Changing Natural History of HER2–Positive Breast Cancer Metastatic to the Brain in the Era of New Targeted Therapies

Patients with breast cancer brain metastases historically have a poor prognosis. In this single-institution cohort study of patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer brain metastases, we found no improvement in survival after brain recurrence over time despite wide adoption of HER2–targeted therapies. This highlights the importance of continued development of novel brain penetrant therapies for patients with HER2–positive metastatic disease to extend survival and improve quality of life. Given the wide adoption of human epidermal growth factor receptor 2 (HER2)-targeted therapies for advanced HER2–positive breast cancer, we studied the natural history of patients with HER2–positive breast cancer brain metastases (BCBM) over time. Patients with HER2–positive BCBM identified from a prospectively maintained database at the University of North Carolina were divided into 3 cohorts by year of BCBM diagnosis. Cohorts were selected by year of HER2–targeted therapy US Food and Drug Administration approval. Overall survival (OS), time to first metastasis, time to BCBM, and BCBM survival were estimated by the Kaplan-Meier method. Associations between OS after BCBM and clinical variables were assessed by Cox proportional hazards regression models. One hundred twenty-three patients were identified. Median age was 51 years, and 58% were white and 31% African American. OS from initial breast cancer diagnosis improved over time: 3.6 years (95% confidence interval [CI], 2.8-6.1) in the 1998-2007 cohort, 6.6 years (95% CI, 4.5-8.6) in the 2008-2012 cohort, and 7.6 years (95% CI, 4.4-9.6) in the 2013-2015 cohort (P = .05). While time from initial diagnosis to first metastasis did not differ (P = .12), time to BCBM increased over time (2.6 years [95% CI, 1.3-3.5] for 1998-2007; 2.6 years [95% CI, 2.1-4.3] for 2008-2012, and 3.3 years [95% CI, 2.2-6] for 2013-2015; P = .05). Although OS from BCBM did not significantly differ by cohort, patients who received HER2–targeted therapy after BCBM had a prolonged OS (2.1 years [95% CI, 1.6-2.6] vs. 0.65 years [95% CI, 0.4-1.3]; P = .001). OS from initial breast cancer diagnosis significantly improved over time for patients with HER2–positive breast cancer who develop BCBM, now exceeding 7 years; survival from BCBM diagnosis may now exceed 2 years.