Abstract
Introduction Circulating tumor cells (CTCs) correlate with worse prognosis in patients with metastatic breast cancer, but there are little data on CTCs in operable patients. We hypothesized that primary tumor characteristics would predict the likelihood of identifying CTCs in patients with operable breast cancer. Methods Clinical and pathological data from 92 patients with operable breast cancer were collected. The CellSearch system was used to detect CTCs in 30 ml of peripheral blood. CTCs were defined as nucleated cells lacking CD45 but expressing cytokeratins 8, 18, or 19. Univariate analysis was performed to determine if the presence of any primary tumor characteristic was predictive of CTCs. As a secondary objective we evaluated if nodal or bone marrow status was predictive of CTCs. Results Thirty-eight percent of patients (35/92) had evidence of CTCs, with a median number of 1.0 CTC per CTC positive patient (range 1–22). HER2 status was the sole primary tumor characteristic that reliably predicted the presence of CTCs (P = 0.01, risk ratio = 3.66). No significant association was found between the presence of CTCs and tumor size (T), estrogen receptor (ER) status, progesterone receptor (PR) status, grade, histologic type, degree of nodal involvement (N), lymphovascular invasion (LVI) or Ki-67 proliferation. Bone marrow micrometastases were found in 17/64 (26.6%) of the patients but did not correlate with the presence of CTCs. Conclusion HER2 status was the only primary tumor characteristic that correlated with the presence of CTCs. Long-term follow-up will be required to determine the significance of CTCs in operable breast cancer.
Similar content being viewed by others
References
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
Lang JE, Hall CS, Singh B et al (2007) Significance of micrometastasis in bone marrow and blood of operable breast cancer patients: research tool or clinical application? Expert Rev Anticancer Ther 7:1463–1472
Wulfing P, Borchard J, Buerger H et al (2006) HER2-positive circulating tumor cells indicate poor clinical outcome in stage I to III breast cancer patients. Clin Cancer Res 12:1715–1720
Pierga JY, Bonneton C, Vincent-Salomon A et al (2004) Clinical significance of immunocytochemical detection of tumor cells using digital microscopy in peripheral blood and bone marrow of breast cancer patients. Clinical Cancer Research 10:1392–1400
Meng S, Tripathy D, Shete S et al (2004) HER-2 gene amplification can be acquired as breast cancer progresses. Proc Natl Acad Sci USA 101:9393–9398
Xenidis N, Perraki M, Kafousi M et al (2006) Predictive and prognostic value of peripheral blood cytokeratin-19 mRNA-positive cells detected by real-time polymerase chain reaction in node-negative breast cancer patients. J Clin Oncol 24:3756–3762
Zach O, Kasparu H, Wagner H et al (2002) Prognostic value of tumour cell detection in peripheral blood of breast cancer patients. Acta Med Austriaca Suppl 59:32–34
Gaforio JJ, Serrano MJ, Sanchez-Rovira P et al (2003) Detection of breast cancer cells in the peripheral blood is positively correlated with estrogen-receptor status and predicts for poor prognosis. Int J Cancer 107:984–990
Stathopoulos EN, Sanidas E, Kafousi M et al (2005) Detection of CK-19 mRNA-positive cells in the peripheral blood of breast cancer patients with histologically and immunohistochemically negative axillary lymph nodes. Ann Oncol 16:240–246
Benoy IH, Elst H, Philips M et al (2006) Real-time RT-PCR detection of disseminated tumour cells in bone marrow has superior prognostic significance in comparison with circulating tumour cells in patients with breast cancer. Br J Cancer 94:672–680
Naume B, Borgen E, Beiske K et al (1997) Immunomagnetic techniques for the enrichment and detection of isolated breast carcinoma cells in bone marrow and peripheral blood. J Hematother 6:103–114
Racila E, Euhus D, Weiss AJ et al (1998) Detection and characterization of carcinoma cells in the blood. Proc Natl Acad Sci U S A 95:4589–4594
Zhou L, Wang K, Tan W et al (2006) Quantitative intracellular molecular profiling using a one-dimensional flow system. Analytical chemistry 78:6246–6251
Ring A, Smith IE, Dowsett M (2004) Circulating tumour cells in breast cancer. Lancet Oncol 5:79–88
Cristofanilli M, Budd GT, Ellis MJ et al (2004) Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 351:781–791
Tibbe AG, Miller MC, Terstappen LW (2007) Statistical considerations for enumeration of circulating tumor cells. Cytometry A 71:154–162
Allard WJ, Matera J, Miller MC et al (2004) Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res 10:6897–6904
Riethdorf S, Fritsche H, Muller V et al (2007) Detection of circulating tumor cells in peripheral blood of patients with metastatic breast cancer: a validation study of the CellSearch system. Clin Cancer Res 13:920–928
Rack B, Schindlbeck C, Janni W et al (2006) Incidence of circulating tumor cells (CTCs) in peripheral blood of breast cancer patients at primary diagnosis—a potential tool for risk stratification, ASCO Annual Meeting (J Clin Oncol (ed) (2006) 2006 ASCO Annual Meeting Proceedings Part I 24(18S: June 20 Supplement):20053)
Rack B, Schindlbeck C, Hofmann S et al (2007) Circulating tumor cells (CTCs) in peripheral blood of primary breast cancer patients, ASCO Annual Meeting. J Clin Oncol (2007) 2007 ASCO Annual Meeting Proceedings Part I 25(18S: June 20 Supplement):10595
Nimeus-Malmstrom E, Ritz C, Eden P et al (2006) Gene expression profilers and conventional clinical markers to predict distant recurrences for premenopausal breast cancer patients after adjuvant chemotherapy. Eur J Cancer 42:2729–2737
Pantel K, Schlimok G, Braun S et al (1993) Differential expression of proliferation-associated molecules in individual micrometastatic carcinoma cells. J Natl Cancer Inst 85:1419–1424
Smith I, Procter M, D Gelber R et al (2007) 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 369:29–36
Alvarado M, Brissaud C, Scott J et al (2007) Disseminated tumor cells correlate with estrogen receptor positivity in operable breast cancer patients. San Antonio Breast Cancer Symposium
Meng S, Tripathy D, Shete S et al (2006) uPAR and HER-2 gene status in individual breast cancer cells from blood and tissues. Proc Natl Acad Sci USA 103:17361–17365
Ignatiadis M, Xenidis N, Perraki M et al (2007) Different prognostic value of cytokeratin-19 mRNA positive circulating tumor cells according to estrogen receptor and HER2 status in early-stage breast cancer. J Clin Oncol 25:5194–5202
Hayes DF, Walker TM, Singh B et al (2002) Monitoring expression of HER-2 on circulating epithelial cells in patients with advanced breast cancer. Int J Oncol 21:1111–1117
McShane LM, Altman DG, Sauerbrei W et al (2005) Reporting recommendations for tumor marker prognostic studies (REMARK). J Natl Cancer Inst 97:1180–1184
Cristofanilli M, Broglio KR, Guarneri V et al (2007) Circulating tumor cells in metastatic breast cancer: biologic staging beyond tumor burden. Clin Breast Cancer 7:471–479
Acknowledgements
Grant support: DAMD17-03-1-0669 (A. Lucci) and NIH grant R21-DK067682 (A. Lucci).
Author information
Authors and Affiliations
Corresponding author
Additional information
Presented in part at the 2007 Society of Surgical Oncology Cancer Symposium.
Rights and permissions
About this article
Cite this article
Lang, J.E., Mosalpuria, K., Cristofanilli, M. et al. HER2 status predicts the presence of circulating tumor cells in patients with operable breast cancer. Breast Cancer Res Treat 113, 501–507 (2009). https://doi.org/10.1007/s10549-008-9951-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10549-008-9951-2