In a recent study , high mammographic breast density (MBD) correlated with neoadjuvant chemotherapy (NAC) resistance with lower pathological complete responses (pCRs) found in patients with higher MBD versus lower MBD (19.5% v 30.5%, p=0.006) although impact on survival was not studied. Epithelial-Mesenchymal Transition (EMT), the transition of cells from an epithelial into a mesenchymal phenotype, is driven by induction of EMT-driver transcription factors (EMT-TFs). A pre-clinical study demonstrated induction of an EMT phenotype in artificial dense stroma and consequent chemoresistance . We have further shown that EMT induction correlates with poor survival after NAC (ref).
However, MBD and EMT have not been measured in the same patient in any context. Thus, the clinical interplay of these phenomena, generally and in treatment resistance is unexplored. Here we have identified the key EMT-TFs induced by NAC. We are proceeding to validate the inverse relationship between higher MBD and pCR rates, extend it to breast cancer survival and explore the link between high MBD, EMT-induction, and chemotherapy resistance.
In a pilot cohort of 50 NAC-treated locally advanced breast cancers, pre-NAC biopsies and post-NAC surgical specimens were analysed for expression changes in a panel of EMT-TFs using Nanostring assays. Snail-3 showed significantly greater induction in relapsers compared to non-relapsers (OR=1.8, p=0.04) with a borderline significantly greater induction of Twist-1 (OR=2.4, p=0.08) in relapsers in addition.
In a separate cohort of 240 patients contralateral cranio-caudal view mammograms from the time of diagnosis are being assessed for MBD employing Cumulus software. Percent MBD will be assessed both as a continuous variable and by quartiles. Associations between MBD, EMT before and after chemotherapy, pCR and relapse-free survival will be presented. The role of the identified EMT-TFs (SNAIL-3/Twist-1) in the interplay between MBD, EMT and outcome is being explored and will also be reported.