免疫细胞浸润情况对于乳腺癌患者的全身治疗效果和生存结局至关重要。
2019年5月8日，欧洲癌症治疗研究组织、欧洲癌症组织、欧洲乳腺癌专科医师学会《欧洲癌症杂志》在线发表德国乳腺癌研究协作组、慕尼黑科技大学、法兰克福大学赫斯特医院、卡塞尔伊丽莎白医院、奥尔登堡大学医院、法兰克福大学医院、柏林大学医院、红十字会柏林医院、汉堡大学医学中心、埃尔兰根纽伦堡大学医院综合癌症中心、基尔大学石勒苏益格荷尔斯泰因医院、海德堡大学国家肿瘤疾病中心、汉堡耶路撒冷医院、亚琛科技大学、马尔堡菲利普大学、德国癌症联盟的GAIN研究报告，分析了高风险淋巴结阳性乳腺癌辅助化疗患者肿瘤浸润淋巴细胞、程序性细胞死亡蛋白1（PD-1）和程序性细胞死亡蛋白配体1（PD-L1）与生存结局的相关性。
GAIN: A Study to Compare ETC vs. EC-TX and Ibandronate vs. Observation in Patients With Node-positive Primary Breast Cancer (NCT00196872)
该研究对1318例福尔马林固定石蜡包埋的乳腺癌组织标本，通过苏木精伊红染色分析肿瘤浸润淋巴细胞，通过免疫组化分析PD-1和PD-L1（SP263）表达。对肿瘤浸润淋巴细胞、PD-1、PD-L1、分子亚型、生存结局、化疗方案的相关性进行统计学检验。化疗方案包括：
ddEPC组：剂量密集表柔比星＋紫杉醇＋环磷酰胺
ddECPX组：剂量密集表柔比星＋环磷酰胺＋紫杉醇＋卡培他滨
结果，肿瘤浸润淋巴细胞总密度的显著相关因素：
免疫细胞PD-1表达水平（P<0.0001）
免疫细胞PD-L1表达水平（P<0.0001）
肿瘤细胞PD-L1表达水平（P=0.0051）
三阴性乳腺癌（P<0.0001）
HER2阳性乳腺癌（P<0.0001）
根据多因素比例风险回归分析，ddEPC组与ddECPX组相比：
无肿瘤浸润淋巴细胞：无病生存较差（风险比：0.69，95%置信区间：0.44～1.06，P=0.0915）
有肿瘤浸润淋巴细胞：无病生存相似（风险比：1.24，95%置信区间：0.92～1.67，P=0.1566）
肿瘤浸润淋巴细胞对于不同化疗方案患者无病生存的影响显著（P=0.0336）
三阴性乳腺癌有与无PD-1阳性免疫细胞相比，无病生存显著较好（风险比：0.50，95%置信区间：0.25～0.99，P=0.0457）。
PD-L1表达水平对患者生存结局的影响不显著。
因此，该研究结果表明，对于淋巴结阳性高风险乳腺癌患者，肿瘤浸润淋巴细胞与PD-1、PD-L1的表达水平显著相关，三阴性乳腺癌、HER2阳性乳腺癌的肿瘤浸润淋巴细胞总密度显著较高，肿瘤浸润淋巴细胞对于不同化疗方案患者无病生存的影响显著。此外，PD-1阳性免疫细胞对于三阴性乳腺癌的预后影响较大，PD-L1高表达于免疫细胞而非肿瘤细胞，对于生存结局无预后价值。
Eur J Cancer. 2019 May 8;114:76-88.
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.
Aurelia Noske, Volker Mobus, Karsten Weber, Sabine Schmatloch, Wilko Weichert, Claus-Henning Kohne, Christine Solbach, Barbara Ingold Heppner, Katja Steiger, Volkmar Müller, Peter Fasching, Thomas Karn, Marion van Mackelenbergh, Frederik Marmé, Wolfgang D. Schmitt, Christian Schem, Elmar Stickeler, Sybille Loibl, Carsten Denkert.
Technical University of Munich, Germany; Hospital Frankfurt Hochst, Academic Hospital of the University Frankfurt, Germany; German Breast Group, Neu-Isenburg, Germany; Elisabeth-Krankenhaus Kassel, Kassel, Germany; University Hospital Oldenburg, Oldenburg, Germany; University Hospital Frankfurt, Germany; Charité University Hospital, Berlin, Germany; DRK Kliniken Berlin, Germany; University Medical Center Hamburg-Eppendorf, Hamburg, Germany; University Hospital Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany; University Hospital Schleswig-Holstein, Kiel, Germany; National Center for Tumor Diseases, Heidelberg, Germany; Krankenhaus Jerusalem, Hamburg, Germany; RWTH Aachen, Germany; Philipps-University Marburg, Germany; German Cancer Consortium, Partner Site Munich, Germany; German Cancer Consortium, Partner Site Charité, Berlin, Germany.
HIGHLIGHTS
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.
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) 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
DOI: 10.1016/j.ejca.2019.04.010
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