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

Abstract

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.

• 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 (JAMA Oncol) Vol. 3 Issue 11 Pg. e172085 (Nov 09 2017) ISSN: 2374-2445 [Electronic] United States
• PMID: 28750133 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Antineoplastic Agents, Immunological
• Biomarkers, Tumor
• Protein Kinase Inhibitors
• Quinazolines
• Taxoids
• Lapatinib
• Docetaxel
• ERBB2 protein, human
• Receptor, ErbB-2
• Trastuzumab
• Paclitaxel

Topics

• Aged
• Antineoplastic Agents, Immunological (therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Biomarkers, Tumor (analysis, antagonists & inhibitors)
• Breast Neoplasms (drug therapy, enzymology, immunology, pathology)
• Clinical Trials, Phase III as Topic
• Disease-Free Survival
• Docetaxel
• Female
• Humans
• Kaplan-Meier Estimate
• Lapatinib
• Lymphocytes, Tumor-Infiltrating (immunology)
• Middle Aged
• Multicenter Studies as Topic
• Multivariate Analysis
• Neoplasm Metastasis
• Paclitaxel (therapeutic use)
• Patient Selection
• Predictive Value of Tests
• Proportional Hazards Models
• Prospective Studies
• Protein Kinase Inhibitors (therapeutic use)
• Quinazolines (therapeutic use)
• Randomized Controlled Trials as Topic
• Receptor, ErbB-2 (analysis, antagonists & inhibitors)
• Retrospective Studies
• T-Lymphocytes, Cytotoxic (immunology)
• Taxoids (therapeutic use)
• Time Factors
• Trastuzumab (therapeutic use)
• Treatment Outcome