Mechanisms of resistance to estrogen receptor modulators in ER+/HER2- advanced breast cancer

Area of Science:

• Oncology
• Endocrinology
• Genomics

Background:

• Estrogen receptor-positive (ER+) breast cancer is primarily treated with endocrine therapy, offering overall survival (OS) benefits.
• However, approximately one-third of ER+ breast tumors develop resistance to endocrine therapy over time.
• Mechanisms of resistance involve ERα signaling, receptor tyrosine kinases, cell cycle pathways, and epigenetic alterations.

Purpose of the Study:

• To review current understanding of endocrine resistance mechanisms in ER+/HER2- advanced breast cancer.
• To highlight key pathways and genetic alterations contributing to resistance.
• To discuss novel combination strategies for overcoming endocrine resistance.

Main Methods:

• Review of literature on endocrine resistance in ER+ breast cancer.
• Focus on the Cyclin D-CDK4/6-RB axis, PI3K pathway, and histone deacetylases (HDACs).
• Analysis of genomic alterations in ESR1 and PIK3CA genes.

Main Results:

• Combined hormone therapy with targeted agents (CDK4/6 inhibitors, PI3K/mTOR inhibitors) improves progression-free survival and OS.
• Genomic evolution, including ESR1 and PIK3CA mutations, plays a crucial role in adaptive resistance.
• Targeting cell cycle and signaling pathways offers new therapeutic avenues.

Conclusions:

• Understanding resistance mechanisms is critical for improving ER+ breast cancer treatment.
• Combination therapies targeting specific pathways and addressing genomic alterations hold significant potential.
• Future research should focus on novel combinations to enhance clinical outcomes and overcome endocrine resistance.