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Breast cancer metastasis: markers and models

Nature Reviews Cancer volume 5, pages 591–602 (2005)Cite this article

Key Points

  • Current prognostic criteria only poorly predict the metastasis risk for an individual breast cancer patient. Therefore, many women receive cytotoxic chemotherapy unnecessarily.

  • Gene-expression signatures of human primary breast tumours predict more accurately than current prognostic criteria which patients are destined to relapse and ultimately die of metastatic breast cancer, and should therefore receive adjuvant therapy.

  • New molecular insights challenge the traditional model of metastasis, and indicate that the metastatic capacity of breast tumours is an inherent feature, and not necessarily a late, acquired phenotype.

  • Local breast cancer might have a 'non-metastatic, good-prognosis' stem cell of origin; metastasizing systemic breast cancer might have a 'metastatic, poor-prognosis' stem cell of origin.

Abstract

Breast cancer starts as a local disease, but it can metastasize to the lymph nodes and distant organs. At primary diagnosis, prognostic markers are used to assess whether the transition to systemic disease is likely to have occurred. The prevailing model of metastasis reflects this view — it suggests that metastatic capacity is a late, acquired event in tumorigenesis. Others have proposed the idea that breast cancer is intrinsically a systemic disease. New molecular technologies, such as DNA microarrays, support the idea that metastatic capacity might be an inherent feature of breast tumours. These data have important implications for prognosis predicition and our understanding of metastasis.

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Figure 1: Most common metastasis sites of breast cancer at autopsy.
Figure 2: Models of the metastatic process.
Figure 3: New models of the metastatic process in breast cancer.
Figure 4: An integrative model of breast cancer metastasis.

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Acknowledgements

We apologize to those authors whose work we could not cite directly due to space constraints. We would like to thank A. Berns, R. Bernards, R. Kortlever and S. Rodenhuis for advice and critical reading of the manuscript. B.W. and L.J.v.V. are supported by the Dutch Cancer Society, the Netherlands Genomics Initiative and the EU 6th Framework Programme.

Author information

Authors and Affiliations

  1. Division of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Britta Weigelt & Laura J. van't Veer

  2. Division of Diagnostic Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Johannes L. Peterse & Laura J. van't Veer

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  1. Britta Weigelt
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  3. Laura J. van't Veer
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Correspondence to Laura J. van't Veer.

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Laura J. van't Veer is a founder of Agendia B.V., Amsterdam.

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DATABASES

Entrez Gene

cytokeratin-5

cytokeratin-8

cytokeratin-17

cytokeratin-18

cytokeratin-19

ERBB2

MMP1

MMP9

PAI1

PAI2

uPA

uPAR

National Cancer Institute

breast cancer

FURTHER INFORMATION

Adjuvant Online

Breast International Group

EORTC

Netherlands Cancer Institute

WHO Classification of Tumours

Glossary

ADJUVANT THERAPY

Cytotoxic chemotherapy and/or endocrine therapy after surgical removal and/or radiotherapy of the primary tumour. Adjuvant therapy is used to ensure that all microscopic disseminated cancer cells are destroyed.

PROGNOSTIC MARKER

A characteristic of a patient or tumour at the time of diagnosis that can be used to estimate the chance of the disease recurring in the absence of therapy.

MULTIVARIATE ANALYSIS

A statistical test that examines more than two variables at the same time.

PROSPECTIVE STUDY

A study in which a selected group of patients is followed over time to determine differences in the rate at which disease develops in relation to the investigated factor. These factors might include drugs, procedures or diets.

PREDICTIVE MARKER

A characteristic of a patient that is associated with the response or lack of response to a particular therapy.

MICROMETASTASIS

Micrometastases were originally defined as small occult metastases of less than 0.2 cm in diameter. Nowadays, the term also includes disseminated tumour cells that are present in peripheral blood, bone marrow or lymph nodes.

ENZYME-LINKED IMMUNOSORBENT ASSAY

(ELISA). A sensitive test to quantitatively determine small amounts of a particular protein in a solution. In an ELISA the interaction between the protein of interest and a specific antibody is detected by an enzyme that is linked to the antibody and converts a colourless substrate to a coloured product.

RETROSPECTIVE STUDY

A study in which data are collected and analysed after all measurements, interventions or events in the participants have taken place.

METAGENE

Metagenes are linear combinations of individual gene-expression values. They have the potential to classify and predict cellular phenotypes resulting from deregulation of oncogenic pathways.

EXPERIMENTAL METASTASIS ASSAY

Assays in which cultured tumour cells or minced tumours are introduced into blood vessels or organs of mice and examined for their in vivo growth and tumour formation.

LURIA–DELBRUCK FLUCTUATION ANALYSIS

A method to estimate mutation rates in cell populations, originally designed for bacteria.

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Weigelt, B., Peterse, J. & van't Veer, L. Breast cancer metastasis: markers and models. Nat Rev Cancer 5, 591–602 (2005). https://doi.org/10.1038/nrc1670

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