Elsevier

The Lancet Oncology

Volume 13, Issue 7, July 2012, Pages 688-695
The Lancet Oncology

Articles
Circulating tumour cells in non-metastatic breast cancer: a prospective study

https://doi.org/10.1016/S1470-2045(12)70209-7Get rights and content

Summary

Background

The identification of circulating tumour cells correlate with poor prognosis in metastatic breast cancer, but there are few data describing the importance of circulating tumour cells in patients with non-metastatic disease. Our aim was to establish if circulating tumour cells predicted worse outcome in patients with non-metastatic breast cancer.

Methods

We prospectively collected data on circulating tumour cells at the time of definitive surgery from chemonaive patients with stage 1–3 breast cancer from February, 2005, to December, 2010. We deemed eligible all patients with operable breast cancer presenting at The University of Texas MD Anderson Cancer Center (Houston, TX, USA). Patients were ineligible if they had bilateral breast cancer or any other malignancy within 5 years of the diagnosis of the present cancer. We measured circulating tumour cells with the CellSearch System (Veridex, Raritan, NJ). We correlated findings of circulating tumour cells with standard tumour characteristics, including tumour size and grade; oestrogen and progesterone receptor and human epidural growth factor receptor 2 (HER2) status; and axillary lymph node status with χ2 or Fisher exact tests. We assessed outcomes at a median follow-up of 35 months. Log-rank test and Cox regression analysis was applied to establish the association of circulating tumour cells with progression-free and overall survival.

Findings

No patients reported adverse events or complications from blood collections. We identified one or more circulating tumour cells in 73 (24%) of 302 patients. Detection of one or more circulating tumour cells predicted both decreased progression-free survival (log-rank p=0·005; hazard ratio [HR] 4·62, 95% CI 1·79–11·9) and overall survival (log-rank p=0·01; HR 4·04, 1·28–12·8).

Interpretation

The presence of one or more circulating tumour cells predicted early recurrence and decreased overall survival in chemonaive patients with non-metastatic breast cancer. These results suggest that assessment of circulating tumour cells might provide important prognostic information in these patients.

Funding

Society of Surgical Oncology, Morgan Welch Inflammatory Breast Cancer Program, The University of Texas MD Anderson Cancer Center, and the State of Texas Rare and Aggressive Breast Cancer Research Program.

Introduction

Patients with breast cancer are staged on the basis of primary tumour size, regional lymph-node status, and the presence or absence of obvious distant metastatic disease at the time of initial diagnosis. Axillary lymph node status remains the best predictor of outcome in operable breast cancer. However, about 25% of patients with breast cancer with localised disease and without axillary lymph-node metastasis will develop systemic relapse after successful primary treatment, whereas almost 30% of these patients with axillary lymph-node metastasis will not relapse within 5–10 years of primary treatment.1, 2, 3 These disparate data suggest that micrometastatic haematogenous spread happens in a substantial number of patients with operable breast cancer and is independent of lymphatic involvement. In patients with breast cancer, early dissemination of tumour cells from heterogeneous breast tumours into the bloodstream is often undetectable by standard high-resolution imaging technologies, since these tumour cells are rare (as few as 1 in 1×106 cells). Only recently have advances in isolation, enrichment, and detection methods allowed clinical researchers to accurately and reproducibly detect occult tumour cells.

The number of circulating tumour cells in peripheral blood before the receipt of systemic treatment has been shown to be an independent predictor of progression-free survival and overall survival in metastatic breast cancer,4 and the identification of circulating tumour cells at any time during systemic therapy correlated with increased mortality rates in patients with metastatic disease.5 Circulating tumour cells have been reported in 10–60% of patients with stage 1–3 non-metastatic breast cancer by various types of detection assays, including density-gradient separation and cytokeratin-19 mRNA amplification,6, 7, 8 density-gradient separation and subsequent cytokeratin immunostaining,9 density gradient and immunomagnetic separation and subsequent cytokeratin immunostaining,10, 11 human epidural growth factor receptor 2 (HER2) immunostaining,12 or the CellSearch (Veridex, Raritan, NJ) method.13, 14, 15, 16, 17 With the CellSearch method, our group has previously identified circulating tumour cells in 31% of patients with T1 or T2 tumours, suggesting that occult dissemination can happen early in disease progression.18 So far, few data have been published on the prognostic importance of circulating tumour cells in early stage breast cancer.

We present a prospective study designed to establish if circulating tumour cells predict survival in patients who are chemonaive with non-metastatic breast cancer. We postulated that identification of circulating tumour cells within the blood would independently predict shorter survival, irrespective of axillary lymph node status or standard tumour markers. If the presence of circulating tumour cells were to contribute independently to the currently available prognostic factors, this information might be useful in disease staging and in identifying patients who might benefit from additional adjuvant therapies.

Section snippets

Participants

Between February, 2005, and December, 2010, we assessed chemonaive patients with stage 1–3 breast cancer undergoing surgery for their primary tumour. We deemed eligible all patients with operable breast cancer presenting at The University of Texas MD Anderson Cancer Center (Houston, TX, USA). We ruled out non-response bias by comparing differences in presenting clinical stages between participants and those who elected not to participate. Patients with bilateral breast cancer or any other

Results

We enrolled 302 patients into our study (table 1). Mean age was 54 years, and median follow-up time was 35 months (table 1). No adverse events or complications were reported from blood collections. 73 patients (24%) had one or more circulating tumour cells, 29 patients (10%) had two or more circulating tumour cells, and 16 patients (5%) had three or more circulating tumour cells per 7·5 mL of blood (table 2). No primary tumour characteristic predicted the presence of one or more circulating

Discussion

Our findings show that the presence of one or more circulating tumour cells per 7·5 mL blood is an independent predictor of relapse and death in chemonaive patients with non-metastatic breast cancer. At present, clinical practice does not use this information to make treatment decisions or to stage disease (panel). In our sample cohort, we identified that 25% of patients had at least one circulating tumour cell. Neither tumour size nor any other primary tumour characteristic reliably predicted

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