| Summary: | <i>Background:</i> Colorectal cancers (CRC) with brain metastases (BM) are scarcely described. The main objective of this study was to determine the molecular profile of CRC with BM. <i>Methods:</i> We included 82 CRC patients with BM. <i>KRAS</i>, <i>NRAS</i>, <i>BRAF</i> and mismatch repair (MMR) status were investigated on primary tumors (<i>n</i> = 82) and BM (<i>n</i> = 38). ALK, ROS1, cMET, HER-2, PD-1, PD-L1, CD3 and CD8 status were evaluated by immunohistochemistry, and when recommended, by fluorescence in situ hybridization. <i>Results:</i> In primary tumors, <i>KRAS</i>, <i>NRAS</i> and <i>BRAF</i> mutations were observed in 56%, 6%, and 6% of cases, respectively. No <i>ROS1</i>, <i>ALK</i> and <i>cMET</i> rearrangement was detected. Only one tumor presented <i>HER-2</i> amplification. Molecular profiles were mostly concordant between BM and paired primary tumors, except for 9% of discordances for <i>RAS</i> mutation. CD3, CD8, PD-1 and PD-L1 expressions presented some discordance between primary tumors and BM. In multivariate analysis, multiple BM, lung metastases and PD-L1+ tumor were predictive of poor overall survival. <i>Conclusions:</i> CRCs with BM are associated with high frequency of <i>RAS</i> mutations and significant discordance for <i>RAS</i> mutational status between BM and paired primary tumors. Multiple BM, lung metastases and PD-L1+ have been identified as prognostic factors and can guide therapeutic decisions for CRC patients with BM.
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