ERBB2 Comprehensive Profiling and Prognostication in Stage III Colon Cancer: Findings From PETACC8 and IDEA-France Cohorts

BACKGROUND & AIMS: ERBB2 pathway activation, through amplification or activating mutations, represents a new target for colon cancer (CC) treatment. Molecular methods were compared with the gold standard for assessing ERBB2 status, and the prognostic value of ERBB2 amplification, mutations, and expression was determined using data from 2 phase 3 trials involving nearly 3000 patients with stage III CC. METHODS: In the PETACC8 trial, immunohistochemistry and fluorescence in situ hybridization, DNA, and RNA analysis were performed on 1813, 1719, and 1733 samples, respectively. In the IDEA-France trial, DNA and RNA sequencing was performed on 1129 and 1263 samples. The breast cancer SCAN-B cohort (N 1/4 3409) served as an external reference. A new molecular ERBB2-amplified status was defined using ERBB2 next generation sequencing score, RNA sequencing expression, and clustering based on ERBB2 neighboring gene expression. Concordance between diagnostic techniques and the association between time to recurrence (TTR) and ERBB2-status were evaluated. RESULTS: The prevalence of the molecular ERBB2amplified group was 1.85% in PETACC8 and 1.5% in IDEA France, with a concordance of 0.81 (95% CI, 0.70-0.92) with the gold standard immunohistochemistry and fluorescence in situ hybridization method in PETACC8. A nonlinear relationship was observed between TTR and ERBB2 expression, with extreme groups showing a less favorable prognosis (P < .0001) in both colon and breast cancers. Patients with molecular ERBB2-amplified status or mutations had the poorest prognosis, followed by low-expression and intermediate-expression groups (3-year TTR of 67.0%, 71.2%, and 77.9%, respectively). In multivariate analysis, the low-expression group had significantly shorter TTR (hazard ratio, 1.28; 95% CI, 1.07-1.52). CONCLUSIONS: The molecular definition of ERBB2 status could represent a cost-effective alternative in stage III CC. ERBB2 alterations and low RNA expression significantly reduced TTR, highlighting the complex role of ERBB2.