History of autoimmune disease (Hazard ratio [HR] 3.4, 95% confidence interval [CI] 1.3–8.5), ER/PR negative with low HER2 (ER-/PR-, HR 4.9, 95% CI 1.8–13.0), baseline shortness of breath prior to T-DXd (HR 3.9, 95% CI 1.4–10.8), greater lines of therapy prior to T-DXd (HR 1.2 per line, 95% CI 1-1.4), prior ICI treatment (HR 3.9, 95% CI 1.3–11.7) and baseline ILAs (HR 17.3, 95% CI 6.5–45.7) were associated with an increased risk for pneumonitis. Here, ESR1 is linked to autoimmune disease.