Patients with ERBB2-amplified cancers without mutations in MAPK pathway components had a median PFS on first line HER2-targeted therapy of 21 months (95% Confidence Interval [CI]: 17, 30 months), compared to 9.9 months for MAPK-altered patients (95% CI: 5.5, 17 months), suggesting that activation of MAPK signaling limits the efficacy of anti-HER2 agents and contributes to poor patient outcomes (Hazard Ratio [HR]: 2.03, 95% CI: 1.18, 3.51; multivariate p = 0.011, univariate log-rank p = 0.023). Here, ERBB2 is linked to cancer.