Molecular adaptation to neoadjuvant immunotherapy in triple-negative breast cancer

Denkert C, Schneeweiss A, Rey J, Karn T, Hattesohl A, Weber KE, Rachakonda S, Braun M, Huober J, Jank P, Sinn HP, Zahm DM, Felder B, Hanusch C, Teply-Szymanski J, Marmé F, Fehm T, Thomalla J, Sinn BV, Stiewe T, Marczyk M, Blohmer JU, van Mackelenbergh M, Schem C, Staib P, Link T, Müller V, Stickeler E, Stover DG, Solbach C, Metzger-Filho O, Jackisch C, Geyer CE, Fasching P, Pusztai L, Nekljudova V, Untch M, Loibl S (2024)

Publication Type: Journal article

Publication year: 2024

Journal

Book Volume: 5

Article Number: 101825

Journal Issue: 11

DOI: 10.1016/j.xcrm.2024.101825

Abstract

Therapy-induced molecular adaptation of triple-negative breast cancer is crucial for immunotherapy response and resistance. We analyze tumor biopsies from three different time points in the randomized neoadjuvant GeparNuevo trial (NCT02685059), evaluating the combination of durvalumab with chemotherapy, for longitudinal alterations of gene expression. Durvalumab induces an activation of immune and stromal gene expression as well as a reduction of proliferation-related gene expression. Immune genes are positive prognostic factors irrespective of treatment, while proliferation genes are positive prognostic factors only in the durvalumab arm. We identify stromal-related gene expression as a contributor to immunotherapy resistance and poor therapy response. The results provide evidence from clinical trial cohorts suggesting a role for stromal reorganization in therapy resistance to immunotherapy and in the generation of an immune-suppressive microenvironment, which might be relevant for future therapy approaches targeting the tumor stroma parallel to immunotherapy, such as combinations of immunotherapy with anti-angiogenic therapy.

Authors with CRIS profile

Involved external institutions

Charité - Universitätsmedizin Berlin Germany (DE) Universitätsklinikum Schleswig-Holstein (UKSH) Germany (DE) Krankenhaus Jerusalem Germany (DE) St.-Antonius-Hospital Eschweiler Germany (DE) Universitätsklinikum Carl Gustav Carus Dresden Germany (DE) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE) Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen Germany (DE) The Ohio State University Wexner Medical Center (OSUMC) United States (USA) (US) Universitätsklinikum Frankfurt am Main (KGU) Germany (DE) Dana–Farber Cancer Institute United States (USA) (US) Sana Kliniken AG Germany (DE) University of Pittsburgh Medical Center (UPMC) United States (USA) (US) Yale School of Medicine United States (USA) (US) Universitätsklinikum Heidelberg Germany (DE) SRH Wald-Klinikum Gera Germany (DE) GBG Forschungs GmbH (German Breast Group) Germany (DE) LMU Klinikum Germany (DE) Universitätsklinikum Gießen und Marburg (UKGM) Germany (DE) Universitätsklinikum Mannheim Germany (DE) Centrum für Integrierte Onkologie Aachen Bonn Köln Düsseldorf (CIO ABCD) Germany (DE) Silesian University of Technology Gliwice Poland (PL) HELIOS Kliniken Germany (DE) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) Kantonsspital St.Gallen Switzerland (CH)

How to cite

APA:

Denkert, C., Schneeweiss, A., Rey, J., Karn, T., Hattesohl, A., Weber, K.E.,... Loibl, S. (2024). Molecular adaptation to neoadjuvant immunotherapy in triple-negative breast cancer. Cell Reports Medicine, 5(11). https://doi.org/10.1016/j.xcrm.2024.101825

MLA:

Denkert, Carsten, et al. "Molecular adaptation to neoadjuvant immunotherapy in triple-negative breast cancer." Cell Reports Medicine 5.11 (2024).

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