DNA arrays predictive markers of chemosensitivity to epirubicin-cyclophosphamide (EC) then docetaxel (ECD) primary chemotherapy for localized breast cancer
Authors: Sabrina Carpentier, Fabien Valet, Charles Decraene, Frederique Spyratos, Patricia de Cremoux, Jean Philippe Meyniel, Veronique Scott, Jacqueline Lehmann-Che, Brigitte Sigal, Marie-Christine Mathieu, Philippe Bertheau, Jean Marc Guinebretriere, Jean Yves Pierga, Suzette Delaloge, Etienne Brain, Michel Marty, Sergio Roman-Roman, Bernard Asselain, Emmanuel Barillot
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

3620 

Purpose The aim of this study is to develop a multigene predictor of pathologic complete response (pCR) to sequential ECD primary chemotherapy for localized breast cancer in a French prospective multicentre trial (including 340 pts) and to compare this gene signature with previously published prognostic or predictive gene signatures.    Patients and Methods The first 170 patients from the planed interim analysis underwent core biopsy to obtain RNA from the tumor for transcriptional profiling using Affymetrix U133Plus 2.0 arrays: 159 core biopsies were available. Of 146 with ≥30 % tumor cells and among them 100 (70%) gave high quality RNA for transcriptome analysis [RIN ≥7]. The sampling was representative of the whole population. Arrays were normalized by a new version of the GCRMA [Wu, 2004] and non-hybridized probesets were filtered out. Exploratory analysis of transcriptomic data were performed using hierarchical clustering and PCA. Statistical analysis was performed using a logistic regression model. Moreover SAM [Tusher, 2000] was used to detect differentially expressed genes. Multivariate analysis were applied on the selected subset of probesets using the logistic regression model. Finally, pathways of interest were highlighted by Gene Set Analysis (GSA) [Efron & Tibshirani, 2006].    Results Among the first 170 first patients, a pCR was observed in 13% HER2-negative or HER2-positive patients not receiving neoadjuvant trastuzumab and in 30% of HER2 positive patients treated with trastuzumab. Univariate and multivariate analysis confirmed the predictive value of classical variables (ER, grade) on pCR. Unsupervised gene expression array profiling identified triple-negative subtype as a separate subgroup. Using SAM analysis with a FDR (false discovery rate) of 5%, 216 genes were identified to be differentially expressed in the different pCR categories. Logistic regression analysis identified four genes as a valuable predictor of pCR rate. The statistical properties of a single score derived from the model will be discussed in the presentation (specificity, sensitivity, validation..). Among the genes highlighted by our study, we retrieved genes reported in other signatures (Hess, 2006, Van de Vijver, 2002).    Conclusions This study provides a highly sensitive and specific gene profile able to identify a subgroup of patients with 70% pCR rates after primary ECD chemotherapy regimen. Confirmatory study will be performed on the second cohort of 170 patients. Major genes identified in this signature will be further validated using quantitative RT-PCR.