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While current guidelines recommend the analysis of established cancer driver genes in BM tissue, little is known about its real\u2010life implementation and relevance on oncological treatment strategies. This retrospective multicenter study includes patients with BM from melanoma, lung and breast cancer operated between 2010 and 2022. Clinical records were evaluated for BM molecular analyses of predefined cancer drivers and their discordance to extracranial tumor sites, that is, ALK, BRAF, EGFR, KRAS, NTRK for lung, HER2, estrogen\/progesterone receptor, BRCA1\/2 for breast cancer and BRAF, KIT, NRAS among others for melanoma. Adjustment of systemic therapies based on BM molecular profiles was analyzed. Among 1431 BMs screened for availability of molecular analysis, molecular profiling was performed at least partially in 723 BMs (51%). In cases with matched extracranial tumor samples (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009276), discordant alterations were found in 18% of lung, 4.7% of melanoma and 45% of breast cancer BMs. Molecular BM analyses informed systemic therapy adjustments in 13%\u201327% of patients depending on the primary tumor. Overall survival was significantly better in patients who underwent BM profiling, especially when operated in recensst years (median 19.3 vs. 9.9\u2009months;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.0001) and in patients with breast cancer who had a change in systemic therapies upon BM profiling (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.0085). In conclusion, molecular profiling of BM allows selecting available treatment options for a substantial subset of patients. This study underscores the need for more systematic molecular testing in BM patients to guide systemic treatment decisions.\n                  <\/jats:p>","DOI":"10.1002\/ijc.70611","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T08:14:26Z","timestamp":1781770466000},"page":"2562-2574","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Clinical Implementation and Oncological Relevance of\u00a0Molecular Profiling in Brain Metastases Patients\u2014A Multicenter Retrospective Cohort Study"],"prefix":"10.1002","volume":"159","author":[{"given":"Maria","family":"Nikolaeva","sequence":"first","affiliation":[{"name":"Department of Neurosurgery University Hospital and University of Zurich  Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacopo","family":"Bellomo","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery University 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