EPCO-50. MOLECULAR DETERMINANTS OF CENTRAL NERVOUS SYSTEM TROPISM AND PROGRESSION IN COLORECTAL CANCER

Abstract BACKGROUND Brain metastases (BM) from colorectal cancer (CRC) are associated with dismal prognosis, but little is understood regarding their molecular characteristics. We identified genomic features that predispose to brain tropism, differentiate BM from extracranial disease, and predict early intracranial progression (IP) after BM-directed therapy. METHODS We analyzed next-generation sequencing (NGS) of tumor biopsies from three subgroups of CRC patients: patients with BM (BM+, n=379), patients with extracranial metastases (EM) but without BM (BM-/EM+, n=3968), and patients without metastatic disease (BM-/EM-, n=1061). NGS was performed with MSK-IMPACT, a targeted panel of >300 genes. First, we compared genomic alterations in primary tumors (PT) among the BM+, BM-/EM+, and BM-/EM- subgroups. Second, we focused on patients in the BM+ subgroup who received stereotactic radiosurgery (SRS) for limited BM, comparing tumor genomic alterations from different anatomic sites: BM (n=32), EM (n=62), and PT (n=68). Third, we focused on the 32 resected BM, identifying genomic alterations that predicted early IP, defined as new BM, leptomeningeal disease, or enlargement of existing BM, within 6 months of postoperative SRS. RESULTS PT of BM+ patients demonstrated lower rates of microsatellite instability, increased frequency of BRAF alterations, and fewer APC alterations compared with PT of BM-/EM+ and BM-/EM- patients. Among BM+ patients, SMAD4, MYC, and CDK8 alterations were enriched among resected BM specimens, compared with EM and PT specimens. Resected BM of patients with early IP demonstrated increased frequency of SMAD4 alterations, particularly biallelic SMAD4 loss, and decreased frequency of MYC alterations, compared with resected BM of patients without early IP. CONCLUSION Alterations in key driver genes are associated with initial development and progression of CRC BM. BRAF alterations are enriched in PT of patients who develop BM. SMAD4 alterations are enriched in BM compared to extracranial disease and furthermore predict early IP after BM-targeted therapy.