# Impact of Anti-HER2 Therapies on Overall Survival in Patients with HER2-Positive Metastatic Breast Cancer: Focusing on Intracranial Efficacy of Emerging Treatments

## TL;DR

This review examines how anti-HER2 therapies improve survival in HER2-positive breast cancer patients, especially those with brain metastases.

## Contribution

The paper provides a focused analysis on the intracranial efficacy of emerging HER2-targeted therapies.

## Key findings

- Trastuzumab and pertuzumab significantly extended overall survival in HER2-positive metastatic breast cancer patients.
- T-DXd showed notable intracranial activity with a 64.9% objective response rate in patients with active brain metastases.
- Tucatinib reduced intracranial progression by 68% and improved survival in patients with brain metastases.

## Abstract

Many patients with breast cancer overproduce the protein HER2, which drives aggressive tumor growth. Therapies directed at HER2 have substantially extended survival; however, up to one-third of patients still experience spread to the brain, where management is particularly challenging. This review synthesizes evidence on the significant classes of HER2-targeted therapy—monoclonal antibodies, antibody–drug conjugates, and small-molecule inhibitors—highlighting survival outcomes and activity in the brain. We appraise results from pivotal clinical trials, delineate the most effective current options, and address unresolved questions such as optimal sequencing, integration with local treatments, and selection according to tumor characteristics. We aim to provide a clear, patient-centered overview that informs clinical practice, guides future research, and supports strategies to prevent and control brain involvement.

Therapies targeting human epidermal growth factor receptor 2 (HER2) have substantially improved overall survival in patients with HER2-positive metastatic breast cancer. Approximately 31% of these patients develop brain metastases, representing a significant therapeutic challenge. This review classifies anti-HER2 therapies into three categories: monoclonal antibodies (MABs), antibody-drug conjugates (ADCs), and tyrosine kinase inhibitors (TKIs). The mechanisms of action and clinical impacts of these agents are examined, with particular attention to intracranial efficacy. The introduction of trastuzumab increased overall survival (OS) from 20.3 to 25.1 months compared to chemotherapy alone. The addition of pertuzumab further extended survival to 57.1 months, as demonstrated in the CLEOPATRA trial. Among ADCs, T-DM1 improved OS to 29.9 months versus 25.9 months in the EMILIA trial, while T-DXd extended OS to 52.6 months in DESTINY-Breast03. T-DXd also demonstrated notable intracranial activity, achieving a 64.9% objective response rate in patients with active brain metastases. In the HER2CLIMB trial, tucatinib reduced intracranial progression by 68% and improved OS (24.7 vs. 19.2 months) in patients with active brain metastases. Recent advances have increased median OS from approximately 20 months prior to trastuzumab to over 50 months with current therapies. Future research should focus on optimizing treatment sequencing, refining biomarker-driven approaches, and developing targeted strategies for brain metastases to further improve long-term survival outcomes.