Impact of extracranial disease status on survival after initial central nervous system (CNS) involvement and radiation therapy in HER2+ breast cancer brain metastases (BCBM).
Authors: Noteware Laura , Ramirez Luis , Dalal Nicole , Herndon James Emmett , Floyd Scott R. , Van Swearingen Amanda E.D. , Anders Carey K. , Sammons Sarah 
Published: June 2021

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Background: BCBMs are very common in metastatic HER2+ breast cancer. CNS-directed local therapy is the gold standard for treatment, followed by systemic HER2-targeted therapies. In patients with HER2+ BCBM and stable extracranial disease (ECD), consensus guidelines recommend continuing current systemic therapy after local therapy. Our goal was to determine the implications of ECD status at time of HER2+ BCBM first CNS involvement on outcomes including intracranial progression-free survival (PFS1) and overall survival (OS). Methods: Retrospective analysis was performed on data extracted from 77 patients with HER2+ BCBM who received CNS radiation at Duke between 2006 and 2020 following initial documentation of CNS involvement. Demographics, dates of metastatic and intracranial diagnosis, ECD status at first CNS involvement, systemic therapy, and outcomes were collected. The primary endpoint was PFS1 defined as the time from first CNS radiation to the subsequent documentation of intracranial progression (RANO-BM). OS was defined as time from first CNS radiation and first metastatic disease to date of death or last known alive. ECD status was defined by RECIST1.1 from systemic staging scans within 30 days of first CNS involvement. Results: In this patient cohort of HER2+ BCBMs undergoing CNS radiation at first CNS involvement, >50% of patients had extracranial disease control: no ECD (25%) or stable/responding disease (31%). 52% of patients’ tumors were ER+. Median age was 50 years (range 27 – 75). Most patients (58%) developed first CNS involvement during adjuvant or first/second line metastatic therapy. For first CNS radiation, 49% received SRS and 48% WBRT. All patients with no ECD presented with isolated CNS disease as first metastatic presentation. Median OS in this cohort from initial metastatic disease to death was markedly worse for patients with no ECD (25.3m, 95% CI: 16.8 to 35.3) compared to those with progressive or stable/responding ECD (48.8m, 95% CI: 28.1 to 65; and 52.9 months, 95% CI: 43.7 to 73.3, respectively; p=0.03). Median OS from first CNS involvement to death was not statistically different amongst groups. This analysis did not detect median PFS1 differences based on ECD after first CNS radiation: progressive ECD (6.3m), no ECD (8.7m), or stable/responding ECD (10.6m) (p=0.13), though clinically meaningful differences were observed. Conclusions: Patients with isolated HER2+ BCBM with no ECD at the time of their initial CNS involvement (25% of population) have substantially worse OS compared to patients who present with ECD and develop CNS metastases later in their disease course. This population with isolated CNS disease at metastatic presentation deserves investigation of novel treatment algorithms, including earlier introduction of brain penetrable HER2-targeted agents.