HER2-targeted trastuzumab shows “on-time” benefit but late RFS drop-off in HER2+ lobular breast cancer

Trastuzumab (anti-HER2 monoclonal antibody) outcomes were dissected by histology in the Phase III adjuvant NCCTG N9831 trial (NCT00005970), comparing HER2+ invasive lobular carcinoma (ILC; n=122) vs invasive ductal carcinoma (IDC; n=3182). ILC appeared to gain similar relative benefit from adjuvant trastuzumab as the overall N9831 population (HR 0.58 vs 0.67), with similar 5-year RFS (77.1% ILC vs 82.7% IDC), but a larger late RFS attrition from years 5→15 (77.1%→57.7%, ~20% absolute drop) than IDC (82.7%→72.7%, ~10% drop); 15-year OS was also lower in ILC (65.2% vs 76.7%). In a Caris real-world trastuzumab-treated cohort (n=1328; ILC n=26), ILC had worse mOS vs non-ILC (33.7 vs 68.6 months; HR 2.01, p=0.04), but not significantly worse vs IDC specifically (HR 1.77, p=0.11); immune/WTS deconvolution suggested ILC enrichment for B cells/Tregs/M2 macrophages plus higher MHC-II expression and lower proliferation/DNA repair signatures—features that may help explain why standard 1-year adjuvant HER2 therapy (a long-standing backbone of care) doesn’t fully “sterilize” late relapse risk.