Abstract Background The combination of pyrotinib and capecitabine has shown promising efficacy in patients with HER2-positive metastatic breast cancer and brain metastases (BMs). However, it remains uncertain whether the timing of local radiotherapy affect overall survival (OS) on the basis of this systemic regimen. The purpose of our study is to investigate the impact on OS of the addition of brain radiotherapy to the treatment with pyrotinib and capecitabine in patients with HER2-positive breast cancer BMs in a real-world clinical practice setting. Methods This is a multicenter, retrospective-prospective, real-world study conducted across 41 centers in China (NCT05359120). Patients diagnosed with HER2-positive breast cancer and BMs, with complete diagnostic and treatment records available in hospital electronic medical record systems were eligible for this study. Enrolled patients were categorized into three cohorts based on the radiotherapy status while undergoing systemic treatment: those who were radiotherapy-naïve (Cohort A), those who received whole-brain radiotherapy (WBRT) and/or stereotactic radiosurgery (SRS) within three months of initiating systemic treatment (Cohort B), and those who received systemic treatment more than three months after radiotherapy (Cohort C). Systemic treatment was defined as pyrotinib (no less than 240 mg once daily) combined with capecitabine (no less than 50% of 1000 mg/m2 twice daily on days 1-14 of each 21-day cycle) until disease progression or unacceptable toxicity. The endpoints included OS and progression-free survival(PFS). Here we present the results of Cohort A and B. Results From September 2018 to January 2024, a total of 287 female patients were enrolled in the study. In Cohort A, 27.4% (37/135) of patients presented with symptomatic BMs, while 52.5% (64/122) in Cohort B. Additionally, a greater percentage of patients in Cohort A (88.9%) had active BMs compared to those in Cohort B (61.5%).As of May 6, 2025, the median follow-up duration was 35.9 months (95% CI: 34.3-37.5) in Cohort A and 45.3 months (95% CI: 41.9-48.6) in Cohort B. The median OS was 35.4 months (95% CI: 31.4-39.4) in Cohort A and 37.3 months (95% CI: 27.4-47.2) in Cohort B, with no statistically significant difference between the two groups (p = 0.793). Similarly, the median progression-free survival (PFS) was comparable between Cohort A and Cohort B, at 15.0 months (95% CI: 11.7-18.3) and 15.5 months (95% CI: 12.1-18.9), respectively (p = 0.073). Conclusion To our knowledge, this is the largest study of pyrotinib plus capecitabine in HER2-positive breast cancer patients with BMs. No significant difference was observed in OS or PFS between the two groups: priority systemic therapy with pyrotinib plus capecitabine until disease progression or unacceptable toxicity, or systemic therapy concurrently with radiotherapy. Therefore, future studies should further elucidate the characteristics of patients most likely to benefit from specific systemic-local treatment combinations and enabling personalized therapeutic strategies for HER2-positive breast cancer patients with BMs. These findings warrant prospective clinical investigation. Research Sponsor: None. Citation Format: L. Niu, X. Liang, S. Wang, S. Zhang, Z. Lv, H. Li, Y. Zhao, Y. Yin, Y. Song, G. Sun, B. Zhao, L. Cai, Q. Ouyang, C. Geng, H. Yao, X. Wu, Z. Chen, Z. Jiang, H. Li, M. Yan. Pyrotinib plus capecitabine with or withoutradiotherapyin patients with HER2-positive metastatic breast cancer and brain metastases: Amulticenter, retrospective-prospective, real-world study in China (Post-PERMEATE) abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-02-10.
Niu et al. (Tue,) studied this question.