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The Novel Association of Early Apoptotic Circulating Tumor Cells with Treatment Outcomes in Breast Cancer Patients.

ABSTRACT: Stemness and epithelial-mesenchymal plasticity are widely studied in the circulating tumor cells of breast cancer patients because the roles of both processes in tumor progression are well established. An important property that should be taken into account is the ability of CTCs to disseminate, particularly the viability and apoptotic states of circulating tumor cells (CTCs). Recent data demonstrate that apoptosis reversal promotes the formation of stem-like tumor cells with pronounced potential for dissemination. Our study focused on the association between different apoptotic states of CTCs with short- and long-term treatment outcomes. We evaluated the association of viable CTCs, CTCs with early features of apoptosis, and end-stage apoptosis/necrosis CTCs with clinicopathological parameters of breast cancer patients. We found that the proportion of circulating tumor cells with features of early apoptosis is a perspective prognosticator of metastasis-free survival, which also correlates with the neoadjuvant chemotherapy response in breast cancer patients. Moreover, we establish that apoptotic CTCs are associated with the poor response to neoadjuvant chemotherapy, and metastasis-free survival expressed at least two stemness markers, CD44 and CD133.

SUBMITTER: Grigoryeva ES

PROVIDER: S-EPMC9408919 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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The Novel Association of Early Apoptotic Circulating Tumor Cells with Treatment Outcomes in Breast Cancer Patients.

Grigoryeva Evgeniya S ES Tashireva Liubov A LA Alifanov Vladimir V VV Savelieva Olga E OE Vtorushin Sergey V SV Zavyalova Marina V MV Cherdyntseva Nadezhda V NV Perelmuter Vladimir M VM

International journal of molecular sciences 20220822 16

Stemness and epithelial-mesenchymal plasticity are widely studied in the circulating tumor cells of breast cancer patients because the roles of both processes in tumor progression are well established. An important property that should be taken into account is the ability of CTCs to disseminate, particularly the viability and apoptotic states of circulating tumor cells (CTCs). Recent data demonstrate that apoptosis reversal promotes the formation of stem-like tumor cells with pronounced potentia ...[more]

PMID: 36012742

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Project description:PURPOSE:Liquid 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. METHODS:A 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. RESULTS:Of 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. CONCLUSIONS:We 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.

Project description:Background and aimsThe aim of this study was to characterize circulating tumor cells (CTCs) during neoadjuvant chemotherapy (NACT) in early and locally advanced breast cancer (LABC) patients. Using ultrasound, tumor volume measurement was compared with the presence and the molecular nature of CTCs over multiple time intervals corresponding to treatment periods.MethodsA total of 20 patients diagnosed with breast cancer (BC) of different histotypes were monitored during the NACT period and in the follow-up period (~5 years). Peripheral blood for CTCs (n = 115) was taken prior to NACT, after two to three chemotherapy cycles, after the completion of NACT (before surgery) and at some time points during adjuvant therapy. CTCs were enriched using a size-based filtration method (MetaCell®) capturing viable cells, which enabled vital fluorescence microscopy. A set of tumor-associated (TA) genes and chemoresistance-associated (CA) genes was analyzed by qPCR in the enriched CTC fractions.ResultsThe analysis of tumor volume reduction after administration of anthracyclines (AC) and taxanes (TAX) during NACT showed that AC therapy was responsive in 60% (12/20) of tumors, whereas TAX therapy was responsive in 30% (6/20; n.s.). After NACT, CTCs were still present in 70.5% (12/17) of patients (responders versus non-responders, 61.5% versus 100%; not significant).In triple-negative BC (TNBC) patients (n = 8), tumor volume reduction was observed in 75% cases. CTCs were significantly reduced in 42.9% of all HER2-negative BC patients. In HER2+ tumors, CTC reduction was reported in 16.6% only. Relapses were also more prevalent in the HER2-positive patient group (28.5 versus 66.6%).During NACT, the presence of CTCs (three tests for each patient) identified patients with relapses and indicated significantly shorter progression-free survival (PFS) rates (p = 0.03). Differentiation between progressive disease and non-progressive disease was obtained when the occurrence of excessive expression for CA genes in CTCs was compared (p = 0.024). Absence of tumor volume reduction was also significantly indicative for progressive disease (p = 0.0224).Disseminated CTCs in HER2-negative tumors expressed HER2 in 29% of samples collected during the overall follow-up period (16/55), and in 32% of samples during the follow-up of NACT (10/31). The change accounted for 78.5% of HER2-negative patients (11/14) in total, and 63.6% of the conversion cases occurred during NACT (7/11). For the remaining four patients (36.3%), conversion to HER2+ CTCs occurred later during adjuvant therapy. We believe there is the possibility of preventing further progression by identifying less responsive tumors during NACT using CTC monitoring, which could also be used effectively during adjuvant therapy.

Dataset Information

The Novel Association of Early Apoptotic Circulating Tumor Cells with Treatment Outcomes in Breast Cancer Patients.

Publications

The Novel Association of Early Apoptotic Circulating Tumor Cells with Treatment Outcomes in Breast Cancer Patients.

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