Integrated molecular and immune phenotype of HER2-positive breast cancer and response to neoadjuvant therapy: a NeoALTTO exploratory analysis.

Background: Little is known about the efficacy of HER2-targeted therapy in patients with breast cancer showing different HER2-pathway dependence and immune phenotypes. Herein, we report a NeoALTTO exploratory analysis evaluating the clinical value of 22 types of tumor-infiltrating immune cells by CIBERSORT and 5 immune-related metagenes in the overall patient population, and in subgroups defined by the TRAR-classifier as HER2-addicted (TRAR-low) or not (TRAR-high). Methods: Association of baseline TRAR, immune-related metagenes, and CIBERSORT data with pathological complete response (pCR) and event free survival (EFS) were assessed using logistic and Cox regression models. Results: 226 patients were analyzed: 80 (35%) achieved a pCR, and 64 (28%) experienced a relapse with a median follow-up of 6.7 (interquartile range 6.1-6.8) years; 108 cases were classified as TRAR-low, and 118 TRAR-high. Overall, γδ T-cell fraction (OR 2.69, 95%CI 1.40-5.18), and no immune-related metagenes were predictive of pCR. Notably, LCK predicted pCR to combination (OR 2.53, 95%CI 1.12-5.69), but not to single agent trastuzumab or lapatinib [OR 0.74, 95%CI 0.45-1.22 (p-value for interaction= 0.01)]. Integrating LCK with γδ cells in a multivariate model added to the discriminatory capability of clinical and molecular variables with a shift in AUC from 0.80 (95%CI 0.74-0.86) to 0.83 (95%CI 0.78-0.89). In TRAR-low cases, activated mast cells, Interferon and MHCII were reduced, and STAT1, HCK1, and γδ T-cells were associated with pCR. Conclusion: Immuno-phenotyping holds the promise to complement current predictive models in HER2-positive breast cancer and to assist in new therapeutic development.