HER2 Expression Dynamics in Breast Cancer Brain Metastases and Its Impact on Survival

Background

Breast cancer is one of the most common cancers among women worldwide, and brain metastases (BrMs) pose a significant challenge for patients. In recent years, with the prolonged survival of breast cancer patients, the incidence of brain metastases has gradually increased, particularly in patients with HER2-positive (HER2+) and triple-negative breast cancer (TNBC). HER2 is an important biomarker, and its expression level not only influences treatment strategies for breast cancer but is also closely related to patient prognosis. Recently, HER2-low expression has emerged as a new therapeutic target, especially in the context of antibody-drug conjugates (ADCs) such as Trastuzumab Deruxtecan (T-DXd). The impact of HER2-low expression on treatment efficacy and patient survival has become a focal point of research.

However, data on the dynamic changes in HER2 expression between primary breast tumors and brain metastases, as well as its impact on patient survival, remain limited. To address this issue, a research team from the Dana-Farber Cancer Institute conducted a retrospective study to explore the changes in HER2 expression between primary breast tumors and brain metastases and to evaluate the impact of HER2-low expression on overall survival (OS).

Source of the Study

The study was conducted by Alyssa M. Pereslete, Melissa E. Hughes, Alyssa R. Martin, and other researchers, primarily from the Dana-Farber Cancer Institute and Harvard Medical School. The findings were published online on August 30, 2024, in the journal Neuro-Oncology, under the title “HER2 Expression in Primary Breast Tumors and Brain Metastases: Dynamics and Impact on Survival.”

Study Process and Results

1. Study Population and Data Collection

The research team reviewed clinical data from 197 breast cancer patients with brain metastases treated at the Dana-Farber Cancer Institute between 2003 and 2023. All patients underwent surgical resection of brain metastases, and HER2 expression status in both primary tumors and brain metastases was documented. HER2 expression status was classified according to ASCO/CAP guidelines as HER2-positive (HER2+, 3+ or 2+/ISH amplified), HER2-low (1+ or 2+/ISH negative), and HER2-negative (HER2–0).

2. Analysis of HER2 Expression Dynamics

The results showed that 81% of brain metastases exhibited HER2 expression, with 61% being HER2+, 20% HER2-low, and 19% HER2–0. Compared to primary tumors, HER2 expression in brain metastases showed significant changes:

• HER2+ Primary Tumors: 97% of HER2+ primary tumors retained HER2+ expression in brain metastases, with only 2.7% switching to HER2-low.
• HER2–0 Primary Tumors: 35% of HER2–0 primary tumors gained HER2-low expression in brain metastases, and 5.4% even switched to HER2+.
• HER2-low Primary Tumors: 52% of HER2-low primary tumors showed changes in HER2 expression in brain metastases, with 21% switching to HER2+ and 31% switching to HER2–0.

3. Survival Analysis

The research team further analyzed the impact of HER2 expression status on patient survival. The results showed:

• HER2+ Brain Metastases Patients: Compared to HER2-low patients, HER2+ patients had a significantly lower risk of death (HR = 0.41, p = 0.0006).
• HER2-low vs. HER2–0 Patients: There was no significant difference in survival between the two groups (HR = 0.96, p = 0.9).

4. Conclusions and Significance

This study is the first to systematically describe the dynamic changes in HER2 expression between primary breast tumors and brain metastases, revealing the prevalence of HER2-low expression in brain metastases and its impact on patient survival. The findings indicate that HER2 expression in brain metastases is highly variable, particularly with HER2–0 primary tumors often gaining HER2 expression in brain metastases, providing new insights for clinical treatment. Additionally, the study emphasizes the importance of developing non-invasive diagnostic tools to accurately assess HER2 expression in brain metastases, enabling more precise treatment strategies for patients.

Highlights of the Study

1. Systematic Description of HER2 Expression Dynamics: This study is the first to provide a detailed description of HER2 expression dynamics between primary breast tumors and brain metastases in a large sample, filling a gap in this field of research.
2. Impact of HER2-low Expression on Survival: The study reveals the prevalence of HER2-low expression in brain metastases and its impact on patient survival, providing new evidence for HER2-low as a therapeutic target.
3. Urgent Need for Non-Invasive Diagnostic Tools: The study underscores the importance of developing non-invasive diagnostic tools to accurately assess HER2 expression in brain metastases, enabling more precise treatment strategies for patients.

Research Value

This study not only provides new theoretical foundations for the treatment of breast cancer brain metastases but also offers significant support for the clinical application of HER2-low expression as a therapeutic target. The findings suggest that dynamic changes in HER2 expression in brain metastases may influence treatment choices and patient prognosis. Further research is needed to validate these findings and explore more effective treatment strategies.