Changing Levels of Circulating Tumor Cells in Monitoring Chemotherapy Response in Patients with Metastatic Breast Cancer
Department of Obstetrics and Gynaecology, University of Tuebingen, Calwer Strasse 7, 72076 Tuebingen, Germany. Anticancer research
(Impact Factor: 1.83).
The detection of >5 circulating tumor cells (CTCs)/7.5 ml blood in patients being treated for metastatic breast cancer (MBC) has recently been shown to be predictive for therapy efficacy. The aim of this study was to investigate whether changing CTC levels during the course of chemotherapy treatment would also be useful in monitoring response to treatment.
CTC levels were determined in 58 MBC patients at the beginning and after 3 cycles of chemotherapy. Changes in CTC level (either negative CTCs (<5 CTCs/7.5 ml blood) turning positive, vice versa, or a change of ±25%) were correlated to radiologic Response Evaluation Criteria In Solid Tumors (RECIST) criteria, as well as serum CA 15-3 measurements, and were evaluated for their capability to predict survival.
Changing CTC levels significantly correlated with response to therapy as measured by radiologic RECIST criteria (p<0.001), and serum CA 15-3 level changes (p=0.017). Patients with decreasing CTC levels survived significantly longer than patients with increasing CTC levels (17.67±5.90 months versus 4.53±0.54 months, p<0.001).
The observation of changes in CTC level during the course of chemotherapy is useful in monitoring therapy efficacy and is correlated with overall survival. Further prospective trials should investigate the clinical usefulness of determining changes in CTC level during chemotherapy of MBC.
Available from: Samantha Elizabeth Bowyer
- "The number of CTCs prior to initiation, during and after therapy has been shown to be indicative of the length of progression free survival (PFS) and of overall survival (OS) [4,10,11]. Temporal monitoring of CTC numbers during and after therapy showed that a decrease in CTCs correlated reasonably well with the clinical course of disease and also appears useful for evaluating the patient’s response to therapy [4,8,12,13]. Moreover the predictive value for survival based on CTC enumeration has been shown to be superior to standard monitoring tests such as prostate-specific antigen (PSA) in castration-resistant prostate cancer  and tumour imaging in metastatic breast cancer . "
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New effective treatments for metastatic melanoma greatly improve survival in a proportion of patients. However biomarkers to identify patients that are more likely to benefit from a particular treatment are needed. We previously reported on a multimarker approach for the detection of heterogenous melanoma circulating tumour cells (CTCs). Here we evaluated the prognostic value of this multimarker quantification of CTCs and investigated whether changes in CTC levels during therapy can be used as a biomarker of treatment response and survival outcomes.
CTCs were captured by targeting the melanoma associated markers MCSP and MCAM as well as the melanoma stem cell markers ABCB5 and CD271. CTCs were quantified in 27 metastatic melanoma patients treated by surgery or with vemurafenib, ipilimumab or dacarbazine. Patients were enrolled prospectively and CTC counts performed at baseline (prior to treatment), during and after treatment.
Baseline CTC numbers were not found to be prognostic of overall survival nor of progression free survival. However, a low baseline CTC number was associated with a rapid response to vemurafenib therapy. A decrease in CTCs after treatment initiation was associated with response to treatment and prolonged overall survival in vemurafenib treated patients.
Measuring changes in CTC numbers during treatment is useful for monitoring therapy response in melanoma patients and for providing prognostic information relating to overall survival. Further studies with larger sample sizes are required to confirm the utility of CTC quantification as a companion diagnostic for metastatic melanoma treatment.
Available from: Eric Schuur
- "Hayes et al. , as well as other early publications using the CELLSEARCH System  , tested the prognostic value of CTC measurement during therapy, demonstrating that CTC counts during ongoing therapy were significantly associated with prognosis. Additional studies since 2007 have demonstrated the prognostic value of CTC counts in patients with MBC at initiation of a new line of therapy       and during ongoing therapy       , confirming that CTC values obtained during treatment have essentially the same prognostic value for PFS and OS as baseline measurements and may be useful for monitoring disease status. Within these two prognostic categories (≥5 CTC and <5 CTC), there is evidence of additional prognostic information. "
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ABSTRACT: Circulating tumor cells (CTCs) were discovered nearly 150 years ago but have only recently been recognized as a feature of most solid tumors due to their extremely low concentration in the peripheral circulation. Several technologies have been developed to isolate and analyze CTCs, which can now be routinely accessed for clinical information. The most mature of these (the CELLSEARCH system) uses immunomagnetic selection of epithelial cell adhesion molecule to isolate CTCs for analysis. Studies using this system have demonstrated that categorization of patients into high and low CTC groups using a validated decision point is prognostic in patients with metastatic breast, colorectal, or prostate cancer. Initial attempts to use CTC counts to guide therapeutic decisions appeared to yield positive results and key concepts in clinical application of CTC information, including the CTC cutoff, predictive value in disease subtypes, and comparison to current evaluation methods, have been demonstrated. Clinical studies of the impact of CTC counts in routine clinical practice are ongoing; however, recent published evidence on the clinical use of CTCs in metastatic breast cancer continues to support these concepts, and experience in the community oncology setting also suggests that CTC enumeration can be useful for therapy management.
Available from: Haifeng Luo
- "Some markers have shown promising results in a limited number of studies, e.g. Ki67 , p53 , multidrug resistance-associated protein  and circulating tumor cells , . Recent studies have revealed that a large number of miRNAs are deregulated in drug resistant or sensitive cancer cell lines . "
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ABSTRACT: Chemotherapy is an important component in the treatment paradigm for breast cancers. However, the resistance of cancer cells to chemotherapeutic agents frequently results in the subsequent recurrence and metastasis. Identification of molecular markers to predict treatment outcome is therefore warranted. The aim of the present study was to evaluate whether expression of circulating microRNAs (miRNAs) can predict clinical outcome in breast cancer patients treated with adjuvant chemotherapy.
Circulating miRNAs in blood serum prior to treatment were determined by quantitative Real-Time PCR in 56 breast cancer patients with invasive ductal carcinoma and pre-operative neoadjuvant chemotherapy. Proliferating cell nuclear antigen (PCNA) immunostaining and TUNEL were performed in surgical samples to determine the effects of chemotherapy on cancer cell proliferation and apoptosis, respectively. Among the miRNAs tested, only miR-125b was significantly associated with therapeutic response, exhibiting higher expression level in non-responsive patients (n = 26, 46%; p = 0.008). In addition, breast cancers with high miR-125b expression had higher percentage of proliferating cells and lower percentage of apoptotic cells in the corresponding surgical specimens obtained after neoadjuvant chemotherapy. Increased resistance to anticancer drug was observed in vitro in breast cancer cells with ectopic miR-125b expression; conversely, reducing miR-125b level sensitized breast cancer cells to chemotherapy. Moreover, we demonstrated that the E2F3 was a direct target of miR-125b in breast cancer cells.
These data suggest that circulating miR-125b expression is associated with chemotherapeutic resistance of breast cancer. This finding has important implications in the development of targeted therapeutics for overcoming chemotherapeutic resistance in novel anti-cancer strategies.
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