Genomics correlates of brain metastasis and progression in colorectal cancer

BACKGROUND: Brain metastasis (BM) in colorectal cancer (CRC) is a rare event that undermines longevity and neurocognitive function. However, the molecular basis of BM in CRC is poorly understood. We analyzed next-generation sequencing (NGS) from patients with CRC to identify genomic features associated with BM and intracranial progression (IP). METHODS: Patients with CRC who had NGS between 2014 and 2024 were included. Sequenced tumor specimens were classified by the anatomic site of biopsy as primary tumors (PT), extracranial metastases (EM), or BM. Sequenced PT specimens were compared to identify genomic differences between patients who did and did not develop BM. Among patients with BM, sequenced tumor specimens were compared to identify genomic differences by anatomic site. Sequenced BM samples were compared to identify genomic differences between patients who did and did not experience IP after BM-directed local therapy. RESULTS: This analysis included 5526 patients with NGS of CRC, including 269 patients with BM. PT of patients who developed BM more frequently contained alterations in the KRAS, BRAF, and SMAD4, compared with PT of patients without BM. Among patients with BM, resected BM specimens had greater tumor mutation burden, fraction of genome altered, and frequency of TP53, SMAD4, and MYC alterations, compared with extracranial tumor specimens. Patients with BM carrying SMAD4 or PI3K pathway alterations showed a trend toward earlier IP after BM-directed therapy. CONCLUSIONS: This study identifies novel genomic associations with intracranial metastasis and progression in CRC, suggesting a potential basis for personalized clinical management.