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Originally published as JCO Early Release 10.1200/JCO.2005.03.9115 on February 27 2006

Journal of Clinical Oncology, Vol 24, No 11 (April 10), 2006: pp. 1665-1671
© 2006 American Society of Clinical Oncology.
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Multicenter Validation of a Gene Expression–Based Prognostic Signature in Lymph Node–Negative Primary Breast Cancer

John A. Foekens, David Atkins, Yi Zhang, Fred C.G.J. Sweep, Nadia Harbeck, Angelo Paradiso, Tanja Cufer, Anieta M. Sieuwerts, Dmitri Talantov, Paul N. Span, Vivianne C.G. Tjan-Heijnen, Alfredo F. Zito, Katja Specht, Heinz Hoefler, Rastko Golouh, Francesco Schittulli, Manfred Schmitt, Louk V.A.M. Beex, Jan G.M. Klijn, Yixin Wang

From the Department of Medical Oncology, Erasmus Medical Center, Daniel den Hoed Cancer Center, Rotterdam; Department of Chemical Endocrinology, Radboud University Nijmegen Medical Centre; Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands; Veridex LLC, San Diego, CA; Frauenklinik und Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität, München, Germany; National Cancer Institute, Bari, Italy; and the Institute of Oncology, Ljubljana, Slovenia

Address reprint requests to John A. Foekens, PhD, Erasmus Medical Center, Josephine Nefkens Institute, Room BE-426, Rotterdam, the Netherlands; e-mail: j.foekens{at}erasmusmc.nl

PURPOSE: We previously identified in a single-center study a 76-gene prognostic signature for lymph node-negative (LNN) breast cancer patients. The aim of this study was to validate this gene signature in an independent more diverse population of LNN patients from multiple institutions.

PATIENTS AND METHODS: Using custom-designed DNA chips we analyzed the expression of the 76 genes in RNA of frozen tumor samples from 180 LNN patients who did not receive adjuvant systemic treatment.

RESULTS: In this independent validation, the 76-gene signature was highly informative in identifying patients with distant metastasis within 5 years (hazard ratio, [HR], 7.41; 95% CI, 2.63 to 20.9), even when corrected for traditional prognostic factors in multivariate analysis (HR, 11.36; 95% CI, 2.67 to 48.4). The actuarial 5- and 10-year distant metastasis-free survival were 96% (95% CI, 89% to 99%) and 94% (95% CI, 83% to 98%), respectively, for the good profile group and 74% (95% CI, 64% to 81%) and 65% (53% to 74%), respectively for the poor profile group. The sensitivity for 5-yr distant metastasis-free survival was 90%, and the specificity was 50%. The positive and negative predictive values were 38% (95% CI, 29% to 47%) and 94% (95% CI, 86% to 97%), respectively. The 76-gene signature was confirmed as a strong prognostic factor in subgroups of estrogen receptor-positive patients, pre- and postmenopausal patients, and patients with tumor sizes 20 mm or smaller. The subgroup of patients with estrogen receptor-negative tumors was considered too small to perform a separate analysis.

CONCLUSION: Our data provide a strong methodologic and clinical multicenter validation of the predefined prognostic 76-gene signature in LNN breast cancer patients.

Supported in part by the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research.

Presented as an abstract at the San Antonio Breast Cancer Symposium, San Antonio, TX, December 8-11, 2005.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.


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