In the case of brain metastases, the optimal timing of BBBD in relation to treatments for the systemic primary must also be considered: should BBBD be included upfront and in conjunction with systemic therapies of established effectiveness (e.g., Herceptin for Her2 positive breast cancer), in the absence of evidence of metastases, or should this be isolated to patients with established metastases only? This evidence concerns the gene ERBB2 and breast cancer.