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Purpose: Presence of disseminated tumour cells (DTCs) in the bone marrow (BM) has been described as a surrogate of residual disease in patients with early breast cancer (EBC). PADDY (Pooled Analysis of DTC Detection in Early Breast Cancer) is a large international analysis of pooled data that aimed to assess the prognostic impact of DTCs in patients with EBC., Experimental Design: Individual patient data were collected from 11 centres. Patients with EBC and available follow-up data in whom BM sampling was performed at the time of primary diagnosis before receiving any anticancer treatment were eligible. DTCs were identified by antibody staining against epithelial cytokeratins. Multivariate Cox regression was used to compare the survival of DTC-positive versus DTC-negative patients., Results: In total, 10,307 patients were included. Of these, 2814 (27.3%) were DTC-positive. DTC detection was associated with higher tumour grade, larger tumour size, nodal positivity, oestrogen receptor and progesterone receptor negativity, and HER2 positivity (all p < 0.001). Multivariate analyses showed that DTC detection was an independent prognostic marker for overall survival, disease-free survival and distant disease-free survival with hazard ratios (HR) and 95% confidence intervals (CI) of 1.23 (95% CI: 1.06-1.43, p = 0.006), 1.30 (95% CI: 1.12-1.52, p < 0.001) and 1.30 (95% CI: 1.08-1.56, p = 0.006), respectively. There was no association between locoregional relapse-free survival and DTC detection (HR 1.21; 95% CI 0.68-2.16; p = 0.512)., Conclusions: DTCs in the BM represent an independent prognostic marker in patients with EBC. The heterogeneous metastasis-initiating potential of DTCs is consistent with the concept of cancer dormancy., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ADH, FAT and SYB report a grant from Exact Sciences. TNF received personal fees from AstraZeneca, Novartis, Roche, Pfizer, Esai, Tesaro, Teva, Celgene, Daichi Sankyo, MSD, Menarini. PAF reports grants from Cepheid, Novartis and Biontech, personal fees from Novartis, Roche, Pfizer, Celgene, Daiichi-Sankyo, TEVA, Astra Zeneca, Merck Sharp & Dohme, Myelo Therapeutics, Macrogenics, Eisai, Puma and Lilly. CAK is a member of the SAB of HiberCell, New York. All other authors declare no potential conflicts of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background/aim: By definition, tumor cells do not pass the epithelial basement membrane in pre-invasive lesions. However, recently, it was shown that hematogenous tumor cell dissemination already takes place in patients with ductal carcinoma in situ (DCIS), giving disseminated tumor cells (DTCs) in the bone marrow the opportunity to interact with the peripheral immune system. We, therefore, investigated the relationship between DTCs and the peripheral innate and adaptive immune system of DCIS patients, as immunosurveillance might also be impaired in pre-invasive lesions., Materials and Methods: We analyzed the peripheral immune status of 115 DCIS patients by flow cytometry. Results were correlated with presence of DTCs, that were detected in the bone marrow by immunocytochemistry (pan-cytokeratin antibody A45-B/B3) using the automated cellular imaging system (ACIS) according to the international society of hematotherapy and graft engineering (ISHAGE) evaluation criteria. Apoptotic DTCs were characterized by positive M30 staining and cytomorphological criteria., Results: In contrast to breast cancer, we found no significant correlation between appearance of DTCs and quantitative distribution of T-cell sub-populations, B and NK-cells neither in the bone marrow nor in the peripheral blood. Moreover, DTCs did not affect the expression of important immunomodulatory antigens for functional integrity of specific immune response such as, TCR-ζ, CD28 or CD95. Interestingly, 39% of DTCs were positive for M30 expression and showed cytomorphological signs of apoptosis., Conclusion: In contrast to breast cancer, DTCs of DCIS seem to be less immunogenic, which might result in a diverging way to evade immunosurveillance., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Disseminated tumor cells (DTC) can be detected in a high proportion of patients with localized solid malignancies. In prostate cancer (PC), determination of DTCs is critically discussed as there are conflicting results on their prognostic value. The aim of the present study was to evaluate the presence and prognostic role of DTCs in PC patients with a high risk of disease recurrence., Methods: 248 patients with clinically localized PC undergoing radical prostatectomy with features of increased risk of recurrence (PSA ≥10 ng/ml or Gleason score ≥ 4 + 3 = 7 or pT ≥3) were included. All patients underwent intraoperative bone marrow (BM) aspiration biopsy. BM cells were evaluated by immunocytochemistry for cytokeratines and the apoptosis marker caspase-cleaved cytokeratin 18 (M30). Results of immunocytochemistry were correlated with clinical and pathological parameters and clinical outcome of the patients., Results: Of 248 patients, 47 (19.0%) had evidence of DTCs at time of radical prostatectomy. In 17 of these 47 patients (36.2%), DTCs expressed the apoptosis marker M30. We observed no correlation between the presence of DTCs and tumor stage, nodal stage, prostate-specific antigen, or Gleason score. After a median-follow-up of 58 months (23-76), no differences in rates of biochemical recurrence, development of metastases and cancer-specific death were observed between patients with and without DTCs while apoptosis markers had no role., Conclusions: In a single-centre cohort of patients with increased risk for disease recurrence, the presence of DTCs at the time of prostatectomy does not influence clinical outcome. For the first time in patients with PC, DTCs were evaluated for immunocytological features indicating apoptosis. Due to conflicting results of studies on DTCs, BM biopsies at time of radical prostatectomy cannot be recommended as a standard procedure in patients with clinically localized PC., (© 2015 Wiley Periodicals, Inc.)

Background: This is the largest single-centre study to determine the prognostic relevance of disseminated tumour cells (DTCs) from the bone marrow (BM) of stage I-III breast cancer patients. Additionally, we aimed to analyse the impact of DTC detection on adjuvant bisphosphonate (BP) treatment efficacy., Methods: BM aspirates were collected during primary surgery for early breast cancer (EBC; T1-4, N0-2, M0) at Tuebingen University, Germany, between January 2001 and January 2013. DTCs were identified by immunocytochemistry (pancytokeratin antibody A45/B-B3) and cytomorphology. We retrospectively estimated the influence of DTC detection and BP treatment on disease-free survival (DFS) and overall survival (OS) using univariate (log-rank test) and multivariate (cox regression) analysis., Findings: BM aspirates were available from 3141 patients. In 803 (26%) of these, DTCs were detectable. As compared to DTC-negative patients, DTC-positive patients more frequently had larger tumors (p<0.001), lymph node involvement (p<0.001), hormonal receptor positive tumours (p<0.001) and HER2-positive tumours (p=0.048). DTC-positive patients were at an increased risk of relapse (hazard ratio (HR) 1.74, 95% confidence interval (CI) 1.34-2.25, p<0.001) and death (HR 1.44 95% CI 1.13-1.86, p=0.004). In the multivariate analysis DTCs were an independent predictor of DSF and OS. Additionally, BP treatment had no significant influence on DFS or OS in DTC-negative patients, while it was significantly associated with increased DFS (p<0.001) and OS (p=0.006) in DTC-positive patients., Interpretation: These data confirm the clinical validity of DTCs from the BM for prognostication of early breast cancer patients. Further studies are warranted to determine whether DTCs are predictive for adjuvant treatment efficacy using bisphosphonates., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The presence of disseminated tumor cells (DTC) in the bone marrow (BM) of early breast cancer patients at initial surgery as well as during follow-up predicts an unfavorable outcome. This study aimed to assess whether adjuvant systemic therapy has the ability to eradicate DTC and to determine the clinical impact of DTC-persistence. Between 12 and 24 months after an initial BM aspiration during primary surgery (BMA1) a second and third bone marrow aspiration (BMA2 and BMA3, respectively) was performed. DTC were identified by immunocytochemistry (pancytokeratin antibody A45-B/B3) and cytomorphology. A total of 190 patients who were DTC-positive at BMA1 were eligible for this retrospective analysis. DTC persisted in 35 of 190 (19 %) patients at BMA2 and in 11 of 71 (16 %) patients at BMA3. DTC-persistence at BMA3 was significantly lower in patients that received adjuvant endocrine therapy (p = 0.017). At BMA2, DTC-positive patients were at an increased risk of disease recurrence (HR: 4.17, 95 % CI: 1.51-11.50, p = 0.003) and death (HR: 5.02, 95 % CI: 1.156-21.83, p = 0.031). At BMA3, the presence of DTC was associated with shorter disease free survival (HR: 3.20, 95 % CI: 1.05-9.78, p = 0.010). In conclusion, a majority of initially DTC-positive primary breast cancer patients turned negative during adjuvant treatment. As DTC-persistence predicted an adverse outcome, serial DTC-determination can identify patients that will probably benefit from additional or a switch of adjuvant therapy.

Background: The presence of disseminated tumor cells (DTC) in bone marrow (BM) of breast cancer patients is associated with reduced clinical outcome. Bisphosphonate treatment was shown to eradicate DTC from BM in several studies. This controlled randomized open-label multi-center study aimed to investigate the influence of zoledronic acid (ZOL) on DTC and survival of breast cancer patients (Clinical Trial Registration Number: NCT00172068)., Methods: Patients with primary breast cancer and DTC-positive bone marrow were randomized to treatment with ZOL plus adjuvant systemic therapy (n = 40) or adjuvant systemic therapy alone (n = 46) between 03/2002 and 12/2004. DTC were identified by immunocytochemistry using the pancytokeratin antibody A45B/B3 and by cytomorphology. The change in DTC numbers at 12 months and 24 months versus baseline, as well as patient outcomes were evaluated., Results: 86 patients could be included into survival analysis (median follow-up: 88 months, range: 8-108 mths). Patients in the control group were more likely to die during follow-up than those in the ZOL-group (11% vs. 2%, p = 0.106). 15% of patients in the control group presented with relapse whereas only 8% of ZOL group patients developed metastatic or recurrent disease during follow-up (p = 0.205). At 24 months, 16% of patients from the control group were still DTC positive, whereas all patients treated with ZOL became DTC negative (p = 0.032). Patients presenting with persistent DTC 12 months after diagnosis had significantly shorter overall survival (p = 0.011)., Conclusions: Bisphosphonate therapy contributes to eradication of disseminated tumor cells. The positive influence of bisphosphonates on survival in the adjuvant setting may be due to their effects on DTC., Trial Registration: ClinicalTrials.gov Identifier: NCT00172068 [Zoledronic Acid in the Treatment of Breast Cancer With Minimal Residual Disease in the Bone Marrow (MRD-1)].

Overexpression of the HER2-receptor in early breast cancer (EBC) patients is associated with aggressive tumor behavior. However, women suffering from HER2-positive EBC benefit from trastuzumab treatment. As the HER2 status of the primary tumor may differ from that of disseminated tumor cells (DTC) in bone marrow (BM), the aim of this study was (1) to compare the HER2 status of the primary tumor (prim-HER2-status) with that of DTC (DTC-HER2-status) and (2) to analyze the influence of the DTC-HER2-status on patient survival. For this purpose, BM aspirates from 569 EBC patients were analyzed for the presence of DTC. The DTC-HER2-status was identified by a double-staining procedure against cytokeratin and the HER2-receptor. DTC were detected in 151 (27 %) patients. The concordance between the HER2 status of DTC and the primary tumor was 51 %. In patients with detectable DTC, mean disease-free survival was 77.44 (95 % CI 74.72-80.17) months for DTC-HER2-negative and 55.15 (95 % CI 48.57-61.79) months for DTC-HER2-positive patients (p = 0.044). The multivariate analysis showed that the DTC-HER2-status was an independent predictor of disease-free survival. In conclusion, the presence of HER2-positive DTC in EBC patients is associated with an increased risk of relapse. Due to the low concordance between the HER2 status of the primary tumor and DTC, only a minority (13 %) of the DTC-HER2-positive patients was treated with trastuzumab. These patients might, however, benefit from HER2-directed therapy.

Introduction: Neoadjuvant systemic therapy of primary breast cancer (PBC) patients offers the possibility to monitor treatment response. However, patients might have metastatic relapse despite achieving a pathologic complete response (pCR). This indicates that local response to therapy must not be representative for systemic treatment efficacy. Therefore, the aim of this study was to compare local response with systemic tumor cell dissemination by determining the presence of disseminated tumor cells (DTCs), including apoptotic tumor cells, in the bone marrow (BM) of PBC patients after neoadjuvant chemotherapy (NACT)., Methods: DTCs were detected by immunocytochemistry (pancytokeratin antibody A45-B/B3) and cytomorphology (DTC status). The presence of apoptotic tumor cells was determined by using the M30 antibody (M30 status). This antibody detects a neo-epitope that is expressed only during early apoptosis., Results: BM aspirates from 400 PBC patients that had completed NACT were eligible for this study. Of these, 167 (42%) patients were DTC positive (DTC status). The M30 status was investigated in 308 patients. Apoptotic (M30-positive) tumor cells were detected in 89 (29%) of these. Whereas the DTC status was not correlated (P = 0.557) to local treatment response (that is, pCR or a clinical complete/partial response), the presence of M30-positive tumor cells was significantly higher in patients that responded to therapy (P = 0.026). Additionally, DTC-positive patients were at an increased risk for disease relapse (hazard ratio, 1.87; 95% CI, 1.11 to 3.15; P = 0.019)., Conclusion: The presence of DTC is independent of therapy response of the primary tumor. As patients that are DTC positive after NACT have an unfavorable outcome, they might benefit from additional systemic treatment.

Objectives: Numerous studies have shown that the presence of clinically occult disseminated tumor cells (DTC) in the bone marrow (BM) of breast cancer patients is associated with an unfavourable clinical outcome. Immunocytochemistry (ICC) remains the gold standard for their detection. Assays based on RT-PCR are available; however so far they have not been used for routine detection of DTC. Therefore, the purpose of this study was to evaluate a newly established molecular method for the detection of DTC., Materials and Methods: BM aspirates from 405 patients were examined. Half of the samples were immediately inserted into ICC and the other half was examined with our newly established molecular method based on RT-PCR. Immunocytochemistry was performed according to the Consensus Recommendations of the German, Austrian, and Swiss Societies of Senology and ISHAGE Working Group (A45B-B3 antibody). RT-PCR was conducted as a one-step real-time assay Cytokeratin 19-mRNA was amplified., Results: In 142 of 405 (35%) aspirates disseminated tumor cells were detected by RT-PCR. In 34% of patients DTC were detected by ICC. 48% of the BM samples were positive by at least one method. In 73% of the patients identical results were obtained (p<0,001)., Conclusion: Our newly established molecular assay for the detection of disseminated tumor cells, and thus minimal residual disease, is sensitive, fast and reproducible, and has a potential to be used as a confirmatory or alternative test for DTC detection.

Introduction: The presence of disseminated tumor cells (DTC) in the bone marrow (BM) of breast cancer patients is associated with poor prognosis. Several studies demonstrated that tumor cell dissemination may occur in gynecologic cancer and affect clinical outcome. The aim of our study was to evaluate the incidence of DTC and to assess their prognostic significance in patients with gynecologic malignancies., Methods: Bone marrow aspirates from 377 patients with primary ovarian (112), endometrial (141), cervical (102), and vulvar cancer (22) undergoing surgery at the Department of Gynecology and Obstetrics, University Hospital, Tuebingen, Germany between November 2001 and November 2007, were included into the study. Disseminated tumor cells were identified by immunocytochemistry using the pancytokeratin antibody A45B/B3 and by cytomorphology., Results: Disseminated tumor cells were detected in 19% of BM aspirates from patients with gynecological malignancies. Incidences of DTC in ovarian, endometrial, cervical, and vulvar cancer were 25%, 16%, 19%, and 5%, respectively. For patients with ovarian and endometrial cancer, no correlation with established clinicopathological factors was observed. In case of cervical cancer, BM positivity was correlated with International Federation of Gynecology and Obstetrics stage, tumor size, and nodal involvement. Bone marrow positivity of ovarian cancer patients was correlated with significantly shorter disease-free survival (P = 0.035). For other tumor entities, no association between BM status and clinical outcome could be observed., Conclusions: We conclude that up to 25% of patients with loco-regionally restricted gynecologic malignancies present with DTC at the time of diagnosis. For ovarian cancer patients, BM status affected clinical outcome.

Introduction: The role of circulating tumor cells (CTCs) in blood of primary breast cancer patients is still under investigation. We evaluated the incidence of CTCs in blood, we evaluated the correlation between CTCs and disseminated tumor cells (DTCs) in the bone marrow (BM), and we characterized CTCs for the expression of HER2, the estrogen receptor (ER) and the progesterone receptor (PR)., Methods: Blood of 431 patients with primary breast cancer were analyzed for EpCAM, MUC1 and HER2 transcripts with the AdnaTest BreastCancer (AdnaGen AG, Germany). Expression of the ER and PR was assessed in an additional RT-PCR. BM aspirates from 414 patients were analyzed for DTCs by immunocytochemistry using the pan-cytokeratin antibody A45-B/B3., Results: DTCs were found in 107/414 patients (24%), CTCs were detected in 58/431 (13%) patients. DTCs were associated with PR status of the primary tumor (P = 0.04) and CTCs significantly correlated with nodal status (P = 0.04), ER (P = 0.05), and PR (P = 0.01). DTCs in the BM weakly correlated with CTCs (P = 0.05) in blood. Interestingly, the spread of CTCs was mostly found in triple-negative tumors (P = 0.01) and CTCs in general were mostly found to be triple-negative regardless of the ER, PR and HER2 status of the primary tumor., Conclusions: (1) Due to the weak concordance between CTCs and DTCs the clinical relevance may be different. (2) The biology of the primary tumor seems to direct the spread of CTCs. (3) Since the expression profile between CTCs and the primary tumor differs, the consequence for the selection of adjuvant treatment has to be evaluated.

Introduction: Isolated disseminated tumour cells (DTC) are regarded as surrogate markers for minimal residual disease in breast cancer. Characterisation of these cells could help understand the known limitations of adjuvant therapy. Of particular interest is their oestrogen-receptor (ER) status because endocrine adjuvant therapy remains a cornerstone of breast cancer treatment., Methods: Bone marrow (BM) aspirates from 254 patients with primary breast cancer were included in this study. A double immunofluorescence staining procedure was established for the identification of cytokeratin (CK) positive/Eralpha-positive cells. ERalpha status of the primary tumour was assessed immunohistochemically using the same antibody against ERalpha., Results: In 107 of 254 (42%) breast cancer patients, CK-positive cells could be detected in the BM. More than one DTC in the BM was observed in 38 of the 107 patients. The number of detected cells ranged between 1 and 55 cells per 2 x 10(6) mononuclear cells. DTCs demonstrated ERalpha positivity in 12% of the patients. The ERalpha expression was heterogeneous in 10 of the 38 (26%) patients with more than one DTC. The concordance rate of ERalpha status between primary tumour and DTC was 28%. Only 12 of 88 patients with ERalpha-positive tumours also had ERalpha-positive DTCs., Conclusions: Primary tumours and DTCs displayed a concordant ERalpha status in only 28% of cases. Most of the DTCs were ERalpha negative despite the presence of an ERalpha-positive primary tumour. These findings further underline the distinct nature of DTCs and may explain the failure rates seen in conventional endocrine adjuvant therapy.

Introduction: The presence of disseminated tumor cells in the bone marrow of breast cancer patients has proven to be an independent prognostic factor. The aim of this study was to investigate the status of tumor cell dissemination after primary systemic therapy in relation to therapy response., Methods: Bone marrow aspirates were obtained from 120 patients after completion of primary systemic therapy. Disseminated tumor cells were detected by immunocytochemistry using the APAAP method. Bone marrow status was correlated with clinicopathological factors as well as tumor response to primary systemic therapy., Results: Sixty out of 120 patients had disseminated tumor cells in their bone marrow aspirates (50%). Response rates were 18% for pathologic complete remission, 52% for partial remission, 28% for no change and 3% for progression. Despite complete remission, 36% of these patients were bone marrow positive. In the partial remission group, the positivity rate was 48%. About 61% of patients with stable disease had disseminated tumor cells in their bone marrow. A trend to higher positivity rates was observed in the poor responder group compared to responders (61% vs. 38%, P = 0.1)., Conclusion: Primary systemic therapy does not completely eradicate disseminated tumor cells in the bone marrow of breast cancer patients. The biological role of persistent disseminated tumor cells needs to be further investigated to optimize current and future therapeutic strategies.

Objectives: The presence of disseminated tumor cells (DTC) in breast cancer patients is associated with poor prognosis. However, there are limited data about the prevalence and prognostic impact of DTC in patients with gynecological tumors. The aim of this study was to evaluate the presence of DTC in the bone marrow (BM) of patients with gynecological cancers and to correlate their presence with established prognostic factors., Methods: BM aspirates of 201 patients with primary ovarian (n=69), cervical (n=54) and endometrial cancer (n=78), undergoing surgery at the Department of Gynecology and Obstetrics, University Hospital, Tuebingen, Germany between 1/2002 and 01/2006, were included into the study. Cytokeratin (CK)-positive cells were identified by immunocytochemistry using the pancytokeratin antibody A45B/B3., Results: The bone marrow positivity rate was 36% in ovarian, 26% in cervical and 17% in endometrial cancer, respectively. Presence of DTC was significantly correlated with FIGO (International Federation of Gynecology and Obstetrics) tumor stage (p<0.05). The recurrence rate was 14% in patients with CK-positive cells compared to 8% in CK-negative patients (p=0.2). There was no correlation between DTC and other established prognostic factors including nodal status or grading except for cervical cancer. Patients with positive lymph node status were more likely to be bone marrow positive compared to those with negative lymph node status (p<0.05)., Conclusions: Disseminated tumor cells seem to be a general phenomenon in epithelial tumors even though their clinical impact remains to be evaluated. The hypothesis that bone marrow is the homing site of disseminated tumor cells is further supported by these data since gynecological tumors only rarely metastasize to the skeletal system.

Numerous single-institutional studies and a large pooled analysis have demonstrated that the presence of disseminated tumor cells (DTCs) in the bone marrow (BM) from patients with primary, nonmetastatic breast cancer (Stages I-III) is associated with impaired prognosis. To date, sampling of BM and assessment of DTCs is not considered a routine procedure in the clinical management of breast cancer patients; however, emerging data suggest a future role for risk stratification and monitoring of therapeutic efficacy. Because these clinical options need to be evaluated in trials to verify the principle of this concept in the clinical setting, agreement on the standardized detection of DTCs is necessary. Consequently, the German, Austrian, and Swiss Societies for Senology recently formed a panel 1) to review and discuss the existing methodologies, 2) to find a consensus for a standardized detection of DTCs, and 3) to explore the options for its clinical implementation.

We assessed the accuracy of automated cell imaging systems when compared to manual evaluation of cytospin slides in determining the presence of cytokeratin-positive, disseminated breast cancer cells in bone marrow aspirates. A total of 298 cytospin slides of bone marrow aspirates were first evaluated by individual screening by one expert immunocytologist. Subsequently, all 298 slides were evaluated by the Automated Cell Imaging System (ACIS) by ChromaVisiontrade mark. Two separate analysis cycles were performed using ACIS. The results of the two ACIS analysis cycles were almost identical: in 293 out of 298 samples (98.3%), identical numbers of disseminated breast cancer cells were detected. In the remaining five samples (1.7%), the result of the two ACIS analysis cycles differed by only one tumor cell. By using the manual technique, 120 cytospin samples were found to be positive. ACIS was able to detect additional tumor cells in 64 cases. Not once did ACIS miss tumor cells when compared to the manual technique. Using ACIS, we were able to determine the bone marrow status of patients with nonmetastatic breast cancer faster, with greater accuracy, and with greater reproducibility than with the manual technique., (Copyright 2005 Wiley-Liss, Inc.)

Patients with an elevated level of cathepsin D in breast cancer tissue have an adverse prognosis. This study evaluated the prognostic relevance of cathepsin D detection in disseminated tumour cells in bone marrow. Bone marrow was sampled intraoperatively from both anterior iliac crests in 290 patients with primary breast cancer. Interphase cells were enhanced and stained immunocytologically with two antibodies: BM2, which detects tumour-associated glycoprotein TAG 12, which is typically expressed by almost all breast cancer cells, and the anti-cathepsin D antibody. 67 of 149 BM2-positive women (45%) developed metastatic disease (median follow-up time: 69 months). Of these, 15 were cathepsin D-positive (22%). Patients with cathepsin D-positive cells in bone marrow (n = 26; 9%) had a significantly shorter metastasis-free interval (38 months) compared with women who were cathepsin D-negative (64.5 months). The worst prognosis was seen in patients positive for both markers (30.5 months), followed by those who were cathepsin D-negative and BM2-positive (48 months). The detection of cathepsin D on disseminated tumour cells characterises a subgroup of patients with a poorer prognosis who should undergo more aggressive adjuvant systemic therapy.

Background The presence of disseminated tumor cells (DTCs) in bone marrow of patients with early breast cancer (EBC) has been correlated with increased risk of metastatic disease or locoregional relapse. Zoledronic acid (ZOL) treatment has reduced DTCs in the bone marrow of patients with EBC in several studies. This controlled study sought to confirm these observations. Patients and methods Patients with EBC and DTC-positive bone marrow were randomized (N = 96) to treatment with ZOL plus adjuvant systemic therapy or adjuvant systemic therapy alone. The change in DTC numbers at 12 months versus baseline was measured. Results DTC-positive patients treated with ZOL were more likely to become DTC-negative after 12 months of treatment compared with the controls (67% versus 35%; P = 0.009). At 12 months, DTC counts decreased to a mean of 0.5 ± 0.8 DTCs in the ZOL group and to 0.9 ± 0.8 DTCs in the control group. In addition, ZOL was generally well tolerated. Conclusions Treatment with ZOL improves elimination of DTCs. Further studies are needed to determine whether the reduction in DTCs by ZOL provides clinical benefit. [ABSTRACT FROM PUBLISHER]