Endocrine therapy, using tamoxifen or an aromatase inhibitor, remains a 
first-line treatment for estrogen receptor 1 (ESR1) positive breast cancer. 
However, tumor resistance limits the duration of response. The clinical efficacy 
of fulvestrant, a selective ER degrader (SERD) that triggers receptor 
degradation, has confirmed that ESR1 often remains engaged in endocrine therapy 
resistant cancers. Recently developed, selective ER modulators (SERMs)/SERD 
hybrids (SSHs) that facilitate ESR1 degradation in breast cancer cells and 
reproductive tissues have been advanced as an alternative treatment for advanced 
breast cancer, particularly in the metastatic setting. RAD1901 is one SSH 
currently being evaluated clinically that is unique among ESR1 modulators in 
that it readily enters the brain, a common site of breast cancer metastasis. In 
this study, RAD1901 inhibited estrogen activation of ESR1 in vitro and in vivo, 
inhibited estrogen-dependent breast cancer cell proliferation and xenograft 
tumor growth, and mediated dose-dependent downregulation of ESR1 protein. 
However, doses of RAD1901 insufficient to induce ESR1 degradation were shown to 
result in the activation of ESR1 target genes and in the stimulation of 
xenograft tumor growth. RAD1901 is an SSH that exhibits complex pharmacology in 
breast cancer models, having dose-dependent agonist/antagonist activity 
displayed in a tissue-selective manner. It remains unclear how this unique 
pharmacology will impact the utility of RAD1901 for breast cancer treatment. 
However, being the only SERD currently known to access the brain, RAD1901 merits 
evaluation as a targeted therapy for the treatment of breast cancer brain 
metastases.