OBJECTIVE: Cancer of unknown primary with brain metastases (CUP-BM) represents a distinct and challenging disease entity characterized by an extremely poor prognosis. Currently, there is a lack of systematic research on its prognostic factors. This study aimed to analyze the prognostic factors associated with CUP-BM. METHODS: Patients diagnosed with CUP-BM between 2010 and 2022 were identified from the SEER database. Kaplan-Meier survival curves were utilized to analyze survival differences among various histological subtypes. Univariate and multivariate Cox proportional hazards regression analyses were employed to identify prognostic factors and construct a prognostic nomogram model. Subgroup analysis was conducted to assess the robustness of age as a prognostic factor and explore potential interaction effects with other variables. RESULTS: A total of 700 eligible CUP-BM patients were included. The neuroendocrine subtype demonstrated the most favorable prognosis. Multivariate analysis revealed that histological type, chemotherapy, liver metastasis, lung metastasis, bone metastasis, and age were independent prognostic factors for overall survival (OS). The constructed nomogram exhibited satisfactory predictive performance (bias-corrected C-index = 0.663). Subgroup analysis showed that age remained a significant prognostic factor in most clinical strata, although its effect varied across subgroups defined by metastatic burden and histological subtype. CONCLUSION: Neuroendocrine histology and chemotherapy were associated with improved survival, while adenocarcinoma histology, age greater than 60 years, and the presence of liver, lung, or bone metastasis were identified as poor prognostic factors for CUP-BM. The nomogram exhibited good calibration and discrimination capability for prognostic prediction in CUP-BM patients. Notably, the prognostic impact of age was substantially attenuated in patients with extensive metastatic burden, highlighting the importance of individualized risk assessment.
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