TRANSBIG multi-centre independent validation of the Rotterdam 76-gene prognostic signature for patients with node-negative breast cancer

Desmedt C,  Piette F, Cardoso F, Y. Wang, Loi S, Lallemand F, Klijn J, Haibe-Kains B, Viale G, Delorenzi M, Zhang Y, Saghatchian d'Assignies M, Bergh J, Lidereau R, Ellis P, Harris A, Foekens J, Buyse M, Piccart M, Sotiriou C

 Background: Wang et al. (Lancet 2005) recently reported a 76-gene signature able to predict the development of distant metastases within 5 years in N- untreated primary BC patients, which interestingly was built on considering estrogen receptor (ER) positive patients separately from ER negative patients. The aim of this study was to validate these results in a multi-centre independent population.

Materials methods: We used frozen
archival tumor material from N- pts aged <61, and receiving only locoregional therapy at 5 cancer centers, previously described by our group (Piccart et al., SABCS 2004). Gene expression profiling (Affymetrix) was performed at the Jules Bordet Institute blinded to
clinical data, independent of VeridexTM. Genomic high and low risk groups were defined by VeridexTM blinded to clinical data. Statistical analyses were performed by an independent statistical office. Univariate analyses were done with the genomic risk (high
vs low determined with the 76-gene signature) and adjusted for the clinical risk as defined by Adjuvant! Online for time to distant metastases (TDM), and overall survival (OS).

Results: This analysis refers to 198/302 pts from the initial validation population (83 pts excluded due to not enough RNA materials and 21 who failed quality control), followed for a median of 14.0 years. Distant metastases were found in 51 patients.  The actual 5- and 10-year TDM were 98 % (88-100) and 94 % (83-98) respectively for the good profile group and  76 % (68-82) and 73 % (65-79) for the poor profile group. The actual 5- and 10-year OS were 98 % (88-100) and 87 % (73-94) respectively for the good profile group and  84 % (77-89) and 72 % (63-78) for the poor profile group. The sensitivity for 5- and 10-year TDM were 97 % and 93 %, and the specificity were 34 % and 31 %. We observed a strong time dependency of this signature, leading to an adjusted HR of 13.58 (1.85-99.63) and 8.20 (1.10-60.90) at 5 years, and 5.11 (1.57-16.67) and 2.55 (1.07-6.10) at 10 years for TDM and OS respectively.

Conclusion: This independent multi-center validation adds to the growing evidence that gene expression signatures are of clinical relevance, especially to identify patients at high risk of early distant metastases.