Relevance of tumour-infiltrating lymphocytes, PD-1 and PD-L1 in patients with high-risk, nodal-metastasised breast cancer of the German Adjuvant Intergroup Node-positive study
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Relevance of tumour-infiltrating lymphocytes, PD-1 and PD-L1 in patients with high-risk, nodal-metastasised breast cancer of the German Adjuvant Intergroup Node-positive study. / Noske, Aurelia; Möbus, Volker; Weber, Karsten; Schmatloch, Sabine; Weichert, Wilko; Köhne, Claus-Henning; Solbach, Christine; Ingold Heppner, Barbara; Steiger, Katja; Müller, Volkmar; Fasching, Peter; Karn, Thomas; van Mackelenbergh, Marion; Marmé, Frederik; Schmitt, Wolfgang D; Schem, Christian; Stickeler, Elmar; Loibl, Sybille; Denkert, Carsten.
In: EUR J CANCER, Vol. 114, 06.2019, p. 76-88.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Relevance of tumour-infiltrating lymphocytes, PD-1 and PD-L1 in patients with high-risk, nodal-metastasised breast cancer of the German Adjuvant Intergroup Node-positive study
AU - Noske, Aurelia
AU - Möbus, Volker
AU - Weber, Karsten
AU - Schmatloch, Sabine
AU - Weichert, Wilko
AU - Köhne, Claus-Henning
AU - Solbach, Christine
AU - Ingold Heppner, Barbara
AU - Steiger, Katja
AU - Müller, Volkmar
AU - Fasching, Peter
AU - Karn, Thomas
AU - van Mackelenbergh, Marion
AU - Marmé, Frederik
AU - Schmitt, Wolfgang D
AU - Schem, Christian
AU - Stickeler, Elmar
AU - Loibl, Sybille
AU - Denkert, Carsten
N1 - Copyright © 2019 Elsevier Ltd. All rights reserved.
PY - 2019/6
Y1 - 2019/6
N2 - 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.
AB - 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.
KW - Adult
KW - Biomarkers, Tumor/metabolism
KW - Chemotherapy, Adjuvant/methods
KW - Female
KW - Germany
KW - Humans
KW - Lymphocytes, Tumor-Infiltrating/immunology
KW - Middle Aged
KW - Prognosis
KW - Programmed Cell Death 1 Receptor/therapeutic use
KW - Prospective Studies
KW - Triple Negative Breast Neoplasms/drug therapy
U2 - 10.1016/j.ejca.2019.04.010
DO - 10.1016/j.ejca.2019.04.010
M3 - SCORING: Journal article
C2 - 31075727
VL - 114
SP - 76
EP - 88
JO - EUR J CANCER
JF - EUR J CANCER
SN - 0959-8049
ER -