Which patients with colorectal cancer develop brain metastases? A multicenter analysis of clinical and molecular predictors.

218 Background: Brain metastases from colorectal cancer (CRC) are rare but clinically significant events with limited data available. This study aimed to evaluate the clinicopathological and molecular features, as well as survival outcomes, of CRC patients who developed brain metastases across multiple centers. Methods: We retrospectively reviewed CRC patients treated at eight oncology centers. Clinical variables (age, sex, tumor location, timing of brain metastasis), molecular markers (MSI, KRAS, NRAS, BRAF, HER2), and survival outcomes were analyzed. Overall survival (OS) was calculated from CRC diagnosis, and post-brain metastasis survival from the time of cranial involvement. Results: Among 5617 CRC patients, 94 (1.7%) were identified with brain metastases. The cohort included 57 men (60.6%) and 37 women (39.4%), with a median age of 60 years (range, 26.9–81.3). Primary tumor location was rectum in 42 patients (44.7%), left colon in 31 (33.0%), and right colon in 21 (22.3%). Brain metastases occurred significantly more frequently in left-sided and rectal primaries compared with right-sided tumors (77.7% vs 22.3%, χ²=28.8, p<0.001). Molecular profiling revealed: MSI-H 6.1% (5/82), KRAS mutation 46.3% (38/82), NRAS mutation 2.7% (2/75), BRAF mutation 8.1% (6/74), and HER2 positivity 10.8% (8/74). Notably, HER2 positivity appeared higher than the expected prevalence reported in unselected metastatic CRC cohorts. Brain metastases developed after a median of 1.8 years (range, 0–7.4); 8 patients (13.6%) had de novo brain metastasis, while 51 (86.4%) developed interval metastases. At last follow-up, 83.7% of patients had died. Median OS from diagnosis was 31.2 months, while median survival after brain metastasis was only 4.8 months. Conclusions: Our multicenter analysis demonstrates that CRC brain metastases occur most often in left-sided and rectal tumors, with an unexpectedly high rate of HER2 positivity and left-sided BRAF mutations. This pattern may reflect a unique molecular biology that distinguishes CRC patients at risk of cranial involvement and could inform future strategies for surveillance and targeted therapy. To our knowledge, this represents one of the largest multicenter series investigating CRC patients with brain metastases.