Central nervous system metastases in hereditary breast cancer according to germline pathogenic variants: A real-world cohort study.

Abstract

2035 Background: Hereditary breast cancer (HBC) accounts for approximately 5–10% of cases and involves pathogenic germline variants (PGVs) beyond BRCA1/2 . While metastatic patterns differ by tumor subtype, data on central nervous system (CNS) metastases according to germline genetics remain scarce. We evaluated the incidence, clinical characteristics and survival outcomes of CNS metastases in metastatic according to PGV subgroup. Methods: A cohort retrospective study included patients aged ≥18 years with invasive or microinvasive breast cancer and confirmed PGVs treated between 2019 and 2025 at A.C. Camargo Cancer Center. Clinical, histopathologic, and molecular data were analyzed in R. Associations were assessed using chi-square or Kruskal–Wallis tests. Survival outcomes were estimated by Kaplan–Meier. CNS-related progression-free survival (CNS-PFS) was defined from treatment initiation after CNS metastasis to intracranial progression or death. Overall survival after CNS metastasis (OS post-CNS) was defined from CNS metastasis to death. Median survival times with 95% confidence intervals (CIs) were reported. Results: Among 1,353 individuals evaluated, 463 patients with pathogenic germline variants (PGVs) were included. Median age at diagnosis was 43.7 years, and 99.6% were women. The most frequent PGVs were BRCA1 (32.0%), BRCA2 (22.2%), and TP53 (12.1%). BRCA1 carriers were diagnosed earlier than other genotypes (p = 0.0005). CNS metastases occurred in 21 patients (4.5%), mainly among BRCA -associated PGVs and TP53 , with additional cases in PALB2 , ATM , and RAD -related variants; none occurred in CHEK2 , FANCA , or Lynch-associated variants. CNS involvement was mainly parenchymal-only (71.4%), with meningeal-only (19.0%) or combined disease (9.5%). Lesions were supratentorial-only in 47.1% and both supra- and infratentorial in 47.1%. Diagnosis was symptom-driven in 70.0%. Single CNS metastasis occurred in 38.9%, and local therapy alone was most commonly used (66.7%). No statistically significant differences in CNS metastatic patterns were observed across PGV subgroups (p > 0.05). Median OS after CNS diagnosis was 14 months (95% CI, 5–NR), and median CNS-PFS was 17 months (95% CI, 7–NR). Conclusions: In metastatic HBC, CNS metastases are uncommon but preferentially occur among patients harboring BRCA -associated and TP53 pathogenic germline variants. Germline genetics may contribute to distinct metastatic phenotypes and support risk-adapted CNS surveillance strategies and therapeutic strategies in metastatic HBC.