Cut-Off Analysis of CTC Change under Systemic Therapy for Defining Early Therapy Response in Metastatic Breast Cancer

Deutsch, Thomas M.; S, Stefanovic; Feißt, Manuel; Fischer, C; Riedel, Fabian; Fremd, Carlo; Domschke, Christoph; Pantel, Klaus; Hartkopf, Andreas D.; Sütterlin, Marc; Brucker, Sara; Schneeweiß, Andreas; Wallwiener, Markus

doi:10.3390/cancers12041055

Cited by 21 publications

(26 citation statements)

References 44 publications

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“…Within the last decade, liquid biopsy has become a frequently studied tool with a high potential for disease management [ 27 , 28 , 29 ], and has gained acceptance for prognosis and treatment decision-making in MBC [ 30 , 31 ]. Since one of the major advantages of liquid biopsies is the possibility for longitudinal assessment by repeated minimally invasive sampling, single liquid biopsies have already been studied as potential monitoring markers in MBC [ 9 , 12 , 13 , 14 , 15 , 17 , 32 ]. Here, we conducted a longitudinal multi-parametric liquid biopsy study, including the characterization of CTC mRNA, EV mRNA, and cfDNA—all isolated from a minimized blood volume.…”

Section: Discussionmentioning

confidence: 99%

“…In breast cancer (BC), the leading cancer in women worldwide [ 5 ], an increase in circulating tumor cell (CTC) count [ 6 ] and an increase in circulating tumor DNA (ctDNA) concentration have been shown to correlate with disease progression [ 7 , 8 ]. More specifically, in metastatic BC (MBC) patients, a reduction of the apoptotic CTC count by ≥50% (after one completed treatment cycle) correlated with stable disease, while a reduction of apoptotic CTCs ≤ 10% was specific for early disease progression in 74% of the cases [ 9 ]. In primary BC, the persistent detection of Cytokeratin-19-positive CTCs during the first 5 years after surgery has been related to an increased risk of late relapse [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

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Longitudinal Multi-Parametric Liquid Biopsy Approach Identifies Unique Features of Circulating Tumor Cell, Extracellular Vesicle, and Cell-Free DNA Characterization for Disease Monitoring in Metastatic Breast Cancer Patients

Keup

Suryaprakash

Storbeck

et al. 2021

Cells

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Dynamics of mRNA from circulating tumor cells (CTCs), mRNA from extracellular vesicles (EVs), and cell-free DNA (cfDNA) were assessed to examine the relevance of a longitudinal multi-parametric liquid biopsy strategy. Eighteen milliliters of blood was drawn from 27 hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) patients at disease progression and at two subsequent radiologic staging time points. CTC mRNA and EV mRNA were analyzed using multi-marker qPCR, and cfDNA was analyzed using targeted next-generation sequencing (NGS). The presence of ERBB2 or ERBB3 overexpression signals in CTCs significantly correlated with disease progression (87% specificity, 36% sensitivity, p-value = 0.023), and the presence of either ERBB3 signals in CTCs or EVs or cfDNA variants in ERBB3 also showed a significant association with progressive MBC. Fluctuations during treatment were detected in the EV fraction with the appearance of hitherto undetected ERCC1 signals correlating with progressive disease (97% specificity, 18% sensitivity, p-value = 0.030). Allele frequency development of ESR1 and PIK3CA variants detected at subsequent staging time points could be used as a predictor for therapy success and, importantly, might help guide therapy decisions. The three analytes, each with their own unique features for disease monitoring, were shown to be complementary, underlining the usefulness of the longitudinal multi-parametric liquid biopsy approach.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Longitudinal Multi-Parametric Liquid Biopsy Approach Identifies Unique Features of Circulating Tumor Cell, Extracellular Vesicle, and Cell-Free DNA Characterization for Disease Monitoring in Metastatic Breast Cancer Patients

Keup

Suryaprakash

Storbeck

et al. 2021

Cells

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“…2 and 3. As described in multiple studies previously, less reduction or persistence of CTCs under therapy correlates with PD [13,16,39,42,43]. Therefore, patients were not only divided in groups with < or ≥ 5 CTCs but also in < or ≥ 1 CTC at enrollment and after 4 weeks of therapy.…”

Section: Discussionmentioning

confidence: 99%

HER2-targeted therapy influences CTC status in metastatic breast cancer

Deutsch

Riethdorf

Fremd

et al. 2020

Breast Cancer Res Treat

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Purpose As an independent, negative-prognostic biomarker for progression-free survival (PFS) and overall survival (OS), circulating tumor cells (CTCs) constitute a promising component for developing a liquid biopsy for patients with metastatic breast cancer (MBC). The effects of HER2-targeted therapy such as trastuzumab, pertuzumab, T-DM1, and lapatinib on CTC status and longitudinal enumeration were assessed in this trial. Methods CTC status of 264 patients with MBC was analyzed prior to and after 4 weeks of a new line of palliative systemic therapy. CTCs were assessed using CellSearch®. Three groups were compared: patients with HER2-positive MBC receiving ongoing HER2-targeted therapy (n = 28), patients with de novo HER2-positive MBC and no HER2-targeted therapy in the last 12 months prior to enrollment and start of HER2-targeted therapy (n = 15), and patients with HER2-nonamplified disease and no HER2-targeted therapy (n = 212). Results Positive CTC status (≥ 5 CTC/7.5 ml blood) at enrollment was observed in the 3 groups for 17.9, 46.7, and 46.2% (p = 0.02) of patients, respectively. At least one CTC/7.5 ml was seen in 28.6, 53.3, and 67.0% (p < 0.001) of these patients. Furthermore, 3.6, 40.0, and 3.3% (p < 0.001) of the patients had at least one HER2-positive CTC. After 4 weeks of therapy 7.1, 0.0, and 31.1% (p = 0.001) of patients had still a positive CTC status (≥ 5 CTC/7.5 ml blood). At least one CTC/7.5 ml was still observed in 25.0, 20.0, and 50.5% (p = 0.004) of the patients. Furthermore, 7.1, 0.0, and 1.9% (p = 0.187) had at least one HER2-positive CTC. After 3 months of therapy, 35.7, 20.0, and 28.3% (p = 0.536) showed disease progression. Conclusions HER2-targeted therapy seems to reduce the overall CTC count in patients with MBC. This should be taken into account when CTC status is used as an indicator for aggressive or indolent metastatic tumor disease.

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“…However, a few CTCs survive this challenge and, when coupled with a favorable microenvironment, develop into metastasis [ 10 , 11 ]. Although cutoffs can vary by type of tumor, five or more CTCs in a 7.5 mL blood sample is considered CTC positive in breast cancer [ 12 , 13 ]. An increasing number of studies have emphasized the significance of CTCs in mediating breast cancer metastasis.…”

Section: Breast Cancer and Circulating Tumor Cellsmentioning

confidence: 99%

Cellular Mechanisms of Circulating Tumor Cells During Breast Cancer Metastasis

Park

Brown

Kim

2020

IJMS

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Circulating tumor cells (CTCs) are cancer cells that detach from the primary site and travel in the blood stream. A higher number of CTCs increases the risk of breast cancer metastasis, and it is inversely associated with the survival rates of patients with breast cancer. Although the numbers of CTCs are generally low and the majority of CTCs die in circulation, the survival of a few CTCs can seed the development of a tumor at a secondary location. An increasing number of studies demonstrate that CTCs undergo modification in response to the dynamic biophysical environment in the blood due in part to fluid shear stress. Fluid shear stress generates reactive oxygen species (ROS), triggers redox-sensitive cell signaling, and alters the function of intracellular organelles. In particular, the mitochondrion is an important target organelle in determining the metastatic phenotype of CTCs. In healthy cells, mitochondria produce adenosine triphosphate (ATP) via oxidative phosphorylation in the electron transport chain, and during oxidative phosphorylation, they produce physiological levels of ROS. Mitochondria also govern death mechanisms such as apoptosis and mitochondrial permeability transition pore opening to, in order eliminate unwanted or damaged cells. However, in cancer cells, mitochondria are dysregulated, causing aberrant energy metabolism, redox homeostasis, and cell death pathways that may favor cancer invasiveness. In this review, we discuss the influence of fluid shear stress on CTCs with an emphasis on breast cancer pathology, then discuss alterations of cellular mechanisms that may increase the metastatic potentials of CTCs.

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Cut-Off Analysis of CTC Change under Systemic Therapy for Defining Early Therapy Response in Metastatic Breast Cancer

Cited by 21 publications

References 44 publications

Longitudinal Multi-Parametric Liquid Biopsy Approach Identifies Unique Features of Circulating Tumor Cell, Extracellular Vesicle, and Cell-Free DNA Characterization for Disease Monitoring in Metastatic Breast Cancer Patients

Longitudinal Multi-Parametric Liquid Biopsy Approach Identifies Unique Features of Circulating Tumor Cell, Extracellular Vesicle, and Cell-Free DNA Characterization for Disease Monitoring in Metastatic Breast Cancer Patients

HER2-targeted therapy influences CTC status in metastatic breast cancer

Cellular Mechanisms of Circulating Tumor Cells During Breast Cancer Metastasis

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