Circulating endothelial cells and angiogenic serum factors during neoadjuvant chemotherapy of primary breast cancer.
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ABSTRACT:
SUBMITTER: Furstenberger G
PROVIDER: S-EPMC2361171 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Aerobic exercise training (AET) is an effective adjunct therapy to attenuate the adverse side-effects of adjuvant chemotherapy in women with early breast cancer. Whether AET interacts with the antitumor efficacy of chemotherapy has received scant attention. We carried out a pilot study to explore the effects of AET in combination with neoadjuvant doxorubicin-cyclophosphamide (AC+AET), relative to AC alone, on: (i) host physiology [exercise capacity (VO2 peak), brachial artery flow-mediated dilation (BA-FMD)], (ii) host-related circulating factors [circulating endothelial progenitor cells (CEP) cytokines and angiogenic factors (CAF)], and (iii) tumor phenotype [tumor blood flow ((15)O-water PET), tissue markers (hypoxia and proliferation), and gene expression] in 20 women with operable breast cancer. AET consisted of three supervised cycle ergometry sessions/week at 60% to 100% of VO2 peak, 30 to 45 min/session, for 12 weeks. There was significant time × group interactions for VO2 peak and BA-FMD, favoring the AC+AET group (P < 0.001 and P = 0.07, respectively). These changes were accompanied by significant time × group interactions in CEPs and select CAFs [placenta growth factor, interleukin (IL)-1β, and IL-2], also favoring the AC+AET group (P < 0.05). (15)O-water positron emission tomography (PET) imaging revealed a 38% decrease in tumor blood flow in the AC+AET group. There were no differences in any tumor tissue markers (P > 0.05). Whole-genome microarray tumor analysis revealed significant differential modulation of 57 pathways (P < 0.01), including many that converge on NF-κB. Data from this exploratory study provide initial evidence that AET can modulate several host- and tumor-related pathways during standard chemotherapy. The biologic and clinical implications remain to be determined.
| S-EPMC3800005 | biostudies-literature
Project description:Circulating tumor DNA (ctDNA) correlates with tumor burden and provides early detection of treatment response and tumor genetic alterations in breast cancer (BC). In this study, we aimed to identify genetic alterations during the process of tumor clonal evolution and examine if ctDNA level well indicated clinical response to neoadjuvant chemotherapy (NAC) and BC recurrence. We performed targeted ultra-deep sequencing of plasma DNAs, matched germline DNAs and tumor DNAs from locally advanced BC patients. Serial plasma DNAs were collected at diagnosis, after the 1st cycle of NAC and after curative surgery. For the target enrichment, we designed RNA baits covering a total of ?202kb regions of the human genome including a total of 82 cancer-related genes. For ctDNA, 15 serial samples were collected and 87% of plasma SNVs were detected in 13 BC samples that had somatic alterations in tumor tissues. The TP53 mutation was most commonly detected in primary tumor tissues and plasma followed by BRCA1 and BRCA2. At BC diagnosis, the amount of plasma SNVs did not correlate with clinical stage at diagnosis. With respect to the therapeutic effects of NAC, we found two samples in which ctDNA disappeared after the 1st NAC cycle achieved a pathologic complete response (pCR). In addition, the amount of ctDNA correlated with residual cancer volume detected by breast MRI. This targeted ultra-deep sequencing for ctDNA analysis would be useful for monitoring tumor burden and drug resistance. Most of all, we suggest that ctDNA could be the earliest predictor of NAC response.
| S-EPMC5689695 | biostudies-other
Project description:Background:Neoadjuvant chemotherapy (NCT) is the standard treatment for patients with locally advanced breast cancer (LABC). The aim of this study was to verify this relationship, and to estimate the clinical value of aneuploid circulating endothelial cells (CECs) in LABC patients with different NCT responses. Methods:Breast cancer patients received an EC4-T4 NCT regimen. Peripheral blood mononuclear cells were obtained before NCT, and after the first and last NCT courses. A novel subtraction enrichment and immunostaining fluorescence in situ hybridization (SE-iFISH) strategy was applied for detection of circulating rare cells (CRCs). CECs (CD45-/CD31+/DAPI+) and circulating tumor cells (CTCs) with different cytogenetic abnormalities related to chromosome?8 aneuploidy were analyzed in LABC patients subjected to NCT. Results:A total of 41 patients were enrolled. Firstly, CD31+/EpCAM+ aneuploid endothelial-epithelial fusion cells were observed in LABC patients. Further, aneuploid CECs in the peripheral blood showed a biphasic response during NCT, as they initially increased and then decreased, whereas a strong positive correlation was observed between aneuploid CECs and CTC numbers. Conclusion:We determined that aneuploid CEC dynamics vary in patients with different response to chemotherapy. Elucidating the potential cross-talk between CTCs and aneuploid CECs may help characterize the process associated with the development of chemotherapy resistance and metastasis.
| S-EPMC7238307 | biostudies-literature
Project description:We evaluated the prognostic implications of the circulating tumor cell (CTC) count in non-metastatic, HER2-negative breast cancer patients who failed to achieve pathologic complete response (pCR) after neoadjuvant chemotherapy (NCT). A total of 173, non-metastatic breast cancer patients treated with NCT were prospectively enrolled. CTCs were obtained from blood drawn pre-NCT and post-NCT using a SMART BIOPSY SYSTEM isolation kit (Cytogen Inc., Seoul, Korea) with immunofluorescence staining. Excluding 26 HER2-positive patients, Relapse-free survival (RFS) and overall survival (OS) related to the CTC count and the association of the CTC count with the treatment response to given therapy were analyzed in 147 HER2-negative patients. Among 147 HER2-negative patients, 28 relapses (19.0%) and 13 deaths (8.8%, all breast cancer-specific) were observed during a median follow-up of 37.3 months. One hundred and seven patients (72.8%) were hormone receptor-positive, and 40 patients (27.2%) had triple-negative breast cancer (TNBC). One or more CTCs were identified in 88 of the 147 patients (59.9%) before NCT and 77 of the 134 patients (52.4%) after NCT. In the entire HER2-negative patient cohort, the initial nodal status was the most significant factor influencing RFS and OS. In TNBC, 11 patients (27.5%) achieved pCR and patients that failed to achieve pCR with ≥ 5 CTCs after NCT, showed worse RFS (HR, 10.66; 95% CI, 1.80-63.07; p = 0.009) and OS (HR, 14.00; 95% CI, 1.26-155.53; p = 0.032). The patients with residual tumor and a high number of the CTCs after NCT displayed the worse outcome. These findings could provide justification to launch a future, well designed trial with longer follow-up data to obtain regulatory approval for clinical use of the assay, especially for the ER-positive, HER2-negative breast cancer subset.
| S-EPMC7562710 | biostudies-literature
Project description:Background This study sought to predict the early responses to neoadjuvant chemotherapy (NACT) of patients with primary conventional osteosarcoma (COS) using the apparent diffusion coefficient (ADC) and to evaluate the factors affecting the tumor necrosis rate (TNR). Methods The data of 41 patients who underwent magnetic resonance imaging (MRI) and diffusion-weighted imaging sequence scans before NACT, 5 days after the end of the first phase of NACT, after the end of the whole course of chemotherapy, were prospectively collected. ADC1 refers to the ADC before chemotherapy, ADC2 refers to the ADC after the first phase of chemotherapy, and ADC3 refers to the ADC before surgery. The change in values before and after the first phase of chemotherapy was calculated as follows: ADC2-1 = ADC2 − ADC1. The change in values before and after the last phase of chemotherapy was calculated as follows: ADC3-1 = ADC3 − ADC1. The change in values after the first phase and the last phase of chemotherapy was calculated as follows: ADC3-2 = ADC3 − ADC2. We recorded the patient characteristics, including age, gender, pulmonary metastasis, alkaline phosphatase (ALP), and lactate dehydrogenase (LDH). The patients were divided into the following 2 groups based on their histological TNR after postoperative: (I) the good-response group (≥90% necrosis, n=13) and (II) the poor-response group (<90% necrosis, n=28). Changes in the ADCs were compared between the good-response and poor-response groups. The different ADCs between the 2 groups were compared, and a receiver operating characteristic analysis was performed. A correlation analysis was performed to assess the correlations of the clinical features, laboratory features, and different ADCs with patients’ histopathological responses to NACT. Results The ADC2 (P<0.001), ADC3 (P=0.004), ADC3-1 (P=0.008), ADC3-2 (P=0.047), and ALP before NACT (P=0.019) were significantly higher in the good-response group than in the poor-response group. The ADC2 [area under the curve (AUC) =0.723; P=0.023], ADC3 (AUC =0.747; P=0.012), and ADC3-1 (AUC =0.761; P=0.008) showed good diagnostic performance. Based on the univariate binary logistic regression analysis, the ADC2 (P=0.022), ADC3 (P=0.009), ADC2-1 (P=0.041), and ADC3-1 (P=0.014) were correlated with the TNR. However, based on the multivariate analysis, these parameters were not significantly correlated with the TNR. Conclusions In patients with COS who are undergoing neoadjuvant chemotherapy, the ADC2 is a promisingindicator for predicting tumor response to chemotherapy in early.
| S-EPMC10240025 | biostudies-literature
Project description:The interaction between tumor cells and their microenvironment is an essential aspect of tumor development. Therefore, understanding how this microenvironment communicates with tumor cells is crucial for the development of new anti-cancer therapies. MicroRNAs (miRNAs) are small non-coding RNAs that inhibit gene expression. They are secreted into the extracellular medium in vesicles called exosomes, which allow communication between cells via the transfer of their cargo. Consequently, we hypothesized that circulating endothelial miRNAs could be transferred to tumor cells and modify their phenotype. Using exogenous miRNA, we demonstrated that endothelial cells can transfer miRNA to tumor cells via exosomes. Using miRNA profiling, we identified miR-503, which exhibited downregulated levels in exosomes released from endothelial cells cultured under tumoral conditions. The modulation of miR-503 in breast cancer cells altered their proliferative and invasive capacities. We then identified two targets of miR-503, CCND2 and CCND3. Moreover, we measured increased plasmatic miR-503 in breast cancer patients after neoadjuvant chemotherapy, which could be partly due to increased miRNA secretion by endothelial cells. Taken together, our data are the first to reveal the involvement of the endothelium in the modulation of tumor development via the secretion of circulating miR-503 in response to chemotherapy treatment.
| S-EPMC4496353 | biostudies-other
Project description:Response to neoadjuvant chemotherapy (NAC) in triple negative breast cancer (TNBC) is highly prognostic and determines whether adjuvant chemotherapy is needed if residual tumor is found at surgery. To evaluate the predictive and prognostic values of circulating tumor DNA (ctDNA) in this setting, we analyzed tumor and serial bloods from 26 TNBC patients collected prior, during, and after NAC. Individual digital droplet PCR assays were developed for 121 variants (average 5/patient) identified from tumor sequencing, enabling ctDNA detection in 96% of patients at baseline. Mutant allele frequency at baseline was associated with clinical characteristics. Levels drastically fell after one cycle of NAC, especially in patients whose tumors would go on to have a pathological complete response (pCR), but then rose significantly before surgery in patients with significant residual tumor at surgery (p?=?0.0001). The detection of ctDNA early during treatment and also late at the end of NAC before surgery was strongly predictive of residual tumor at surgery, but its absence was less predictive of pCR, especially when only TP53 variants are considered. ctDNA detection at the end of neoadjuvant chemotherapy indicated significantly worse relapse-free survival (HR?=?0.29 (95% CI 0.08-0.98), p?=?0.046), and overall survival (HR?=?0.27 95% CI 0.075-0.96), p?=?0.043). Hence, individualized multi-variant ctDNA testing during and after NAC prior to surgery has prognostic and predictive value in early TNBC patients.
| S-EPMC7477566 | biostudies-literature
Project description:The aim of our study was to analyze the effect of taxane-based chemotherapy on tumor angiogenesis in patients with advanced epithelial ovarian cancer.Within a prospective phase II trial, 32 patients with stage IIIC and IV ovarian cancer were treated with either two or three cycles of neoadjuvant chemotherapy prior to cytoreductive surgery. Carboplatin (AUC5) and docetaxel (75 mg/m2) were administered intravenously in a 3-weekly schedule. Changes in intratumor microvessel density (MVD) were assessed with immunohistochemistry by staining pre- and posttreatment surgical tumor specimens with panendothelial, neovascular and lymphatic vessel markers.Mean values of MVD defined by CD31, CD34, CD105 and D2-40 antibodies showed 12.3, 21.0, 2.7 and 3.1 vessels per high power field (HPF) before chemotherapy and increased after treatment to 15.3, 21.8, 4.8 and 3.6 per HPF, respectively. These changes were significant for CD31 (p = 0.04) and for CD105 (p = 0.02).Taxane-based chemotherapy appears to promote tumor vascularization when administered every 3 weeks. A possible explanation is the secondary recovery of MVD in response to immediate cytotoxic and antiangiogenic effects of the chemotherapy. If confirmed prospectively, these findings favor shorter treatment intervals of taxane-based chemotherapy to counteract proangiogenic recovery.
| S-EPMC2873383 | biostudies-literature
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.
| S-EPMC8283058 | biostudies-literature
Project description:Patients with large or nonoperable breast cancers often receive neoadjuvant chemotherapy to facilitate full resection of the tumor and enable conservation of the breast. However, currently available methods for evaluation of response during therapy are limited and the actual effect of the treatment is only recognized at surgery upon completion of chemotherapy. Timely assessment of response could allow individual tailoring of the treatment and save noneffective drugs and unnecessary toxicity. Here, we suggest that tumor derived DNA methylation in the serum may reflect changes in tumor burden and allow early recognition of responders versus nonresponders. In this pilot study, we collected 7 consecutive serum samples from 52 patients with locally advanced breast cancer during neoadjuvant chemotherapy. We selected RASSF1, which was methylated in more than 80% of the tumors, for serum analysis. Using the "methylation sensitive PCR and high resolution melting," we detected RASSF1 methylation in the serum of 21 patients prior to therapy. In four patients who achieved complete pathological response, RASSF1 methylation in the serum became undetectable early during therapy. In contrast, in 17 patients that had partial or minimal pathological response, serum RASSF1 methylation persisted longer or throughout the treatment (complete versus partial response p = 0.02). These findings support further development of this assay for monitoring response during neoadjuvant therapy.
| S-EPMC3904188 | biostudies-literature