Abstract P6-05-02: Molecular genetic grading in breast cancer: Development and validation of a prognostic marker

Background: Histopathological grading is an important part for the characterization of breast cancer with regard to prognosis and treatment options. 30-60% of breast cancer patients have a grade 2 (G2) malignancy resulting in an intermediate prognosis and the challenge of finding individualized adequate treatment options. Moreover, the lack of objectivity of the grading system is criticized. With the genetic analysis of breast cancer, the deciphering of its genes and gene expression profiling using microarray technology is a new way of classifying breast cancer Patients, Materials, and Methods. Tumor tissue from 229 breast cancer patients collected from January 2009 - June 2010 was examined. A histological grading of the tumors was determined and gene expression profiling was performed by microarray technology (Agilent Technologies). Gene expression data were reduced and a novel molecular grade index (MGI-9) was defined as a G1 versus G3 classifier by SAM (Significance Analysis of Microarray) and PAM (Prediction Analysis of Microarray). The validity of the newly defined MGI-9 as a prognostic factor was tested by applying it to three published data sets with external follow-up information for a total of 760 patients Results: The significance analysis of gene expression profiles of 229 breast cancer patients using SAM showed more than 11,000 significantly differentially expressed genes according to the grading classes G1-2-3. The number of differentially expressed genes was reduced to 228 genes by SAM analysis using only the G1 vs. G3 cases (63 patients). PAM analysis resulted in a more reduced classifier of 44 molecular probes and we could show that a subset of 9 genes gave similar classification results and could reliably used in FFPE Material. The new MGI-9 index was tested in thee external data sets (GSE1456, GSE2034 and GSE3494) and could subdivide the histological G2 group in two molecular subgroups G2A and G2B with significant impact on survival in all test scenarios. Conclusion: The results show that MGI 9-gene molecular grade index is more informative than the conventional histopathological grading system. In order to validate MGI-9 a prospective, randomized study with long-term follow-up for local recurrence rate and distant metastases is urgently needed. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-05-02.