Circulating tumor cells in breast cancer—current status and perspectives

doi:10.1016/j.critrevonc.2015.10.010

Critical Reviews in Oncology/Hematology

Volume 97, January 2016, Pages 22-29

https://doi.org/10.1016/j.critrevonc.2015.10.010 Get rights and content

Highlights

•
Presence of circulating tumor cells (CTCs) is associated with worse survival in early and metastatic breast cancer.
•
The phenotype of CTCs may differ from the primary tumor.
•
Evaluation of CTCs may serve as a “liquid biopsy” in metastatic breast cancer.
•
Treatment decisions based on CTC presence and characteristics are currently tested in clinical trials.

Abstract

The phenomenon of tumor cell dissemination through the blood stream has been known since the 19th century. Circulating tumor cells (CTCs) may be detected in peripheral blood of patients with breast cancer and may serve as a surrogate marker for minimal residual disease. Prognostic relevance of CTCs has already been demonstrated in early and metastatic breast cancer and commercially available detection systems are currently employed in various clinical trials. Since peripheral blood is an easily accessible compartment, serial reevaluation of CTCs is possible and may contribute to better therapy monitoring. Another potential of CTCs lies in the characterization of tumor cells. Expression profiles may differ between CTCs and primary tumor, which may result in different responses to treatment. Assessment of molecular features of CTCs may be an important step for the optimization of adjuvant and metastatic systemic therapy.

Introduction

The phenomenon of hematogenous dissemination of malignant cells shed from solid tumors has been explored by several researchers in 19th century (Ashworth, 1869, Paget, 1889). Single cancer cells may leave the primary tumor early in the course of disease, disperse through the body via blood stream and serve as precursors of subsequent metastatic growth at secondary organs. The features of the tumor cell, the microenvironment at the ’homing site’ and the interaction between those two are crucial for understanding the mechanisms governing the metastatic cascade. Evaluation and characterization of cancer cells in the bone marrow and blood has become a major focus of translational oncologic research in the last two decades. Circulating tumor cells may be detected in most solid tumor of epithelial origin, but no cancer entity has been studied in this context as extensively as breast cancer.

First data on the prognostic relevance of minimal residual disease (MRD) were provided by the analysis of bone marrow aspirates from breast cancer (BC) patients. In 2005, a large meta-analysis of more than 4700 patients with early BC showed that presence of disseminated tumor cells (DTCs) in bone marrow is associated with poor clinical outcome (Braun et al., 2005). Since one important disadvantage of bone marrow sampling is the invasiveness of the procedure, subsequent studies focused on the easily accessible circulating tumor cells (CTCs) in peripheral blood. The following review will address the current role and future potential of CTCs as a diagnostic tool in early and metastatic breast cancer.

Section snippets

Methods for detection of CTCs

CTCs have to be detected among a background of a huge number of blood cells. Therefore challenges in detection and enrichment of CTCs are mainly due to this low frequency and to the heterogeneity of CTCs which is directly correlated to the heterogeneity of the primary tumor. Current technologies refer to these two challenges. Beside the enumeration of CTCs, whose clear prognostic relevance could be shown in multiple clinical studies (Cristofanilli et al., 2005, Rack et al., 2014),

Clinical role of CTCs

Clinical value of CTC detection differs between metastatic and early breast cancer. Both the presence of CTCs and their immunocytochemical/molecular features are currently being evaluated in several clinical trials (Table 1).

Conclusions

Evaluation of CTCs in the peripheral blood of breast cancer patients holds great promise, and many clinical applications are currently being tested. Beyond prognostic value in early and metastatic breast cancer, characterization of CTCs may contribute to our better understanding of the metastatic cascade. Assessment of potential therapeutic targets on CTCs opens new prospects for improving individualized treatment approaches. In this context, first clinical trials investigating therapy choices

Dr Malgorzata Banys-Paluchowski, MD, is a gynaecologist and senior breast surgeon at the Breast Cancer Center, Marienkranhenhaus Hamburg, Germany. She was born in Wroclaw, Poland and received her Medical Degree from Tuebingen University, Germany. Dr Banys-Paluchowski is skilled in the surgical and systemic treatment of breast cancer and gynaecological malignancies. Her research focuses on hematogenous tumor cell dissemination in solid tumors.

References (85)

F.C. Bidard et al.
Prognosis of women with stage IV breast cancer depends on detection of circulating tumor cells rather than disseminated tumor cells
Ann. Oncol.
(2008)
F.C. Bidard et al.
Single circulating tumor cell detection and overall survival in nonmetastatic breast cancer
Ann. Oncol.
(2010)
F.C. Bidard et al.
Clinical validity of circulating tumour cells in patients with metastatic breast cancer: a pooled analysis of individual patient data
Lancet Oncol.
(2014)
F.-C. Bidard et al.
Clinical validity of circulating tumour cells in patients with metastatic breast cancer: a pooled analysis of individual patient data
Lancet Oncol.
(2014)
M.B. Freidin et al.
An assessment of diagnostic performance of a filter-based antibody-independent peripheral blood circulating tumour cell capture paired with cytomorphologic criteria for the diagnosis of cancer
Lung Cancer
(2014)
A. Giordano et al.
Circulating tumor cells in immunohistochemical subtypes of metastatic breast cancer: lack of prediction in HER2-positive disease treated with targeted therapy
Ann. Oncol.
(2012)
C. Helissey et al.
Circulating tumor cell thresholds and survival scores in advanced metastatic breast cancer: the observational step of the CirCe01 phase III trial
Cancer Lett.
(2015)
M. Ignatiadis et al.
Molecular detection and prognostic value of circulating cytokeratin-19 messenger RNA-positive and HER2 messenger RNA-positive cells in the peripheral blood of women with early-stage breast cancer
Clin. Breast Cancer
(2007)
A. Lucci et al.
Circulating tumour cells in non-metastatic breast cancer: a prospective study
Lancet Oncol.
(2012)
F. Nole et al.
Variation of circulating tumor cell levels during treatment of metastatic breast cancer: prognostic and therapeutic implications
Ann. Oncol.
(2008)

S. Paget

Distribution of secondary growths in cancer of the breast

Lancet

(1889)

J.Y. Pierga et al.

High independent prognostic and predictive value of circulating tumor cells compared with serum tumor markers in a large prospective trial in first-line chemotherapy for metastatic breast cancer patients

Ann. Oncol.

(2012)

H. Schneck et al.

Analysing the mutational status of PIK3CA in circulating tumor cells from metastatic breast cancer patients

Mol. Oncol.

(2013)

S. Agelaki et al.

Efficacy of lapatinib in therapy-resistant HER2-positive circulating tumor cells in metastatic breast cancer

PloS One

(2015)

C. Alix-Panabieres et al.

Circulating tumor cells: liquid biopsy of cancer

Clin. Chem.

(2013)

T.R. Ashworth

A case of cancer in which cells similar to those in tumors were seen in the blood after death

Aust. Med. J.

(1869)

M. Banys et al.

The influence of removal of primary tumor on incidence and phenotype of circulating tumor cells in primary breast cancer

Breast Cancer Res. Treat.

(2012)

I.H. Benoy et al.

Real-time RT-PCR detection of disseminated tumour cells in bone marrow has superior prognostic significance in comparison with circulating tumour cells in patients with breast cancer

Br. J. Cancer

(2006)

H. Bernhard et al.

Adoptive transfer of autologous, HER2-specific, cytotoxic T lymphocytes for the treatment of HER2-overexpressing breast cancer

Cancer Immunol. Immunother.

(2008)

F.C. Bidard et al.

Clinical application of circulating tumor cells in breast cancer: overview of the current interventional trials

Cancer Metastasis Rev.

(2013)

F.C. Bidard et al.

Time-dependent prognostic impact of circulating tumor cells detection in non-metastatic breast cancer: 70-month analysis of the REMAGUS02 study

Int. J. Breast Cancer

(2013)

V. Bozionellou et al.

Trastuzumab administration can effectively target chemotherapy-resistant cytokeratin-19 messenger RNA-positive tumor cells in the peripheral blood and bone marrow of patients with breast cancer

Clin. Cancer Res.

(2004)

S. Braun et al.

A pooled analysis of bone marrow micrometastasis in breast cancer

N. Engl. J. Med.

(2005)

L.H. Broersen et al.

Clinical application of circulating tumor cells in breast cancer

Cell Oncol. (Dordr.)

(2014)

G.T. Budd et al.

Circulating tumor cells versus imaging – predicting overall survival in metastatic breast cancer

Clin Cancer Res.

(2006)

G.M. Cann et al.

mRNA-Seq of single prostate cancer circulating tumor cells reveals recapitulation of gene expression and pathways found in prostate cancer

PLoS One

(2012)

M. Cristofanilli et al.

Circulating tumor cells, disease progression, and survival in metastatic breast cancer

N. Engl. J. Med.

(2004)

M. Cristofanilli et al.

Circulating tumor cells: a novel prognostic factor for newly diagnosed metastatic breast cancer

J. Clin. Oncol.

(2005)

S.J. Dawson et al.

Analysis of circulating tumor DNA to monitor metastatic breast cancer

N. Engl. J. Med.

(2013)

S.J. Dawson et al.

Circulating tumor DNA to monitor metastatic breast cancer

N. Engl. J. Med.

(2013)

G. De et al.

Circulating tumor cells and [18F]fluorodeoxyglucose positron emission tomography/computed tomography for outcome prediction in metastatic breast cancer

J. Clin. Oncol.

(2009)

Early Breast Cancer Trialists’ Collaborative Group

Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials

Lancet

(2005)

T. Fehm et al.

Circulating free DNA: a new surrogate marker for minimal residual disease?

Breast Cancer Res. Treat.

(2011)

T. Fehm et al.

ERalpha-status of disseminated tumour cells in bone marrow of primary breast cancer patients

Breast Cancer Res.

(2008)

T. Fehm et al.

Detection and characterization of circulating tumor cells in blood of primary breast cancer patients by RT-PCR and comparison to status of bone marrow disseminated cells

Breast Cancer Res.

(2009)

T. Fehm et al.

HER2 status of circulating tumor cells in patients with metastatic breast cancer: a prospective, multicenter trial

Breast Cancer Res. Treat.

(2010)

J.C. Fischer et al.

Diagnostic leukapheresis enables reliable detection of circulating tumor cells of nonmetastatic cancer patients

Proc. Natl. Acad. Sci. U. S. A.

(2013)

B. Franken et al.

Circulating tumor cells, disease recurrence and survival in newly diagnosed breast cancer

Breast Cancer Res.

(2012)

M. Giuliano et al.

Circulating tumor cells as prognostic and predictive markers in metastatic breast cancer patients receiving first-line systemic treatment

Breast Cancer Res.

(2011)

C. Hall et al.

Circulating tumor cells after neoadjuvant chemotherapy in stage I–III triple-negative breast cancer

Ann. Surg. Oncol.

(2015)

W. Harb et al.

Mutational analysis of circulating tumor cells using a novel microfluidic collection device and qPCR assay

Transl. Oncol.

(2013)

D.F. Hayes et al.

Circulating tumor cells at each follow-up time point during therapy of metastatic breast cancer patients predict progression-free and overall survival

Clin Cancer Res.

(2006)

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Citation Excerpt :
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View full text

Circulating tumor cells in breast cancer—current status and perspectives

Highlights

Abstract

Introduction

Section snippets

Methods for detection of CTCs

Clinical role of CTCs

Conclusions

Ann. Oncol.

Ann. Oncol.

Lancet Oncol.

Lancet Oncol.

Lung Cancer

Ann. Oncol.

Cancer Lett.

Clin. Breast Cancer

Lancet Oncol.

Ann. Oncol.

Lancet

Ann. Oncol.

Mol. Oncol.

Efficacy of lapatinib in therapy-resistant HER2-positive circulating tumor cells in metastatic breast cancer

PloS One

Circulating tumor cells: liquid biopsy of cancer

Clin. Chem.

A case of cancer in which cells similar to those in tumors were seen in the blood after death

Aust. Med. J.

The influence of removal of primary tumor on incidence and phenotype of circulating tumor cells in primary breast cancer

Breast Cancer Res. Treat.

Real-time RT-PCR detection of disseminated tumour cells in bone marrow has superior prognostic significance in comparison with circulating tumour cells in patients with breast cancer

Br. J. Cancer

Adoptive transfer of autologous, HER2-specific, cytotoxic T lymphocytes for the treatment of HER2-overexpressing breast cancer

Cancer Immunol. Immunother.

Clinical application of circulating tumor cells in breast cancer: overview of the current interventional trials

Cancer Metastasis Rev.

Time-dependent prognostic impact of circulating tumor cells detection in non-metastatic breast cancer: 70-month analysis of the REMAGUS02 study

Int. J. Breast Cancer

Trastuzumab administration can effectively target chemotherapy-resistant cytokeratin-19 messenger RNA-positive tumor cells in the peripheral blood and bone marrow of patients with breast cancer

Clin. Cancer Res.

A pooled analysis of bone marrow micrometastasis in breast cancer

N. Engl. J. Med.

Clinical application of circulating tumor cells in breast cancer

Cell Oncol. (Dordr.)

Circulating tumor cells versus imaging – predicting overall survival in metastatic breast cancer

Clin Cancer Res.

mRNA-Seq of single prostate cancer circulating tumor cells reveals recapitulation of gene expression and pathways found in prostate cancer

PLoS One

Circulating tumor cells, disease progression, and survival in metastatic breast cancer

N. Engl. J. Med.

Circulating tumor cells: a novel prognostic factor for newly diagnosed metastatic breast cancer

J. Clin. Oncol.

Analysis of circulating tumor DNA to monitor metastatic breast cancer

N. Engl. J. Med.

Circulating tumor DNA to monitor metastatic breast cancer

N. Engl. J. Med.

Circulating tumor cells and [18F]fluorodeoxyglucose positron emission tomography/computed tomography for outcome prediction in metastatic breast cancer

J. Clin. Oncol.

Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials

Lancet

Circulating free DNA: a new surrogate marker for minimal residual disease?

Breast Cancer Res. Treat.

ERalpha-status of disseminated tumour cells in bone marrow of primary breast cancer patients

Breast Cancer Res.

Detection and characterization of circulating tumor cells in blood of primary breast cancer patients by RT-PCR and comparison to status of bone marrow disseminated cells

Breast Cancer Res.

HER2 status of circulating tumor cells in patients with metastatic breast cancer: a prospective, multicenter trial

Breast Cancer Res. Treat.

Diagnostic leukapheresis enables reliable detection of circulating tumor cells of nonmetastatic cancer patients

Proc. Natl. Acad. Sci. U. S. A.

Circulating tumor cells, disease recurrence and survival in newly diagnosed breast cancer

Breast Cancer Res.

Circulating tumor cells as prognostic and predictive markers in metastatic breast cancer patients receiving first-line systemic treatment

Breast Cancer Res.

Circulating tumor cells after neoadjuvant chemotherapy in stage I–III triple-negative breast cancer

Ann. Surg. Oncol.

Mutational analysis of circulating tumor cells using a novel microfluidic collection device and qPCR assay

Transl. Oncol.

Circulating tumor cells at each follow-up time point during therapy of metastatic breast cancer patients predict progression-free and overall survival

Clin Cancer Res.