The persistence of isolated tumor cells in bone marrow from patients with breast carcinoma predicts an increased risk for recurrence

Abstract

BACKGROUNDThe prognostic significance of isolated tumor cells (ITCs) in bone marrow (BM) from patients with breast carcinoma at the time of their primary diagnosis recently was been confirmed by a large pooled analysis. If the persistence of ITCs after adjuvant therapy confers a similar risk for recurrence, then it would be an indication to consider secondary adjuvant therapy.METHODSThe authors analyzed BM aspirates from 228 patients during recurrence‐free follow‐up at a median interval ± standard deviation (SD) of 21.3 ± 29.1 months after a primary diagnosis of breast carcinoma (pathologic T1 [pT1]–pT2, pN0–pN3, pM0). Carcinoma cells were detected using a standardized immunoassay with monoclonal antibody A45‐B/B3 directed against cytokeratin (CK). Patients were followed for a median ± SD of 49.8 ± 32.1 months after their primary diagnosis.RESULTSPersistent ITCs in BM were detected in 12.7% of patients (n = 29 patients). Positive BM status was more frequent (15.7%) within the first 21 months after primary diagnosis than after a follow‐up > 21 months (9.7%). The Kaplan–Meier estimate for mean recurrence‐free survival was 149.7 months (95% confidence interval [95% CI], 139.6–159.8 months) in patients with negative BM status and 86.5 months (95% CI, 65.7–107.4 months; P = 0.0003) in patients with positive BM status at the time patients underwent follow‐up BM aspiration. Patients who were without evidence of persistent ITCs had a significantly longer overall survival (162.1 months; 95% CI, 152.1–172.0 months) compared with patients who had positive BM status (overall survival, 98.7 months; 95% CI, 79.7–117.9 months; P = 0.0008). In multivariate Cox regression analysis that included BM status, tumor size, lymph node status, and histopathologic grade, evidence of ITCs was an independent significant predictor for reduced disease‐free survival (relative risk [RR], 4.57; P < 0.0001) and overall survival (RR, 5.57; P = 0.002). Persistent ITCs had the greatest prognostic relevance when they were detected between 25 months and 42 months after primary diagnosis (RR, 7.68).CONCLUSIONSEvidence of persistent ITCs in BM from patients with breast carcinoma indicated an increased risk for subsequent recurrence. Prospective trials should investigate the benefit of secondary adjuvant treatment on the basis of BM marrow status. Cancer 2005. © 2005 American Cancer Society.

EpCAM (CD326) finding its role in cancer

“…Numerous studies have shown that the occurrence and number of CK þ DTC in bone marrow of various cancers correlates with a poor survival prognosis of patients Janni et al, 2005;Pantel and Woelfle, 2005). A proportion of DTC in bone marrow is also positive for EpCAM and their depletion in breast cancer patients has been demonstrated by anti-EpCAM monoclonal antibody edrecolomab.…”

A concept for the standardized detection of disseminated tumor cells in bone marrow from patients with primary breast cancer and its clinical implementation

“…26 Repeated bone marrow aspiration performed under local anesthesia also can be performed to obtain information regarding the persistence of DTCs. [18][19][20][21] Bone marrow aspirate is then transferred into heparinized tubes. 10,[13][14][15]18,23,24,27 Ethylenediamine tetraacetic acid 24 or sodium citrate 28 also may be used as anticoagulant.…”

“…[19][20][21] Patients with high-risk breast cancer (>3 involved axillary lymph nodes or extensive invasion of cutaneous lymph vessels) who were receiving standard taxane or anthracycline-containing chemotherapy were monitored by bone marrow analy- A bone marrow sample of 5 mL to 10 mL should be aspirated from anterior and/or posterior iliac crests and collected in tubes containing either heparin or ethylenediamine tetraacetic acid 2. Storage within the range from þ48C to þ208C until further processing of the samples, preferably within 24 hours 3.…”

“…16 Numerous studies (Table 1) have now demonstrated that the detection of DTCs in bone marrow is associated with a poor prognosis, a finding that recently was confirmed in a pooled analysis study of >4700 patients with Stage I, II, or III breast cancer. 17 Beyond the conclusive data on the prognostic relevance of the presence of DTCs at the time of diagnosis, monitoring of therapeutic efficacy and assessment of residual risk during event-free followup [18][19][20][21] represent a promising option for the clinical utility of DTC detection. Acceptable standards for DTC detection need to be defined to allow prospective clinical trials.…”

Detection of human mammaglobin mRNA in serial peripheral blood samples from patients with non-metastatic breast cancer is not predictive of disease recurrence

“…The detection of circulating tumour cells has been reported by several groups in patients with localised [3][4][5][6] and metastatic [7] breast cancer. Circulating tumour cells may lead to the development of metastases and their detection in the peripheral blood of breast cancer patients may thus impact on patient's prognosis [8].…”