Molecular and cellular composition changes after neoadjuvant letrozole and palbociclib in early luminal breast cancer.

The NeoPAL trial compares neoadjuvant letrozole-palbociclib (LP) with chemotherapy (CT) in 103 patients with high-risk early luminal breast cancer. At surgery, the Nanostring BC360™ proliferation score and Ki67 expression are reduced in both arms, together with upregulation of immune-related signatures. Overall, there is very little difference in the changes observed with LP as compared to CT, even in signatures related to response to estrogen - CDK4/6 manipulation. Deconvolution of bulk RNA-seq data reveals high content at baseline in cancer cells, immunosuppressive cancer-associated fibroblasts, FOXP3+ CD4+ regulatory T lymphocytes and TREM2+ macrophages. In contrast, myoepithelial cells, normal-like fibroblasts, FOLR2+ macrophages and SELL+ CD4+ T lymphocytes accumulate after treatment in both arms. A low-ROR score is observed at surgery in 63.3% and 43.5% of patients in LP and CT arms, respectively. No 3-year breast cancer-specific survival event is observed in these patients. These data provide a rationale for chemotherapy-sparing trials in this setting.