Abstract
BACKGROUND: Approximately one third of patients with HER2-positive (+) metastatic breast cancer (MBC) develop brain metastases (BrM). In light of discordant control of extracranial metastases (ECM) versus BrM for standard-of-care antibody-based therapies for these patients, and the frequent use of radiation and surgical therapies particularly for patients with CNS-centric disease, we sought to determine the proportion of HER2+ MBC patients with BrM who suffered neurologic death in the CNS-only and intracranial-plus-extracranial metastasis settings, and the clinical risk factors of such. METHODS: Clinicopathologic data for HER2+ MBC patients with BrM treated at an NCI-designated Comprehensive Cancer Center between August 2010 and April 2022 were collected, including disease burden at cancer presentation, the timing and pattern of BrM and ECM, and neurologic complications. CNS-related death was defined as any mortality caused by BrM, leptomeningeal progression, or BrM-associated complication. RESULTS: 275 patients were included. 58/275 (21%) presented with CNS as only and first site of metastasis; the remaining (217/275, 79%) developed BrM synchronously with or subsequent to ECM. 125/275 (45%) had de novo MBC, and nearly all patients were treated with CNS therapies (254/275 [92%] received at least one radiation treatment and 88/275 [32%] underwent BrM resection). After a median follow-up of 2.5 years, 193/275 (70%) patients died, of whom 105 (54%) of CNS-related cause. The median OS was 3 years (95% CI=1.47-5.14) and 2 years (95% CI=1.74-2.34) for patients with CNS-only versus BrM concurrently/subsequent to ECM, respectively (p=0.059). The cumulative incidence of CNS-related death at 5 years was 40% (95%CI=33-46%). CONCLUSIONS: Almost half of patients with HER2+ BrM suffered neurologic death. Patients with CNS-only disease had better OS than patients with synchronous/preceding ECM, suggesting that overall burden of disease affects mortality. With high rates of durable extracranial control with HER2-directed therapies, new strategies to prevent and eradicate CNS disease are urgent.