Nature Communications | Neoadjuvant nab-paclitaxel and pembrolizumab in hormone receptor-positive breast cancer

This article evaluates the efficacy and safety of neoadjuvant nab-paclitaxel and pembrolizumab in patients with hormone receptor-positive, HER2-negative breast cancer and explores predictive biomarkers. Results show a low overall pathological complete response rate, but baseline PD-L1 expression levels and inflammatory gene signatures were found to correlate with treatment response, while high estrogen response gene expression was associated with poor response.

Literature Overview
This article titled 'Efficacy, safety, and predictive biomarkers of neoadjuvant nab-paclitaxel and pembrolizumab in hormone receptor-positive, HER2-negative breast cancer' was published in the journal Nature Communications. It retrospectively summarizes a neoadjuvant immunotherapy regimen for hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer patients, aiming to investigate the efficacy and safety of monotherapy followed by combination therapy with nab-paclitaxel and pembrolizumab, and to evaluate changes in PD-L1 expression as the primary endpoint. The study also analyzed gene expression profiles associated with treatment response.

Background Knowledge
HR+/HER2- is the most common breast cancer subtype, accounting for 60-70% of all invasive cases. This subtype exhibits low immunogenicity, characterized by low PD-L1 expression, limited tumor-infiltrating lymphocytes (TILs), and low tumor mutation burden (TMB), leaving the effectiveness of immune checkpoint inhibitors (ICIs) in this population uncertain. Previous studies have shown that combining ICIs with chemotherapy in neoadjuvant settings can improve pathological complete response (pCR) rates in certain subtypes, but the response mechanisms in HR+/HER2- remain unclear. In addition, it is not yet known whether treatment sequence affects efficacy. This study used randomization to investigate how different treatment sequences affect PD-L1 expression and TILs, and analyzed gene expression features in relation to treatment response. The research also assessed the potential role of the gut microbiome in treatment response, providing a basis for future personalized therapies.

Research Methods and Experiments
This study was a randomized, single-center trial involving 29 patients with stage II/III HR+/HER2- breast cancer. Participants were randomly assigned to either a two-week monotherapy phase with nab-paclitaxel or pembrolizumab, followed by combination therapy. The primary endpoint was the change in PD-L1 expression from baseline to post-monotherapy, while whole-exome and RNA sequencing were performed to identify potential biomarkers. The study also evaluated three-year event-free survival (EFS) and treatment-related adverse events (TRAEs). Additionally, the gut microbiome was analyzed for changes across treatment phases and its potential association with treatment response.

Key Conclusions and Perspectives

• The overall pCR rate was 17%, with 13% in patients who received additional neoadjuvant AC therapy and 21% in those who did not. PD-L1 expression did not significantly change after monotherapy, and the primary endpoint was not met.
• Treatment was generally well tolerated, with 80% of patients showing radiological response to combination therapy and a three-year EFS of 86%. Common adverse events included peripheral neuropathy, alopecia, and diarrhea, with no grade 5 toxicities observed.
• Higher baseline PD-L1 expression and inflammatory gene signatures were associated with better treatment response, while elevated estrogen response gene expression was linked to poor outcomes. Additionally, estrogen signaling was found to be negatively correlated with antigen-presenting gene expression.
• Gut microbiome analysis revealed that arginine and nucleotide synthesis pathways were associated with treatment response. Microbial fatty acid synthesis gene abundance decreased during chemotherapy but remained stable during immune checkpoint inhibition.

Conclusion
This randomized trial demonstrates that the combination of nab-paclitaxel and pembrolizumab as neoadjuvant therapy is generally well tolerated in HR+/HER2- breast cancer patients but does not significantly increase PD-L1 expression. The study found that high baseline PD-L1 expression and inflammatory gene signatures were associated with improved treatment response, whereas high expression of estrogen response genes was linked to poor response. Additionally, gut microbiome analysis identified specific metabolic pathways associated with treatment response. Future research should further examine how treatment sequence affects the immune microenvironment and explore optimal combinations of biomarkers to refine personalized therapeutic strategies.

Folding Stability

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Prediction of absolute protein stability ΔG by protein sequence inverse folding model ESM-IF. Traditional physical methods (e.g., FoldX, Rosetta, etc.) for predicting protein stability ΔG rely on high-confidence structural pdb, and if there are too many mutations, the structural confidence decreases and the prediction results are poor. Benchmark results at ProteinGym show that the generative model ESM-IF predicts protein mutation stability ΔΔG of DMS data at best-in-class level in zero-shot. The method is an extension of mutation prediction by using the ESM-IF model to directly predict the absolute ΔG value of intact protein folding stability. It was tested with a prediction error RMSE ≈ 1.5 kcal/mol and a correlation coefficient of 0.7, representing a major breakthrough in predicting the folding stability ΔΔG of proteins.