Outcome of primary-breast-cancer patients with micrometastases: a long-term follow-up study

doi:10.1016/S0140-6736(98)10175-7

The Lancet

Volume 354, Issue 9174, 17 July 1999, Pages 197-202

https://doi.org/10.1016/S0140-6736(98)10175-7 Get rights and content

Summary

Background

Bone-marrow micrometastases have been found in patients with primary breast cancer. We report long-term follow-up of women with primary breast cancer, diagnosed between 1981 and 1986, who had multiple aspirates taken at the time of initial surgery.

Methods

350 women with primary breast cancer were examined immunocytochemically with antibody to epithelial membrane antigen. We investigated associations with various prognostic factors as well as the effect of micrometastases on relapse-free survival and overall survival.

Findings

At median follow-up of 12·5 years, 151 patients had metastatic disease and 136 patients had died from breast cancer. 10-year relapse-free and overall survival were 43·9% (95% CI 33·4–54·7) and 44·9% (34·2–55·9) in patients with micrometastases, and 62·7% (56·5–68·6) and 65·7% (59·4–71·5) in patients without micrometastases at presentation (p=0·001). For relapse-free survival and overall survival, allowing for tumour size, lymph-node status, and vascular invasion, the effect of micrometastases decreased and was no longer significant, with a hazard ratio of 1·09 (0·74–1·61) for relapse-free survival and 1·21 (0·84–1·75) for overall survival.

Interpretation

The presence of bone-marrow micrometastases in patients with primary breast cancer is associated with a shorter relapse-free survival and overall survival, but is not an independent prognostic factor. This immunocytochemical technique may be of value in patients for whom pathological tumour size and lymph-node status are unavailable (ie, patients receiving primary medical treatment).

Introduction

Most women who present with primary breast cancer eventually relapse or die of their disease. The search continues for prognostic factors that will accurately predict which patients require adjuvant therapy to try to prevent or delay recurrent disease. Interest was generated when micrometastases in bone marrow were first identified in patients with breast cancer by use of immunocytochemical techniques.1, 2 Several studies were set up to identify these cells in large cohorts of women with primary breast cancer throughout Europe and USA to replicate the findings,3, 4, 5, 6, 7 and to assess their clinical importance.8, 9, 10, 11, 12, 13, 14, 15

The presence of micrometastases was associated with poor prognostic factors such as involvement of lymph nodes and large tumour size,³ and early results suggested that patients who had micrometastases were at increased risk of recurrent disease, especially in bone.⁸ Other studies showed similar results for different antibodies.10, 11, 12, 13 The relation between the development of bone metastases and detection of tumour cells in the bone marrow was not consistent, and some investigators suggested that the site of relapse was not specific.11, 12, 14, 15 Likewise, the presence of micrometastases was significantly associated with early recurrence: Cote and colleagues¹³ reported estimated 2-year recurrence rates of 3% and 33% for 49 patients without and with micrometastases, respectively, after a median follow-up of 33 months. Harbeck and colleagues¹⁶ reported a series of 100 patients (median follow-up 34 months) in which 15% and 39% of patients without and with micrometastases relapsed. They found no significant correlation between the presence of micrometastases and other prognostic factors.

A larger series included 727 patients, of whom 313 (43·3%) had micrometastases at presentation.¹⁵ The presence of micrometastases was strongly associated with poor prognostic factors, and after a median follow-up of 36 months was an independent factor associated with decreased disease-free and overall survival.

We report updated findings of women with primary breast cancer who had bone marrow analysed at the time of surgery, at a median follow-up of 12·5 years.

Section snippets

Patients

Between July, 1981, and August, 1986, 380 consecutive women with primary breast cancer presenting to the breast units of St George's, the Royal Marsden, and St Helier Hospitals in London, UK, had multiple marrow aspirates taken under general anaesthetic just before initial surgery. Each patient provided written informed consent and was screened for metastatic disease by clinical examination, measurement of plasma alkaline-phosphatase and γ-glutamyltransferase activity, chest radiography,

Results

Bone-marrow micrometastases were found in 89 (25%) of 350 patients with primary breast cancer at the time of initial surgery. The presence of micrometastases was related to increasing tumour size, presence of involved lymph nodes, and presence of vascular invasion, but not to oestrogen status or menopausal status (table 1). Follow-up information on patients 10–15 years after presentation is given (theoretical median follow-up 152 months [range 111–191]). For patients who remained alive, the

Discussion

Identification of women who are at high risk of relapse after complete excision of the primary breast cancer is the main aim after surgery. The detection of circulating tumour cells in the bone marrow at the time of surgery showed early promise of a method to distinguish more effectively women who could be separated into high-risk and low-risk categories.

In our previous study¹⁴ (median follow-up 6 years) we found that presence of bone-marrow micrometastases predicted a poorer outlook than for

References (26)

JL Mansi et al.
Bone marrow micrometastases in primary breast cancer: prognostic significance after 6 years follow-up
Eur J Cancer
(1991)
P Thomas et al.
Keratins versus epithelial membrane antigen in tumor diagnosis: an immunohistochemical comparison of five monoclonal antibodies
Hum Pathol
(1987)
GS Pinkus et al.
Epithelial membrane antigen: a diagnostic discriminant in surgical pathology: immuno-histochemical profile in epithelial, mesenchymal, and hematopoietic neoplasms using paraffin sections and monoclonal antibodies
Hum Pathol
(1985)
JL Mansi et al.
Detection of tumour cells in bone marrow of patients with prostatic carcinoma by immunocytochemical techniques
J Urol
(1988)
F Lindemann et al.
Prognostic significance of micrometastatic tumour cells in bone marrow of colorectal cancer patients
Lancet
(1992)
DP Dearnaley et al.
Increased detection of mammary carcinoma cells in marrow smears using antisera to epithelial membrane antigen
Br J Cancer
(1981)
DP Dearnaley et al.
Detection of isolated mammary carcinoma cells in marrow of patients with primary breast cancer
J R Soc Med
(1983)
WH Redding et al.
Detection of micrometastases in patients with primary breast cancer
Lancet
(1983)
G Porro et al.
Monoclonal antibody detection of carcinoma cells in bone marrow biopsy specimens from breast cancer patients
Cancer
(1988)
A Thor et al.
Comparison of monoclonal antibodies for the detection of occult breast carcinoma metastases in bone marrow
Breast Cancer Res Treat
(1988)

RJ Cote et al.

Monoclonal antibodies detect occult breast carcinoma metastases in bone marrow of patients with early stage disease

Am J Surg Pathol

(1988)

G Ellis et al.

Monoclonal antibodies for the detection of occult carcinoma cells in bone marrow of breast cancer patients

Cancer

(1989)

JL Mansi et al.

Micrometastases in bone marrow in patients with primary breast cancer: evaluation as an early predictor of bone metastases

BMJ

(1987)

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ArticlesOutcome of primary-breast-cancer patients with micrometastases: a long-term follow-up study

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Patients

Results

Discussion

Eur J Cancer

Hum Pathol

Hum Pathol

J Urol

Lancet

Increased detection of mammary carcinoma cells in marrow smears using antisera to epithelial membrane antigen

Br J Cancer

Detection of isolated mammary carcinoma cells in marrow of patients with primary breast cancer

J R Soc Med

Detection of micrometastases in patients with primary breast cancer

Lancet

Monoclonal antibody detection of carcinoma cells in bone marrow biopsy specimens from breast cancer patients

Cancer

Comparison of monoclonal antibodies for the detection of occult breast carcinoma metastases in bone marrow

Breast Cancer Res Treat

Monoclonal antibodies detect occult breast carcinoma metastases in bone marrow of patients with early stage disease

Am J Surg Pathol

Monoclonal antibodies for the detection of occult carcinoma cells in bone marrow of breast cancer patients

Cancer

Micrometastases in bone marrow in patients with primary breast cancer: evaluation as an early predictor of bone metastases

BMJ

Articles
Outcome of primary-breast-cancer patients with micrometastases: a long-term follow-up study