Role of Cytotoxic Tumor-Infiltrating Lymphocytes in Predicting Outcomes in Metastatic HER2-Positive Breast Cancer
Authors: 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
Journal: JAMA Oncology (2017)

<h3>Importance</h3> 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<i>ERBB2</i>)–targeted therapy in patients with HER2-positive breast cancer. <h3>Objective</h3> To investigate the role of TILs, particularly cytotoxic CD8<sup>+</sup>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. <h3>Design, Setting, and Participants</h3> 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&amp;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. <h3>Interventions</h3> Treatment with trastuzumab or lapatinib in combination with taxane chemotherapy (paclitaxel or docetaxel) for 24 weeks. <h3>Main Outcomes and Measures</h3> 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. <h3>Results</h3> Of the 647 treated women (mean [SD] age, 55.0 [10.8] years), 614 had tumor tissue samples scored for H&amp;E sTILs and 427 for CD8 biomarker assessments. Overall H&amp;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<sup>+</sup>sTIL counts (observed hazard ratio, 2.94; 95% CI, 1.40-6.17;<i>P</i> = .003) and among those with high CD8<sup>+</sup>sTIL counts (observed hazard ratio, 1.36; 95% CI, 1.05-1.75;<i>P</i> = .02), confirmed in stepwise multivariate analysis (interaction<i>P</i> = .04). Other immunohistochemistry biomarkers were not associated with prognostic or predictive effects. <h3>Conclusions and Relevance</h3> 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. <h3>Trial Registration</h3> clinicaltrials.gov Identifier:NCT00667251