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J Breast Cancer. 2018 Dec;21(4):406-414. English. Original Article. https://doi.org/10.4048/jbc.2018.21.e61
Byun KD , Hwang HJ , Park KJ , Kim MC , Cho SH , Ju MH , Lee JH , Jeong JS .
Department of Surgery, Dong-A University College of Medicine, Busan, Korea.
Breast Medical Center, Dong-A University College of Medicine, Busan, Korea.
Department of Pathology, Dong-A University College of Medicine, Busan, Korea. jsjung1@dau.ac.kr
Department of Radiology, Dong-A University College of Medicine, Busan, Korea.
Abstract

Purpose

T-cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3) is an emerging immune response molecule related to T-cell anergy. There has been tremendous interest in breast cancer targeting immune checkpoint molecules, especially in the triple-negative breast cancer (TNBC). This study was designed to investigate TIM-3 expression on tumor infiltrating lymphocytes (TILs), its relationships with clinicopathological para-meters and expression of programmed death receptor 1 (PD-1)/programmed death receptor ligand 1 (PD-L1), and its prognostic role.

Methods

Immunohistochemistry on tissue microarray blocks produced from 109 samples of invasive ductal carcinoma type TNBC was performed with antibodies toward TIM-3, PD-1, PD-L1 and breast cancer-related molecular markers. Associations between their expression and clinicopathological parameters as well as survival analyses were performed.

Results

TIM-3 was expressed in TILs from all 109 TNBCs, consisting of 17 cases (< 5%), 31 cases (6%–25%), 48 cases (26%–50%), and 13 cases (>51%). High TIM-3 was significantly correlated with younger patients (p=0.0101), high TILs (p=0.0029), high tumor stage (p=0.0018), high PD-1 (p=0.0001) and high PD-L1 (p=0.0019), and tended to be associated with higher histologic grade, absence of extensive in situ components and microcalcification. High TIM-3 expression was significantly associated with a combinational immunophenotype group of high PD-L1 and high PD-1 (p < 0.0001). High TIM-3 demonstrated a significantly better disease-free survival (DFS) (p < 0.0001) and longer overall survival (OS) (p=0.0001), together with high TILs and high PD-1. In univariate survival analysis, high TIM-3 showed reduced relapse risk (p < 0.0001) and longer OS (p=0.0003), together with high PD-1 expression. In multivariate analysis, high TIM-3 was statistically significant in predicting prognosis, showing better DFS (hazard ratio [HR], 0.0994; 95% confidence interval [CI], 0.0296–0.3337; p=0.0002) and longer OS (HR, 0.1109; 95% CI, 0.0314–0.3912; p=0.0006).

Conclusion

In this study, we demonstrate that TIM-3 expression is an independent positive prognostic factor in TNBC, despite its association with poor clinical and pathologic features.

Copyright © 2019. Korean Association of Medical Journal Editors.