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.

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. 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. 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. 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. NCT00196872. • Tumour infiltrating lymphocyts (TILs) are predictive for dose-dense EPC therapy as compared to dose dense EC-PwX in node-positive breast cancer. • TILs correlate with PD-1 and PD-L1 expression. • TILs, PD-1 and PD-L1 show the highest levels in triple-negative breast cancer (TNBC). • TILs and PD-1–positive immune cells have prognostic impact in TNBC. • PD-L1 expression is more common in immune than in tumor cells but has no prognostic value. [ABSTRACT FROM AUTHOR]