Immune-related Gene Expression Predicts Response to Neoadjuvant Chemotherapy but not Additional Benefit from PD-L1 Inhibition in Women with Early Triple-negative Breast Cancer

Abstract

Purpose: We evaluated mRNA signatures to predict response to neoadjuvant PD-L1 inhibition in combination with chemotherapy in early triple-negative breast cancer. Experimental Design: Targeted mRNA sequencing of 2559 transcripts was performed in FFPE samples from 162 patients of the GeparNuevo trial. We focused on validation of four predefined gene-signatures and differential gene expression analyses for new predictive markers. Results: Two signatures (G6-Sig, IFN-Sig) were predictive for treatment response in a multivariate model including treatment arm (G6-Sig: OR 1.558, 95 % CI 1.130-2.182; P = 0.008, IFN-Sig: OR 1.695, 95 % CI 1.234-2.376; P = 0.002), while the CYT metric predicted pCR in the durvalumab arm, and the Prolif-Sig in the placebo arm. Expression of PD-L1 mRNA was associated with better response on both arms, indicating that increased levels of PD-L1 are a general predictor of neoadjuvant therapy response. In an exploratory analysis, we identified seven genes that were higher expressed in responders in the durvalumab arm but not the placebo arm: HLA-A, HLA-B, TAP1, GBP1, CXCL10, STAT1, CD38. These genes were associated with cellular antigen processing and presentation and interferon signaling. Conclusions: Immune-associated signatures are associated with pCR after chemotherapy but might be of limited use for the prediction of response to additional immune-checkpoint blockade. Gene expression related to antigen presentation and interferon signaling might be interesting candidates for further evaluation.