Breast cancer is the second most common origin of brain metastasis after lung cancer. Brain metastasis in breast cancer is commonly found in patients with advanced course disease and has a poor prognosis because the blood–brain barrier is thought to be a major obstacle to the delivery of many drugs in the central nervous system. Therefore, local treatments including surgery, stereotactic radiation therapy, and whole-brain radiation therapy are currently considered the gold standard treatments. Meanwhile, new targeted therapies based on subtype have recently been developed. Some drugs can exceed the blood–brain barrier and enter the central nervous system. New technology for early detection and personalized medicine for metastasis are warranted. In this review, we summarize the historical overview of treatment with a focus on local treatment, the latest drug treatment strategies, and future perspectives using novel therapeutic agents for breast cancer patients with brain metastasis, including ongoing clinical trials.

Human epidermal growth factor receptor 2 (HER2) protein, which is characterized by the amplification of ERBB2, is a molecular target for HER2-overexpressing breast cancer. Many targeted HER2 strategies have been well developed thus far. Furthermore, intratumoral heterogeneity in HER2 cases has been observed with immunohistochemical staining and has been considered one of the reasons for drug resistance. Therefore, we conducted an integrated analysis of the breast cancer single-cell gene expression data for HER2-positive breast cancer cases from both scRNA-seq data from public datasets and data from our cohort and compared them with those for luminal breast cancer datasets. In our results, heterogeneous distribution of the expression of breast cancer-related genes (ESR1, PGR, ERBB2, and MKI67) was observed. Various gene expression levels differed at the single-cell level between the ERBB2-high group and ERBB2-low group. Moreover, molecular functions and ERBB2 expression levels differed between estrogen receptor (ER)-positive and ER-negative HER2 cases. Additionally, the gene expression levels of typical breast cancer-, CSC-, EMT-, and metastasis-related markers were also different across each patient. These results suggest that diversity in gene expression could occur not only in the presence of ERBB2 expression and ER status but also in the molecular characteristics of each patient.

Background: Biomarkers to predict the recurrence risk are required to optimize perioperative treatment. Adjuvant chemotherapy for patients with human epidermal growth factor 2-positive (HER2-positive) early breast cancer is decided by pathological responses of neoadjuvant chemotherapy (NAC). However, whether pathological responses are appropriate biomarkers is unclear. Currently, there are several studies using minimal residual disease (MRD) as a predictor of prognosis in solid tumors. However, there is no standard method for detecting MRD. Objectives: This study aimed at prospectively evaluating the relationship between MRD detection and recurrence in Asian patients with HER2-positive early breast cancer. Design: Prospective, observational, single-group, and exploratory. This study will include 60 patients from 2 institutions in Japan and the Philippines. The invasive disease-free survival (IDFS) rates of the MRD-positive and MRD-negative groups are compared in patients with HER2-positive early breast cancer who undergo surgery after receiving NAC. Methods and analysis: Circulating tumor DNA (ctDNA) levels of patients will be evaluated 6 times: before NAC, after NAC, after surgery, and annually after surgery for 3 years. We will analyze the genetic profile of blood and tissue samples using the Todai OncoPanel (TOP) and the methylation level of DNA. The primary endpoint is IDFS. Secondary endpoints include overall survival (OS) and disease-free survival (DFS). Patient enrollment began in June 2022, and new participants are still being recruited. Ethics: This study has been approved by the National Cancer Center Hospital Certified Review Board in March 2022 and has been approved by the Research Ethics Board of the participating center. Discussion: Our findings will contribute to determining whether MRD detection using TOP is useful for predicting the recurrence of HER2-positive early breast cancer. If this is proven, MRD detected by TOP could be used in the future as a biomarker to assist in the de-/escalation of treatment strategies in the next interventional trial, thereby avoiding overtreatment in patients at low risk, and in the addition of intensive treatment modalities for those in patients at high risk.