A Six-Epithelial-Mesenchymal Transition Gene Signature May Predict Metastasis of Triple-Negative Breast Cancer.

ABSTRACT

PURPOSE: Pathological complete response (pCR) to neoadjuvant chemotherapy (NACT) is associated with favourable outcomes of patients with triple-negative breast cancer (TNBC). However, a proportion of TNBC patients with the residual disease do not relapse and achieve long-term survival. The aim of this study was to identify biomarkers that predict clinical outcomes in these patients. PATIENTS AND METHODS: A retrospective series of 10 TNBC patients who displayed non-pCR to NACT were included in the discovery cohort. Total RNA from pre-NACT core biopsies and paired surgical specimens were subjected to the Affymetrix Human Transcriptome Array. Gene set enrichment analysis (GSEA) was used to identify signal pathways and gene signatures associated with metastasis. The Cox proportional hazard model and Kaplan-Meier survival curves were employed to assess the prognostic value of the identified signature in two independent TNBC datasets included in Gene Expression Omnibus (GEO). RESULTS: The epithelial-mesenchymal transition (EMT) pathway was markedly more enriched in pre- (NES = 1.92; p.adjust = 0.019) and post-NACT samples (NES = 2.02; p.adjust = 0.010) from patients who developed metastasis after NACT. A subset of 6 EMT genes including LUM, SFRP4, COL6A3, MMP2, CXCL12, and HTRA1 were expressed constantly at higher levels in samples from patients who progressed to metastatic disease. The potential of the 6-EMT gene signature to predict TNBC metastasis after NACT was validated with a GEO dataset (HR=0.36, p=0.0008, 95% CI 0.200-0.658). Moreover, the signature appeared of predictive value in another GEO dataset of TNBC patients who received surgery followed by adjuvant chemotherapy (HR = 0.46, 95% CI 0.225-0.937). CONCLUSION: Expression analysis of the 6-EMT gene signature at diagnosis may be of predictive value for metastasis in TNCB patients who did not achieve pCR to NACT and for patients treated with surgery in combination with adjuvant therapy.