Breast cancer is the most common
cancer in women. It is a heterogeneous disease, encompassing different biological subtypes that differ in histological features, outcomes, clinical behaviour and different molecular subtypes.
Therapy has progressed substantially over the past years with a reduction both for locoregional and systemic
therapy. Endocrine
therapies have considerably reduced
cancer recurrence and mortality. Despite the major diagnostic and therapeutic innovations, resistance to
therapy has become a main challenge, especially in metastatic
breast cancer, and became a major factor limiting the use of endocrine therapeutic agents in ER positive breast
cancers. Approximately 50% of patients with ER positive metastatic disease achieve a complete or partial response with endocrine
therapy. However, in the remaining patients, the benefit is limited due to resistance, intrinsic or acquired, resulting in
disease progression and poor outcome.Tumour heterogeneity as well as acquired genetic changes and
therapeutics pressure have been involved in the endocrine
therapy resistance. Nowadays, targeted sequencing of genes involved in
cancer has provided insights about genomic tumour evolution throughout treatment and resistance driver mutations. Several studies have described multiple alterations in
receptor tyrosine kinases, signalling pathways such as Phosphoinositide-3-kinase-protein
kinase B/Akt/mTOR (PI3K/Akt/mTOR) and
Mitogen-activated protein kinase (MAPK), cell cycle machinery and their implications in endocrine treatment failure.One of the current concern in
cancer is personalized
therapy. The focus has been the discovery of new potentially predictive
biomarkers capable to identify reliably the most appropriate
therapy regimen and which patients will experience disease relapse. The major concern is also to avoid overtreatment/undertreatment and development of resistance.This review focuses on the most promising predictive
biomarkers of resistance in
estrogen receptor-positive
breast cancer and the emerging role of circulating free-
DNA as a powerful tool for longitudinal monitoring of tumour molecular profile throughout treatment.