Accurate prediction of response to endocrine therapy in breast cancer patients: current and future biomarkers

Abstract

Approximately 70% of patients have breast cancers that are oestrogen receptor alpha positive (ER+) and are therefore candidates for endocrine treatment. Many of these patients relapse in the years during or following completion of adjuvant endocrine therapy. Thus, many ER+ cancers have primary resistance or develop resistance to endocrine therapy during treatment. Recent improvements in our understanding of how tumours evolve during treatment with endocrine agents have identified both changes in gene expression and mutational profiles, in the primary cancer as well as in circulating tumour cells. Analysing these changes has the potential to improve the prediction of which specific patients will respond to endocrine treatment. Serially profiled biopsies during treatment in the neoadjuvant setting offer promise for accurate and early prediction of response to both current and novel drugs and allow investigation of mechanisms of resistance. In addition, recent advances in monitoring tumour evolution through non-invasive (liquid) sampling of circulating tumour cells and cell-free tumour DNA may provide a method to detect resistant clones and allow implementation of personalized treatments for metastatic breast cancer patients. This review summarises current and future biomarkers and signatures for predicting response to endocrine treatment, and discusses the potential for using approved drugs and novel agents to improve outcomes. Increased prediction accuracy is likely to require sequential sampling, utilising preoperative or neoadjuvant treatment and/or liquid biopsies and an improved understanding of both the dynamics and heterogeneity of breast cancer.

Keywords: Endocrine therapy; Liquid biopsy; Response prediction; Sequential sampling.

Fig. 1

A combined approach for individualised prediction of endocrine treatment response. Profiling of biopsy samples during neoadjuvant drug treatment may help to match drugs to patients and to predict treatment response. Neoadjuvant assessment should be combined with long-term follow-up of individual tumour changes acquired during treatment via non-invasive (liquid biopsy) sampling. Profiling circulating tumour cells (CTCs) and circulating tumour DNA (ctDNA) can be used to monitor continuous benefit from adjuvant treatment and to detect disease progression. In future practice, a combination of these approaches with predictive biomarkers would provide a more accurate prediction of endocrine therapy response

Fig. 2

Drugs used in endocrine treatment of breast cancer. Schematic diagram of current and novel drugs currently in clinical trial with their target signalling molecules. CDK cyclin-dependent kinase, E2 oestradiol-17 beta, EGFR epidermal growth factor receptor, ER oestrogen receptor, HDAC histone deacetylase, HER2 human epidermal growth factor receptor, IGF-1R insulin-like growth factor-1 receptor, MAPK mitogen-activated protein kinase, mTOR mammalian target of rapamycin, PI3K phosphoinositide-3-kinase, SERD selective oestrogen receptor degrader, SERM selective oestrogen receptor modulator, T testosterone, VEGF vascular endothelial growth factor, VEGFR VEGF receptor