摘要：
Background: Triple-negative (TN) breast cancer, a lack of understanding of the driving oncogenic mechanisms and thus therapeutic targets has left this an understudied 'Cinderella' in breast cancer phase III trials. No publication has been addressed on recurrent signature and pathway signaling of Asia TN breast cancer. The gene expression difference between Eastern and Western breast cancer is also unknown.Material and Methods: 185 represent breast cancer cases including 43 Luminal A, 31 Luminal B, 35 Her-2 type, 51 TN and remaining 25 unclassified were selected from our tissue bank. Using Agilent microarray chip, we explored gene expression profile of these patients. For direct western and eastern comparison, 195 Caucasian breast cancer gene expression profile using the same Agilent platform were downloaded wedsite. In TN breast cancers, excluding 3 cases with stage IV disease at diagnosis, 11 patients developed distant recurrence during follow up. For these 48 patients, recurrent model was established by two step Cox proportional hazard regression: in first step, 35 candidate recurrent genes were selected from 20173 genes with significant level less than 0.0005. Then, we randomly choose 4 genes from the 35 candidate genes to construct recurrent model to avoid overfitting. TN related signaling pathways were discovered using Ingenuity Pathway Analysis(IPA) and GSEA(Gene Set Enrichment Analysis).Results: Using non-supervised analysis, we found the eastern and western breast cancers have their own TN cancer clustering phenomenon, obviously in a different cluster.This represented the eastern and western breast cancer have fundamental differences. The model including PKRAG3, MORC2, GRB7, FAM43A showed the best recurrence prediction power in 52360 combination models(R Square 0.71). This model was cross-validated by Vector machine(SVM) with leave one out setting. The overall accuracy was 87.5%. The sensitivity and specificity were 72.7% and 91.9%. This model was failed to predict recurrence in Luminal or Her-2 Molecular type. With IPA, we found 9 TN related pathway. The top two were cAMP-mediated and Ephrin Receptor signaling. 10 pathways were found from GSEA. Nicotinate, Olfactory transduction and Axon guidance were on the top of the list. Further functional study is on going.Discussion: This is the first study to compare the gene expression between eastern and western breast cancer on the same gene expression platform. The gene expression profile is fundamentally different between eastern and western TN breast cancers. This phenomenon infers different biological behavior and drug sensitivity may exist among different ethnic groups. We established recurrent prediction model unique for Taiwanese TN breast cancer by four genes with high accuracy. We can develop commercial recurrent kit after further clinical validation.Figure available in online version.Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-04-03.
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