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Breast cancer brain metastases pose significant clinical challenges and are associated with poor outcomes, and researchers are exploring new treatment strategies.

As noted by the authors of a review in , preclinical and clinical studies have provided insights into the biology of brain metastases, and there have been promising advances in systemic therapies that can penetrate the blood brain barrier.

"The prevention of primary and secondary brain metastases in breast cancer is an evolving field, incorporating immunotherapy, precision medicine, and therapeutic combinations to advance patient care and outcomes," wrote Akshara S. Raghavendra, MD, MS, and Nuhad K. Ibrahim, MD, both of the University of Texas MD Anderson Cancer Center in Houston.

Neither were available for an interview, and the following responses are from the review.

What is an example of a systemic therapy able to penetrate the blood brain barrier that is being studied for treating breast cancer brain metastases?

Temozolomide, an alkylating agent known for its effective penetration through the blood brain barrier, has been studied in the context of brain metastases. Several phase II studies have indicated improved response rates when temozolomide is combined with radiotherapy. None of these studies, however, showed a significant improvement in overall survival.

A of combination therapy with temozolomide and capecitabine for breast cancer brain metastases found the combination was well tolerated and showed significant antitumor activity, with an 18% objective response rate in the brain. (Overall survival was not addressed in the trial.)

In a , the combination of temozolomide and cisplatin demonstrated synergistic effects. Over 30% of patients with brain metastases from breast cancer had improvement after receiving this combination treatment, and another 16% maintained a stable condition.

These findings suggest the potential for additional combination therapies, including targeted agents, antibody-drug conjugates, and temozolomide.

How are researchers investigating preventing brain metastases in breast cancer?

In the , symptomatic or progressive central nervous system (CNS) recurrences were observed in 20 patients (8.3%) treated with neratinib-paclitaxel compared with 41 (17.3%) in the trastuzumab-paclitaxel group (RR 0.48, P=0.002).

And in the , brain metastases recurrence occurred in a lower proportion of patients in the neratinib-capecitabine group compared with the lapatinib-capecitabine group (cumulative incidence of intervention 22.8% vs 29.2%, respectively).

These data serve as a proof of concept and a basis of hypothesis generation that neratinib may serve as a CNS metastasis prevention agent.

What strategies are being explored to address the neurocognitive dysfunction associated with whole-brain radiation therapy?

Memantine, an N-methyl-d-aspartate (NMDA) receptor antagonist, mitigates NMDA receptor stimulation, offering benefits in vascular dementia and neuroprotection in preclinical animal models of brain irradiation.

, a double-blind, placebo-controlled phase III trial, explored the use of memantine in preventing cognitive dysfunction in patients with brain metastases undergoing whole-brain radiation therapy. In this study involving 508 patients, the memantine arm had a cognitive failure rate of 53.8% compared with 64.9% for the placebo arm, suggesting potential effectiveness in mitigating cognitive decline during brain irradiation.

Studies such as , using standardized cognitive assessments, have shown that hippocampal-sparing techniques such as intensity-modulated radiotherapy/shielding can significantly reduce cognitive decline compared with conventional whole-brain radiation therapy.

Finally, what is the state of research into treating brain or CNS metastases in patients with triple-negative breast cancer (TNBC) and leptomeningeal disease (LMD)?

Despite limited data availability, ongoing clinical studies aim to improve treatment strategies for TNBC. These treatments include chemotherapy with capecitabine, platinum-based agents, and topoisomerase inhibitors such as etirinotecan pegol (NKTR-102).

A is evaluating safety, objective response rate, and systemic and CNS-specific progression-free survival in patients with CNS disease, including those with LMD, treated with pembrolizumab.

The published literature underscores the need for clinical trials involving poly(ADP-ribose) polymerase inhibitors -- including niraparib, olaparib, talazoparib, and veliparib -- or alternative anti-breast cancer medications that can penetrate the CNS to treat brain metastases in patients with breast cancer with germline BRCA mutations.

This imperative is particularly crucial for individuals with recurrent TNBC, including those with and without gBRCA mutations.

Read the review here.