Circulating tumor cells in immunohistochemical subtypes of metastatic breast cancer: Lack of prediction in HER2-positive disease treated with targeted therapy

Department of Hematopathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Annals of Oncology (Impact Factor: 7.04). 09/2011; 23(5):1144-50. DOI: 10.1093/annonc/mdr434
Source: PubMed


Circulating tumor cells (CTCs) are associated with inferior prognosis in metastatic breast cancer (MBC). We hypothesized that the relationship between CTCs and disease subtype would provide a better understanding of the clinical and biologic behavior of MBC.
We retrospectively analyzed 517 MBC patients treated at a single institution. Subtypes of primary tumors were analyzed by immunohistochemical (IHC) or fluorescent in situ hybridization analyses and CTCs were enumerated by CellSearch(®) at starting a new therapy. Overall survival (OS) and progression-free survival durations for each IHC subtype were determined.
At a median follow-up of 24.6 months, 276 of 517 (53%) patients had died. The median OS for patients with <5 and ≥ 5 CTCs were 32.4 and 18.3 months, respectively (P < 0.001). Except in HER2+ patients, the prognostic value of CTCs was independent of disease subtype and disease site.
In this large retrospective study, CTCs were strongly predictive of survival in all MBC subtypes except HER2+ patients who had been treated with targeted therapy. Our results clearly demonstrate the value of enumerating CTCs in MBC and strongly suggest an interesting biological implication in the HER2+ subset of patients that need to be further explored.

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    • "The clinical impact of CTCs in various immunohistochemical subtypes of breast cancer, was shown in a study by Giordano.[44] They found that baseline CTC enumeration had good prognostic value in all breast cancer subtypes except HER2+ cancer. "
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    ABSTRACT: Circulating tumor cell (CTC) measurement in peripheral blood of patients with breast cancer offers prognostic information. In this review, we will try to identify evidence that could be used for prognosis, predictive power to draw this tool to clinical utility. We reviewed 81 manuscripts, and categorized those in discovery datasets, prognostic factors in metastatic breast cancer, identification of clinical utility in early breast cancer and in novel approaches. With each patient responding differently to chemotherapy, more efficient markers would improve clinical outcome. Current CTC diagnostic techniques use epithelial markers predominantly; however, the most appropriate method is the measurement of circulating DNA. It has been hypothesized that micrometastasis occurs early in the development of tumors. That implies the presence of CTCs in nonmetastatic setting. The origin of stimulus for malignant transformation is yet unknown. The role of microenvironment as a stimulus is also being investigated. It has been shown that CTCs vary in numbers with chemotherapy. The markers, which are followed-up in the primary tumors, are also being studied on the CTCs. There is discordance of the human epidermal growth factor receptor-2 status between the primary tumor and CTCs. This review summarizes our current knowledge about the CTCs. With genetic profiling and molecular characterization of CTCs, it is possible to overcome the diagnostic difficulties. Evidence for clinical utility of CTC as prognostic and predictive marker is increasing. Appropriate patient stratification according to CTC determination among other tests, would make personalized cancer therapy more feasible.
    Full-text · Article · Jun 2014 · Journal of Carcinogenesis
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    • "As BM sampling is a comparatively invasive procedure, recent reports have focused on the detection of CTC in the peripheral blood of PBC patients [63-65]. Whereas CTC detection in metastatic breast cancer patients has proven to be of prognostic relevance [66-68], their role in PBC is less well described, and results on an association between CTC and response to NACT or prognosis are inconclusive [60,69-71]. This is probably owing to methodologic differences and a lower sensitivity of CTC analysis [25]. "
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    ABSTRACT: Neoadjuvant systemic therapy of primary breast cancer (PBC) patients offers the possibility to monitor treatment-response. However, patients might suffer from metastatic relapse despite achieving a pathological complete response (pCR). This indicates that local response to therapy must not be representative for systemic treatment-efficacy. Therefore, the aim of this study was to compare local response with systemic tumor cell dissemination by determining the presence of disseminated tumor cells (DTC), including apoptotic tumor cells, in the bone marrow (BM) of PBC patients after neoadjuvant chemotherapy (NACT). DTC were detected by immunocytochemistry (pancytokeratin antibody A45-B/B3) and cytomorphology (DTC-status). The presence of apoptotic tumor cells was determined using the M30 antibody (M30-status). This antibody detects a neo-epitope that is expressed only during early apoptosis. BM aspirates from 400 PBC patients that had completed NACT were eligible for this study. Of these, 167 (42%) patients were DTC-positive (DTC-status). The M30-status was investigated in 308 patients. Apoptotic (M30-positive) tumor cells were detected in 89 (29%) of these. Whereas the DTC-status was not correlated (p = 0.557) to local treatment response (that is pCR or a clinical complete/partial response), the presence of M30-positive tumor cells was significantly higher in patients that responded to therapy (p = 0.026). Additionally, DTC-positive patients were at an increased risk for disease relapse (hazard ratio: 1.87, 95% CI: 1.11 -- 3.15, p = 0.019). The presence of DTC is independent from therapy response of the primary tumor. As patients that are DTC-positive after NACT have an unfavorable outcome, they might benefit from additional systemic treatment.
    Full-text · Article · Oct 2013 · Breast cancer research: BCR
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    • "In addition to detection, the molecular characterization of CTCs is now recognized as a valuable tool that can provide real-time information to distinguish subgroups of patients who can benefit from certain types of therapy [18,19]. Unfortunately, previous studies failed to illustrate the prognostic value of CTCs in HER2-positive MBC patients using CellSearch [20]. Although recent studies have made great efforts to compare HER2 statuses between tumor tissue and CTCs [18,19,21-29], a satisfactory CTC HER2-positive criterion has not yet been established. "
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    ABSTRACT: Background This study was initiated to investigate the prognostic significance of circulating tumor cell (CTC) enumeration and the predictive value of CTC HER2 expression for efficient anti-HER2 therapy in HER2-positive metastatic breast cancer (MBC) patients. Methods Sixty HER2-positive MBC patients were enrolled in the present study. Before the initiation of systemic treatment, CTCs from 7.5 ml of blood were analyzed using the CellSearch system. The progression-free survival (PFS) of the patients was estimated using Kaplan-Meier survival curves. Results CTCs were detected in 45% (27/60) of the patients, who had shorter median PFS than those without CTCs (2.5 vs. 7.5 months, P = 0.0125). Furthermore, referring to the standard HER2 testing that uses immunohistochemistry (IHC), we proposed a CTC HER2-positive criterion, defined as >30% of CTCs over-expressing HER2. Among patients undergoing anti-HER2 therapy, those with HER2-positive CTCs had longer PFS (8.8 vs. 2.5 months, P = 0.002). Among patients with HER2-positive CTCs, the median PFS for those receiving anti-HER2 therapy was significantly longer than those who were not (8.8 vs. 1.5 months, P = 0.001). Notably, up to 52% (14/27) of the HER2-positive patients were CTC HER2-negative, and anti-HER2 therapy did not significantly improve the median PFS in these patients (2.5 vs. 0.9 months, P = 0.499). Conclusions Our findings underscore the necessity of a comprehensive CTC analysis, which may provide valuable prognostic and predictive information for optimizing individually tailored therapies in HER2-positive MBC patients. To test this idea, additional large cohort, multi-center and prospective clinical trials are needed.
    Full-text · Article · Apr 2013 · BMC Cancer
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