Abstract CS1-3: Systemic Therapy for Breast Cancer Brain Metastases
Authors: Lin N 
Published: March 2020

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 incorporating systemic approaches. 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. The combination of neratinib and capecitabine led to a CNS response rate = 49% in the prospective, TBCRC 022 trial, in a population of heavily pre-treated patients. The TBCRC 022 trial is now enrolling to a cohort who will receive ado-trastuzumab emtansine + neratinib. 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 (HER2CLIMB; NCT02614794). Finally, there is evidence that monoclonal antibodies and antibody drug conjugates may have CNS activity; for example, trastuzumab-emtansine has been reported to lead to CNS regressions in up to 40% of patients, based upon case series from several institutions, and in preliminary data from the PATRICIA study, the regimen of high dose trastuzumab (6 mg/kg weekly) plus pertuzumab was associated with CNS responses and prolonged stable disease in a subset of patients. 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. Results of the JPBO study demonstrate modest CNS efficacy of abemaciclib in patients with ER+ breast cancer, but the CNS ORR was &lt;10%. 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. An ongoing randomized trial testing carboplatin +/- veliparib is asking the question of whether a PARP inhibitor may add to platinum efficacy both intracranially and extracranially. Finally, 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 (NKTR-102, Nal-IRI, tesetaxel, ANG1005) which have been engineered to improve upon CNS penetration and/or CNS residence time are in clinical development and testing.
Citation Format: N Lin. Systemic Therapy for Breast Cancer Brain Metastases [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr CS1-3.