Key determinants include tumor biology (HER2 expression across the positive–low spectrum, intratumoral heterogeneity, hormone-receptor coexpression, ERBB2/PIK3CA alterations), disease pattern and tempo (especially CNS involvement), and host features (immune milieu/TILs, performance status, comorbidities, prior toxicities such as ILD risk with T-DXd). Here, PIK3CA is linked to interstitial lung disease.