Editor’s Note: HER2-positive breast cancer has a high incidence of brain metastases. In the era when treatment relied primarily on local therapies, patient survival outcomes were poor. The PERMEATE study demonstrated that the small-molecule tyrosine kinase inhibitor (TKI) pyrotinib combined with capecitabine showed favorable intracranial activity in this patient population. The BROPTIMA study further suggested that the addition of brain radiotherapy to pyrotinib plus capecitabine could improve progression-free survival; however, overall survival data remain unavailable. To date, high-level evidence is still lacking regarding optimization of treatment strategies for brain metastases and the impact of radiotherapy timing on quality of life and overall survival.
At the 2025 San Antonio Breast Cancer Symposium (SABCS), Professor Yan Min’s team from The Affiliated Cancer Hospital of Zhengzhou University (Henan Cancer Hospital) presented a nationwide multicenter real-world study reporting preliminary survival outcomes of two cohorts treated with pyrotinib plus capecitabine with or without radiotherapy in patients with HER2-positive breast cancer brain metastases (Abstract No. PS5-02-10). Oncology Frontier invited Associate Chief Physician Niu Limin from Henan Cancer Hospital to introduce and interpret this study.
Study Overview
Background Pyrotinib combined with capecitabine has demonstrated encouraging efficacy in patients with HER2-positive breast cancer brain metastases, and the addition of radiotherapy may further improve intracranial disease control. However, the optimal timing of local radiotherapy when combined with systemic therapy and its impact on overall survival remain unclear. Based on nationwide multicenter real-world data, this study analyzed 287 patients with HER2-positive breast cancer brain metastases treated with pyrotinib plus capecitabine, aiming to explore how different timings of brain radiotherapy affect overall survival in real-world clinical practice.
Methods This was a multicenter, bidirectional retrospective–prospective real-world study conducted across 41 centers in China (NCT05359120). Eligible patients were diagnosed with HER2-positive breast cancer with brain metastases and had complete diagnostic and treatment records in hospital electronic medical systems. Patients were divided into three cohorts according to radiotherapy status at the initiation of systemic treatment: Cohort A included patients who had not received prior radiotherapy; Cohort B included patients who received whole-brain radiotherapy and/or stereotactic radiosurgery within three months of starting systemic therapy; Cohort C included patients who initiated systemic therapy more than three months after completing radiotherapy. The systemic treatment regimen consisted of pyrotinib at a starting dose of at least 240 mg per day combined with capecitabine at a starting dose of at least 500 mg/m² twice daily on days 1–14 of a 21-day cycle, continued until disease progression, unacceptable toxicity, or withdrawal of consent. Study endpoints included overall survival, progression-free survival, and central nervous system progression-free survival. This report focuses on the results of Cohorts A and B.
Results Between September 2018 and January 2024, a total of 287 patients were enrolled, including 135 patients in Cohort A and 122 patients in Cohort B. The proportions of patients with active brain metastases were 88.9% in Cohort A and 61.5% in Cohort B, while the proportions with central nervous system symptoms were 27.4% and 52.5%, respectively.
As of May 6, 2025, the median follow-up times were 35.9 months for Cohort A and 45.3 months for Cohort B. Although Cohort B demonstrated a significantly longer CNS progression-free survival compared with Cohort A, with medians of 20.7 months versus 15.5 months respectively, this advantage did not translate into improvements in overall progression-free survival or overall survival. Median progression-free survival was 15.0 months in Cohort A and 15.5 months in Cohort B, with no statistically significant difference. Median overall survival was 35.4 months in Cohort A and 37.3 months in Cohort B, also without a statistically significant difference.
Investigator’s Perspective With recent advances in drug development, HER2-positive breast cancer brain metastases now have access to systemic therapies with demonstrated intracranial activity, making optimization of the sequencing between local and systemic treatments a key clinical question. Based on the PERMEATE study, our team initiated the Post-PERMEATE real-world study involving 41 centers nationwide to explore how different timings of radiotherapy affect long-term survival.
The results indicate that, on the basis of pyrotinib combined with capecitabine, early or concurrent radiotherapy did not provide additional benefits in overall progression-free survival or overall survival compared with delayed radiotherapy, even though CNS progression-free survival was improved. Therefore, for patients without symptoms or with controllable local symptoms, a strategy of prioritizing systemic therapy with central nervous system activity and deferring brain radiotherapy to avoid early radiotherapy-related neurotoxicity appears to be a feasible option. This real-world study provides evidence to support individualized treatment decision-making for patients with HER2-positive breast cancer brain metastases. Future prospective studies are warranted to further define the optimal sequencing of various treatment modalities.
Professor Yan Min Department of Breast Surgery, Henan Cancer Hospital Deputy Director, Henan Breast Disease Diagnosis and Treatment Center Chief Physician, MD, Master’s Supervisor
Dr. Niu Limin MD, Associate Chief Physician Department of Breast Surgery, The Affiliated Cancer Hospital of Zhengzhou University (Henan Cancer Hospital)
