Prognostic and Treatment-Specific Predictive Implications of HER2 Expression in RAS Wild-Type Metastatic Colorectal Cancer: A Multicenter Retrospective Real-World Study

Background: Human epidermal growth factor receptor 2 (HER2) alterations have been implicated as mechanisms of resistance to anti-epidermal growth factor receptor (anti-EGFR) therapy in metastatic colorectal cancer (mCRC). We aimed to evaluate the predictive and prognostic significance of HER2 expression in patients with RAS wild-type mCRC in a real-world setting. Methods: We conducted a multicenter retrospective cohort study across ten oncology centers in Turkey, including patients with RAS wild-type mCRC treated between 2015 and 2022. Clinical outcomes, including progression-free survival (PFS) and overall survival (OS), were compared between HER2-positive and HER2-negative groups. Multivariable Cox proportional hazards models were used to identify independent predictors of survival outcomes. Results: Among 204 patients, 28 (13.7%) were HER2-positive. Baseline characteristics were generally comparable; however, HER2-positive patients showed a trend toward higher-grade tumors and were significantly less likely to receive anti-EGFR therapy. HER2-positive patients had significantly shorter PFS compared to HER2-negative patients (median 10 vs. 13 months; p = 0.006). In multivariable analysis, HER2 positivity remained an independent predictor of shorter PFS (HR 1.76, 95% CI 1.01–3.07; p = 0.045). In the subgroup of 144 patients receiving anti-EGFR therapy, HER2-positive patients also demonstrated significantly shorter PFS (median 9.0 vs. 14.0 months; p = 0.023). No significant differences in OS were observed between groups. Conclusions: HER2 positivity is associated with reduced response to anti-EGFR therapy and independently predicts shorter PFS in patients with RAS wild-type mCRC. These findings further support the role of HER2 as a clinically relevant biomarker in RAS wild-type mCRC, particularly in predicting response to anti-EGFR therapy, while highlighting the need for optimized patient selection strategies in the era of HER2-targeted treatments.