Publication
Molecular adaptation to neoadjuvant immunotherapy in triple-negative breast cancer.
Journal Paper/Review - Nov 19, 2024
Denkert Carsten, Schneeweiss Andreas, Rey Julia, Karn Thomas, Hattesohl Akira, Weber Karsten E, Rachakonda Sivaramakrishna, Braun Michael, Huober Jens, Jank Paul, Sinn Hans-Peter, Zahm Dirk-Michael, Felder Bärbel, Hanusch Claus, Teply-Szymanski Julia, Marme Frederik, Fehm Tanja N, Thomalla Jörg, Sinn Bruno Valentin, Stiewe Thorsten, Marczyk Michal, Blohmer Jens-Uwe, van Mackelenbergh Marion T, Schem Christian, Staib Peter, Link Theresa, Müller Volkmar, Stickeler Elmar, Stover Daniel G, Solbach Christine, Metzger-Filho Otto, Jackisch Christian, Geyer Charles E, Fasching Peter Andreas, Pusztai Lajos, Nekljudova Valentina, Untch Michael, Loibl Sibylle
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Brief description/objective
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.