4. Therapy monitoring

Gold standard for evaluation of therapy response involves clinical examination, measurement of tumor markers, and radiologic imaging. CTCs provide a blood biomarker for early carcinogenesis, cancer progression, and treatment effectiveness. The identification of circulating tumor cells under therapy correlates with poor prognosis in metastatic breast cancer, but there are few data describing the importance of circulating tumor cells in patients with early breast cancer.

However, changes in CTC count generally did not correlate with tumor's response to neoadjuvant chemotherapy. In the REMAGUS02 trial, the CTC count of 85 patients was analyzed after neoadjuvant chemotherapy [25]. No correlation between CTC dynamics and pathological response was found after neoadjuvant treatment. Analog results were shown in the Gepar Quattro trial [26]. Riethdorf et al. analyzed blood samples from 213 nonmetastasized breast cancer patients before and after preoperative chemotherapy. Interestingly, in 22% of patients, CTCs could be detected by CellSearch™ before neoadjuvant treatment, whereas positivity rates decreased to 11% after chemotherapy. However, neither CTC count before nor after preoperative chemotherapy was predictive to pathological response of the

The Clinical Relevance of Circulating Tumor Cells in Early Breast Cancer

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Although there are several ongoing trials investigating the role of CTCs as a decision tool in metastatic breast cancer, there are only few studies investigating the clinical utility of isolated tumor cells encountered in the blood stream in early breast cancer. This might be due to technical challenges of CTC research in early breast cancer. Up to date, treatment decisions in early breast cancer are still based on the phenotype of the primary tumor without considering the disease evolution. Nevertheless, features of minimal residual disease may differ from those of the primary tumor. Riethdorf et al. examined the HER2 status of CTCs in HER2-negative primary breast cancer [26]. In 19% of patients with HER2 negative BC, CTCs expressing the HER2 receptor were detected in peripheral blood [26]. Anti-HER2-targeted treatment is not eligible for these patients, which might result in undertherapy and higher risk for relapse. Georgoulias et al. showed an increased DFS and reduced number of relapses among patients with persistent HER2-positive CTCs detected after completion of adjuvant therapy and administration of trastuzumab [27]. In this small Phase II trial (n = 75), additional therapy with trastuzumab resulted in a 75% reduction of patients with detectable CTCs in the trastuzumab arm compared to 17.9% in the control group. Based on these results, this therapeutic approach is currently investigated in the TREAT CTC randomized trial (NCT01548677) [28]. Patients with HER2 negative early breast cancer with persistent CTCs after (neo) adjuvant chemotherapy were randomized concerning additional trastuzumab treatment. HER2 status of CTCs was assessed; nevertheless, treatment decisions were only based on CTC presence. However, the TREAT CTC

trial was closed for patient recruitment. To date, there are no published results yet.

Concerning treatment decisions, additional molecular profiling of CTCs may provide important additional information to CTC count. Several studies revealed intra- and intertumoral heterogeneity and demonstrated differences in phenotypes and genotypes between CTCs and primary tumors [29]. Therefore, detection and molecular characterization of CTCs are of great interest for selection of proper medical treatments and prevention of therapeutic resistance. In metastatic breast cancer, clinical significance of CTC subtype for guiding treatment decisions and evaluating therapy response is currently investigated within the German DETECT trials (NCT01619111).

primary tumor.

5. Treatment decisions based on CTCs

Regarding adjuvant treatment modalities of patients with early breast cancer, the SUCCESS trial and a trial by Xenidis et al. are the only trials in which CTCs were monitored [8, 19]. In the SUCCESS trial, CTCs were analyzed in 1492 patients with early breast cancer before adjuvant chemotherapy and post-chemotherapy using the CellSearch™ system [8]. The 36-month OS was 92.8% for persistently CTC-positive patients and 97.6% for persistently CTC-negative patients. Regarding the DFS, the Kaplan-Meyer estimate was 85.9% for persistently CTCpositive patients and 93.9% for persistently CTC-negative patients. This large prospective trial of patients with early breast cancer suggests the independent prognostic relevance of CTCs both before and after adjuvant chemotherapy. In line, the presence of persistent CTCs 2 years after completion of adjuvant chemotherapy in clinically disease-free patients predicted worse clinical survival [20]. Xenidis et al. analyzed blood samples of 237 patients who were initially positive before start of taxane-based or taxane-free adjuvant chemotherapy [19]. After a median follow-up of 71 months, patients treated with taxane-based regimen had a longer DFS compared to patients receiving taxane-free regimen. Positive effects on median survival in the taxane group were reflected by a shift toward CTC-negative status: 50% of patients in the taxane-treated group turned CTC negative compared to only 33% of patients in the taxane-free arm [19]. In the phase III SUCCESS C trial (NCT00847444), 3547 patients with HER2-negative early breast cancer were randomized to either six cycles of docetaxel and cyclophosphamide (DOC-C) or to epirubicin, 5-fluorouracil, and cyclophosphamide followed by three cycles of docetaxel (FEC-DOC). Data on CTC prevalence after adjuvant chemotherapy between both treatment arms were available for 1766 patients. First results revealed no significant difference of CTC prevalence at the time of last chemotherapy cycle between patients randomized to FEC-DOC or DOC-C (11.5 vs. 13.6%). The comparable prevalence of CTCs may indicate that anthracycline-free chemotherapy is equally effective to anthracycline-containing chemotherapy in HER2-negative, hormone receptor-positive early breast cancer. However, this interpretation needs to be confirmed by data of the final survival analysis [21].

In the neoadjuvant setting, four studies explored the association of CTCs and clinical outcomes. In a small study of Hall et al. focusing on 57 patients with triple negative breast cancer, CTC persistence after neoadjuvant treatment was an independent predictor of worse clinical outcomes [22]. The study showed a significant correlation between CTC presence and shorter relapse-free and overall survival after completion of neoadjuvant therapy. This is in contrast to other studies in which conflicting results were reported in the neoadjuvant setting [14, 23, 24]. These studies also aimed to explore the signatures of CTC dynamics and pathological changes in the primary tumor during neoadjuvant chemotherapy. In several clinical trials pathological complete response is used as an endpoint because of its ability to predict long-term survival.

However, changes in CTC count generally did not correlate with tumor's response to neoadjuvant chemotherapy. In the REMAGUS02 trial, the CTC count of 85 patients was analyzed after neoadjuvant chemotherapy [25]. No correlation between CTC dynamics and pathological response was found after neoadjuvant treatment. Analog results were shown in the Gepar Quattro trial [26]. Riethdorf et al. analyzed blood samples from 213 nonmetastasized breast cancer patients before and after preoperative chemotherapy. Interestingly, in 22% of patients, CTCs could be detected by CellSearch™ before neoadjuvant treatment, whereas positivity rates decreased to 11% after chemotherapy. However, neither CTC count before nor after preoperative chemotherapy was predictive to pathological response of the primary tumor.
