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Original Investigation
November 9, 2017

Role of Cytotoxic Tumor-Infiltrating Lymphocytes in Predicting Outcomes in Metastatic HER2-Positive Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial

Author Affiliations
  • 1Department of Pathology and Laboratory Medicine, Genetic Pathology Evaluation Centre, University of British Columbia, Vancouver, Canada
  • 2Canadian Cancer Trials Group, Queen’s University, Kingston, Ontario, Canada
  • 3Department of Pathology and Laboratory Medicine, University of Ottawa, The Ottawa Hospital, Ottawa, Canada
  • 4British Columbia Cancer Agency, Vancouver, Canada
JAMA Oncol. 2017;3(11):e172085. doi:10.1001/jamaoncol.2017.2085
Key Points

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