Immune Subtyping Identifies Patients With Hormone Receptor-Positive Early-Stage Breast Cancer Who Respond to Neoadjuvant Immunotherapy (IO): Results From Five IO Arms of the I-SPY2 Trial

PURPOSE Neoadjuvant immunotherapy (IO) has become the standard of care for early-stage triple-negative breast cancer (TNBC), but not yet for other subtypes. We previously developed a clinical-grade mRNA-based immune classifier (ImPrint) predicting response to IO that is now being used in I-SPY2.2 as part of the response predictive subtypes. We report the performance of ImPrint in hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR1HER2-) patients from five IO arms. METHODS A total of 204 HR1HER2- (MammaPrint high-risk) patients from five IO arms (anti-PD-1, anti-PD-L1/poly [ADP-ribose] polymerase inhibitor combination, anti-PD-1/toll-like receptor 9 dual-IO combination, and anti-PD-1 6 lymphocyte activation gene 3 dual-IO combination) and 191 patients from the chemotherapy-only control arm were included in this analysis. Patients were classified as ImPrint1 (likely sensitive) versus ImPrint- (likely resistant), using pretreatment mRNA. Performance of ImPrint for predicting pathologic complete response (pCR) to IO-containing arms was characterized and compared with tumor grade (III), MammaPrint (ultra) High2 risk (MP2), and estrogen receptor (ER)-low (ER ≤ 10%). RESULTS Overall, the pCR rate across the five IO arms was 33%. 26% of HR1HER2-patients were ImPrint1, and pCR rates with IO were 75% in ImPrint1 versus 17% in ImPrint-, with the highest pCR rate >90% in a dual-IO arm. In the control arm, pCR rates were 33% in ImPrint1 and 8% in ImPrint-. Tumor grade (III), MP2, and ER-low showed pCR rates in IO of 45%, 56%, and 63%, respectively, with lower pCR odds ratios (OR < 7.5) compared with ImPrint (OR 5 14.5). CONCLUSION Using an accurate selection strategy, HR1HER2- patients could achieve pCR rates similar to what is seen with best neoadjuvant therapies in TNBC and HER21 (ie, pCR rate >65%-70%). ImPrint, an Food and Drug Administration IDE-enabled assay, may represent a way to identify HR1HER2- patients for IO that best balances likely benefit versus risk of serious immune-related adverse events.