Sequencing Circulating Cell-Free DNA: The Potential to Refine Precision Cancer Medicine.

Abstract

Most cancer treatments benefit only a minority of the patients who receive them. This is particularly true for molecularly targeted drugs, unless we know which patients to target. The completion of the first human reference genome in 2003 and the introduction of massively parallel sequencing (MPS)2 technology in 2004 ushered in the “genomic era” of cancer research and triggered the concept of precision cancer medicine, in which treatment is tailored to the genetic make-up of an individual's tumor. Since then, efforts from large-scale cancer genome sequencing projects, such as The Cancer Genome Atlas, have led to the discovery of many important cancer genes [for example, isocitrate dehydrogenase 1 ( IDH 1)3 and isocitrate dehydrogenase 2 ( IDH2 ) for glioblastoma multiforme and acute myeloid leukemia, respectively] as well as new targets for therapy. Today, affordable targeted MPS-based assays have become commonplace in the clinical research setting, particularly in cancer centers with early-phase drug development programs, as molecular screening tools to triage patients for molecularly targeted therapies. Molecular testing is traditionally conducted with tumor tissue derived from a diagnostic biopsy or an archival resection sample. However, the existence of intratumoral, intermetastatic, and intrametastatic genetic heterogeneity implies that the genomic analysis of a single tissue sample may represent an incomplete view of the genetic landscape of the tumor. The presence of genetic heterogeneity is particularly relevant in patients with heavily pretreated advanced cancers. In such cases, the current molecular profile of the disease may be substantially different from that of the archival tissue obtained several years prior. Recent studies evaluating the clonal relationships among primary and metastatic cancers have demonstrated that seeding metastases require very few additional driver or founder mutations beyond those found in the primary tumors. However, as the metastatic lesion grows, it acquires new mutations with each cell division, providing …