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.
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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)