Molecular adaptation to neoadjuvant immunotherapy in triple-negative breast cancer
Carsten Denkert, Andreas Schneeweiss, Julia Rey, Thomas Karn, Akira Hattesohl, Karsten E. Weber, Sivaramakrishna Rachakonda, Michael Braun, Jens Huober, Paul Jank, Hans‐Peter Sinn, Dirk-Michael Zahm, Bärbel Felder, Claus Hanusch, Julia Teply‐Szymanski, Frederik Marmé, Tanja Fehm, Jörg Thomalla, Bruno V. Sinn, Thorsten Stiewe, Michał Marczyk, Jens‐Uwe Blohmer, Marion van Mackelenbergh, Christian Schem, Peter Staib, Theresa Link, Volkmar Müller, Elmar Stickeler, Daniel G. Stover, Christine Solbach, Otto Metzger, Christian Jackisch, Charles E. Geyer, Peter A. Fasching, Lajos Pusztai, Valentina Nekljudova, M. Untch, S. Loibl
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. • Inhibition of PD-L1 leads to the activation of immune and stromal gene expression • Immune, proliferation, and stromal gene sets are linked to therapy response and prognosis • Stromal gene expression is associated with reduced pCR rate and prognosis • The results are relevant for response prediction and new combination therapy concepts Denkert et al. evaluate the longitudinal changes in tumor tissue of triple-negative breast cancer in a clinical trial cohort treated with neoadjuvant immunotherapy plus chemotherapy. The role of different gene sets in the prediction of therapy response and prognosis was analyzed, with a focus on immune, proliferation, and stromal genes.