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Lei et al. J Cancer Metastasis Treat 2019;5:38 I http://dx.doi.org/10.20517/2394-4722.2019.12 Page 3 of 16

and promoters of ER target genes. The C-terminal domains include the ligand-binding domain (LBD)
and ligand-dependent activation function 2 (AF2) domain required for dimerization and transactivation.
The LBD is required not only for estrogenic ligands but is also the domain that controls responses to anti-
estrogen antagonists. The hinge domain contains the nuclear localization sequence and connects the activity
[6]
from the ligand-independent AF1 and ligand-dependent AF2 together to fully promote activation of ER .

Standard-of-care endocrine therapies that target ER itself include selective estrogen receptor modulators
(SERMs), such as tamoxifen, and selective estrogen receptor degraders (SERDs), such as fulvestrant, that
bind to the LBD. Aromatase inhibitors (AIs), such as letrozole, anastrozole, and exemestane, block the
production of estrogens from androgens resulting in lower levels of circulating estrogen in the body. Despite
the success of these agents in reducing relapse rates when given prophylactically after breast surgery and
chemotherapy (adjuvant treatment), endocrine therapy resistance and the development of lethal metastatic
disease is common and a major clinical problem. A major clinical feature of the disease is the long-term
persistence of disseminated tumor cells despite endocrine therapy, with relapse risk continuing for decades
[7]
after diagnosis . The etiology of endocrine therapy resistance is complex and tremendous efforts have been
[8]
made to uncover diverse mechanisms .
Downstream signaling events from aberrantly activated growth factor receptor tyrosine kinases (RTKs)
such as epidermal growth factor receptor (EGFR) and HER2 (ERBB2) have been shown to phosphorylate
[9]
and increase ER transcriptional activity in a hormone-independent manner . ER+ tumors that exhibit
ERBB2 amplification have reduced ER expression, reduced sensitivity to ER targeted therapies, and
[10]
poor outcomes . Nonetheless, co-targeting ER+/HER2+ breast cancer has been clinically successful.
Experimental models have extended these ideas to other RTKs that are expressed by ER+ breast cancer.
Interestingly, these investigations revealed a non-genomic or transcription-independent function of ER
[11]
[12]
in association with EGFR and insulin-like growth factor receptor (IGF1-R) at the plasma membrane.
However, clinical trials testing the use of EGFR inhibitors in endocrine treatment resistant ER+ breast cancer
[13]
have produced modest or negative results suggesting that further insight into underlying mechanisms for
RTKs and ER interactions are required for successful translation of this aspect of ER function.
[14]
Since PIK3CA is the most frequently mutated gene in ER+ breast cancer , targeting components of the
PI3K-AKT-mTOR pathway has also been described to treat endocrine refractory disease. Preclinical models
demonstrated enhanced activation of the PI3K pathway in long-term estrogen deprived (LTED) ER+ breast
cancer cells and a negative feedback system by which PI3K inhibition increases ER activity, potentially
[15]
explaining the effectiveness of combinatorial mTOR and ER inhibition . The use of an mTOR inhibitor,
everolimus, in combination with endocrine therapy, significantly improves progression-free survival (PFS)
[16]
for patients failing previous endocrine therapies , although side effects are severe and stratification of
patients for this treatment is essential. Treatment with a pan-PI3K inhibitor, buparlisib, in combination
with fulvestrant increased PFS with compared to fulvestrant alone in patients with ER+ locally advanced
[17]
or metastatic breast cancer (BELLE-3 clinical trial) . Greater benefit was observed in patients treated
with buparlisib harboring PIK3CA mutations. However, significant toxicities in buparlisib treated patients
have stopped further clinical trials of the drug in this setting. In contrast to pan-PI3K inhibitors, alpelisib,
an agent that specifically targets the alpha isoform of PIK3CA, has been shown to overcome the toxicities
associated with pan-PI3K treatment. Apelisib greatly improved PFS in patients when given in combination
with fulvestrant to patients with endocrine-refractory, advanced ER+ breast cancer harboring PIK3CA
[18]
mutations . There was no significant benefit to PFS in patients with non-PIK3CA mutant tumors suggesting
that PIK3CA status is a potential biomarker to predict response to PI3K inhibition. Results from studies
also further suggest that targeting specific mutant isoforms of PI3K reduces toxicities leading to increased
tolerability and therefore can be given for a longer duration compared to other pan-PI3K agents such as
buparlisib.