Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. No. 17, Panjiayuan Nanli, Chaoyang District, Beijing 100021, China.
Objective: To develop and validate a prediction model for the pathological complete response (pCR) to neoadjuvant chemotherapy (NCT) of triple-negative breast cancer (TNBC).
Methods: We systematically searched Gene Expression Omnibus, ArrayExpress, and PubMed for the gene expression profiles of operable TNBC accessible to NCT. Molecular heterogeneity was detected with hierarchical clustering method, and the biological profiles of differentially expressed genes were investigated by Gene Ontology, Kyoto Encyclopedia of Genes and Genomes analyses, and Gene Set Enrichment Analysis (GSEA). Next, machine-learning algorithms including random-forest analysis and least absolute shrinkage and selection operator (LASSO) analysis were synchronously performed and, then, the intersected proportion of significant genes was undergone binary logistic regression to fulfill variables selection. The predictive response score (pRS) system was built as the product of the gene expression and coefficient obtained from the logistic analysis. Last, the cohorts were randomly divided in a 7:3 ratio into training cohort and validation cohort for the introduction of a robust model, and a nomogram was constructed with the independent predictors for pCR rate.
Results: A total of 217 individuals from four cohort datasets (GSE32646, GSE25065, GSE25055, GSE21974) with complete clinicopathological information were included. Based on the microarray data, a six-gene panel (ATP4B, FBXO22, FCN2, RRP8, SMERK2, TET3) was identified. A robust nomogram, adopting pRS and clinical tumor size stage, was established and the performance was successively validated by calibration curves and receiver operating characteristic curves with the area under curve 0.704 and 0.756, respectively. Results of GSEA revealed that the biological processes including apoptosis, hypoxia, mTORC1 signaling and myogenesis, and oncogenic features of EGFR and RAF were in proactivity to attribute to an inferior response.
Conclusions: This study provided a robust prediction model for pCR rate and revealed potential mechanisms of distinct response to NCT in TNBC, which were promising and warranted to further validate in the perspective.
Keywords: triple-negative breast cancer, neoadjuvant chemotherapy, pathological complete response, nomogram, molecular heterogeneity