Gordon Daly1,2, Gavin Dowling2, Aisling Hegarty1,2, Michael Flanagan1,2, Mihaela Ola1, Ramón Fallon1, Sinéad Cocchiglia1, Vikrant Singh1, Katherine Sheehan3, Fiona Bane1, Jason McGrath1, Louise Watson1, Sandra Hembrecht1,2, Bryan Hennessy4, Patrick Morris4, Arnold Hill1,2,4, Damir Varešlija4,5, Leonie Young1,4
1Department of Surgery, University of Medicine and Health Sciences, Royal College of Surgeons in Ireland RCSI, Dublin, Ireland;
2Department of Surgery, Beaumont Hospital, Beaumont, Dublin, Ireland;
3Department of Pathology, RCSI University of Medicine and Health Sciences, Dublin, Ireland;
4Beaumont RCSI Cancer Centre, Beaumont Hospital, Dublin, Ireland;
5School of Pharmacy and Biomolecular Sciences, Sciences, Royal College of Surgeons in Ireland RCSI, University of Medicine and Health Sciences, Dublin, Ireland
Background: Divergent estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) status with breast cancer disease progression has important consequences for clinical management and long-term survival. Molecular subtype expression is dynamic and influenced by therapeutic intervention and the metastatic environment. There remains however, a lack of data regarding the mechanism of subtype switching and subsequent clinical consequences.
Methods: A clinical study of neoadjuvant HER2 inhibitor treated patients (n=161) was undertaken to determine the consequence of treatment and metastatic environment on receptor subtype. HER2 status, ER expression levels and global DNA methylation was assessed in pre-treatment biopsies, in post-treatment samples in patients with residual disease and, where relevant, in metastatic tumour samples (total, n=22).
Results: Overall gains in ER tumour expression were significantly associated with improved disease-free survival (n=72, P<0.05) post-treatment. Mapping of the methylation landscape revealed global gains in hypomethylation following treatment (n=7 matched tumours, 16 samples) in contrast to hypermethylation on metastasis (n=5 matched tumours, 14 samples). Differential methylation of key signalling pathways, including estrogen response, epithelial to mesenchymal transition and PI3K/AKT/mTOR, is conserved between post-treatment and metastasis. However, where core pathway genes were hypomethylated following treatment, there was a shift to hypermethylation on metastasis, facilitating alterations in the tumour phenotype.
Conclusions: This study unlocks DNA methylation as a key process in breast cancer progression providing vital insights into the effects of targeted HER2 treatment. This work provides a clear rationale to develop combined HER2 inhibitor and endocrine therapeutic strategies to enhance long-term survival in HER2 positive patients.
Keywords: Breast cancer; DNA methylation; ESR1; HER2 inhibitor; neoadjuvant therapy
