Endocrine therapy represents the first and most efficacious targeted treatment for women with estrogen receptor-positive (ER+) breast cancer. In the last four decades several hormonal agents have been successfully introduced in clinical practice as both palliative therapy for advanced disease and adjuvant treatment for prevention of tumor relapse. Nevertheless, the intrinsic and acquired resistance occurs in a significant proportion of patients, limiting the efficacy of endocrine treatments. Several molecular mechanisms have been proposed to be responsible for endocrine resistance. Loss of ER expression, altered activity of ER coregulators, deregulation of apoptosis and cell cycle signaling, and hyperactive receptor tyrosine kinase (RTK) and stress/cell kinase pathways can collectively orchestrate the development and sustenance of pharmacologic resistance to endocrine therapy. Preclinical and clinical evidence documents the plasticity in ER expression levels and signaling. As such, ER can either drive gene transcription and tumor progression directly or crosstalk with alternate RTK and cellular kinase signaling pathways, resulting in modulation of its own expression levels and transcriptional program. For this reason a therapeutic approach based on the combination of agents targeting both ER and RTK signaling represents a promising strategy to be tested. Among many RTKs, EGFR, HER2, and PI3K have been found to be viable targets for the combination therapy strategy, at least in the preclinical setting. However, early results from clinical trials testing combination strategies have been discordant, suggesting the need for better approaches to simultaneously inhibit multiple escape pathways and to select the patients who may benefit the most from these strategies.
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