A multi-omics analysis of advanced triple-negative breast cancer identifies predictors to chemo-immunotherapy and on-treatment dynamics.

Authors

Nicolaas Van Renne, Elisa Agostinetto, Andrea Joaquín García, Marie Morfouace, Marcin Możejko, Zoë Denis, Sophie Déglise, Bernd Bodenmiller, Henoch S Hong, David Venet, Marcela Carausu, Robin Liechti, Stéphanie Tissot, Sylvie Rusakiewicz, Mattia Rediti, Xavier Catteau, Daniel Schulz, Delphine Loirat, Daniel Herrero Saboya, Philippe Aftimos, Matteo Benelli, Angel L Guerrero-Zotano, Andrea Gombos, Hans Wildiers, Jip Van Dinter, Ariane Sickinghe, Nicolas Penel, Jean-Charles Goeminne, Júlio Oliveira, Birute Brasiuniene, Emanuela Romano, Justin M Balko, Marleen Kok, Ewa Szczurek, Christos Sotiriou, Laurence Buisseret

Published in

Cell reports. Medicine. Pages 103080. Sep 29, 2026. Epub Sep 29, 2026.

Abstract

No validated biomarkers beyond PD-L1 currently guide immune checkpoint inhibition (ICI) in advanced triple-negative breast cancer (TNBC), and how tumors remodel their microenvironment in response to ICI remains incompletely understood. We perform a temporal analysis of patients with advanced TNBC treated with chemo-immunotherapy in the SYNERGY trial (NCT03616886; n = 84) and the EORTC-1553-SPECTA initiative (NCT02834884; n = 38) using RNA sequencing, whole-exome sequencing, multiplex immunofluorescence, and imaging mass cytometry. A transcriptomic progression-free survival (PFS)-based risk signature stratifies outcomes and is validated across ICI-treated cohorts, while showing context-dependent behavior in non-ICI settings. Favorable outcomes are associated with immune-enriched tumors with organized lymphoid architecture, while poor outcomes are linked to fibrotic, angiogenic microenvironments with frequent PI3K alterations. Upon treatment, early progression was characterized by fibrovascular remodeling, macrophage expansion, and upregulation of alternative immunosuppressive mediators. These findings establish fibrovascular and myeloid reprogramming as a coordinated resistance program, identify actionable therapeutic targets, and support microenvironment stratification in future ICI-based trials.

PMID:
42810342
Bibliographic data and abstract were imported from PubMed on 30 Sep 2026.

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