Endocrine-Resistant Breast Cancer: Mechanisms and Treatment

Abstract

Background: Endocrine treatment is one of the most effective therapies for estrogen receptor-positive breast cancer. However, most tumors will develop resistance to endocrine therapy as the cancer progresses. This review focuses on the mechanisms and markers of endocrine-resistant breast cancer. In addition, current and future strategies to overcome endocrine resistance are discussed. Summary: Several molecular mechanisms of endocrine resistance have been identified, including alterations in the ESR1 gene or in the PIK-3CA/mTOR pathway. Meanwhile, CDK4/6, mTOR, and PI3K inhibition have shown to improve the efficacy of endocrine treatment and new promising approaches are being developed. Key Message: Overcoming primary or acquired resistance to endocrine treatment remains a major challenge. Since the molecular mechanisms of endocrine resistance are manifold, optimal combination and sequencing strategies will have to be developed in the future.

A Phase Ib Dose Escalation Trial of RO4929097 (a γ-secretase inhibitor) in Combination with Exemestane in Patients with ER + Metastatic Breast Cancer (MBC)

“…Exemestane was used at 25 mg/d. Doses of RO4929097 were escalated on a standard 3+3 design over 5 doses (20,30,45,90, and 140 mg). Patients were fully evaluated for dose limiting toxicity (DLT) for 3 weeks.…”

Continuous versus intermittent extended adjuvant letrozole for breast cancer: final results of randomized phase III SOLE (Study of Letrozole Extension) and SOLE Estrogen Substudy

“…The better understanding of mechanisms leading to endocrine resistance in breast cancer has allowed the development of new targeted therapies. 12 It is now clear that mechanisms of resistance include aberrations in the expression of ER leading to the up-regulation of its downstream pathways. 26 Mutation in the ESR1 gene coding for ER occurred in 20%-40% of metastatic breast cancers treated by ET.…”

“…26 Mutation in the ESR1 gene coding for ER occurred in 20%-40% of metastatic breast cancers treated by ET. 12 An interruption of this treatment could allow the loss of the mutation or delay its appearance and subsequent resistance. Among the downstream effectors of the ER pathway, the cyclin-dependent kinase 4/6 (CDK4/6) complex, which controls cell cycle progression, represents a new promising target in adjuvant ET.…”

“…For example, mutation in ESR1 gene coding for ER, occurred in around 20%-40% of metastatic breast cancers previously treated with ET. 12 Animal model studies showed that resistance to AIs can be reversed by intermittent treatment with letrozole, suggesting prolongation of the sensitivity of tumoral cells to AIs due to the restoration of estrogen levels during the interruption of the treatment. 13 Indeed, cells deprived of estrogen for several years showed a spontaneous growth in vitro and the addition of minimal concentrations of estrogens induced a cytotoxic effect demonstrating a proapoptotic role of estrogens in breast cancer cells.…”

Luminal Breast Cancer: The Head of Janus in Breast Oncology

“…Furthermore, primary and secondary endocrine resistance in early and metastatic luminal BC remains an unsolved clinical problem. Hartkopf et al [8] summarized current evidence on resistance mechanisms in HR+/ DOI: 10.1159/000509891 HER2-BC as well as strategies to overcome it by use of CDK 4/6, PI3-K, and mTOR inhibitors with focus on advanced disease. Some of these drugs have significantly changed the course of disease in the metastatic setting.…”