Computationally Derived Spatial Immune Signature Identifies Trastuzumab Responders in HER2+ Breast Cancer: NSABP B-41 Clinical Trial Validation.

purposeTrastuzumab-based chemotherapy has improved outcomes in human epidermal growth factor receptor 2 (HER2)-positive breast cancer, but treatment benefit varies among patients. Predictive signatures are needed to identify patients most likely to respond to these therapies. EXPERIMENTAL

designWe developed Density and Spatial architecture of Tumor-Infiltrating Lymphocytes (DeSTIL), a computational signature derived from hematoxylin and eosin slides. The signature captures spatial organization of immune cells and interactions with nonimmune cells. DeSTIL was trained on HER2+ breast cancer slides from The Cancer Genome Atlas (n = 250) and validated in a phase III National Surgical Adjuvant Breast and Bowel Project (NSABP) B-41 randomized clinical trial (n = 221), which compared chemotherapy plus trastuzumab, lapatinib, or combination. The DeSTIL scores were dichotomized into positive and negative groups, and event-free survival (EFS) was assessed using Cox proportional hazards with interaction terms.

resultsIn NSABP B-41, DeSTIL-positive patients (n = 61) showed significantly improved event-free survival (EFS) with trastuzumab compared with the combination arm [hazard ratio (HR) = 0.09; 95% confidence interval (CI) = 0.01-0.77; P = 0.006] and a significant signature-treatment interaction (P = 0.024). No EFS difference was observed in DeSTIL-negative patients (n = 160). Gene expression analysis supported the image-derived signature stratifying DeSTIL-positive and DeSTIL-negative tumors. In an exploratory pathologic complete response analysis, a classifier trained on University Hospitals Cleveland slides achieved AUCs of 0.70 in the training cohort and 0.63 in the trastuzumab arm of the NSABP B-41 validation cohort.

conclusionsDeSTIL identifies a subset of HER2+ patients who derive greater benefit from trastuzumab. These findings support the potential of computationally derived immune architecture to inform selection of standard HER2-targeted therapies.