Incidence and risk factors of brain metastases in radically resected melanoma patients: a large international cohort study

Background: Melanoma has the highest risk of brain metastasis (BM) among common solid tumors. Data on risk factors of developing BM in stage II-III melanoma are scarce. We investigated the incidence, timing, and risk factors associated with BM development in stage II-III melanoma patients. Patients and methods: We carried out a multicenter retrospective cohort study. Clinical and pathological data on consecutive melanoma patients diagnosed, treated, and followed up in four Italian and one Polish referral melanoma centers were retrieved. A conditional inference tree (CIT) was derived to stratify patients according to their risk of BM occurrence based on prognostic factors. Results: Between 1998 and 2023, we identified 8992 patients, of whom 5021 had stage II-III disease and were included in the main outcome analysis. The incidence of BM in the whole population was 6.9% (344/5021 patients). The number of patients needed to detect one BM after the primary resection was 105 [95% confidence interval (CI) 79-142] in the first year, 40 (95% CI 33-49) in the second year, and 71 (95% CI 52-102) in the fifth year. At multivariable analysis, older patients {≥60 years versus <40 years [odds ratio (OR) 0.63, 95% CI 0.43-0.92, P = 0.0156)} and Breslow thickness (BT) >4 mm (versus <2 mm; OR 0.68, 95% CI 0.46-1.01, P = 0.0574) were associated with a lower risk of BM versus extracranial recurrence only, while male sex (OR 1.47, 95% CI 1.11-1.93, P = 0.0065) and ulceration (OR 1.33, 95% CI 1.00-1.76, P = 0.0499) were associated with a higher risk. According to CIT, the highest absolute risk (13.5%) was observed in patients with ulcerated melanoma, BT >4 mm, and a positive sentinel lymph node biopsy. Conclusions: Our study identifies stage II-III melanoma patients at a high risk of BM and provides clinically useful information for tailoring follow-up.