Development and External Validation of a Transcriptomic Prognostic Signature in Triple-Negative Breast Cancer Treated with Neoadjuvant Chemotherapy

Purpose Triple-negative breast cancer (TNBC) subtype is the most aggressive representative of breast cancer; it does not have any reliable prognostic biomarkers for clinical stratification of the risk associated with the disease. This study is designed for the development and external validation of a transcriptome-based prognostic gene signature which can be utilised for stratifying TNBC patients in accordance with the survival risk. Methods The clinical data, along with the gene expression gathered from the GEO dataset GSE25066, were utilised as an initial “discovery” cohort for building a prognostic model. The univariate Cox proportional hazards regression method was utilised for gene mapping from a probe; low-variability genes were filtered along with the identification of survival-associated genes. Moreover, this feature selection was further refined for the construction of a multigene prognostic model utilising the LASSO-penalised Cox regression method. These 17 genes were analysed, and the risk score was calculated likewise. This risk score was used to categorise the patients into high-risk groups and low-risk groups. Finally, external validation of this prognostic model was carried out in (GSE58812), which is an independent GEO dataset utilising risk cut-off and identical gene coefficients. Results This study depicted that in the discovery cohort, disease-free survival was poorer in high-risk patients, as compared to low-risk patients. Gene signature in the validation cohort successfully predicted metastasis-free survival, which is an identifiable indicator of reproducibility in the independent datasets. Upon functional enrichment analysis of the signature genes, it was indicated that these genes are key determinants of cellular response to stress, regulation of metabolism, repairing DNA, along with major transcriptionally controlled biological processes in TNBC metastatic progression and chemotherapy resistance. Conclusion This study suggests a well-developed transcriptomic framework which provides a baseline for further clinical investigations and futuristic translational research. It also identifies and highlights a prognostic signature of 17 genes, which is reproducible and biologically relevant.