Cancer Research UK Cambridge Institute Departments of Pathology Oncology, University of Cambridge, Cambridge.
Cancer Research UK Cambridge Institute Oncology, University of Cambridge, Cambridge.
Ann Oncol. 2014 Aug;25(8):1536-43. doi: 10.1093/annonc/mdu191. Epub 2014 Jun 9.
T-cell infiltration in estrogen receptor (ER)-negative breast tumours has been associated with longer survival. To investigate this association and the potential of tumour T-cell infiltration as a prognostic and predictive marker, we have conducted the largest study of T cells in breast cancer to date.
Four studies totalling 12 439 patients were used for this work. Cytotoxic (CD8+) and regulatory (forkhead box protein 3, FOXP3+) T cells were quantified using immunohistochemistry (IHC). IHC for CD8 was conducted using available material from all four studies (8978 samples) and for FOXP3 from three studies (5239 samples)-multiple imputation was used to resolve missing data from the remaining patients. Cox regression was used to test for associations with breast cancer-specific survival.
In ER-negative tumours [triple-negative breast cancer and human epidermal growth factor receptor 2 (human epidermal growth factor receptor 2 (HER2) positive)], presence of CD8+ T cells within the tumour was associated with a 28% [95% confidence interval (CI) 16% to 38%] reduction in the hazard of breast cancer-specific mortality, and CD8+ T cells within the stroma with a 21% (95% CI 7% to 33%) reduction in hazard. In ER-positive HER2-positive tumours, CD8+ T cells within the tumour were associated with a 27% (95% CI 4% to 44%) reduction in hazard. In ER-negative disease, there was evidence for greater benefit from anthracyclines in the National Epirubicin Adjuvant Trial in patients with CD8+ tumours [hazard ratio (HR) = 0.54; 95% CI 0.37-0.79] versus CD8-negative tumours (HR = 0.87; 95% CI 0.55-1.38). The difference in effect between these subgroups was significant when limited to cases with complete data (P heterogeneity = 0.04) and approached significance in imputed data (P heterogeneity = 0.1).
The presence of CD8+ T cells in breast cancer is associated with a significant reduction in the relative risk of death from disease in both the ER-negative [supplementary Figure S1, available at Annals of Oncology online] and the ER-positive HER2-positive subtypes. Tumour lymphocytic infiltration may improve risk stratification in breast cancer patients classified into these subtypes. NEAT ClinicalTrials.gov: NCT00003577.
雌激素受体（ER）阴性乳腺癌中的 T 细胞浸润与更长的生存时间有关。为了研究这种关联以及肿瘤 T 细胞浸润作为预后和预测标志物的潜力，我们进行了迄今为止最大规模的乳腺癌 T 细胞研究。
本研究共纳入了 4 项研究，总计 12439 例患者。采用免疫组织化学（IHC）定量检测细胞毒性（CD8+）和调节性（叉头框蛋白 3，FOXP3+）T 细胞。CD8 的 IHC 检测使用了来自所有 4 项研究的可用材料（8978 例样本），FOXP3 的 IHC 检测则使用了来自 3 项研究的材料（5239 例样本）——对于其余患者的缺失数据，则采用多重插补法进行处理。采用 Cox 回归检验与乳腺癌特异性生存的相关性。
在 ER 阴性肿瘤（三阴性乳腺癌和人表皮生长因子受体 2（HER2）阳性）中，肿瘤内 CD8+T 细胞的存在与乳腺癌特异性死亡风险降低 28%（95%置信区间 [CI] 16%至 38%）相关，肿瘤间质内的 CD8+T 细胞与风险降低 21%（95%CI 7%至 33%）相关。在 ER 阳性、HER2 阳性肿瘤中，肿瘤内的 CD8+T 细胞与风险降低 27%（95%CI 4%至 44%）相关。在 ER 阴性疾病中，在 National Epirubicin Adjuvant Trial 中，CD8+肿瘤患者接受蒽环类药物治疗的获益明显大于 CD8-肿瘤患者[风险比（HR）=0.54；95%CI 0.37 至 0.79]（HR=0.87；95%CI 0.55 至 1.38）。当仅限于具有完整数据的病例时，这些亚组之间的效应差异具有统计学意义（P 异质性=0.04），在插补数据中接近显著（P 异质性=0.1）。
在 ER 阴性[补充图 S1，可在《肿瘤学年鉴》在线版查看]和 ER 阳性、HER2 阳性亚型中，乳腺癌中 CD8+T 细胞的存在与疾病死亡风险的相对降低显著相关。肿瘤淋巴细胞浸润可能会改善这些亚型患者的风险分层。NEAT ClinicalTrials.gov：NCT00003577。
