H&E-Based Gene-Expression Signature Stratifies pCR 8% vs 59% in ISPY2 Neoadjuvant Breast-Cancer Study

A transformer model capable of inferring 38 gene-expression signatures directly from biopsy H&E slides was applied to 579 HER2-negative patients in the I-SPY2 trial (chemotherapy ± immunotherapy). An estrogen-regulated / proliferation / apoptosis / interferon signature predicted pathologic complete response (pCR) with an area under the receiver operating characteristic curve (AUROC) of 0.794—outperforming both a clinicopathologic model (AUROC 0.705) and pathologist-scored tumor-infiltrating lymphocytes (TILs) (AUROC 0.664). Patients in the high-score tertile achieved a 58.6% pCR rate, compared to 7.6% in the low-score group—a difference that held across hormone receptor status, chemotherapy-only arms (36.8% vs. 6.4%), and two external cohorts (AUROC 0.74–0.85).