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

## TL;DR

This study compares the effects of letrozole-palbociclib and chemotherapy on early-stage breast cancer, finding similar outcomes in immune response and tumor reduction.

## Contribution

The study provides translational insights showing that letrozole-palbociclib is as effective as chemotherapy in reducing tumor proliferation and immune response in high-risk luminal breast cancer.

## Key findings

- Letrozole-palbociclib and chemotherapy both reduce proliferation and upregulate immune-related signatures.
- Stromal remodeling and immune cell accumulation are similar in both treatment arms.
- Low ROR scores correlate with excellent 3-year breast cancer-specific survival.

## Abstract

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.

•We report here the translational analysis from the NeoPAL trial in luminal breast cancer•Neoadjuvant letrozole-palbociclib yields similar proliferation reduction to chemotherapy•Upregulation of immune signatures and stromal remodeling are similar in both arms•Achievement of a low ROR score correlates with excellent survival

We report here the translational analysis from the NeoPAL trial in luminal breast cancer

Neoadjuvant letrozole-palbociclib yields similar proliferation reduction to chemotherapy

Upregulation of immune signatures and stromal remodeling are similar in both arms

Achievement of a low ROR score correlates with excellent survival

Cottu et al. report the translational analysis of the NeoPAL trial. They show that neoadjuvant letrozole-palbociclib and chemotherapy yield comparable reductions in proliferation, enhanced immune activity, and stromal remodeling in early luminal breast cancer. Low-ROR scores predict favorable survival. These data support chemotherapy-sparing approaches for patients with high-risk luminal disease.