Aurelia Noske1, Volker Möbus2, Karsten Weber3, Sabine Schmatloch4, Wilko Weichert5, Claus-Henning Köhne6, Christine Solbach7, Barbara Ingold Heppner8, Katja Steiger5, Volkmar Müller9, Peter Fasching10, Thomas Karn7, Marion van Mackelenbergh11, Frederik Marmé12, Wolfgang D Schmitt13, Christian Schem14, Elmar Stickeler15, Sybille Loibl3, Carsten Denkert16. 1. Institute of Pathology, Technical University of Munich, School of Medicine, Germany. Electronic address: a.noske@medica.ch. 2. Department of Gynecology and Obstetrics, Hospital Frankfurt Höchst, Academic Hospital of the University Frankfurt, Germany. 3. German Breast Group (GBG), Neu-Isenburg, Germany. 4. Breast Unit, Elisabeth-Krankenhaus Kassel, Kassel, Germany. 5. Institute of Pathology, Technical University of Munich, School of Medicine, Germany; German Cancer Consortium (DKTK), Partner Site Munich, Germany. 6. Department of Oncology, University Hospital Oldenburg, Oldenburg, Germany. 7. Department of Gynecology and Obstetrics, University Hospital Frankfurt, Germany. 8. Institute of Pathology, Charité University Hospital, Berlin, Germany; Institute of Pathology, DRK Kliniken Berlin, Germany. 9. Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 10. Department of Gynecology and Obstetrics, University Hospital Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany. 11. University Hospital Schleswig-Holstein, Kiel, Germany. 12. Department of Gynecology and National Center for Tumor Diseases (NCT), Heidelberg, Germany. 13. Institute of Pathology, Charité University Hospital, Berlin, Germany. 14. Breast Unit Krankenhaus Jerusalem, Hamburg, Germany. 15. Department of Gynecology and Obstetrics, RWTH Aachen, Germany. 16. Institute of Pathology, Charité University Hospital, Berlin, Germany; Institute of Pathology, Philipps-University Marburg, Germany; German Cancer Consortium (DKTK), Partner Site Charité, Berlin, Germany.
Abstract
BACKGROUND: Immune cell infiltration in breast cancer is important for the patient's prognosis and response to systemic therapies including immunotherapy. We sought to investigate the prevalence of tumour-infiltrating lymphocytes (TILs) and their association with immune checkpoints such as programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) in high-risk, node-positive breast cancer of the adjuvant German Adjuvant Intergroup Node-positive (GAIN-1) trial. PATIENTS AND METHODS: We evaluated TILs by haematoxylin and eosin staining and PD-1 and PD-L1 (SP263 assay) expression by immunohistochemistry in 1318 formalin-fixed, paraffin-embedded breast carcinomas. The association of TILs with PD-1, PD-L1, molecular intrinsic subtypes, outcome and therapy regimens (dose-dense [dd] epirubicin, paclitaxel and cyclophosphamide [EPC] and dd epirubicin, cyclophosphamide, paclitaxel and capecitabine [EC-PwX]) was statistically tested. RESULTS: Overall TILs density was significantly associated with the expression of PD-1 and PD-L1 in immune cells (each p < 0.0001) and PD-L1 in tumour cells (p = 0.0051). TILs were more common in triple-negative breast cancer (TNBC) and human epidermal growth factor receptor 2 (HER2)-positive tumours (each p < 0.0001). On multivariate Cox regression analyses, patients with breast cancer without TILs had an unfavourable disease-free survival (DFS) in the EPC arm compared with the EC-PwX arm (hazard ratio [HR] = 0.69 [0.44-1.06], p = 0.0915); but no differences were seen in tumours with TILs (HR = 1.24 [0.92-1.67], p = 0.1566, interaction p = 0.0336). PD-1-positive immune cells in TNBC were associated with a significantly better DFS (HR = 0.50 [0.25-0.99], p = 0.0457). PD-L1 expression had no impact on patient outcome. CONCLUSIONS: TILs predict the benefit of intensified ddEPC compared with ddEC-PwX therapy in node-positive, high-risk breast cancer. TILs, PD-1 and PD-L1 are linked to each other indicating tumour immunogenicity. Moreover, PD-1-positive immune cells have a positive prognostic impact in TNBC. CLINICAL TRIAL: NCT00196872.
BACKGROUND: Immune cell infiltration in breast cancer is important for the patient's prognosis and response to systemic therapies including immunotherapy. We sought to investigate the prevalence of tumour-infiltrating lymphocytes (TILs) and their association with immune checkpoints such as programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) in high-risk, node-positive breast cancer of the adjuvant German Adjuvant Intergroup Node-positive (GAIN-1) trial. PATIENTS AND METHODS: We evaluated TILs by haematoxylin and eosin staining and PD-1 and PD-L1 (SP263 assay) expression by immunohistochemistry in 1318 formalin-fixed, paraffin-embedded breast carcinomas. The association of TILs with PD-1, PD-L1, molecular intrinsic subtypes, outcome and therapy regimens (dose-dense [dd] epirubicin, paclitaxel and cyclophosphamide [EPC] and dd epirubicin, cyclophosphamide, paclitaxel and capecitabine [EC-PwX]) was statistically tested. RESULTS: Overall TILs density was significantly associated with the expression of PD-1 and PD-L1 in immune cells (each p < 0.0001) and PD-L1 in tumour cells (p = 0.0051). TILs were more common in triple-negative breast cancer (TNBC) and humanepidermal growth factor receptor 2 (HER2)-positive tumours (each p < 0.0001). On multivariate Cox regression analyses, patients with breast cancer without TILs had an unfavourable disease-free survival (DFS) in the EPC arm compared with the EC-PwX arm (hazard ratio [HR] = 0.69 [0.44-1.06], p = 0.0915); but no differences were seen in tumours with TILs (HR = 1.24 [0.92-1.67], p = 0.1566, interaction p = 0.0336). PD-1-positive immune cells in TNBC were associated with a significantly better DFS (HR = 0.50 [0.25-0.99], p = 0.0457). PD-L1 expression had no impact on patient outcome. CONCLUSIONS: TILs predict the benefit of intensified ddEPC compared with ddEC-PwX therapy in node-positive, high-risk breast cancer. TILs, PD-1 and PD-L1 are linked to each other indicating tumour immunogenicity. Moreover, PD-1-positive immune cells have a positive prognostic impact in TNBC. CLINICAL TRIAL: NCT00196872.
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