Longitudinal transcriptomic profiling identifies predictors of response to neoadjuvant chemoimmunotherapy in TNBC

Triple-negative breast cancer (TNBC) is immunogenic, but only a subset of patients benefits from neoadjuvant immune checkpoint inhibitors combined with chemotherapy. Predictive biomarkers to guide patient selection and treatment adaptation are lacking. In the multinational phase 3 NeoTRIPaPDL1 trial, 280 patients with high-risk TNBC received neoadjuvant carboplatin plus nab-paclitaxel (CT) or CT with atezolizumab (CT/A). The graphical abstract shows results of the analysis. Tumor biopsies were collected at baseline and on the first day of the second cycle. At baseline, in the CT-A arm higher proliferation and lower stromal and metabolic programs were associated with increased pathologic complete response (pCR) rate. Absence of tumor cells in early on-treatment biopsies strongly predicted pCR in both arms. Comparison of on-treatment with baseline samples revealed a reduced proliferation and increased immune and stromal signatures. These changes were more pronounced in tumors achieving pCR, particularly in patients receiving chemoimmunotherapy. While several baseline metabolic signatures were associated with outcome, most lost predictive value on-treatment, where immune-related programs became the dominant correlates of response. The authors conclude that longitudinal transcriptomic profiling revealed dynamic tumor and microenvironment remodeling during neoadjuvant therapy in TNBC.