Best of the Best Oral Presentation Clinical Oncology Society of Australia Annual Scientific Meeting 2020

Epithelial Mesenchymal Transition, Mammographic Breast Density, and Chemo-resistance in Breast Cancer (#73)

Erik (Rik) Thompson 1 , Veenoo Agarwal 2 , Lisa Spalding 2 , Tony Blick 1 , Alexander Dobrovic 3 , Andrew Redfern 2
  1. IHBI and School of Biomedical Sciences, Queensland University of Technology and Translational Research Institute, Wooloongabba, QLD, Australia
  2. Department of Medicine, School of Medicine, University of Western Australia, Fiona Stanley Hospital Campus, Perth, WA, Australia
  3. Translational Genomics & Epigenomics Lab, , University of Melbourne Department of Surgery at the Austin Hospital, Melbourne, VIC, Australia

EMT involves the transition of cells from an epithelial phenotype to a mesenchymal phenotype. MBD refers to the proportion of 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 models suggesting chemoresistance may result. High MBD in patients being treated for breast cancer (BrCa) also associates with chemoresistance, correlating with lower pathological complete response rates (pCR), in a pilot study (1). Linking these two stimuli, EMT can also be induced by artificial high-density stroma, where it also leads to chemoresistance in vitro (2).

We assessed the link between poor outcome after NAC and EMT in a clinical patient cohort, and looked to confirm the association of high MBD with poor chemoresponse.

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.

A sub-group of 50 patients within the second cohort was assessed for expression changes in EMT transcription factors (EMT-TFs) using nanostring assays, 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).

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.

  1. Elsamany et al Breast 201524:576
  2. Raviraj et al. Clin Exp Metastasis 2012 29:273