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

The NeoPAL trial compared neoadjuvant letrozole-palbociclib (LP) with chemotherapy (CT) in 103 patients with high-risk early luminal breast cancer. At surgery, the Nanostring BC360™ proliferation score was reduced in both arms, together with a lower median Ki67 expression in the LP arm than in the CT arm (1% (IQR 0-5) vs 5% (IQR 2-15) and upregulation of immune-related signatures (all p<0.01). Overall, there was very little difference in the changes analyzed in the letrozole and palbociclib arm compared to the CT arm, even in signatures that would be expected of response to estrogen - CDK4/6 manipulation. Deconvolution of bulk RNA-seq data revealed 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 accumulated after treatment (p: 0.046 to 7.2e-07). All changes were similar between the LP and CT arms. A low-ROR score was observed at surgery in 63.3% and 43.5% of patients in both LP and CT arms, respectively (p=0.10). No 3-year breast cancer-specific survival event was observed in these patients. These data demonstrate that LP is as effective as CT, and provide a rationale for chemotherapy-sparing trials in this setting