Introduction. In non-metastatic breast cancer patients, the REMAGUS02 neoadjuvant study was the first to report a significant impact of circulating tumor cells (CTCs) detection by the CellSearch system on the distant metastasis-free survival (DMFS) and overall survival (OS) endpoints. However, these results were only reported after a short follow-up. Here, we present the updated data, with a longer follow-up. Material and Methods. CTC count was performed before and after neoadjuvant chemotherapy in 118 patients and correlated to survival. Results. CTC count results were available before and/or after neoadjuvant chemotherapy in 115 patients. After a median follow-up of 70 months, detection of ≥1 CTC/7.5？mL before chemotherapy ( ) was significantly associated with DMFS ( ) and OS ( ), whereas postchemotherapy CTC detection ( ) had no significant impact. In multivariable analysis, prechemotherapy CTC and triple negative phenotype were the two independent prognostic factors for survival. We observed that the CTC impact is most significant during the first three years of follow-up. Discussion. We confirm that the detection of CTC is independently associated with a significantly worse outcome, but mainly during the first 3-4 years of follow-up. No prognostic impact is seen in patients who are still relapse-free at this moment. 1. Introduction Over the past decade, two opportunities have been created to study the hematogenous metastatic process in breast cancer patients: disseminated tumor cells (DTCs), which are detected in the bone marrow, and circulating tumors cells (CTCs), which are detected in the blood [1]. In non-metastatic breast cancer patients, a pooled analysis published in 2005 established that bone marrow DTC detection is an independent prognostic factor of later metastatic relapse [2]. Survival data obtained in this analysis, as well as in other studies [3, 4], were based on a long follow-up, generally of more than 5 years, and suggested that the prognostic impact of DTC (i.e., hazard ratio of relapse or death) was rather constant over time in the population at risk. This finding is consistent with the fact that DTCs are quiescent tumor cells and can stay in G0 phase for many years, before metastatic growth. In contrast, CTCs have been mostly studied in metastatic breast cancer patients, with numerous studies reporting that elevated CTC count, either at baseline or during or after treatment, is associated with a worse outcome [5–11]. The FDA-approved CellSearch detection system is currently the most frequently used system in the clinic for CTC
References
[1]
F. C. Bidard, J. Y. Pierga, J. C. Soria, and J. P. Thiery, “Translating metastasis-related biomarkers to the clinic—progress and pitfalls,” Nature Review Clinical Oncology, vol. 10, no. 3, pp. 169–179, 2013.
[2]
S. Braun, F. D. Vogl, B. Naume et al., “A pooled analysis of bone marrow micrometastasis in breast cancer,” The New England Journal of Medicine, vol. 353, no. 8, pp. 793–802, 2005.
[3]
F. C. Bidard, A. Vincent-Salomon, S. Gomme et al., “Disseminated tumor cells of breast cancer patients: a strong prognostic factor for distant and local relapse,” Clinical Cancer Research, vol. 14, no. 11, pp. 3306–3311, 2008.
[4]
W. Janni, F. D. Vogl, G. Wiedswang et al., “Persistence of disseminated tumor cells in the bone marrow of breast cancer patients predicts increased risk for relapse—a European pooled analysis,” Clinical Cancer Research, vol. 17, no. 9, pp. 2967–2976, 2011.
[5]
M. Cristofanilli, G. T. Budd, M. J. Ellis et al., “Circulating tumor cells, disease progression, and survival in metastatic breast cancer,” The New England Journal of Medicine, vol. 351, no. 8, pp. 781–791, 2004.
[6]
S. Dawood, K. Broglio, V. Valero et al., “Circulating tumor cells in metastatic breast cancer: from prognostic stratification to modification of the staging system?” Cancer, vol. 113, no. 9, pp. 2422–2430, 2008.
[7]
S. Nakamura, H. Yagata, S. Ohno et al., “Multi-center study evaluating circulating tumor cells as a surrogate for response to treatment and overall survival in metastatic breast cancer,” Breast Cancer, vol. 17, no. 3, pp. 199–204, 2010.
[8]
F. Nolé, E. Munzone, L. Zorzino et al., “Variation of circulating tumor cell levels during treatment of metastatic breast cancer: prognostic and therapeutic implications,” Annals of Oncology, vol. 19, no. 5, pp. 891–897, 2008.
[9]
F. C. Bidard, C. Mathiot, A. Degeorges et al., “Clinical value of circulating endothelial cells and circulating tumor cells in metastatic breast cancer patients treated first line with bevacizumab and chemotherapy,” Annals of Oncology, vol. 21, no. 9, pp. 1765–1771, 2010.
[10]
M. C. Liu, P. G. Shields, R. D. Warren et al., “Circulating tumor cells: a useful predictor of treatment efficacy in metastatic breast cancer,” Journal of Clinical Oncology, vol. 27, no. 31, pp. 5153–5159, 2009.
[11]
J. Y. Pierga, D. Hajage, T. Bachelot, et al., “High independent prognostic and predictive value of circulating tumor cells compared with serum tumor markers in a large prospective trial in first-line chemotherapy for metastatic breast cancer patients,” Annals of Oncology, vol. 23, no. 3, pp. 618–624, 2012.
[12]
F. C. Bidard, T. Fehm, M. Ignatiadis, et al., “Clinical application of circulating tumor cells in breast cancer: overview of the current interventional trials,” Cancer Metastasis Reviews, 2013.
[13]
J. Y. Pierga, F. C. Bidard, C. Mathiot et al., “Circulating tumor cell detection predicts early metastatic relapse after neoadjuvant chemotherapy in large operable and locally advanced breast cancer in a phase II randomized trial,” Clinical Cancer Research, vol. 14, no. 21, pp. 7004–7010, 2008.
[14]
S. Riethdorf, V. Müller, L. Zhang et al., “Detection and HER2 expression of circulating tumor cells: prospective monitoring in breast cancer patients treated in the neoadjuvant GeparQuattro trial,” Clinical Cancer Research, vol. 16, no. 9, pp. 2634–2645, 2010.
[15]
J. Y. Pierga, T. Petit, T. Delozier, et al., “Neoadjuvant bevacizumab, trastuzumab, and chemotherapy for primary inflammatory HER2-positive breast cancer (BEVERLY-2): an open-label, single-arm phase 2 study,” The Lancet Oncology, vol. 13, no. 4, pp. 375–384, 2012.
[16]
F. C. Bidard, C. Mathiot, S. Delaloge et al., “Single circulating tumor cell detection and overall survival in nonmetastatic breast cancer,” Annals of Oncology, vol. 21, no. 4, pp. 729–733, 2010.
[17]
J. Y. Pierga, S. Delaloge, M. Espié et al., “A multicenter randomized phase II study of sequential epirubicin/cyclophosphamide followed by docetaxel with or without celecoxib or trastuzumab according to HER2 status, as primary chemotherapy for localized invasive breast cancer patients,” Breast Cancer Research and Treatment, vol. 122, no. 2, pp. 429–437, 2010.
[18]
W. J. Allard, J. Matera, M. C. Miller et al., “Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases,” Clinical Cancer Research, vol. 10, no. 20, pp. 6897–6904, 2004.
[19]
L. M. McShane, D. G. Altman, W. Sauerbrei et al., “Reporting recommendations for tumor marker prognostic studies (REMARK),” Journal of the National Cancer Institute, vol. 97, no. 16, pp. 1180–1184, 2005.
[20]
A. Lucci, C. S. Hall, A. K. Lodhi, et al., “Circulating tumour cells in non-metastatic breast cancer: a prospective study,” The Lancet Oncology, vol. 13, no. 7, pp. 688–695, 2012.
[21]
B. Rack, C. Schindlbeck, U. Andergassen, et al., “Prognostic relevance of circulating tumor cells in the peripheral blood of primary breast cancer patients,” Cancer Research, vol. 70, supplement 2, 2010, abstract no. S6-5.
