Abstract
BackgroundThe clinical importance of tumor-infiltrating cluster of differentiation 4 (CD4) T cells is incompletely understood in early breast cancer. We investigated the clinical significance of CD4, forkhead box P3 (FOXP3), and B cell attracting chemokine leukocyte chemoattractant-ligand (C-X-C motif) 13 (CXCL13) in early breast cancer.MethodsThe study is based on the patient population of the randomized FinHer trial, where 1010 patients with early breast cancer were randomly allocated to adjuvant chemotherapy containing either docetaxel or vinorelbine, and human epidermal growth factor receptor 2 (HER2)-positive patients were also allocated to trastuzumab or no trastuzumab. Breast cancer CD4, FOXP3, and CXCL13 contents were evaluated using quantitative real-time polymerase chain reaction (qRT-PCR), and their influence on distant disease-free survival (DDFS) was examined using univariable and multivariable Cox regression and Kaplan-Meier estimates in the entire cohort and in selected molecular subgroups. Interactions between variables were analyzed using Cox regression. The triple-negative breast cancer (TNBC) subset of the HE10/97 randomized trial was used for confirmation.ResultsHigh CXCL13 was associated with favorable DDFS in univariable analysis, and independently in multivariable analysis (HR 0.44, 95% CI 0.29–0.67, P ≤ 0.001), most strongly in TNBC (HR 0.39, 95% CI 0.19–0.79, P = 0.009). No significant interaction with chemotherapy or trastuzumab administration was detected. Neither tumor CD4 content nor FOXP3 content was associated with DDFS. The favorable prognostic influence of CXCL13 was confirmed in the HE10/97 trial patient population with TNBC (HR 0.30, 95% CI 0.09–0.93; P = 0.038).ConclusionsThe results provide a high level of evidence that humoral immunity influences the survival outcomes of patients with early breast cancer, in particular of those with TNBC.Trial registrationThe study reports retrospective biomarker analyses in the prospective FinHer trial and the prospective HE10/97 trial.ISRCTN76560285. Registered on 18 March 2005.ACTRN12611000506998. Registered on 16 May 2011.
Highlights
The clinical importance of tumor-infiltrating cluster of differentiation 4 (CD4) T cells is incompletely understood in early breast cancer
Breast tumor expression of C-X-C motif chemokine ligand 13 (CXCL13) (Table 1) and of forkhead box P3 (FOXP3) (Additional file 5: Table S3) above the median value were both associated with poor histological grade of differentiation, negative estrogen receptor (ER) and progesterone receptor (PR) status, positive human epidermal growth factor receptor 2 (HER2) status, Ki-67 expression above the median value, and with the HER2-positive and the triple-negative breast cancer (TNBC) molecular subtypes, whereas CD4 (Additional file 6: Table S4) expression was not associated with these variables
Survival analyses Cancer CXCL13 expression above the median value was associated with favorable distant disease-free survival (DDFS) (HR 0.71, 95% Confidence interval (CI) 0.51– 0.99; P = 0.044), high FOXP3 content tended to be associated with unfavorable DDFS (HR 1.33, 95% CI 0.95–1.86; P = 0.094), and tumor CD4 content was not associated with DDFS (HR 0.99, 95% CI 0.71–1.39; P = 0.994; Fig. 1)
Summary
The clinical importance of tumor-infiltrating cluster of differentiation 4 (CD4) T cells is incompletely understood in early breast cancer. We investigated the clinical significance of CD4, forkhead box P3 (FOXP3), and B cell attracting chemokine leukocyte chemoattractant-ligand (C-X-C motif) 13 (CXCL13) in early breast cancer. Tumor-infiltrating lymphocytes (TILs) likely have an important, albeit still incompletely understood, prognostic and predictive role in breast cancer. The importance of cluster of differentiation 8 (CD8)-positive (CD8+) cytotoxic T cells is well-established in breast cancer [3], and CD4+ T cells have a central role in orchestrating antitumoral immunity [4, 5]. To elucidate the prognostic role of different subsets of CD4+ T cells in early breast cancer, we focus here on the CD4+ cells, forkhead box P3 (FOXP3) + CD4+ regulatory T cells (Tregs), and CX-C motif chemokine ligand 13 (CXCL13)-positive CD4 + follicular helper T (Tfh) cells. Tfh cells and the CXLC13/CXCR5 axis are crucial for germinal center development and antigen-specific B cell maturation to high-affinity memory cells and antibodysecreting plasma cells [10, 11]
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