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A CTL/M2 macrophage-related four-gene signature predicting metastasis-free survival in triple-negative breast cancer treated with adjuvant radiotherapy

  • Epidemiology
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Abstract

Purpose

This study aimed to develop and validate a prognostic model for metastasis-free survival (MFS) based on genes that may functionally interact with cytotoxic T lymphocytes (CTLs) and M2 macrophages in patients with triple-negative breast cancer (TNBC) who underwent adjuvant radiotherapy.

Methods

The transcriptional and phenotypic profiles of TNBC and other breast cancer subtypes were downloaded from gene expression omnibus (GEO). The abundance of infiltrated immune cells was evaluated through CIBERSORTx or MCP-counter. A weighted linear model, the score for MFS (SMFS), was developed using the least absolute shrinkage and selection operator (LASSO) in GSE58812 and validated in GSE2034 and GSE12276. The biological implication of the SMFS was explored by evaluating its associations with TNBC molecular subtypes and other radiosensitivity- or immune-related signatures.

Results

A model consisting of the PCDH12/ELP3, PCDH12/MSRA, and FAM160B2/MSRA gene expression ratios with non-zero coefficients finally selected by LASSO was developed using GSE58812. In GSE2034 (treatment with adjuvant radiotherapy), the SMFS was significantly associated with MFS in TNBC patients (hazard ratio (HR) = 8.767, 95% confidence interval (CI) 1.856–41.408, P = 0.006) and, to a lesser extent, in non-TNBC patients (HR = 2.888, 95% CI 1.076–7.750, P = 0.035). However, the interaction of subtype (TNBC vs non-TNBC) and the SMFS tended to be significant (Pinteraction = 0.081). In contrast, the SMFS was not significantly associated with MFS in either TNBC patients (P = 0.499) or non-TNBC patients (P = 0.536) in GSE12276 (treatment without radiotherapy). Among the four TNBC molecular subtypes, the c1 and c4 subtypes exhibited higher CTL infiltration and lower SMFS values than the c2 and c3 subtypes. In addition, the SMFS was positively correlated with the abundance of endothelial cells (r = 0.413, P < 0.001).

Conclusion

The proposed model has the potential to predict MFS in TNBC patients after adjuvant radiotherapy, and the SMFS may represent a measurement of tumor immune suppression.

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Data availability

The datasets used and/or analysis during the current study are available from the corresponding author on reasonable request.

Code availability

Not available.

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Acknowledgements

We are grateful to Dr. Lei Lin from the Radiotherapy Center of Daping Hospital for her assistance in clinical radiotherapy-related issues for breast cancer. This research was partially supported by the National Natural Science Foundation of China (81802292).

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Author notes

  1. He Xiao and Dong Wang were equally charged for supervising this study.

Authors and Affiliations

  1. Department of Cancer Center, Daping Hospital & Army Medical Center of PLA, Third Military Medical University (Army Medical University), No. 10 Changjiang Zhilu, Yuzhong District, Chongqing, 400042, China

    Yunfei Ye, Jungang Ma, Qin Zhang, Kai Xiong, Zhimin Zhang, Chuan Chen, He Xiao & Dong Wang

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  1. Yunfei Ye
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Contributions

Conception and design: YY, HX, and DW; development of methodology: YY, HX, and DW; acquisition of data: JM, QZ, and KX; analysis and interpretation of data: YY, HX, and DW; writing, review, and/or revision of the manuscript: YY, JM, QZ, KX, ZZ, CC, HX, and DW; study supervision: YY, HX, and DW.

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Correspondence to Dong Wang.

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All the public raw datasets used in this study have been approved by the Ethics Committees at the corresponding institutions.

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Ye, Y., Ma, J., Zhang, Q. et al. A CTL/M2 macrophage-related four-gene signature predicting metastasis-free survival in triple-negative breast cancer treated with adjuvant radiotherapy. Breast Cancer Res Treat 190, 329–341 (2021). https://doi.org/10.1007/s10549-021-06379-1

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