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日益增加的证据表明，肿瘤浸润淋巴细胞（TIL）与临床结局有相关性，可能预测化疗和人表皮生长因子受体2（HER2，由ERBB2基因编码）靶向疗法用于HER2阳性乳腺癌患者的有效性。 2017年7月27日，《美国医学会杂志肿瘤学分册》在线发表加拿大不列颠哥伦比亚大学、维多利亚女王大学、不列颠哥伦比亚癌症中心的Ⅲ期随机临床研究（MA.31）二次分析报告，对随机接受抗体（曲妥珠单抗）或小分子（拉帕替尼）HER2抑制剂的427例HER2阳性转移性乳腺癌患者进行淋巴细胞生物标志评定，结果发现CD8阳性细胞毒性基质TIL对无进展生存结局有显著预测作用。 加拿大癌症研究组（CCTG）Ⅲ期临床研究（MA.31）于2008年1月17日～2011年12月1日从21个国家入组652例HER2阳性转移性乳腺癌患者，随机接受抗HER2靶向疗法（曲妥珠单抗或拉帕替尼）并联合紫杉类（紫杉醇或多西他赛）化疗，治疗24周。患者既往未接受过针对转移的化疗或HER2靶向疗法。中位随访21.5个月（四分位距：14.3～31.0）。为诊断原发病变而采集的肿瘤组织被用于该特殊亚组研究，对苏木精-伊红（H&E）染色切片进行评分，并利用免疫组化分析对基质TIL（sTIL）和肿瘤内TIL的CD8、FOXP3、CD56、程序性死亡蛋白1（PD-1）表达进行定量。2015年7月15日～2016年7月27日进行数据分析。通过生存曲线分层单变量对数秩检验和多变量比例风险回归，评估生物标志对无进展生存的预后作用；通过治疗分配和生物标志分类之间的相互作用检验，对预测作用进行检查。 结果发现，647例女性（平均年龄55.0±10.8岁）完成治疗，其中614例获得肿瘤组织标本进行H&E染色sTIL评分，其中428例进行CD8生物标志定量。其中215例（35%）H&E染色sTIL总数＞5%（高），但是未见显著预后或预测作用。 根据单变量分层分析发现，拉帕替尼与曲妥珠单抗相比，对进展风险有显著预测作用：
根据多变量回归分析发现，上述结果得到确认（相互作用P=0.04）。 其他免疫组化生物标志无预后或预测作用。 因此，在该Ⅲ期随机临床研究二次分析中，HER2阳性转移性乳腺癌女性的原发肿瘤活检标本原有细胞毒性sTIL水平低，可预测抗体（曲妥珠单抗）与小分子（拉帕替尼）药物相比，抗同一靶点（HER2）的获益最大。 相关阅读 JAMA Oncol. 2017 Jul 27. [Epub ahead of print] Role of Cytotoxic Tumor-Infiltrating Lymphocytes in Predicting Outcomes in Metastatic HER2-Positive Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial. Shuzhen Liu; Bingshu Chen; Samantha Burugu; Samuel Leung; Dongxia Gao; Shakeel Virk; Zuzana Kos; Wendy R. Parulekar; Lois Shepherd; Karen A. Gelmon; Torsten O. Nielsen. University of British Columbia, Vancouver, Canada; Queen's University, Kingston, Ontario, Canada; University of Ottawa, The Ottawa Hospital, Ottawa, Canada; British Columbia Cancer Agency, Vancouver, Canada. This secondary analysis of a phase 3 randomized clinical trial investigates the role of tumor-infiltrating lymphocytes in predicting outcomes in patients with HER2-positive metastatic breast cancer randomized to antibody vs small molecule-based anti-HER2 therapy. QUESTION: Do cytotoxic tumor-infiltrating lymphocytes predict patient response to antibody- (trastuzumab) vs small molecule-based (lapatinib) HER2 inhibitors? FINDINGS: In this secondary analysis of a randomized clinical trial, 427 patients with HER2-positive metastatic breast cancer randomized to trastuzumab vs lapatinib underwent assessment for lymphocyte biomarkers. A significant predictive effect on progression-free survival was observed for CD8+ cytotoxic stromal tumor-infiltrating lymphocytes. MEANING: A low level of preexisting stromal cytotoxic T-cell infiltration in primary tumor biopsy specimens predicts women who benefit from an antibody- vs a small molecule-based drug intervention for HER2-positive breast cancer, in the metastatic setting. IMPORTANCE: 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. OBJECTIVE: 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. INTERVENTIONS: Treatment with trastuzumab or lapatinib in combination with taxane chemotherapy (paclitaxel or docetaxel) for 24 weeks. MAIN OUTCOMES AND MEASURES: 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. RESULTS: 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. CONCLUSIONS AND RELEVANCE: 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. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00667251 DOI: 10.1001/jamaoncol.2017.2085 |
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