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Published on: February 25, 2020
Multidimensional Molecular Profiling of Metastatic Triple-Negative Breast Cancer and Immune Checkpoint Inhibitor
Romualdo Barroso-Sousa1, Juliet Forman2,3,4, Katharine Collier5
1Oncology Center, Hospital Sírio-Libanês, Brasília, Brazil.
Purpose:
In metastatic triple-negative breast cancer (mTNBC), consistent biomarkers of immune checkpoint inhibitor (ICI) therapy benefit remain elusive. We evaluated the immune, genomic, and transcriptomic landscape of mTNBC in patients treated with ICIs.
Methods:
We identified 29 patients with mTNBC treated with pembrolizumab or atezolizumab, either alone (n = 9) or in combination with chemotherapy (n = 14) or targeted therapy (n = 6), who had tumor tissue and/or blood available before ICI therapy for whole-exome sequencing. RNA sequencing and CIBERSORTx-inferred immune population analyses were performed (n = 20). Immune cell populations and programmed death-ligand 1 expression were assessed using multiplexed immunofluorescence (n = 18). Clonal trajectories were evaluated via serial tumor/circulating tumor DNA whole-exome sequencing (n = 4). Association of biomarkers with progression-free survival and overall survival (OS) was assessed.
Results:
Progression-free survival and OS were longer in patients with high programmed death-ligand 1 expression and tumor mutational burden. Patients with longer survival also had a higher relative inferred fraction of CD8+ T cells, activated CD4+ memory T cells, M1 macrophages, and follicular helper T cells and enrichment of inflammatory gene expression pathways. A mutational signature of defective repair of DNA damage by homologous recombination was enriched in patients with both shorter OS and primary resistance. Exploratory analysis of clonal evolution among four patients treated with programmed cell death protein 1 blockade and a tyrosine kinase inhibitor suggested that clonal stability post-treatment was associated with short time to progression.
Conclusion:
This study identified potential biomarkers of response to ICIs among patients with mTNBC: high tumor mutational burden; presence of CD8+, CD4 memory T cells, follicular helper T cells, and M1 macrophages; and inflammatory gene expression pathways. Pretreatment deficiencies in the homologous recombination DNA damage repair pathway and the absence of or minimal clonal evolution post-treatment may be associated with worse outcomes.
Insights
Biomarkers like high tumor mutational burden and specific immune cells can predict response to immune checkpoint inhibitors (ICIs) in metastatic triple-negative breast cancer (mTNBC). Deficiencies in DNA repair and limited clonal evolution may indicate worse outcomes.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Metastatic triple-negative breast cancer (mTNBC) lacks reliable biomarkers for immune checkpoint inhibitor (ICI) therapy effectiveness.
- Understanding the immune, genomic, and transcriptomic profiles of mTNBC is crucial for identifying predictive biomarkers.
Purpose of the Study:
- To evaluate potential biomarkers associated with ICI therapy benefit in patients with mTNBC.
- To correlate immune cell populations, genomic features, and gene expression with progression-free survival and overall survival.
Main Methods:
- Analyzed tumor tissue and blood from 29 mTNBC patients treated with ICIs (pembrolizumab or atezolizumab) +/- chemotherapy/targeted therapy.
- Performed whole-exome sequencing, RNA sequencing, CIBERSORTx immune population inference, and multiplexed immunofluorescence.
- Assessed programmed death-ligand 1 (PD-L1) expression and evaluated clonal trajectories using serial DNA sequencing.
Main Results:
- Higher programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB) correlated with longer progression-free survival and overall survival (OS).
- Increased CD8+ T cells, activated CD4+ memory T cells, M1 macrophages, and follicular helper T cells, along with inflammatory gene pathways, were associated with longer survival.
- Defective homologous recombination DNA damage repair signatures were linked to shorter OS and primary resistance; clonal stability post-treatment correlated with short time to progression.
Conclusions:
- High TMB, specific immune cell infiltrates (CD8+, CD4 memory, M1 macrophages, Tfh), and inflammatory gene pathways are potential biomarkers for ICI response in mTNBC.
- Pretreatment homologous recombination DNA repair deficiencies and minimal post-treatment clonal evolution may predict poorer outcomes.
