Abstract ES3-3: Systemic therapy for breast cancer brain metastases
Authors: Lin N 
Published: May 2019

Abstract
Brain metastases occur in up to half of patients with HER2-positive metastatic breast cancer, 25-45% of patients with metastatic triple-negative breast cancer, and 10-15% of patients with metastatic ER-positive breast cancer. While local approaches such as surgery and radiotherapy can be effective, they do not address extracranial disease, and can be associated with short- and long-term toxicity. As some subsets of patients live longer after a diagnosis of brain metastasis, there is increasing interest in systemic approaches in lieu of repetitive rounds of local therapy. To date, no systemic therapy has gained an indication for the specific treatment of breast cancer brain metastases; however, a number of regimens have been associated with efficacy in the central nervous system (CNS) in non-randomized studies. For patients with HER2-positive breast cancer, the combination of lapatinib and capecitabine has been associated with CNS response rates of 66% in the upfront setting, and 18-38% in patients whose disease has progressed after prior radiotherapy. Several investigational HER2-targeted tyrosine kinase inhibitors have shown promise. The combination of tucatinib, capecitabine and trastuzumab was associated with a CNS response rate of 42% in a small number of patients with brain metastases treated on the phase 1 trial. Notably, patients with brain metastases (either stable or progressive) are allowed on the current tucatinib registration trial (NCT02614794). The combination of neratinib and capecitabine led to a CNS response rate = 49% in a prospective phase 2 trial. Finally, trastuzumab-emtansine has been reported to lead to CNS regressions in up to 40% of patients, based upon case series from several institutions.
For patients with ER-positive breast cancer, endocrine therapies such as tamoxifen and aromatase inhibitors have been reported to induce CNS responses in case reports and small case series. Recently, there has been interest in exploring the role of CDK4/6 inhibitors in patients with brain metastases. Preliminary results of the JPBO study support potential CNS efficacy of abemaciclib in patients with ER+ breast cancer; final results are awaited. To date, no commercially available targeted agents have demonstrated efficacy against brain metastases from triple-negative breast cancer. Trials of immunotherapy approaches in breast cancer have almost completely excluded patients with active/progressive brain metastases and thus, the safety/efficacy profile of immunotherapy in this setting is unknown, though promising data in melanoma and lung cancer would support its exploration in patients with brain metastases from breast cancer.
Despite the fact that most chemotherapeutic agents do not cross the intact blood brain barrier, it appears empirically that the blood-tumor barrier can be sufficiently disrupted to allow for CNS efficacy in the case of established brain metastases. Diverse agents including anthracyclines, capecitabine, platinum salts, and irinotecan have been reported to be associated with CNS response in breast cancer patients. Newer compounds which have been engineered to improve upon CNS penetration and/or CNS residence time are in clinical development and testing.
Citation Format: Lin N. Systemic therapy for breast cancer brain metastases [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr ES3-3.