Abstract
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. 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. 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). 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.
Highlights
Breast cancer is a malignant tumor with a high incidence worldwide and in China [1, 2]
A model consisting of the gene expression ratios of PCDH12/ELP3, PCDH12/MSRA and FAM160B2/MSRA with nonzero coefficients selected by least absolute shrinkage and selection operator (LASSO) was developed in GSE58812
In GSE2034, score for MFS (SMFS) was significantly associated with metastasis-free survival (MFS) in Triple-negative breast cancer (TNBC) patients (HR=8.767, 95% 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)
Summary
Breast cancer is a malignant tumor with a high incidence worldwide and in China [1, 2]. Triple-negative breast cancer (TNBC) accounts for 15–20% of all breast cancers. TNBC has the worst prognosis of all breast cancer subtypes, and the 5-year mortality rate can reach 40% after the initial diagnosis compared with luminal breast cancer [3]. Most distant metastases of TNBC occur within 3 years after the initial diagnosis, with a higher probability of brain metastasis and visceral metastasis [4, 5]. According to the National Comprehensive Cancer Network (NCCN) guidelines of breast cancer, due to the young age of onset and the lack of targets for endocrine therapy and anti-HER2 therapy, radiotherapy (RT) and chemotherapy are usually used as adjuvant treatments in TNBC [6]. Several transcriptomic signatures have been proposed for predicting the efficacy of RT for breast cancer [7,8,9], there are currently no such indicators specific to TNBC. Screening the population suitable for RT in TNBC is a problem worthy of study
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
