      Median cfDNA yield per plasma sample was 28ng (range 7 - 236ng). We applied z-score statistics to estimate the levels of tumor-derived mutant allele fractions in cfDNA based on sWGS data. We trained the algorithm using a separate cohort of cfDNA data from >100 patients with metastatic solid tumors to classify samples by mutant allele fraction (MAF) as either low (<5% MAF) or high (>5% MAF) tumor-derived DNA. In the subset of 10 patients with unknown drivers, two were estimated to have MAF >5% in cfDNA, and WES recapture was performed. MSK-IMPACT targeted sequencing identified actionable alterations in a subset of patients who did not have sufficient materials for tissue profiling. WES in cases with high tumor-derived DNA content by sWGS identified alterations in genes outside of the MSK-IMPACT panel.

      Conclusion:
      Molecular profiling using cfDNA is feasible in lung cancer and may identify actionable alterations to inform treatment decisions in patients without sufficient tissue for molecular characterization. The application of sWGS to estimate the levels of tumor-derived mutant allele fractions in plasma cfDNA samples may help guide selection of the optimal downstream sequencing strategy.

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