Department of Pathology and Laboratory Medicine, Genetic Pathology Evaluation Centre, University of British Columbia, Vancouver, Canada.
Canadian Cancer Trials Group, Queen's University, Kingston, Ontario, Canada.
JAMA Oncol. 2017 Nov 9;3(11):e172085. doi: 10.1001/jamaoncol.2017.2085.
Accumulating evidence indicates that tumor-infiltrating lymphocytes (TILs) are associated with clinical outcomes and may predict the efficacy of chemotherapy and human epidermal growth factor receptor 2 (HER2, encoded by the gene ERBB2)-targeted therapy in patients with HER2-positive breast cancer.
To investigate the role of TILs, particularly cytotoxic CD8+ T cells, in the prediction of outcomes in patients with HER2-positive metastatic breast cancer randomized to an antibody-based (trastuzumab) vs a small molecule-based (lapatinib) anti-HER2 therapy.
DESIGN, SETTING, AND PARTICIPANTS: The Canadian Cancer Trials Group MA.31 phase 3 clinical trial accrued patients from 21 countries and randomized 652 with HER2-positive metastatic breast cancer to receive trastuzumab or lapatinib, in combination with a taxane, from January 17, 2008, through December 1, 2011. Patients had received no prior chemotherapy or HER2-targeted therapy in the metastatic setting. The median follow-up was 21.5 months (interquartile range, 14.3-31.0). The tumor tissue collected for primary diagnosis was used in this ad hoc substudy. Sections were scored for TILs on hematoxylin-eosin (H&E)-stained sections, and immunohistochemical analysis was performed to assess CD8, FOXP3, CD56, and programmed cell death protein 1 (PD-1) expression on stromal (sTILs) and intratumoral TILs. Data were analyzed from July 15, 2015, through July 27, 2016.
Treatment with trastuzumab or lapatinib in combination with taxane chemotherapy (paclitaxel or docetaxel) for 24 weeks.
Prognostic effects of biomarkers were evaluated for progression-free survival by stratified univariate log-rank test with Kaplan-Meier curves and by multivariate Cox proportional hazards regression; predictive effects were examined with a test of interaction between treatment allocation and biomarker classification.
Of the 647 treated women (mean [SD] age, 55.0 [10.8] years), 614 had tumor tissue samples scored for H&E sTILs and 427 for CD8 biomarker assessments. Overall H&E sTIL counts of greater than 5% (high) were present in 215 cases (35%) but did not show significant prognostic or predictive effects. Univariate stratified analyses detected a significant predictive effect on risk for progression with lapatinib compared with trastuzumab among patients with low CD8+ sTIL counts (observed hazard ratio, 2.94; 95% CI, 1.40-6.17; P = .003) and among those with high CD8+ sTIL counts (observed hazard ratio, 1.36; 95% CI, 1.05-1.75; P = .02), confirmed in stepwise multivariate analysis (interaction P = .04). Other immunohistochemistry biomarkers were not associated with prognostic or predictive effects.
In this secondary analysis of a phase 3 randomized clinical trial, a low level of preexisting cytotoxic sTILs predicted the most benefit from an antibody- vs a small molecule-based drug against the same target.
clinicaltrials.gov Identifier: NCT00667251.
越来越多的证据表明，肿瘤浸润淋巴细胞（TILs）与临床结果相关，并可能预测曲妥珠单抗（HER2 编码基因 ERBB2 的抗体）与拉帕替尼（HER2 靶向小分子）治疗 HER2 阳性乳腺癌患者的化疗和人表皮生长因子受体 2（HER2）疗效。
研究 TILs，特别是细胞毒性 CD8+T 细胞，在预测接受基于抗体（曲妥珠单抗）与基于小分子（拉帕替尼）的抗 HER2 治疗的 HER2 阳性转移性乳腺癌患者结局中的作用。
设计、地点和参与者：加拿大癌症临床试验组 MA.31 是一项 3 期临床试验，从 21 个国家招募了患者，并将 652 名 HER2 阳性转移性乳腺癌患者随机分为接受曲妥珠单抗或拉帕替尼联合紫杉烷治疗，从 2008 年 1 月 17 日至 2011 年 12 月 1 日。患者在转移性环境中没有接受过先前的化疗或 HER2 靶向治疗。中位随访时间为 21.5 个月（四分位间距，14.3-31.0）。本研究使用了用于原发诊断的肿瘤组织。在苏木精-伊红（H&E）染色切片上对 TILs 进行评分，并进行免疫组织化学分析，以评估 CD8、FOXP3、CD56 和程序性细胞死亡蛋白 1（PD-1）在基质（sTILs）和肿瘤内 TILs 上的表达。数据分析于 2015 年 7 月 15 日至 2016 年 7 月 27 日进行。
接受曲妥珠单抗或拉帕替尼联合紫杉烷化疗（紫杉醇或多西他赛）治疗 24 周。
采用分层单变量对数秩检验和 Kaplan-Meier 曲线评估生物标志物的预后作用，并采用多变量 Cox 比例风险回归评估生物标志物的预测作用；采用治疗分配和生物标志物分类之间交互作用的检验来检查预测作用。
在 647 名接受治疗的女性（平均[标准差]年龄，55.0[10.8]岁）中，614 名患者的肿瘤组织样本进行了 H&E sTILs 评分，427 名患者进行了 CD8 生物标志物评估。215 例（35%）存在大于 5%（高）的总体 H&E sTIL 计数，但没有显示出显著的预后或预测作用。单变量分层分析显示，在低 CD8+sTIL 计数的患者（观察危险比，2.94；95%CI，1.40-6.17；P=0.003）和高 CD8+sTIL 计数的患者（观察危险比，1.36；95%CI，1.05-1.75；P=0.02）中，与曲妥珠单抗相比，拉帕替尼具有显著的预测风险作用，在逐步多变量分析中得到证实（交互 P=0.04）。其他免疫组织化学标志物与预后或预测作用无关。
在这项 3 期随机临床试验的二次分析中，预先存在的低水平细胞毒性 sTILs 预测了针对相同靶点的抗体与小分子药物相比获益最大。
clinicaltrials.gov 标识符：NCT00667251。
