38 The overall approach for developing this prognostic profile merely was distinct from that used in the development of the previously discussed Oncotype DX assay, which was derived from a set of 250 preselected candidate genes believed to have prognostic importance in hormone-receptor-positive breast cancer. MammaPrint has been shown to be a prognostic marker, independent of conventional clinical and pathologic factors such as tumor size, hormone receptor status, and HER2 status. MammaPrint was cleared for use by the FDA in 2007, and at publication, was the only FDA-approved breast cancer genomic assay. The biological functions of the 70 genes in the MammaPrint signature are associated with the essential steps necessary for tumor progression and metastasis.

These genes are the hallmarks of cancer-related biology, regulating cell cycle, invasion, metastasis, proliferation, local invasion, survival in circulation, extravasation, and adaptation to the micro-environment as well as angiogenesis. They reflect the acquired malignant characteristics of a cancer cell along with tumor progression and metastasis-related biological activities.39 The MammaPrint signature was designed based on overall expression levels to divide patients into low and high risk groups that correspond with 10-year distant metastasis-free survival rates of >90% or <90%, respectively, in the original datasets involving breast cancer patients who underwent surgery alone without any systemic therapy. MammaPrint was first validated in a series of 295 consecutive invasive breast tumors from patients with early stage breast cancer who were all part of the tumor bank at the Netherlands Cancer Institute (NKI).

The 70-gene profile was found to be a strong independent predictor of clinical outcome, and added to the predictive power of standard clinical-pathologic parameters.40 In a multivariate analysis, MammaPrint was the strongest predictor of 10-year distant metastasis-free survival with a hazard ratio of 4.6 (95% CI, 2.3�C9.2).40 The second Dacomitinib independent validation study for MammaPrint was performed by the TRANSBIG Consortium.41 The 5 participating European hospitals evaluated 302 patients who had received loco-regional therapy but no systemic adjuvant therapy. The median follow-up in this dataset was 13.6 years. The median distant metastasis-free survival at 10 years was 90% and 69% for low- and high-risk groups, respectively.42 On multivariate analysis, MammaPrint was found to provide independent prognostic information beyond what could be determined from patient age, tumor grade, size, or hormone receptor status in a population of node-negative breast cancer patients, none of whom had received any adjuvant endocrine or chemotherapy.