Timing of cranial radiotherapy in HER2-positive breast Cancer brain metastases treated with Pyrotinib: a multicentre real-world cohort study

Background and purpose: Cranial radiotherapy (RT) and pyrotinib both demonstrate efficacy in HER2-positive breast cancer brain metastases (BCBM); however, the optimal sequencing of these modalities remains to be established. We evaluated survival across treatment sequences within a real-world cohort. Materials and methods:This retrospective, two-centre study included 101 patients with HER2-positive BCBM treated with cranial RT plus pyrotinib (June 2018–July 2025). Based on treatment sequence, patients were categorized into: concurrent RT and pyrotinib (Group A, n = 41); RT after intracranial progression on pyrotinib (Group B, n = 38); and pyrotinib upon progression following RT (Group C, n = 22). The primary endpoint was CNS-PFS. Survival outcomes were assessed via Kaplan–Meier estimation and Cox proportional hazards models.Results: At a median follow-up of 43.3 months, 63 patients (62.4%) had died and 70 (69.3%) experienced CNS-PFS events. Median CNS-PFS was 14.8 months (95% CI 10.68–19.92) overall, and 14.3, 15.0, and 21.4 months in groups A, B, and C, respectively ( P = 0.252); median OS was 36.0 months (95% CI 28.0–39.7) overall, and 33.0, 35.4, and 42.0 months in groups A, B, and C, respectively ( P = 0.281). Focal cranial RT was independently associated with longer OS (HR 0.56, 95% CI 0.34–0.94; P = 0.028). Any-grade adverse events occurred in 100 of 101 patients (99.0%); grade ≥ 3 events occurred in 2.4%, 7.9%, and 4.5% of groups A, B, and C, respectively (all P > 0.05), and radiation necrosis occurred in 7 patients (6.9%). An exploratory threshold of RT initiated >3.9 months before pyrotinib (OS 49.9 vs 29.8 months; HR 0.31, 95% CI 0.11–0.91; P = 0.025) did not withstand internal validation.Conclusions: Treatment sequence did not significantly affect OS or CNS-PFS. Focal cranial RT was independently associated with longer survival, and toxicity was manageable. The proposed timing threshold is hypothesis-generating and warrants prospective validation.