In a retrospective cohort study from Memorial Sloan Kettering Cancer Center, which was reported in JAMA Network Open, Ferraro et al found that patients with ERBB2 (formerly HER2 or HER2/neu)-positive breast cancer and central nervous system (CNS) metastases only vs concomitant extracranial metastases experienced longer overall survival but remained at high risk for death from CNS causes.
“The findings suggest that aggressive treatments (both local and systemic) may be warranted to control the intracranial progression of CNS metastases,” the investigators commented.
Study Details
The investigators focused on 274 patients (female: 99.3%; median age = 53.7 years) with ERBB2-positive metastatic breast cancer and CNS disease—including parenchymal brain metastases, leptomeningeal disease, and dural metastases—who were treated between August 2010 and April 2022 at Memorial Sloan Kettering Cancer Center.
Nearly half of the study population (n = 125; 45.6%) presented with de novo metastatic breast cancer. At the time of CNS metastasis diagnosis, 73 patients (26.6%) had disease confined solely to the CNS. For those still alive at the end of follow-up, the median follow-up duration from CNS disease diagnosis was 3.7 years.
Overall survival was estimated using the Kaplan-Meier method. Cumulative incidence analyses were used to assess CNS-related mortality.
Survival Outcomes
According to the investigators, both overall survival and CNS-related death were significantly correlated with the pattern of presentation. The duration of overall survival was found to be shortest in patients with leptomeningeal disease (1.24 years; 95% confidence interval [CI] = 0.89–2.08 years), longer in those with extracranial metastases (2.16 years; 95% CI = 1.87–2.58 years), and longest in those with parenchymal or dural CNS disease only (3.57 years; 95% CI = 2.10–5.63 years) (P = .001).
A total of 192 patients (70.1%) died, of whom 106 (55.2%) died of a CNS-related cause; the most common cause of CNS-related death was brain metastasis progression–associated decline (n = 72 of 192; 37.5%). Patients with CNS-only disease seemed to continue to experience a high risk of death from CNS-related causes, with a 3-year CNS-related death rate of 34.0% (95% CI = 22.8%–45.4%) and 3-year death rate from other causes of 6.1% (95% CI = 1.9%–13.7%). Multivariable modeling for CNS-related death revealed that leptomeningeal disease (hazard ratio [HR] = 1.87; 95% CI = 1.19–2.93; P = .007) and treatment with whole-brain radiotherapy (HR = 1.71; 95% CI = 1.13–2.58; P = .01) were associated with CNS-related death.
The investigators concluded: “More effective CNS-penetrant systemic therapies are urgently needed. As new anti-ERBB2 and other anticancer agents emerge, clinical trials should include patients with CNS disease to evaluate intracranial efficacy from the early stages of drug development. Additionally, trial designs should incorporate endpoints that specifically address CNS outcomes, including CNS-related mortality.”
Nelson S. Moss, MD, of Memorial Sloan Kettering Cancer Center, New York, is the corresponding author of the JAMA Network Open article.
Disclosure: The study was funded in part by a grant from the National Cancer Institute. For full disclosures of the study authors, visit jamanetwork.com.
