The prognostic significance of tumour cell detection in the peripheral blood versus the bone marrow in 733 early-stage breast cancer patients

Breast Cancer Research, Jun 2011

Introduction The detection of circulating tumour cells (CTCs) in the peripheral blood and disseminated tumour cells (DTCs) in the bone marrow are promising prognostic tools for risk stratification in early breast cancer. There is, however, a need for further validation of these techniques in larger patient cohorts with adequate follow-up periods. Methods We assayed CTCs and DTCs at primary surgery in 733 stage I or II breast cancer patients with a median follow-up time of 7.6 years. CTCs were detected in samples of peripheral blood mononuclear cells previously stored in liquid-nitrogen using a previously-developed multi-marker quantitative PCR (QPCR)-based assay. DTCs were detected in bone marrow samples by immunocytochemical analysis using anti-cytokeratin antibodies. Results CTCs were detected in 7.9% of patients, while DTCs were found in 11.7%. Both CTC and DTC positivity predicted poor metastasis-free survival (MFS) and breast cancer-specific survival (BCSS); MFS hazard ratio (HR) = 2.4 (P < 0.001)/1.9 (P = 0.006), and BCSS HR = 2.5 (P < 0.001)/2.3 (P = 0.01), for CTC/DTC status, respectively). Multivariate analyses demonstrated that CTC status was an independent prognostic variable for both MFS and BCSS. CTC status also identified a subset of patients with significantly poorer outcome among low-risk node negative patients that did not receive adjuvant systemic therapy (MFS HR 2.3 (P = 0.039), BCSS HR 2.9 (P = 0.017)). Using both tests provided increased prognostic information and indicated different relevance within biologically dissimilar breast cancer subtypes. Conclusions These results support the use of CTC analysis in early breast cancer to generate clinically useful prognostic information.

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The prognostic significance of tumour cell detection in the peripheral blood versus the bone marrow in 733 early-stage breast cancer patients

Timothy J Molloy 3 Astrid J Bosma 3 Lars O Baumbusch 1 2 Marit Synnestvedt 0 Elin Borgen 5 Hege Giercksky Russnes 5 Ellen Schlichting 0 Laura J van't Veer 3 Bjrn Naume 0 4 0 Division of Surgery and Cancer Medicine, Oslo University Hospital Radiumhospitalet , Postboks 4953, Nydalen, 0424 Oslo , Norway 1 Biomedical Research Group, Department of Informatics, University of Oslo , Postboks 4953, Nydalen, 0424 Oslo , Norway 2 Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet , Postboks 4953, Nydalen, 0424 Oslo , Norway 3 Division of Experimental Therapy, The Netherlands Cancer Institute , Plesmanlaan 121, Amsterdam, 1066 CX , The Netherlands 4 Institute of Clinical Medicine, University of Oslo , Postboks 4953, Nydalen, 0424 Oslo , Norway 5 Department of Pathology, Oslo University Hospital Radiumhospitalet , Postboks 4953, Nydalen, 0424 Oslo , Norway Introduction: The detection of circulating tumour cells (CTCs) in the peripheral blood and disseminated tumour cells (DTCs) in the bone marrow are promising prognostic tools for risk stratification in early breast cancer. There is, however, a need for further validation of these techniques in larger patient cohorts with adequate follow-up periods. Methods: We assayed CTCs and DTCs at primary surgery in 733 stage I or II breast cancer patients with a median follow-up time of 7.6 years. CTCs were detected in samples of peripheral blood mononuclear cells previously stored in liquid-nitrogen using a previously-developed multi-marker quantitative PCR (QPCR)-based assay. DTCs were detected in bone marrow samples by immunocytochemical analysis using anti-cytokeratin antibodies. Results: CTCs were detected in 7.9% of patients, while DTCs were found in 11.7%. Both CTC and DTC positivity predicted poor metastasis-free survival (MFS) and breast cancer-specific survival (BCSS); MFS hazard ratio (HR) = 2.4 (P < 0.001)/1.9 (P = 0.006), and BCSS HR = 2.5 (P < 0.001)/2.3 (P = 0.01), for CTC/DTC status, respectively). Multivariate analyses demonstrated that CTC status was an independent prognostic variable for both MFS and BCSS. CTC status also identified a subset of patients with significantly poorer outcome among low-risk node negative patients that did not receive adjuvant systemic therapy (MFS HR 2.3 (P = 0.039), BCSS HR 2.9 (P = 0.017)). Using both tests provided increased prognostic information and indicated different relevance within biologically dissimilar breast cancer subtypes. Conclusions: These results support the use of CTC analysis in early breast cancer to generate clinically useful prognostic information. - Introduction In recent years breast cancer survival rates have been steadily increasing, partly due to earlier diagnoses as a result of increased awareness and widespread mammography screening programmes. Despite these advances, approximately one-third of patients will develop distant metastasis, which represents the terminal step in the progression of the disease. The relative paucity of accurate prognostic tests has made it difficult to identify these high-risk patients to allow for more optimized adjuvant treatment decisions. Similarly, many patients at low risk of developing disseminated disease undergo toxic adjuvant chemotherapy treatments that are of little benefit. There is consequently a need for new prognostic tests with significantly increased sensitivity and specificity, particularly for those patients at the early stages of their disease. Tumour cells in the bone marrow (disseminated tumour cells (DTCs)) or circulating in the peripheral blood (circulating tumour cells (CTCs)), are potential progenitors of distant metastasis and may, therefore, represent important targets of such tests [1-12]. Indeed, the detection of CTCs and DTCs has been associated with both disease progression in metastatic breast cancer [13-15], as well as disease recurrence and distant spread in early-stage breast cancer [1,3,5,6,16]. Bone marrow has traditionally been the primary compartment in which the prognostic value of the detection of these cells has been investigated, as it is a common homing organ for tumour cells of epithelial origin [17]. While the detection of DTC is of prognostic significance [1,3,5], it has the inherent disadvantage of needing an invasive procedure for sample collection and, additionally, is less suitable for serial sampling for monitoring adjuvant treatment response. The use of peripheral blood as an alternative sampling material has, therefore, gained significant interest in recent years as it does not suffer from these drawbacks. However, there remains a need for good quality studies to confirm the clinical relevance of CTCs in larger patient cohorts, particularly in comparison to DTCs. So far relatively few such studies in early breast cancer have included mature outcome data. Furthermore, only limited data exist on the comparison of CTCs and DTCs in this context, and studies have shown variable (...truncated)


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Timothy J Molloy, Astrid J Bosma, Lars O Baumbusch, Marit Synnestvedt, Elin Borgen, Hege Russnes, Ellen Schlichting, Laura J van't Veer, Bjørn Naume. The prognostic significance of tumour cell detection in the peripheral blood versus the bone marrow in 733 early-stage breast cancer patients, Breast Cancer Research, 2011, pp. R61, 13, DOI: 10.1186/bcr2898