Brain metastases in HER2- positive metastatic gastrointestinal cancers: Incidence, timing, and implications for brain surveillance.

Abstract

e16001 Background: Brain metastases (BM) are considered rare in gastrointestinal (GI) malignancies, and routine brain imaging is not recommended, though often required as eligibility in HER2-positive GI clinical trials. Though HER2-positive GI cancers have a higher risk of BM, there is limited data on their timing and natural history. Methods: We retrospectively analyzed 432 patients with HER2-positive metastatic GI cancers treated between 2000 and 2024. HER2 positivity was defined as immunohistochemistry (IHC) 3+ or ERBB2 amplification identified by next-generation sequencing. BM were confirmed radiographically. Time to BM development was analyzed using a competing-risk framework, with death without BM treated as a competing event. Cumulative incidence functions (CIF) were estimated, and Fine–Gray subdistribution hazard models were used to evaluate factors associated with BM development. Overall survival (OS) was analyzed using Kaplan–Meier methods and multivariable Cox proportional hazards regression. Results: Among 432 patients with HER2-positive metastatic GI cancers, 45% had gastroesophageal cancers, 39% colorectal cancer, 13% biliary tract cancers, and 3% other gastrointestinal cancers. Median OS for the overall cohort was 20.4 months (95% CI 16.1–24.0). Overall, 35 patients (8.1%) developed BM. Using a competing-risk framework, BM was observed within the initial months following metastatic diagnosis, with cumulative incidence estimates of 3.9% by 2 months and 5.3% by 12 months, increasing to 8.9% at 24 months, 10.2% at 5 years, and 14.2% by 8 years. The hazard of BM peaked within the first 2–3 months following metastatic diagnosis and remained non-zero throughout follow-up. In multivariable competing-risk analysis, tumor type was evaluated for association with BM development (gastroesophageal vs colorectal cancer: HR 2.10, 95% CI, 0.97–4.51; P = 0.059), whereas biliary tract cancer was not significantly different from colorectal cancer (HR 0.358, 95% CI, 0.046-2.79, P = 0.3269). Conclusions: In HER2-positive metastatic GI cancers, cumulative incidence of BM at 2 years was 8.9%. Critically, the majority of this risk occurred early with cumulative incidence of 3.9% at 2 months. These findings challenge the perception of BM as a late or rare event in this population and support consideration of brain imaging especially at the diagnosis of metastatic disease.