Does primary neoadjuvant systemic therapy eradicate minimal residual disease? Analysis of disseminated and circulating tumor cells before and after therapy

Kasimir‐Bauer, Sabine; Bittner, Ann‐Kathrin; König, Lisa; Reiter, K.; Keller, Thomas; Kimmig, Rainer; Hoffmann, Oliver

doi:10.1186/s13058-016-0679-3

Cited by 73 publications

(73 citation statements)

References 76 publications

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“…While there have been variable reports of Ki67 in CTCs and CTC clusters (3,57), it has been theorized that CTC clusters are better able to evade cytotoxic/chemotherapeutic drugs due to absence of proliferation as indicated by Ki67 (3,34). This is also corroborated by the higher expression of ERCC1 (treatment resistant marker (58)) in the PV clusters, and further reinforced by the upregulation of ‘EGFR inhibitor resistance’ and ‘HIF-1 signaling’ pathways in the clusters. Hypoxia is theorized to promote epithelial-mesenchymal transition (36), which in turn confers treatment resistance (35).…”

Section: Discussionmentioning

confidence: 61%

Poor Prognosis Indicated by Venous Circulating Tumor Cell Clusters in Early-Stage Lung Cancers

et al. 2017

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Early detection of metastasis can be aided by circulating tumor cells (CTCs), which also show potential to predict early relapse. Due to the limited CTC numbers in peripheral blood in early stages, we investigated CTCs in pulmonary vein blood accessed during surgical resection of tumors. Pulmonary vein (PV) and peripheral vein (Pe) blood specimens from patients with lung cancer were drawn during the perioperative period and assessed for CTC burden using a microfluidic device. From 108 blood samples analyzed from 36 patients, PV had significantly higher number of CTCs compared to pre-operative Pe (p<0.0001) and intra-operative Pe (p<0.001) blood. CTC clusters with large number of CTCs were observed in 50% of patients, with PV often revealing larger clusters. Long term surveillance indicated that presence of clusters in pre-operative Pe blood predicted a trend toward poor prognosis. Gene expression analysis by RT-qPCR revealed enrichment of p53 signaling and extracellular matrix involvement in PV and Pe samples. Ki67 expression was detected in 62.5% of PV samples and 59.2% of Pe samples, with the majority (72.7%) of patients positive for Ki67 expression in PV having single CTCs as opposed to clusters. Gene ontology analysis revealed enrichment of cell migration and immune-related pathways in CTC clusters, suggesting survival advantage of clusters in circulation. Clusters display characteristics of therapeutic resistance, indicating the aggressive nature of these cells. Thus, CTCs isolated from early stages of lung cancer are predictive of poor prognosis and can be interrogated to determine biomarkers predictive of recurrence.

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Section: Discussionmentioning

confidence: 61%

Poor Prognosis Indicated by Venous Circulating Tumor Cell Clusters in Early-Stage Lung Cancers

et al. 2017

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“…Finally, 50 studies were eligible for meta-analysis (Fig. 1)4591112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657.…”

Section: Resultsmentioning

confidence: 99%

Circulating tumor cell status monitors the treatment responses in breast cancer patients: a meta-analysis

Yan

Cui

Chen

et al. 2017

Sci Rep

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Whether circulating tumor cells (CTCs) can be used as an indicator of treatment response in breast cancer (BC) needs to be clarified. We addressed this issue by a meta-analysis. PubMed, EMBase and Cochrane library databases were searched in June 2016. Effect measures were estimated as pooled risk ratio (RR), odds ratio (OR) or mean difference by fixed- or random-effect models, according to heterogeneity of included studies. In total, 50 studies with 6712 patients were recruited. Overall analysis showed that there was a significant reduction of CTC-positive rate (RR = 0.68, 95% CI: 0.61–0.76, P < 0.00001) after treatment. Subgroup analyses revealed that neoadjuvant treatment, adjuvant treatment, metastatic treatment or combination therapy could reduce the CTC-positive rate, but surgery could not; moreover, the reduction was only found in HER2+ or HER2- patients but not in the triple-negative ones. Reduction of CTC-positive rate was associated with lower probability of disease progression (OR = 0.54, 95% CI: 0.33–0.89, P = 0.01) and longer overall survival period (mean difference = 11.61 months, 95% CI: 8.63–14.59, P < 0.00001) as well as longer progression-free survival period (mean difference = 5.07 months, 95% CI: 2.70–7.44, P < 0.0001). These results demonstrate that CTC status can serve as an indicator to monitor the effectiveness of treatments and guide subsequent therapies in BC.

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“…Besides the prognostic impact of CTCs enumeration, the molecular characterization of these cells offers new perspectives that can increase the understanding of CTCs biology and can enable better clinical decisions, which nowadays are not possible through enumeration. In this sense, some studies have explored CTCs in BC by using molecular methods [21][22][23][24][25][26][27][28]. However, only a few have evaluated the characteristics of CTCs after therapy [19,26,[29][30][31], and, to our knowledge, only one has used a negative enrichment approach comparable with ours [32].…”

Section: Discussionmentioning

confidence: 99%

CTCs Expression Profiling for Advanced Breast Cancer Monitoring

Pereira-Veiga¹,

Martínez‐Fernández

Abuín³

et al. 2019

Cancers

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The study of circulating tumor cells (CTCs) has a huge clinical interest in advance and metastatic breast cancer patients. However, many approaches are biased by the use of epithelial markers, which underestimate non-epithelial CTCs phenotypes. CTCs enumeration provides valuable prognostic information; however, molecular characterization could be the best option to monitor patients throughout the disease since it may provide more relevant clinical information to the physicians. In this work, we aimed at enumerating and performing a molecular characterization of CTCs from a cohort of 20 patients with metastatic breast cancer (MBC), monitoring the disease at different time points of the therapy, and at progression when it occurred. To this end, we used a CTC negative enrichment protocol that allowed us to recover a higher variety of CTCs phenotypes. With this strategy, we were able to obtain gene expression data from CTCs from all the patients. In addition, we found that high expression levels of PALB2 and MYC were associated with a worse outcome. Interestingly, we identified that CTCs with an EpCAMhighVIMlowALDH1A1high signature showed both shorter overall survival (OS) and progression-free survival (PFS), suggesting that CTCs with epithelial-stem features had the most aggressive phenotype.

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Does primary neoadjuvant systemic therapy eradicate minimal residual disease? Analysis of disseminated and circulating tumor cells before and after therapy

Cited by 73 publications

References 76 publications

Poor Prognosis Indicated by Venous Circulating Tumor Cell Clusters in Early-Stage Lung Cancers

Poor Prognosis Indicated by Venous Circulating Tumor Cell Clusters in Early-Stage Lung Cancers

Circulating tumor cell status monitors the treatment responses in breast cancer patients: a meta-analysis

CTCs Expression Profiling for Advanced Breast Cancer Monitoring

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