Multidimensional Molecular Profiling of Metastatic Triple-Negative Breast Cancer and Immune Checkpoint Inhibitor Benefit

Romualdo Barroso-Sousa, Juliet Forman, Katharine Collier, Zachary T Weber, Tejas R Jammihal, Katrina Z Kao, Edward T Richardson, Tanya Keenan, Ofir Cohen, Michael P Manos, Ryan C Brennick, Patrick A Ott, F Stephen Hodi, Deborah A Dillon, Victoria Attaya, Tess O'Meara, Nancy U Lin, Eliezer M Van Allen, Scott Rodig, Eric P WinerElizabeth A Mittendorf, Catherine J Wu, Nikhil Wagle, Daniel G Stover, Sachet A Shukla, Sara M Tolaney

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article numbere2100413
Number of pages12
JournalJCO Precision Oncology
StatePublished - Jul 2022
Externally publishedYes


  • Biomarkers, Tumor/genetics
  • Humans
  • Immune Checkpoint Inhibitors/pharmacology
  • Mutation
  • Progression-Free Survival
  • Triple Negative Breast Neoplasms/drug therapy


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