Gene expression combined with gene set enrichment analysis to identify markers of vinorelbine efficacy in breast cancer patients.

Abstract

e21099 Background: Vinorelbine (V) induces mitotic arrest and apoptosis but there are limited data on its effect on gene expression in breast cancer clinical setting. Methods: 43 adult female patients with pathologically confirmed breast cancer and locally advanced or metastatic disease were treated with V 25 mg/m2 days 1, 8, 15 of a 28-day cycle. Gene expression was assessed in archival FFPE tissue using the microarray-based DASL assay (cDNA-mediated Annealing, Selection extension and Ligation) and correlated with time-to-progression (TTP). Using a Gene Set Enrichment Analysis (GSEA), groups of genes that share a common molecular function, chromosomal location, or regulation were identified in patients classified as having either a short (S) (n=25) or a long (L) (n=18) time to progression (TTP) divided by the median (72 days). The GSEA software ( http://www.broadinstitute.org/gsea/index.jsp ) was used for the analysis. Results: GSEA focusing on genes grouped according to similar a) molecular function: 16 out of a set of 43 genes involved in histone binding were enriched in group S (p = 0.002), consistent with higher expression in group S of HIST3H2BB and HIST1H3I as well as a nuclear transcription factor promoting their expression. b) transcription factors: 14 out of 47 genes were enriched in group S (p = 0.004) and corresponds to genes with promoter regions that match c-fos serum response element-binding transcription factor that modulates, for example, ABCC1 and ABCB1 (P-gp/MDR1) solute carriers. c) chromosomal location: in group S, genes were enriched on chromosome 11q21 (20 out of 45 genes p = 0.004) and on chromosome 12p12 (14 out of 22 genes p = 0.002). Conclusions: a) the up-regulation of histone binding genes is consonant with recent discovery of high affinity V binding to histones b) the role of P-gp/MDR1 in V transport is well known c) our observations on chromosome 11q21 and12p12 are novel. DASL expression combined with GSEA highlights gene sets that correlate with clinical outcome and may lead to predictive markers of V efficacy. Further confirmatory analysis is needed due to the limitation of small sample size and multiple comparisons.