The long and winding road to biomarkers for immunotherapy: a retrospective analysis of samples from patients with triple-negative breast cancer treated with pembrolizumab
ESMO OPEN(2024)
Abstract
Background: Immune checkpoint blockade (ICB) in combination with chemotherapy improves outcome of patients with triple -negative breast cancer (TNBC) in metastatic and early settings. The identi fi cation of predictive biomarkers able to guide treatment decisions is challenging and currently limited to programmed death-ligand 1 (PD -L1) expression and high tumor mutational burden (TMB) in the advanced setting, with several limitations. Materials and methods: We carried out a retrospective analysis of clinical -pathological and molecular characteristics of tumor samples from 11 patients with advanced TNBC treated with single -agent pembrolizumab participating in two early -phase clinical trials: KEYNOTE -012 and KEYNOTE -086. Clinical, imaging, pathological [i.e. tumor -in fi ltrating lymphocytes (TILs), PD -L1 status], RNA sequencing, and whole-exome sequencing data were analyzed. We compared our results with publicly available transcriptomic data from TNBC cohorts from TCGA and METABRIC. Results: Response to pembrolizumab was heterogeneous: two patients experienced exceptional long-lasting responses, six rapid progressions, and three relatively slower disease progression. Neither PD -L1 nor stromal TILs were signi fi cantly associated with response to treatment. Increased TMB values were observed in tumor samples from exceptional responders compared to the rest of the cohort ( P = 3.4 x 10 - 4 ). Tumors from exceptional responders were enriched in adaptive and innate immune cell signatures. Expression of regulatory T -cell markers ( FOXP3, CCR4, CCR8, TIGIT ) was mainly observed in tumors from responders except for glycoprotein-A repetitions predominant ( GARP ), which was overexpressed in tumors from rapid progressors. GARP RNA expression in primary breast tumors from the public dataset was signi fi cantly associated with a worse prognosis. Conclusions: The wide spectrum of clinical responses to ICB supports that TNBC is a heterogeneous disease. Tumors with high TMB respond better to ICB. However, the optimal cut-off of 10 mutations (mut)/megabase (Mb) may not re fl ect the complexity of all tumor subtypes, despite its approval as a tumor -agnostic biomarker. Further studies are required to better elucidate the relevance of the tumor microenvironment and its components as potential predictive biomarkers in the context of ICB.
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Key words
triple-negative breast cancer,metastatic breast cancer,immunotherapy,biomarkers,pembrolizumab,tumor mutational burden
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