Determinants of synchronous and metachronous metastatic breast cancer (2000–2024)–an analysis based on data from German cancer registries

Abstract Purpose To investigate the association of molecular breast cancer subtypes with the timing and organ-specific patterns of metastatic disease. Methods We analyzed data from nine German regional cancer registries, including 172 512 women diagnosed with invasive breast cancer between January 2000 and March 2024. Patients were classified as having no metastases, synchronous metastases (within three months of diagnosis), or metachronous metastases. Factors associated with synchronous metastases were assessed using multivariable binary logistic regression adjusted for confounders. Time to first metachronous metastasis was analyzed using multivariable Cox regression. Timing and organ-specific metastatic patterns were compared across subtypes. Results Molecular subtypes were associated with both synchronous and metachronous metastatic disease. Compared with HR+/HER2− tumors, HR−/HER2+ tumors had the highest odds of synchronous metastasis (adjusted OR [aOR] 1.69, 95%CI 1.57 – 1.83), whereas HR−/HER2− tumors showed no increased odds (aOR 0.96, 95%CI 0.90 – 1.02). In contrast, HR−/HER2− tumors had the highest risk of metachronous metastases (adjusted HR [aHR] 1.48, 95%CI 1.41 – 1.55), while HR+/HER2+ tumors showed a lower risk than HR+/HER2− tumors (aHR 0.88, 95%CI 0.84–0.93). Cumulative incidence increased between 5 and 10 years after diagnosis, with late risk among HR-positive tumors. Metastatic patterns differed by subtype, with HR+/HER2− tumors showing predominantly bone metastases, and HR−/HER2− tumors exhibiting more frequent visceral and central nervous system (CNS) involvement. Conclusion Molecular subtypes influence the timing and distribution of metastatic breast cancer. HER2-positive tumors are associated with synchronous metastatic presentation, whereas HR−/HER2− tumors showed the highest risk of metachronous metastasis. These findings support subtype-specific risk assessment and surveillance strategies.