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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. In patients with mTNBC, responses to ICI-containing therapies were associated with high TMB; the presence of CD8+, CD4 memory T cells, follicular helper T cells, and M1 macrophages; and inflammatory gene expression pathways. [ABSTRACT FROM AUTHOR]

PURPOSE: To determine whether specific somatic copy-number alterations detectable in circulating tumor DNA (ctDNA) from patients with metastatic triple-negative breast cancer (mTNBC) are associated with sensitivity to platinum chemotherapy. MATERIALS AND METHODS: In this secondary analysis of a large cohort of patients with mTNBC whose ctDNA underwent ultralow-pass whole-genome sequencing, tumor fraction and somatic copy-number alterations were derived with the ichorCNA algorithm. Seventy-two patients were identified who had received a platinum-based chemotherapy regimen in the metastatic setting. Gene-level copy-number analyses were performed with GISTIC2.0. Cytobands were associated with progression-free survival (PFS) to platinum chemotherapy using Cox proportional hazards models. The Cancer Genome Atlas and Molecular Taxonomy of Breast Cancer International Consortium data sets were interrogated for frequency of significant cytobands in primary triple-negative breast cancer (pTNBC) tumors. RESULTS: Among 71 evaluable patients, 17q21 and 17q22 amplifications were most strongly associated with improved PFS with platinum chemotherapy. There were no significant differences in clinicopathologic features or (neo)adjuvant chemotherapy among patients with 17q22 amplification. Patients with 17q22 amplification (n = 17) had longer median PFS with platinum (7.0 v 3.8 months; log-rank P =.015) than patients without 17q22 amplification (n = 54), an effect that remained significant in multivariable analyses (PFS hazard ratio 0.37; 95% CI, 0.16 to 0.84; P =.02). Among 39 patients who received the nonplatinum chemotherapy agent capecitabine, there was no association between 17q22 amplification and capecitabine PFS (log-rank P =.69). In The Cancer Genome Atlas and Molecular Taxonomy of Breast Cancer International Consortium, 17q22 amplification occurred in more than 20% of both pTNBC and mTNBC tumors, whereas 17q21 was more frequently amplified in mTNBC relative to pTNBC (16% v 8.1%, P =.015). CONCLUSION: The 17q22 amplicon, detected by ctDNA, is associated with improved PFS with platinum chemotherapy in patients with mTNBC and warrants further investigation. 17q22 amplification detected in ctDNA is associated with longer PFS to platinum in metastatic TNBC. [ABSTRACT FROM AUTHOR]