Abstract
PurposeLiquid biopsies, including circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs), can be used to understand disease prognosis, tumor heterogeneity, and dynamic response to treatment in metastatic breast cancer (MBC). We explored a novel, 180-gene ctDNA panel and the association of this platform with CTCs and CTC clusters.MethodsA total of 40 samples from 22 patients with MBC were included in the study. For the primary analysis, all patients had ctDNA sequencing using the PredicinePLUS™ platform. CTCs and CTC clusters were examined using the CellSearch™ System. Clinical and pathological variables were reported using descriptive analyses. Associations between CTC count and specific genomic alterations were tested using the Mann-Whitney U test.ResultsOf 43 sequenced patients, 40 (93%) had at least one detectable genomic alteration with a median of 6 (range 1–22). Fifty-seven different genes were altered, and the landscape of genomic alterations was representative of MBC, including the commonly encountered alterations TP53, PTEN, PIK3CA, ATM, BRCA1, CCND1, ESR1, and MYC. In patients with predominantly hormone-receptor-positive MBC, the number of CTCs was significantly associated with alterations in ESR1 (P < 0.005), GATA3 (P < 0.05), CDH1 (P < 0.0005), and CCND1 (P < 0.05) (Mann-Whitney U test). Thirty-six percent of patients had CTC clusters, which were associated with alterations in CDH1, CCND1, and BRCA1 (all P < 0.05, Mann-Whitney U test). In an independent validation cohort, CTC enumeration confirmed significant associations with ESR1 and GATA3, while CTC clusters were significantly associated with CDH1.ConclusionsWe report on a novel ctDNA platform that detected genomic alterations in the vast majority of tested patients, further indicating potential clinical utility for capturing disease heterogeneity and for disease monitoring. Detection of CTCs and CTC clusters was associated with particular genomic profiles.
Highlights
Liquid biopsies have emerged as clinical tools for prognostication, molecular analysis, and detection of genomic alterations in blood [1]
We demonstrate the analytical validity of this novel circulating tumor DNA (ctDNA) platform and the association of circulating tumor cells (CTCs) and CTC clusters with particular mutational profiles
Sensitive, 180-gene, 565-kb sequencing platform to analyze and report on the landscape of alterations and association of genomic changes with a cohort of predominantly HR+ metastatic breast cancer (MBC) characterized by CTC enumeration and CTC clusters
Summary
Liquid biopsies have emerged as clinical tools for prognostication, molecular analysis, and detection of genomic alterations in blood [1]. In MBC, prior work demonstrated that CTC detection and enumeration defined two subgroups of patients, stage IVindolent (< 5 CTCs per 7.5 mL of blood) and stage IVaggressive (≥ 5 CTCs) [4, 5]. This staging has been previously validated to stratify patients into two predefined cohorts with dramatically different prognostic outcomes, regardless of tumor type, site of disease, or line of therapy. Understanding the genomic changes that define these cohorts of patients is critical
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