Abstract
BACKGROUND: Breast cancer prognosis is the result of complex interactions between tumor biology, treatment, and host factors. While germline genetic variation is increasingly incorporated into breast cancer risk assessment and therapeutic decision-making, its role in determining prognosis remains incompletely defined. This systematic review and meta-analysis synthesizes available evidence on the association between germline genetic variants and breast cancer outcomes, with a focus on pathway-level effects. METHODS: A comprehensive literature search was conducted in PubMed, Scopus, MEDLINE, Web of Science, and QInsight to identify studies published between January 2000 and June 2024. Published articles that evaluated associations between germline genetic variants and breast cancer prognosis were included. Eligible studies reported time-to-event outcomes, including disease-free survival (DFS), overall survival (OS), and other outcomes. Genes harboring prognostic variants were grouped into functional clusters using STRING. Primary analyses consisted of cluster-based multilevel random-effects meta-analyses, while global outcome-based meta-analyses were conducted as secondary, exploratory analyses. The protocol was registered in PROSPERO (CRD42022308746) and followed PRISMA guidelines. RESULTS: Fifty-four studies encompassing 253,768 women were included. Most participants were of European ancestry, with marked underrepresentation of Hispanic (0.21%) and Black (0.25%) populations. Cluster-based meta-analyses identified six biologically coherent pathways associated with adverse prognosis. The ERBB2–PI3K resistance network showed the strongest association with OS (HR = 3.47; 95% CI: 1.54–7.78) and DFS (HR = 1.70; 95% CI: 1.02–1.82). Immune-related cytokine pathways were consistently associated with poorer OS (HR = 2.29; 95% CI: 1.04–5.04) and DFS (HR = 1.49; 95% CI: 1.20–1.85). Germline variation in xenobiotic metabolism genes was significantly associated with OS (HR = 1.65; 95% CI: 1.24–2.20), while DNA repair genes were strongly associated with breast cancer–specific mortality (HR = 3.51; 95% CI: 1.80–6.85). Exploratory global meta-analyses pooling all variants demonstrated overall directional associations with OS (HR = 2.30) and DFS (HR = 1.49), with substantial heterogeneity. CONCLUSIONS: This systematic review and meta-analysis show that germline genetic variation influences breast cancer prognosis in a pathway-specific manner. These findings highlight the importance of biologically informed analytic strategies and underscore the need for large, ethnically diverse studies to validate pathway-level germline prognostic markers and support their integration into personalized breast cancer management. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-026-15808-7.