J Breast Cancer.  2018 Jun;21(2):124-133. 10.4048/jbc.2018.21.2.124.

Lymphocyte-Activation Gene-3 Expression and Prognostic Value in Neoadjuvant-Treated Triple-Negative Breast Cancer

• Wang Y
• Dong T
• Xuan Q
• Zhao H
• Qin L
• Zhang Q

• KMID: 2413930
• DOI: http://doi.org/10.4048/jbc.2018.21.2.124

Abstract

PURPOSE
In this study, we aimed to evaluate lymphocyte-activation gene-3 (LAG-3) expression and its prognostic value in neoadjuvant-treated triple-negative breast cancer (TNBC).
METHODS
LAG-3, programmed death-1 (PD-1), programmed death ligand-1 (PD-L1), and CD8⁺ tumor-infiltrating lymphocyte (TILs) levels were examined using immunohistochemistry in 148 preand 114 post-neoadjuvant chemotherapy (NACT) specimens of human TNBC tissue. Correlations between expression levels and clinicopathological features were analyzed. Prognostic values for combined detection in TNBC following NACT were evaluated.
RESULTS
In pre-NACT specimens, LAG-3 expression showed a significant association with pathological complete response (pCR, p=0.038) and was correlated with PD-1 (p<0.001) and PD-L1 (p=0.008). In post-NACT specimens, high expression of LAG-3 showed significant effects on nodal status (p=0.023) and PD-1 (p<0.001). The expression of immune markers on TILs significantly increased following NACT. Multivariate analysis indicated that only nodal status (odds ratio [OR], 0.226; 95% confidence interval [CI], 0.079-0.644; p=0.005) and high quantities of CD8⁺TILs (OR, 3.186; 95% CI, 1.314-7.721; p=0.010) are independent predictors of pCR. Nodal status (hazard ratio [HR], 2.666; 95% CI, 1.271-5.594; p=0.010), CD8⁺TILs (HR, 0.313; 95% CI, 0.139-0.705; p=0.005), and the LAG-3-high/PD-L1-high group (HR, 2.829; 95% CI, 1.050-7.623; p=0.040) provided prognostic values for patients with TNBC following NACT.
CONCLUSION
CD8+TILs were sensitive predictive markers in response to NACT. High expression of LAG-3 in residual tissues, especially in combination with PD-L1, was associated with poor prognosis.

Keyword

Lymphocyte-activation gene-3 protein; Neoadjuvant therapy; Programmed death-1; Programmed death ligand-1; Triple negative breast neoplasms

MeSH Terms

Biomarkers
Drug Therapy
Humans
Immunohistochemistry
Lymphocytes, Tumor-Infiltrating
Multivariate Analysis
Neoadjuvant Therapy
Polymerase Chain Reaction
Prognosis
Triple Negative Breast Neoplasms*
Biomarkers

Figure

• 

  Figure 1 Expressions of lymphocyte-activation gene-3 (LAG-3), programmed death-1 (PD-1), CD8+ tumor-infiltrating lymphocytes (TILs), and programmed death ligand-1 (PD-L1) in triple-negative breast cancer (TNBC) as observed during immunohistochemistry (×400). High expression of LAG-3 in pre-neoadjuvant chemotherapy (NACT) (A) and in post-NACT (B) specimens; low expression of LAG-3 in TNBC (C); high expression of PD-1 in pre-NACT (D) and in post-NACT (E) specimens; low expression of PD-1 in TNBC (F); high expression of CD8+TILs in pre-NACT (G) and in post-NACT (H) specimens; low expression of CD8+TILs TNBC (I); high expression of PD-L1 in pre-NACT (J) and in post-NACT (K) specimens; low expression of PD-L1 TNBC (L).

• 

  Figure 2 One-to-one correspondence of immune markers between biopsy (pre-neoadjuvant chemotherapy [NACT]) and resected specimens (post-NACT) for all cases. Changes of lymphocyte-activation gene-3 (LAG-3) (A), programmed death-1 (PD-1) (B), CD8+ tumor-infiltrating lymphocytes (TILs) (C), and programmed death ligand-1 (PD-L1) (D) before and after NACT.

• 

  Figure 3 Expression of lymphocyte-activation gene-3 (LAG-3) and combined prognostic value of LAG-3 and other markers (programmed death-1 [PD-1], CD8+ tumor-infiltrating lymphocytes [TILs], and programmed death ligand-1 [PD-L1]) in triple-negative breast cancer. Kaplan-Meier curves showing estimated disease-free survival (DFS) for the LAG-3 expression (A), combined effects of LAG-3 and PD-1 (B), combined effects of LAG-3 and CD8+TILs (C), and combined effects of LAG-3 and PD-L1 (D).

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