Impact of apoptotic circulating tumor cells (aCTC) in metastatic breast cancer

Deutsch, Thomas M.; Riethdorf, Sabine; Nees, Juliane; Hartkopf, Andreas; Schönfisch, Birgitt; Domschke, Christoph; Sprick, Martin R.; Schütz, Florian; Brucker, Sara Y.; S, Stefanovic; Sohn, Christof; Pantel, Klaus; Trumpp, Andreas; Schneeweiß, Andreas; Wallwiener, Markus

doi:10.1007/s10549-016-3997-3

Cited by 23 publications

(27 citation statements)

References 26 publications

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“…Regarding the optimized aCTC cut-off, >50% reduction (n = <50% reduction (n = 49) showed a median PFS of 6 (5-10) vs. 3 (3-5) months (p = 0.0085) and a OS of 24 (17-34) vs. 10 (7-16) months (p < 0.0001). Regarding the optimized iCTC+aCTC >66.7% reduction (n = 57) vs. <66.7% reduction (n = 51) showed a median PFS of 6 (5-10) vs. months (p = 0.0063) and a median OS of 24 [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] vs. 10 (7-15) months (p = 0.0025). The impact of the optimized cut-offs on OS and PFS is shown in Figure 3.…”

Section: Resultsmentioning

confidence: 99%

“…The prognostic value of baseline CTC counts and kinetics of CTC number (CTC kinetics) in relation to systemic therapy has been demonstrated in recent studies [6,10,24]. Thus far, either a change in CTC status or a 25% reduction or increase as a cut-off point has been used to define a significant change in CTC counts, rendering them useful for studying the influence of CTC kinetics on breast cancer prognosis [6,7,13,24,25].…”

Section: Introductionmentioning

confidence: 99%

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

Deutsch

Feißt

et al. 2020

Cancers

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Detection of circulating tumor cells (CTC) can distinguish between aggressive and indolent metastatic disease in breast cancer patients and is thus considered an independent, negative prognostic factor. A clear decline in CTCs is observed in patients who respond to systemic therapy. Nevertheless, CTCs can decrease in patients experiencing disease progression during systemic therapy, too. This study aims to determine the differences between CTC decline in patients responding to therapy and those in whom disease is progressing. Therefore, CTC values were compared at the start and after one cycle of a new line of systemic therapy. In all, 108 initially CTC-positive patients (with ≥5 intact CTCs in 7.5 mL blood) were enrolled in this study and intact and apoptotic CTCs were measured via the CellSearch® system. A cut-off analysis was performed using Youden’s J statistics to differentiate between CTC change in the two groups. Here, 64 (59.3%) patients showed stable disease or partial response vs. 44 (40.7%) presenting disease progression. Median overall survival was 23 (range: 4–92) vs. 7 (2–43) months (p < 0.001). Median intact CTC count at enrollment was 15.0 (5–2760) vs. 30.5 (5–200000) cells (p = 0.39) and 2.5 (0–420) vs. 8.5 (0–15000) cells after one cycle of systemic therapy (p = 0.001). Median apoptotic CTC count at enrollment was 10.5 (0–1500) vs. 9 (0–800) cells (p = 0.475) and 1 (0–200) vs. 3 (0–250) cells after one cycle of systemic therapy (p = 0.01). A 50% reduction in baseline apoptotic CTC count represents the optimal cut-off to differentiate between therapy response and disease progression. An apoptotic CTC reduction of ≤10% is 74% specific for early disease progression.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Deutsch

Feißt

et al. 2020

Cancers

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“…For CTC identification, we used Cellsearch ® (Janssen Diagnostics, Raritan, NJ/Menarini Silicon Biosystems, Inc, Florence, Italy) technology following the standard operating procedures. Briefly, CTCs from two 7.5 ml CellSave tubes per visit were subjected to EpCAM-based ferrofluid selection, immunostaining, and image analysis, taking care to exclude apoptotic cells from CTC analysis in all samples [42,43]. One CellSave tube was used to identify patients with cytokeratin-positive (CK+), CD45-, and HER2-CTCs using phycoerythrin-conjugated antibodies recognizing epithelial cell-specific CKs (predominantly cytokeratins 8, 18, and 19), allophycocyanin (APC)-conjugated antibody directed against the white blood cell marker CD45, and 6-diamidino-2-phenylindole (DAPI) to stain nuclei.…”

Section: Ctc Enrichment Immunostaining and Image Analysismentioning

confidence: 99%

53BP1 Accumulation in Circulating Tumor Cells Identifies Chemotherapy-Responsive Metastatic Breast Cancer Patients

Schochter

Werner

Köstler

et al. 2020

Cancers

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Evidence suggests that the DNA end-binding protein p53-binding protein 1 (53BP1) is down-regulated in subsets of breast cancer. Circulating tumor cells (CTCs) provide accessible "biopsy material" to track cell traits and functions and their alterations during treatment. Here, we prospectively monitored the 53BP1 status in CTCs from 67 metastatic breast cancer (MBC) patients with HER2-CTCs and known hormone receptor (HR) status of the primary tumor and/or metastases before, during, and at the end of chemotherapeutic treatment with Eribulin. Nuclear 53BP1 staining and genomic integrity were evaluated by immunocytochemical and whole-genome-amplification-based polymerase chain reaction (PCR) analysis, respectively. Comparative analysis of CTCs from patients with triple-negative and HR+ tumors revealed elevated 53BP1 levels in CTCs from patients with HR+ metastases, particularly following chemotherapeutic treatment. Differences in nuclear 53BP1 signals did not correlate with genomic integrity in CTCs at baseline or with nuclear γH2AX signals in MBC cell lines, indicating that 53BP1 detected features beyond DNA damage. Kaplan-Meier analysis revealed an increasing association between nuclear 53BP1-positivity and progression-free survival (PFS) during chemotherapy until the final visit. Our data suggest that 53BP1 detection in CTCs could be a useful marker to capture dynamic changes of chemotherapeutic responsiveness in triple-negative and HR+ MBC.Cancers 2020, 12, 930 2 of 18 13.3 months after diagnosis of metastatic sites, TNBC has a particularly poor prognosis. Often patients develop a resistance to first-line chemotherapy very rapidly, resulting in a median duration of first-line palliative chemotherapy of 11.9 weeks [1].Triple-negative tumors are characterized by the lack of HR and HER2 expression, but aside from this common feature this subgroup includes very heterogeneous tumors. A mutation in BRCA1 or 2 is found in up to 20% of triple-negative metastatic patients [2]. The proteins encoded by BRCA genes are critically involved in DNA double-strand break (DSB) repair, more specifically, in the error-free pathway of homologous recombination repair (HRR) [3]. In TNBC, a high prevalence of gene mutations as well as epigenetic changes result in BRCAness, compromising safe DNA repair through HRR [2,4,5]. The DNA damage response factor 53BP1 is crucial in protecting DNA ends in BRCA1-defective cells from resection and entry into error-prone repair pathways [6][7][8]. It has been demonstrated that 53BP1 expression in breast cancer is associated with poor prognosis, particularly in TNBC frequently showing BRCA1 dysfunction [7,9].Due to the lack of predictive targets, chemotherapy was the only treatment option available for a long time. This results in an urgent clinical need for new therapies. During the last years, new drugs such as the Poly(ADP-ribose) polymerase (PARP)-inhibitors targeting HRR-defective tumors were studied in several clinical trials. Two different phase III trials (OlympiaAD and EMBRACA) showed an impro...

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“…50 A recent study has shown that in metastatic breast cancer, intact and apoptotic CTC are predictive of outcome, and therefore separate enumeration of intact CTC and apoptotic CTC is useful in tailoring systemic treatment. 51 Patients with a continuous presence of apoptotic or clustered CTCs in follow-up samples after systemic therapy initiation had worse prognosis than patients without these CTC characteristics. In patients with ≥5 CTC/7.5 mL blood at baseline, morphologic characterization of persistent CTCs could be an important prognostic marker during treatment, in addition to CTC enumeration alone.…”

Section: Breast Cancermentioning

confidence: 94%

“…In addition, apoptotic CTCs are more frequently encountered during follow‐up in dormancy candidate patients who remain disease free compared to those with subsequent late relapse, suggesting that monitoring proliferation and apoptosis in CTCs during clinical dormancy merits further investigation as a tool for predicting late disease recurrence . A recent study has shown that in metastatic breast cancer, intact and apoptotic CTC are predictive of outcome, and therefore separate enumeration of intact CTC and apoptotic CTC is useful in tailoring systemic treatment . Patients with a continuous presence of apoptotic or clustered CTCs in follow‐up samples after systemic therapy initiation had worse prognosis than patients without these CTC characteristics.…”

Section: Circulating Tumor Cellsmentioning

confidence: 99%

Liquid biopsies

Lianidou

Pantel

2019

Genes Chromosomes & Cancer

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127

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Liquid biopsy is based on minimally invasive blood tests and has a high potential to significantly change the therapeutic strategy in cancer patients, providing an extremely powerful and reliable noninvasive clinical tool for the individual molecular profiling of patients in real time. Liquid biopsy approaches include the analysis of circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), circulating miRNAs, and tumor‐derived extracellular vesicles (EVs) that are shed from primary tumors and their metastatic sites into peripheral blood. The major advantage of liquid biopsy analysis is that it is minimally invasive, and can be serially repeated, thus allowing extracting information from the tumor in real time. Moreover, the identification of predictive biomarkers in peripheral blood that can monitor response to therapy in real time holds a very strong potential for novel approaches in the therapeutic management of cancer patients. In this review, we summarize recent knowledge on CTCs and ctDNA and discuss future trends in the field.

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Impact of apoptotic circulating tumor cells (aCTC) in metastatic breast cancer

Cited by 23 publications

References 26 publications

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

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

53BP1 Accumulation in Circulating Tumor Cells Identifies Chemotherapy-Responsive Metastatic Breast Cancer Patients

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