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A Gene Expression Signature that Can Predict the Recurrence of Tamoxifen-Treated Primary Breast Cancer

Authors' Affiliations: ¹ U868 Institut National de la Sante et de la Recherche Medicale, Tumoral Identity and Plasticity, Cancer Research Center of Montpellier, Université Montpellier 1, CRLC Val d'Aurelle-Paul Lamarque; ² Department of Informatics, UMR5160 Centre National de la Recherche Scientifique, Montpellier, France; ³ Department of Pathology, Institut Bergonié, Bordeaux, France; and ⁴ Department of Obstetrics and Gynecology, University of Turin, Turin, Italy

Requests for reprints: Jean-Marie Darbon, Institut National de la Sante et de la Recherche Medicale U868, Centre de Recherche en Cancérologie de Montpellier, CRLC Val d'Aurelle-Paul Lamarque, F-34298 Montpellier cedex 5, France. Phone: 33-467-612-556; Fax: 33-467-613-787; E-mail: jmdarbon{at}valdorel.fnclcc.fr.

Purpose: The identification of a molecular signature predicting the relapse of tamoxifen-treated primary breast cancers should help the therapeutic management of estrogen receptor–positive cancers.

Experimental Design: A series of 132 primary tumors from patients who received adjuvant tamoxifen were analyzed for expression profiles at the whole-genome level by 70-mer oligonucleotide microarrays. A supervised analysis was done to identify an expression signature.

Results: We defined a 36-gene signature that correctly classified 78% of patients with relapse and 80% of relapse-free patients (79% accuracy). Using 23 independent tumors, we confirmed the accuracy of the signature (78%) whose relevance was further shown by using published microarray data from 60 tamoxifen-treated patients (63% accuracy). Univariate analysis using the validation set of 83 tumors showed that the 36-gene classifier is more efficient in predicting disease-free survival than the traditional histopathologic prognostic factors and is as effective as the Nottingham Prognostic Index or the "Adjuvant!" software. Multivariate analysis showed that the molecular signature is the only independent prognostic factor. A comparison with several already published signatures demonstrated that the 36-gene signature is among the best to classify tumors from both training and validation sets. Kaplan-Meier analyses emphasized its prognostic power both on the whole cohort of patients and on a subgroup with an intermediate risk of recurrence as defined by the St. Gallen criteria.

Conclusion: This study identifies a molecular signature specifying a subgroup of patients who do not gain benefits from tamoxifen treatment. These patients may therefore be eligible for alternative endocrine therapies and/or chemotherapy.