Estrogen receptor mutations and their role in breast cancer progression

Abstract

Endocrine therapy is the mainstay of treatment in estrogen receptor-positive breast cancers and significantly reduces disease recurrence and breast cancer-related mortality. However, acquired resistance to therapy has been noted in nearly one-third of women treated with tamoxifen and other endocrine therapies. Mutations in the estrogen receptor have long been speculated to play a role in endocrine therapy resistance but have been rarely detected. However, recent studies utilizing next-generation sequencing on estrogen receptor-positive, metastatic clinical samples have revealed that recurrent ESR1 mutations are far more frequent than previously thought and may play an important role in acquired endocrine therapy resistance. Here we review recent advances in detection and characterization of ESR1 mutations in advanced, endocrine therapy-resistant breast cancers.

Figure 1

Evolution of ESR1 mutations in estrogen receptor-positive breast cancer with endocrine therapy treatment. ESR1 mutations are rare or nonexistent in primary breast tumors and are significantly enriched in metastatic, endocrine therapy-resistant breast cancer. Nearly all ESR1 mutations localize to the ligand-binding domain (LBD) of the estrogen receptor (ER) and often result in constitutive activation of the ER. DBD, DNA-binding domain.