Risk of developing brain/central nervous system (CNS) metastases across multiple <i>ERBB2</i> -altered cancer types: Genotype as shaper of phenotype.

2022 Background: ERBB2 (HER2) alterations are associated with increased risk of brain metastases in breast cancer and non-small cell lung cancer (NSCLC). However, the relationship between ERBB2 alterations and brain metastasis across other tumor types remains unclear. We hypothesized that ERBB2 -altered tumors demonstrate increased propensity for brain metastases across multiple cancer types. Methods: Using the US-based deidentified Flatiron Health-Foundation Medicine Clinico-Genomic Database (FH-FMI CGDB), we analyzed patients with advanced solid tumors who received ≥1 line of therapy. ERBB2 alterations included pathogenic/likely pathogenic variants and amplifications. Brain/CNS metastases were identified via ICD-9/10 codes and validated against manual abstraction in NSCLC patients. Focusing on patients without brain/CNS metastases at diagnosis, we performed Cox proportional hazards analyses to evaluate time from initial diagnosis to first brain/CNS metastasis, modeling death as a competing risk. Multivariable models were adjusted for tumor types. Results: The analysis included 47,653 patients across 16 tumor types. Excluding breast/NSCLC, there were 29,272 patients: 2,149 ERBB2 -altered (7.3%) and 27,123 ERBB2 -wild type. 653 patients (30% of ERBB2 -altered patients) had mutations and 1644 patients (77%) had amplifications (some had both). In a multivariable analysis adjusting for tumor type and excluding breast/NSCLC, ERBB2 alterations independently predicted accelerated brain/CNS metastasis development (HR 1.55, 95% CI 1.29-1.86, p&lt;0.001). In separate disease-specific Cox models, the strongest associations were observed in gastric (HR 2.33, 95% CI 1.68-3.22, p&lt;0.001) and ovarian cancers (HR 2.52, 95% CI 1.45-4.38, p&lt;0.001) as well as breast (HR 1.70, 95% CI 1.48-1.96, p&lt;0.001) and NSCLC (HR 1.33, 95% CI 1.11-1.60, p=0.002). Conclusions: ERBB2 alterations predict a significantly increased risk of accelerated development of brain/CNS metastases independent of tumor types, with the strongest effects observed in gastric and ovarian cancers in addition to breast and lung cancers.