Data Provide More Nuanced View of Brain Lesions in Metastatic HER2+ Breast Cancer

Survival in metastatic HER2-positive breast cancer with brain lesions varied by lesion location and presence or absence of lesions outside the central nervous system (CNS), a large retrospective review suggested.

Patients with leptomeningeal disease (LMD) at diagnosis had a median overall survival (OS) of 1.24 years as compared with 3.57 years among patients with parenchymal or dural lesions. Patients with metastatic disease confined to the CNS remained at high risk of CNS-related death, with a rate of 33.98% at 3 years versus 6.07% for death from other causes.

More than half of all deaths in the entire 274-patient cohort resulted from CNS-related causes, reported Nelson Moss, MD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York City, and co-authors in JAMA Network Open, concluding that “CNS progression was the most common cause of death.”

“Despite high rates of local therapy, patients with CNS-only disease experienced longer survival than those with concomitant extracranial metastasis but still had significant CNS-related mortality,” they wrote. “More effective CNS-penetrant systemic therapies are urgently needed.”

“As new anti-[HER2] and other anticancer agents emerge, clinical trials should include patients with CNS disease to evaluate intracranial efficacy from early stages of drug development,” they added. “Additionally, trial designs should incorporate endpoints that specifically address CNS outcomes, including CNS-related mortality.”

The findings represent a fundamental shift in the interpretation of CNS involvement in HER2-positive metastatic breast cancer, according to the authors of an accompanying editorial.

“No longer just an inexorable harbinger of decline, instead metastatic breast cancer with CNS involvement is reframed by this research as a dynamic landscape imbued with therapeutic potential — a locus of opportunities,” asserted Dario Trapani, MD, of the University of Milan, and co-authors. “Far from being yet another contribution to the already monumental canon of oncology literature, the study … constitutes a critical inflection point that demands that we recalibrate both our clinical expectations and our ambitions not merely as an addition but as a benchmark to shape the future.”

“[The authors] have charted a transformative path forward in the management of [HER2-positive] breast cancer with CNS involvement,” they continued. “The insights from their analysis challenge entrenched paradigms, offering a compelling argument that the CNS is a therapeutic frontier ripe for transformative outcomes. The work stands as a call to the oncology community to integrate multidisciplinary strategies that will elevate both survival and QoL [quality of life] and address patients’ challenges as part of the clinical trial-based research questions.”

Brain metastasis occurs in about a third of patients with advanced HER2-positive breast cancer. Survival in metastatic HER2-positive breast cancer has improved in the past decade with the advent of newer, more effective therapies, but the efficacy of many agents is hypothesized to be driven by extracranial effects rather than in the CNS, Moss and colleagues noted in their introduction.

CNS metastases pose a treatment challenge. Multimodal local approaches offer good local disease control and symptom palliation but also confer potential risks and have unclear effects on OS and CNS-related mortality, the authors noted. Data on the cause of death for these patients remain limited. Better understanding of CNS-related death and its potential correlates may help guide choices for aggressive local therapies.

For this study, the investigators reviewed records for all patients with metastatic HER2-positive breast cancer and CNS disease treated at MSKCC from August 2010 to April 2022. Primary outcomes were OS and CNS-related mortality.

The 274-patient cohort had a median age of 53.7, and 45.6% had de novo metastatic disease. At diagnosis of CNS metastasis, 26.6% of patients had CNS-only disease. The cohort had a median follow-up of 3.7 years from diagnosis of CNS disease among surviving patients.

OS and CNS-related death had significant correlations with the pattern of CNS involvement at diagnosis. OS was lowest for patients with LMD, intermediate for patients with extracranial metastasis (2.16 years), and highest for patients with parenchymal or dural disease only (P=0.001).

Of 192 patients who died during the follow-up period, 55.2% died of CNS-related causes. Patients with CNS-only disease had a high risk of CNS-related death as compared with the risk of death from other causes. Multivariable modeling for CNS-related death showed that LMD and whole-brain radiotherapy were independent predictors of CNS-related death (HR 1.87, 95% CI 1.19-2.93, P=0.007 and HR 1.71, 95% CI 1.13-2.58, P=0.01, respectively).

“CNS-only presentation was associated with improved survival but a higher rate of CNS-related death, supporting an approach of aggressive local therapy for select patients,” the authors concluded.

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