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 and CDK4/6 manipulation. Deconvolution of bulk RNA sequencing (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 the LP and CT arms, respectively. No 3-year breast cancer-specific survival events are observed in these patients. These data provide a rationale for CT-sparing trials in this setting.