Oral Presentation 43rd Lorne Genome Conference 2022

Identification of DNA methylation biomarkers for prediction of response to neoadjuvant chemotherapy in triple-negative breast cancer (#29)

Braydon Meyer 1 , Luu Phuc-Loi 1 2 , Qian Du 1 2 , Dilys Lam 1 , Niantao Deng 1 2 , Alex Swarbrick 1 2 , Vinod Ganju 3 , Susan J Clark 1 2 , Ruth Pidsley 1 2 , Clare Stirzaker 1 2
  1. Garvan Institute of Medical Research, Sydney, NSW, Australia
  2. St Vincent's Clinical School, UNSW, Sydney, NSW, Australia
  3. Hudson Institute of Medical Research, Clayton, VIC, Australia

Background: Triple-negative breast cancer (TNBC) makes up 10-15% of all newly diagnosed breast cancers and is associated with a higher risk of disease recurrence and shorter overall survival compared to other subtypes. Neoadjuvant chemotherapy (NAC) is typically applied in the TNBC setting, with the degree of pathological response to NAC correlating with long-term prognosis. However, the response to NAC in TNBC is highly variable and poorly understood. Therefore, there is a pressing need to develop biomarkers to accurately predict NAC response allowing personalised chemotherapeutic decision-making within the clinic and avoiding unnecessary chemotoxicity from ineffective treatment.

Aim: We aim to identify a DNA methylation-based biomarker panel to accurately predict response to NAC in TNBC patients.

Methods: We performed whole-genome DNA methylation profiling using the Illumina MethylationEPIC BeadChip microarray on 32 diagnostic TNBC patient biopsies from a neoadjuvant chemotherapy clinical trial, the Sequential Evaluation of Tumours Undergoing Preoperative (SETUP) study. Patients were categorised by their response to treatment and differential analysis was undertaken between groups to discover differentially methylated regions (DMRs) and prognostic biomarkers. 

Results: We discovered nine significant differentially methylated regions (adj.P<0.1) in primary diagnostic TNBC biopsies that predict response to NAC. These ‘response-DMRs’ are encriched for gene promoter regions, are all hypermethylated in non-responders and are associated with cancer-related pathways. Using receiver operating characteristic (ROC) analysis we showed that we can also distinguish complete from partial response to NAC with high sensitivity of (AUC=0.891). Furthermore, we found that four of these DMRs are associated with TNBC overall survival (P<0.05).

Conclusions: Our results highlight the potential of DNA methylation biomarkers to be used as predictive biomarkers of response to NAC in TNBC. While further validation and exploratory studies are required, this study shows development of tailor-made biomarkers to specific NAC regimes may be warranted.