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Abstract
Cell-free DNA (cfDNA) and circulating tumor cells (CTCs) exhibit great potential for therapy management in oncology. We aimed to establish a multimodal liquid biopsy strategy that is usable with minimized blood volume to deconvolute the genomic complexity of metastatic breast cancer. CTCs were isolated from 10ml blood of 18 hormone receptor-positive and human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer patients. cfDNA was isolated from plasma generated after CTC depletion and targeted sequencing analyses were conducted. PIK3CA and ESR1 variants were less common in CTC gDNA, while ERBB2 variants were only detected in CTC gDNA. A total of 62% of all cfDNA variants were recovered in the matched CTC gDNA, while 72% of all variants were unique in either cfDNA (14 variants) or CTC gDNA (104 variants). The percentage of patients with no detectable cfDNA variants or CTC gDNA variants was 17%/11%, but a combined analysis identified variants in 94% of all patients. In univariate and multivariate regression models, ESR1 variants in cfDNA and CTC gDNA correlated significantly with survival. We suggest a coordinated analysis of both fractions in order to provide a comprehensive genomic footprint that may contribute to identifying the most suitable therapy for each individual.
Highlights
In oncology, cell-free DNA and, cell-free tumor DNA, defined by the presence of variants, as well as circulating tumor cells (CTCs), are liquid biopsy analytes displaying vast potential for therapy management due to their valuable information about tumor heterogeneity and clonal evolution [1].High levels of ctDNA have been associated with a poor overall survival (OS) and increased tumor burden [2,3]
PIK3CA variant detection in cell-free DNA (cfDNA) was established as a companion diagnostic in clinical practice for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC)
CTCs are viable cells actively migrating into the circulation as potential seeds of metastasis [5], while cfDNA is mostly generated by necrosis and apoptosis and might, instead, present dying cells [15]
Summary
Cell-free DNA (cfDNA) and, cell-free tumor DNA (ctDNA), defined by the presence of variants, as well as circulating tumor cells (CTCs), are liquid biopsy analytes displaying vast potential for therapy management due to their valuable information about tumor heterogeneity and clonal evolution [1].High levels of ctDNA have been associated with a poor overall survival (OS) and increased tumor burden [2,3]. Cell-free DNA (cfDNA) and, cell-free tumor DNA (ctDNA), defined by the presence of variants, as well as circulating tumor cells (CTCs), are liquid biopsy analytes displaying vast potential for therapy management due to their valuable information about tumor heterogeneity and clonal evolution [1]. ESR1 variants in cfDNA were correlated with a shorter duration of endocrine treatment effectiveness in metastatic breast cancer (BC) patients [4]. PIK3CA variant detection in cfDNA was established as a companion diagnostic in clinical practice for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). ESR1 variants were detected in CTCs and might indicate the impaired effect of aromatase inhibitor treatment in MBC patients [11]. A mutational analysis of cfDNA and transcriptional analysis of CTCs using both analytes in parallel from matched minimized blood volume revealed synergistic information [16]
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