02 BOOK OF ABSTRACTS .indd

Gene-expression and DNA-methylation profiling in
breast cancer
John A. Foekens*
Erasmus MC, Josephine Nefkens Institute, Rotterdam, The Netherlands.
High-throughput measures of gene expression and DNA methylation are promising
developments in determining the prognosis of patients. We have developed a
76-gene expression profile that can predict prognosis in lymph-node negative (LNN)
breast cancer patients who had not received adjuvant systemic therapy. To develop
the 76-gene signature we have used a training set of 115 tumors. Validation in
an independent testing set of 171 patients showed the 76-gene signature to be
strongly associated with a poor metastasis-free survival (MFS) (HR: 5.7). Subsequent
multicenter validation including 180 LNN patients confirmed the 76-gene signature
as a strong prognostic factor for poor MFS (HR: 7.4), also in postmenopausal patients
(HR: 9.8). Separately, using a training set of 72 tumors we established a 31-gene
signature that with 100% sensitivity, and 50% specificity, predicted the occurrence
of relapse to the bone in a testing set of 35 untreated LNN patients. Our results
pointed to the involvement of the FGF signaling pathway in preference of tumor
cells that relapse to bone. Further extensive pathway analysis studies including a
total of 345 tumors showed highly distinctive pathways that are associated with
poor prognosis in subgroups of 221 ER-positive and 124 ER-negative tumors. With
respect to DNA methylation analysis, using a microarray-based technology for the
analysis of promoter CpG methylation for 117 candidate genes, we found that
phosphoserine aminotransferase was the strongest factor associated with failure to
tamoxifen therapy in 200 patients with recurrent breast cancer. In LNN patients who
were treated with adjuvant tamoxifen, PITX2 appeared the strongest prognostic
factor, which was confirmed in several multicenter studies. A major advantage of
DNA-methylation analysis is that it can easily be performed by methylation specific
PCRs on DNA isolated from paraffin-embedded tissues as well.
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*In collaboration with Veridex LLC, a Johnson & Johnson Company, San Diego, USA;
the EORTC Receptor and Biomarker Group; and Epigenomics AG, Berlin, Germany,
together with the EpiBreast Group.