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. 2013 Oct;24(10):2515-2521.
doi: 10.1093/annonc/mdt223. Epub 2013 Jun 24.

Clinical relevance of cancer stem cells in bone marrow of early breast cancer patients

A Giordano  1 , H Gao  2 , E N Cohen  2 , S Anfossi  2 , J Khoury  2 , K Hess  3 , S Krishnamurthy  4 , S Tin  2 , M Cristofanilli  5 , G N Hortobagyi  6 , W A Woodward  7 , A Lucci  8 , J M Reuben  9
Affiliations

Clinical relevance of cancer stem cells in bone marrow of early breast cancer patients

A Giordano et al. Ann Oncol. 2013 Oct.

Abstract

Background: Cancer stem cells (CSCs) are epithelial tumor cells that express CD44(+)CD24(-/lo). CSCs can be further divided into those that have aldehyde dehydrogenase (ALDH) activity (Aldefluor(+)) and those that do not. We hypothesized that if CSCs are responsible for tumor dissemination, their presence in bone marrow (BM) would be prognostic in early stages of breast cancer (EBC) patients.

Patients and methods: BM aspirates were collected at the time of surgery from 108 patients with EBC. BM was analyzed for CSCs and ALDH activity by flow cytometry. Overall survival and disease-free survival (DFS) were calculated from the date of diagnosis and analyzed with Kaplan-Meier survival plots. Cox multivariate proportional hazards model was also carried out.

Results: Patients with CSCs in BM had a hazard ratio (HR) of 8.8 for DFS (P = 0.002); patients with Aldefluor(+) CSCs had a HR of 5.9 (P = 0.052) for DFS. All deceased patients (n = 7) had CSCs in BM. In multivariate analysis, the presence of CSCs in BM was a prognostic factor of DFS (HR = 15.8, P = 0.017).

Conclusions: The presence of BM metastasis is correlated with CSCs and these CSCs irrespective of ALDH activity are an independent adverse prognostic factor in EBC patients.

Keywords: CD24; CD44; bone marrow; breast cancer; cancer stem cells; circulating tumor cells.

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Figures

Figure 1.
Figure 1.
Detection of cancer stem cells (CSCs) in patient bone marrow (BM). Up to 10 ml of BM were aspirated from bilateral iliac crests of patients, mononuclear cells (MNC) were isolated by Ficoll-Hypaque density gradient centrifugation; 103 patients underwent analysis by flow cytometry to detect CD326, CD45, CD44, CD24 receptors; 66 patients were assessed for ALDH activity by the Aldefluor assay. CSCs were defined as CD45−CD326+ cells with a CD44+CD24−/lo phenotype. Furthermore, according to the Aldefluor reaction, CSCs were divided into those with ALDH activity (Aldefluor+ CSCs) and those without.
Figure 2.
Figure 2.
(A) Disease-free survival (DFS) and (C) overall survival (OS) Kaplan–Meier curves for all 103 patients according to the presence of cancer stem cells (CSCs) in bone marrow (BM); dashed lines represent patients with CSCs < 0.5% (n = 47); continuous lines represent patients with CSCs ≥ 0.5% (n = 56). (B) DFS and (D) OS Kaplan–Meier curves for 66 patients according to ALDH+ CSCs in BM; dashed lines represent patients with ALDH+ CSCs < 0.5% (n = 52); continuous lines represent patients with Aldefluor+ CSCs ≥ 0.5% (n = 14). Time was measured from the diagnosis to the death for OS and to the first disease recurrence (DFS).
Figure 3.
Figure 3.
(A and B) Disease-free survival (DFS) and (C and D) overall survival (OS) Kaplan–Meier curves according to different prognostic markers: (A) DFS and (C) OS Kaplan–Meier curves for 104 patients according to DTC determined by flow cytometry (CD326); (B) DFS and (D) OS Kaplan–Meier curves for 74 patients according to CTC determined by CellSearch (22.5 ml of peripheral blood). Time was measured from the diagnosis to the death for OS and to the first disease recurrence (DFS).
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