A 13-gene signature predicting rapid development of brain metastases in breast cancer

Brain metastases from breast and other cancers constitute an important part of therapeutic failures and are associated with severe morbidity and mortality. Here, we have examined histopathological data and generated gene expression data in two independent cohorts of primary tumors from HER2-positive advanced breast cancer patients. We report that the combination of estrogen receptor (ER) negativity and expression of a novel 13-gene signature identify a subset of patients with rapid (median, 31 and 41 months in discovery and validation cohorts, respectively) versus slower (median, 66 months and 77 months in discovery and validation cohorts, respectively) development of brain metastases (P<0.0001). The 13-gene signature also predicted rapid brain metastasis formation within the ER-negative subset of patients (P=0.014). Interestingly, three of the genes in the signature (RAD51, BARD1, FANCG) function in DNA double strand break repair. Overexpression of RAD51 in immortal MCF-10A breast epithelial cells altered their three-dimensional acinar morphology to increase the percentage of invasive structures by 6.5 fold, in the presence or absence of HER2 overexpression. In summary, ER negativity and a novel 13-gene signature may have the potential to identify subpopulations at highest immediate risk for the development of brain metastases in HER2-positive advanced breast cancer. Our results also suggest that RAD51, found in the 13-gene signature, may promote aggressiveness in breast epithelial cells. These data may be useful in the design of brain metastasis preventive trials and may prompt new treatment strategies Median normalized data provided Using Illumina DASL Cancer gene panel we analyzed gene expression of 502 oncogenes in 87 breast cancer patients. The data was divided into a training (n=62) and an internal validation set (n=25). Clincal parameters were noted for each patient. The data was analyzed in order to determine whether the 13-gene signature is associated with the brain metastasis-free survival (BMFS) when it was simply classified as being lower or higher than the median.