The long and winding road to biomarkers for immunotherapy: a retrospective analysis of samples from patients with triple-negative breast cancer treated with pembrolizumab.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:38703428", "kind": "science-record", "revision": 4, "content_hash": "sha256:10df10f8e2322eac3ddeb2bbe222fd11951ed02f6608fffef0c6b0fbe6bbdf40", "created_at": "2026-11-01T19:20:40Z", "updated_at": "2026-11-01T22:54:15Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "The long and winding road to biomarkers for immunotherapy: a retrospective analysis of samples from patients with triple-negative breast cancer treated with pembrolizumab.", "doi": "10.1016/j.esmoop.2024.102964", "pmid": "38703428", "authors": ["L Buisseret", "Y Bareche", "D Venet", "E Girard", "A Gombos", "P Emonts", "S Majjaj", "G Rouas", "M Serra", "V Debien", "E Agostinetto", "S Garaud", "K Willard-Gallo", "D Larsimont", "J Stagg", "F Rothé", "C Sotiriou"], "journal": "ESMO open", "year": 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 identification 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.\nMATERIALS 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-infiltrating 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.\nRESULTS: 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 significantly 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 × 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 significantly associated with a worse prognosis.\nCONCLUSIONS: 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 reflect 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.", "claims": [{"id": "claim-method", "statement": "Comparisons between two and more than two conditions were assessed using the two-sided Student’s t-test and Kruskal–Wallis test, respectively. The correlations between two genes or between genes and signatures were investigated using Spearman correlations. Comparisons between two categorical variables were assessed using Fisher’s exact tests. 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