Introduction: The process of Epithelial Mesenchymal Transition (EMT) involves the transition of cells from a differentiated epithelial phenotype to a less differentiated mesenchymal phenotype. Mammographic breast density (MBD) refers to the proportion of high opacity area on a mammogram. EMT may be triggered in cancer cells by a range of therapies including cytotoxic chemotherapy, with cell line and animal suggesting chemoresistance may result. High MBD in patients being treated for BrCa also associates with chemoresistance, correlating with lower pathological complete response rates (pCR) in a pilot study although impact on longer term outcomes was not reported1. Linking these two stimuli, EMT can also be induced by artificial high-density stroma, where it also leads to chemoresistance in vitro2.
Aims: Here we set out to explore the link between poor outcome after NAC and EMT in a clinical patient cohort, and to ascertain the molecular drivers through which EMT is triggered in this setting. Further we looked to confirm the association of high MBD with poor chemoresponse, and to assess whether this chemoresistance is mediated through EMT with the same drivers.
Key Findings: In a pilot cohort of 50 NAC-treated locally advanced BrCas, development of EMT correlated with a significant increase in mortality (78 v 25%, P=0.03). In a subsequent 240-patient cohort MBD higher percent breast density divided by tertile correlated with trends to inferior clinical shrinkage (58 v 40%, P=0.08) and higher relapse rate (35 v 22%, P=0.05). EMT induction is being assessed and correlated with both breast density and outcome in this second cohort. On a sub-group of 50 patients within the second cohort a broad nanostring assay has looked at expression changes transcription factors known to drive EMT (EMT-TFs), to ascertain which factors control EMT in the context of either chemoresistance and/or high breast density. All EMT-TFs measured were numerically more strongly induced in relapsing patients, the change reaching significance for Snail-3 (OR=1.8, P=0.04) and borderline significance for TWIST-1 (OR=2.4, P=0.08). Validation of links between Snail-3 and Twist-1 protein expression with EMT in the full 240 patient cohort is underway.
Implications: Both high MBD and EMT correlate with chemoresistance with a mechanistic association between MBD and EMT being explored. Specific EMT-TFs are implicated, targeting of which could attenuate chemoresistance.
References: 1. Elsamany et al. Breast. 2015 Oct;24(5):576581
2. Raviraj et al. Clin Exp Metastasis 2012, 29(3):273292.
17 Mar 2019 - 20 Mar 2019