Influence of Epithelial-Mesenchymal Transition on Risk of Relapse and Outcome to Eribulin or Cyclin-Dependent Kinase Inhibitors in Metastatic Breast Cancer.

Abstract

The presence of epithelial-mesenchymal transition (EMT) in breast cancer (BC) cells has been linked to worse prognosis and may influence response to systemic treatment. We explored the effect of EMT in tumor samples of patients with metastatic BC on disease-free interval and overall survival in those patients receiving eribulin or cyclin-dependent kinase 4/6 inhibitors (CDK4/6i). Key inclusion criteria included available archived primary BC tissue and, where available, matched metastatic biopsy. Patients received eribulin and/or a CDK4/6i in the metastatic setting. Specimens were assessed for biomarkers by immunohistochemistry (CDH1, AE1/3, VIM, CDH2, ZEB1, pSMAD2, and SMAD4) and gene expression by droplet digital polymerase chain reaction (<i>CDH1</i>, <i>CDH2</i>, <i>SNAI1</i> & <i>2</i>, <i>TWIST1</i>, <i>VIM</i>, <i>PTEN</i>, and <i>ZEB1</i> & <i>2</i>). Between 2002 and 2020, 127 patients were included (95 early-stage disease at diagnosis with metastatic relapse, 32 de novo metastatic disease). In metastatic samples, presence of ZEB1 overexpression was associated with shorter time to recurrence (48.1 months shorter; <i>P</i> = .003), with pSMAD2 overexpression suggesting clinical significance of 52.0 months shorter; <i>P</i> = .01. High gene expression levels for SNAIL1, <i>TWIST1</i>, and <i>PTEN</i> in the primary BC were associated with significantly longer survival in patients who received eribulin (<i>P</i> < .05); high <i>VIM</i> was associated with a clinically relevant trend toward shorter survival after a CDK4/6i (<i>P</i> = .013). We demonstrate in our exploratory study that biomarkers involved in the process of EMT could have a prognostic impact in a cohort of patients with BC uniformly treated and with long-term follow-up. Genes known to be involved in EMT were associated with improved eribulin efficacy, while suggesting a poorer outcome with CDK4/6i.