Abstract
Purpose
Pathological complete response (pCR) is a common endpoint in neoadjuvant chemotherapy (NACT) of primary breast cancer patients (PBC), but does not address the systemic prevalence of minimal residual disease. In this study, we compared pCR with the detection of circulating (CTC) and disseminated tumor cells (DTC) following NACT, as well as their impact on survival.
Methods
Patients with PBC receiving NACT and consecutive surgery were eligible for this study. CTCs were detected using the CellSearch® system and DTCs were determined using immunocytochemistry (cytokeratin staining with the A45-B/B3 antibody). pCR was defined as ypT0/ypTis and ypN0.
Results
58 patients were included in the analysis with a median follow-up of 30 months. Of these, 5 (9%) presented with CTCs and 36 (62%) with DTCs. 16 patients (28%) achieved a pCR. No significant correlation between CTCs, DTCs and pCR and no statistically significant impact on disease free (DFS) or overall survival (OS) was apparent.
Conclusions
Both CTCs and DTCs are detectable after NACT. As we could not show a significant relationship between CTC detection, DTC detection and pCR, all three methods may provide independent information regarding treatment response. Since we were unable to show a significant impact on survival, larger prospective studies that include CTCs and DTCs are needed. These trials should include the molecular characterization of primary tumor tissue, CTCs and DTCs to determine whether these cells are independent subpopulations of malignant cell clones.
Similar content being viewed by others
Abbreviations
- NACT:
-
Neoadjuvant chemotherapy
- PBC:
-
Primary breast cancer
- DFS:
-
Disease free survival
- OS:
-
Overall survival
- pCR:
-
Pathological complete response
- MRD:
-
Minimal residual disease
- DTC:
-
Disseminated tumor cell
- BM:
-
Bone marrow
- CTC:
-
Circulating tumor cell
- HR:
-
Hormone receptor
References
Kaufmann M, von Minckwitz G, Mamounas EP et al (2012) Recommendations from an international consensus conference on the current status and future of neoadjuvant systemic therapy in primary breast cancer. Ann Surg Oncol 19:1508–1516. https://doi.org/10.1245/s10434-011-2108-2
Thompson AM, Moulder-Thompson SL (2012) Neoadjuvant treatment of breast cancer. Ann Oncol 23:x231–x236. https://doi.org/10.1093/annonc/mds324
Rastogi P, Anderson SJ, Bear HD et al (2008) Preoperative chemotherapy: updates of national surgical adjuvant breast and bowel project protocols B-18 and B-27. J Clin Oncol 26:778–785. https://doi.org/10.1200/JCO.2007.15.0235
Mauri D, Pavlidis N, Ioannidis JPA (2005) Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis. JNCI J Natl Cancer Inst 97:188–194. https://doi.org/10.1093/jnci/dji021
Von Minckwitz G, Untch M, Blohmer JU et al (2012) Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol 30:1796–1804. https://doi.org/10.1200/JCO.2011.38.8595
Cortazar P, Zhang L, Untch M et al (2014) Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 384:164–172. https://doi.org/10.1016/S0140-6736(13)62422-8
Braun S, Vogl FD, Naume B et al (2005) A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med 353:793–802. https://doi.org/10.1056/NEJMoa050434
Rack B, Schindlbeck C, Juckstock J et al (2014) Circulating tumor cells predict survival in early average-to-high risk breast cancer patients. J Natl Cancer Inst. https://doi.org/10.1093/jnci/dju066
Hartkopf AD, Wallwiener M, Hahn M et al (2016) Simultaneous detection of disseminated and circulating tumor cells in primary breast cancer patients. Cancer Res Treat 48:115–124. https://doi.org/10.4143/crt.2014.287
Janni WJ, Rack B, Terstappen LWMM et al (2016) Pooled analysis of the prognostic relevance of circulating tumor cells in primary breast cancer. Clin Cancer Res 22:2583–2593. https://doi.org/10.1158/1078-0432.CCR-15-1603
Hartkopf AD, Taran FA, Wallwiener M et al (2014) Prognostic relevance of disseminated tumour cells from the bone marrow of early stage breast cancer patients—results from a large single-centre analysis. Eur J Cancer 50:2550–2559. https://doi.org/10.1016/j.ejca.2014.06.025
Lucci A, Hall CS, Lodhi AK et al (2012) Circulating tumour cells in non-metastatic breast cancer: a prospective study. Lancet Oncol 13:688–695. https://doi.org/10.1016/S1470-2045(12)70209-7
Bidard F-C, Proudhon C, Pierga J-Y (2016) Circulating tumor cells in breast cancer. Mol Oncol 10:418–430. https://doi.org/10.1016/j.molonc.2016.01.001
Pierga J-Y, Bidard F-C, Mathiot C et al (2008) 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. Clin Cancer Res 14:7004–7010. https://doi.org/10.1158/1078-0432.CCR-08-0030
Hall C, Karhade M, Laubacher B et al (2015) Circulating tumor cells after neoadjuvant chemotherapy in stage I–III triple-negative breast cancer. Ann Surg Oncol 22:552–558. https://doi.org/10.1245/s10434-015-4600-6
Hartkopf AD, Taran F-A, Wallwiener M et al (2013) The presence and prognostic impact of apoptotic and nonapoptotic disseminated tumor cells in the bone marrow of primary breast cancer patients after neoadjuvant chemotherapy. Breast Cancer Res 15:R94. https://doi.org/10.1186/bcr3496
Mathiesen RR, Borgen E, Renolen A et al (2012) Persistence of disseminated tumor cells after neoadjuvant treatment for locally advanced breast cancer predicts poor survival. Breast Cancer Res 14:R117. https://doi.org/10.1186/bcr3242
Hall C, Krishnamurthy S, Lodhi A et al (2012) Disseminated tumor cells predict survival after neoadjuvant therapy in primary breast cancer. Cancer 118:342–348. https://doi.org/10.1002/cncr.26202
Fehm T, Braun S, Muller V et al (2006) A concept for the standardized detection of disseminated tumor cells in bone marrow from patients with primary breast cancer and its clinical implementation. Cancer 107:885–892. https://doi.org/10.1002/cncr.22076
Arbeitsgemeinschaft Gynäkologische, Onkologie E.V. (AGO) AGO-Online—Mamma. http://www.ago-online.de/de/infothek-fuer-aerzte/leitlinienempfehlungen/mamma/. Accessed 20 Sep 2016
Kasimir-Bauer S, Bittner A-K, König L et al (2016) Does primary neoadjuvant systemic therapy eradicate minimal residual disease? Analysis of disseminated and circulating tumor cells before and after therapy. Breast Cancer Res 18:20. https://doi.org/10.1186/s13058-016-0679-3
Bidard F-C, Michiels S, Mueller V, et al (2016) IMENEO: international MEta-analysis of circulating tumor cell detection in early breast cancer patients treated by NEOadjuvant chemotherapy. In: San Antonio breast cancer symposium. San Antonio, pp 538–539
Kasimir-Bauer S, Reiter K, Aktas B et al (2016) Different prognostic value of circulating and disseminated tumor cells in primary breast cancer: influence of bisphosphonate intake? Sci Rep 6:26355. https://doi.org/10.1038/srep26355
Bidard F-C, Vincent-Salomon A, Sigal-Zafrani B et al (2007) Prognosis of women with stage IV breast cancer depends on detection of circulating tumor cells rather than disseminated tumor cells. Ann Oncol 19:496–500. https://doi.org/10.1093/annonc/mdm507
Riethdorf S, Müller V, Zhang L et al (2010) Detection and HER2 expression of circulating tumor cells: prospective monitoring in breast cancer patients treated in the neoadjuvant GeparQuattro trial. Clin Cancer Res 16:2634–2645. https://doi.org/10.1158/1078-0432.CCR-09-2042
Hosseini H, Obradović MMS, Hoffmann M et al (2016) Early dissemination seeds metastasis in breast cancer. Nature. https://doi.org/10.1038/nature20785
Becker S, Solomayer E, Becker-Pergola G et al (2007) Primary systemic therapy does not eradicate disseminated tumor cells in breast cancer patients. Breast Cancer Res Treat 106:239–243. https://doi.org/10.1007/s10549-006-9484-5
Pantel K, Braun S, Kutter D et al (1993) Differential expression of proliferation-associated molecules in individual micrometastatic carcinoma cells. J Natl Cancer Inst 85:1419–1424. https://doi.org/10.1093/jnci/85.17.1419
Krawczyk N, Hartkopf A, Banys M et al (2014) Prognostic relevance of induced and spontaneous apoptosis of disseminated tumor cells in primary breast cancer patients. BMC Cancer 14:394. https://doi.org/10.1186/1471-2407-14-394
Stefanovic S, Diel I, Sinn P et al (2016) Disseminated tumor cells in the bone marrow of patients with operable primary breast cancer: prognostic impact in immunophenotypic subgroups and clinical implication for bisphosphonate treatment. Ann Surg Oncol 23:757–766. https://doi.org/10.1245/s10434-015-4895-3
Author information
Authors and Affiliations
Contributions
VPW: data collection, data analysis, manuscript writing. FAT: project development. MW: data collection. MH: data collection. SYB: Project development. ADH: data collection, data analysis, manuscript editing.
Corresponding author
Ethics declarations
Ethical standards
The experiments conducted comply with current German laws.
Conflict of interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Walter, V.P., Taran, FA., Wallwiener, M. et al. Simultaneous detection of circulating and disseminated tumor cells in primary breast cancer patients following neoadjuvant chemotherapy. Arch Gynecol Obstet 297, 785–790 (2018). https://doi.org/10.1007/s00404-018-4669-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00404-018-4669-9