Elsevier

The Lancet

Volume 365, Issue 9460, 19–25 February 2005, Pages 671-679
The Lancet

Articles
Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer

https://doi.org/10.1016/S0140-6736(05)17947-1Get rights and content

Summary

Background

Genome-wide measures of gene expression can identify patterns of gene activity that subclassify tumours and might provide a better means than is currently available for individual risk assessment in patients with lymph-node-negative breast cancer.

Methods

We analysed, with Affymetrix Human U133a GeneChips, the expression of 22 000 transcripts from total RNA of frozen tumour samples from 286 lymph-node-negative patients who had not received adjuvant systemic treatment.

Findings

In a training set of 115 tumours, we identified a 76-gene signature consisting of 60 genes for patients positive for oestrogen receptors (ER) and 16 genes for ER-negative patients. This signature showed 93% sensitivity and 48% specificity in a subsequent independent testing set of 171 lymph-node-negative patients. The gene profile was highly informative in identifying patients who developed distant metastases within 5 years (hazard ratio 5·67 [95% CI 2·59–12·4]), even when corrected for traditional prognostic factors in multivariate analysis (5·55 [2·46–12·5]). The 76-gene profile also represented a strong prognostic factor for the development of metastasis in the subgroups of 84 premenopausal patients (9·60 [2·28–40·5]), 87 postmenopausal patients (4·04 [1·57–10·4]), and 79 patients with tumours of 10–20 mm (14·1 [3·34–59·2]), a group of patients for whom prediction of prognosis is especially difficult.

Interpretation

The identified signature provides a powerful tool for identification of patients at high risk of distant recurrence. The ability to identify patients who have a favourable prognosis could, after independent confirmation, allow clinicians to avoid adjuvant systemic therapy or to choose less aggressive therapeutic options.

Introduction

About 60–70% of patients with lymph-node-negative breast cancer are cured by local or regional treatment alone.1, 2 The most widely used treatment guidelines are the St Gallen3 and the US National Institutes of Health4 consensus criteria. These guidelines recommend adjuvant systemic therapy for 85–90% of lymph-node-negative patients. There is a need for specific definition of an individual patient's risk of disease recurrence to ensure that she receives appropriate therapy. Currently, few diagnostic tools are available to identify at-risk patients. To date, gene-expression patterns have been used to classify breast tumours into clinically relevant subtypes.5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 We report a comprehensive genome-wide assessment of gene expression to identify broadly applicable prognostic markers.5, 6 In this study, we aimed to develop a gene-expression-based algorithm and to use it to provide quantitative predictions on disease outcome for patients with lymph-node-negative breast cancer.

Section snippets

Patients' samples

We selected from our tumour bank at the Erasmus Medical Center (Rotterdam, Netherlands) frozen tumour samples from patients with lymph-node-negative breast cancer who were treated during 1980–95, but who did not receive systemic neoadjuvant or adjuvant therapy. Tumour samples were submitted to our reference laboratory from 25 regional hospitals for measurements of steroid-hormone receptors. Guidelines for primary treatment were similar for all hospitals. Selection of tumours aimed to avoid

Results

The median follow-up for the 198 patients who survived was 101 months (range 20–171). Of the 286 patients included, 93 (33%) showed evidence of distant metastasis within 5 years and were counted as failures in analysis of distant-metastasis-free survival. Five (2%) patients died without evidence of disease and were censored at last follow-up. 83 (29%) died after previous relapse. Therefore, 88 patients (31%) were failures in the analysis of overall survival.

Clinical and pathological features of

Discussion

We provide results of an analysis of primary tumours from 286 patients with lymph-node-negative breast cancer of all age-groups and tumour sizes. The patients had not received adjuvant systemic therapy, so the multigene assessment of prognosis was not subject to potentially confounding contributions by predictive factors related to systemic treatment.

The study revealed a 76-gene signature that accurately predicts distant tumour recurrence. This signature could be applied to all

References (30)

  • CM Perou et al.

    Molecular portraits of human breast tumours

    Nature

    (2000)
  • T Sørlie et al.

    Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications

    Proc Natl Acad Sci USA

    (2001)
  • T Sørlie et al.

    Repeated observation of breast tumor subtypes in independent gene expression data sets

    Proc Natl Acad Sci USA

    (2003)
  • S Gruvberger et al.

    Estrogen receptor status in breast cancer is associated with remarkably distinct gene expression patterns

    Cancer Res

    (2001)
  • L Van't Veer et al.

    Gene expression profiling predicts clinical outcome of breast cancer

    Nature

    (2002)
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