Abstract
Recently, liquid biopsy has emerged as a tool to monitor oncologic disease progression and the effects of treatment. In this study we aimed to determine the clinical utility of liquid biopsy relative to conventional oncological post-treatment surveillance. Plasma cell-free (cf) DNA was collected from six healthy women and 37 patients with breast cancer (18 and 19 with stage III and IV tumors, respectively). CfDNA was assessed using the Oncomine Pan-Cancer Cell-Free Assay. In cfDNA samples from patients with BC, 1112 variants were identified, with only a few recurrent or hotspot mutations within specific regions of cancer genes. Of 65 potentially pathogenic variants detected in tumors, only 19 were also discovered in at least one blood sample. The allele frequencies of detected variants (VAFs) were <1% in cfDNA from all controls and patients with stage III BC, and 24/85 (28.2%) variants had VAFs > 1% in only 8 of 25 (32%) patients with stage IV BC. Copy number variations (CNVs) spanning CDK4, MET, FGFR1, FGFR2, ERBB2, MYC, and CCND3 were found in 1 of 12 (8%) and 8 of 25 (32%) patients with stage III and IV tumors, respectively. In healthy controls and patients without BC progression after treatment, VAFs were <1%, while in patients with metastatic disease and/or more advanced genomic alterations, VAFs > 1% and/or CNV were detected in approximately 30%. Therefore, most patients with stage IV BC could not be distinguished from those with stage III disease following therapy, based on liquid biopsy results.
Highlights
Circulating cell-free DNA comprises double-stranded nucleic acid fragments released into body fluids as a result of rupture or apoptosis and necrosis of normal and diseased cells [1,2]
Distinguishing between circulating tumor-derived DNA (ctDNA) and the wild-type cell-free DNA (cfDNA) representing normal cells depends on evaluation of somatic mutations, including single-nucleotide variations (SNVs), small insertions and deletions, gene fusions, and gene amplifications; somatic mutations are associated with neoplastic cells but are found in morphologically normal cells; for example, Yizhak et al recently reported the detection of various somatic mutations in 29 different normal tissue types [5]
The time gap between sampling primary tumor tissues and serial blood draws performed after neoadjuvant therapy, surgery, and adjuvant radio and/or chemotherapy, allowed confirmation of intra- and inter-person genomic heterogeneity, reflecting high levels of post-treatment mutational mosaicism
Summary
Circulating cell-free DNA (cfDNA) comprises double-stranded nucleic acid fragments released into body fluids as a result of rupture or apoptosis and necrosis of normal and diseased cells [1,2]. Analyses of circulating tumor-derived DNA (ctDNA) in cancer patients are considered an alternative to conventional imaging [4]. Because normal tissues may have more mutations than previously thought, and the amount of somatic mutations increases with age [5], such alterations of non-cancer origin may significantly influence interpretation of liquid biopsy results. It is important to distinguish the presence of mutated clones in normal tissues from patient-specific somatic founder mutations shed from cancers. Putative founder somatic mutations present in all cancer cells can be identified using multisite exome sequencing; obtaining multiple biopsies may be clinically challenging. Subclonal mutations uncovered from a single tissue biopsy may be lost during the clinical course of treatment
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