Towards a comprehensive framework for cell-free DNA analysis: lessons from TRACERx

Molecular mechanisms of oncogenesis in lung cancer have been largely deciphered over the past 20 years. Cell-free DNA (cfDNA) is an emerging but immature clinical tool used to guide genotype-directed cancer care. Currently, FDA-approved clinical use of cfDNA is limited to the cobas EGFR Mutation Test v2 CE-IVD for non-small cell lung cancer (NSCLC) patients unable to undergo a tissue biopsy or with acquired resistance to EGFR-TKIs (1). However, many researchers and clinicians seek to expand the use of cfDNA to a wider range of clinical situations. Plasma genotyping assays are being explored in early detection, identifying minimal residual disease (MRD), monitoring treatment response, tracking resistance, and understanding tumor heterogeneity (2-7). Swanton et al., within the TRACERx [Tracking Non-Small-Cell Lung Cancer (NSCLC) Evolution Through Therapy (Rx)] Consortium, have initiated an extensive trial to assess cfDNA as a biomarker in each of these situations (8). Recently published preliminary TRACERx results provide deep insight into the biology of cfDNA shed and its potential clinical utility (9). Furthermore, the TRACERx team made significant advances in assay development which encourage a reformulation of variant calling in next-generating sequencing (NGS) assays that may improve the sensitivity and specificity of plasma genotyping assays.