Peripheral Blood Monocyte Abundance Predicts Outcomes in Patients with Breast Cancer

Abstract

Biomarkers of response are needed in breast cancer to stratify patients to appropriate therapies and avoid unnecessary toxicity. We used peripheral blood gene expression and cell type abundance to identify biomarkers of response and recurrence in neoadjuvant chemotherapy treated breast cancer patients. We identified a signature of interferon and complement response that was higher in the blood of patients with pathologic complete response. This signature was preferentially expressed by monocytes in single cell RNA sequencing. Monocytes are routinely measured clinically, enabling examination of clinically measured monocytes in multiple independent cohorts. We found that peripheral monocytes were higher in patients with good outcomes in four cohorts of breast cancer patients. Blood gene expression and cell type abundance biomarkers may be useful for prognostication in breast cancer.

Significance: Biomarkers are needed in breast cancer to identify patients at risk for recurrence. Blood is an attractive site for biomarker identification due to the relative ease of longitudinal sampling. Our study suggests that blood-based gene expression and cell type abundance biomarkers may have clinical utility in breast cancer.

FIGURE 1

Expression of immune-related genes in the peripheral blood is associated with good outcome following NAC. A, Schematic describing blood collection timing and downstream analyses. B, GSEA plots for gene sets enriched in blood of patients with pCR relative to RD. C, Expression of IFN/complement and cytotoxicity scores is shown for each sample. D, Cytotoxic, IFN/complement, and combined PIRSs (IFN/complement score minus cytotoxic score) are shown for each sample, stratified by outcome. Box plots show the median, first and third quartiles. P values represent FDR-corrected Wilcoxon tests. E, Single-cell sequencing of PBMCs shows cell type specific expression of each score. Cytotoxic score is shown in red. IFN/complement score is shown in blue. Coexpression would be shown in pink.

FIGURE 2

Monocytes are most abundant in blood of patients with good outcomes following NAC. A, Heatmap showing row standardized (z-score) of CIBERSORTx inferred cell type abundance. Most abundant cell types are listed first. B, CIBERSORTx monocyte values, stratified by outcome. C, Row standardized (z-score) expression of key monocyte related genes in VICC-1 RNA-seq cohort. D, Clinical lab values for relative monocytes pre- and post-NAC. E, Relative monocytes in full and TNBC only synthetic derivative cohort. F, ROC curve for differentiating pCR versus RD in the VICC-SD TNBC only cohort. Box plots show the median, first and third quartiles. P values represent one-tailed Wilcox tests (FDR corrected where applicable).