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Page 12 of 16 Lei et al. J Cancer Metastasis Treat 2019;5:38 I http://dx.doi.org/10.20517/2394-4722.2019.12

be higher as more studies on ESR1 fusions emerge. Additional studies on ESR1 fusions will further support
the causal role ESR1 fusions and have significant diagnostic and clinical implications since pathogenic ESR1
fusions could be used as biomarkers to stratify patients for individualized healthcare in ER+ breast cancer.
Therapeutic vulnerabilities from ESR1 translocated tumors could be an alternative to chemotherapy in
patients with rapidly progressing, endocrine therapy resistant disease.

CONCLUSION
Endocrine therapy resistance and metastasis in ER+ breast cancer patients remain significant clinical
problems. This review has focused on studies describing a spectrum of ESR1 alterations including
amplification, point-mutations, and structural rearrangements in endocrine-refractory, metastatic ER+
breast cancer cases. Results from these studies have provided insights into the underlying mechanisms that
contribute to endocrine therapy resistance and metastasis.

Amplification of the ESR1 locus results in overexpression of oncogenic ER protein in the breast and
potentially reducing sensitivity of ESR1 amplified breast tumors to endocrine therapies and therefore likely
leads to disease progression and metastasis. Point mutations in the LBD of ESR1, the most common of
which are Y537S and D538G, confer an agonist confirmation to such ESR1 mutant proteins resulting in
constitutively active mutant ER transcription factors that lead to activation of ER target genes in a hormone-
[64]
independent manner while also promoting activation of metastasis-associated genes . The finding that ER
LBD mutant proteins are constitutively active in an estrogen-independent manner suggest that therapeutic
strategies which work by blocking estrogen production, such as ovarian ablation and treatment with
AIs, are likely to be ineffective in breast tumors harboring ESR1 point mutations. Indeed, a significant
proportion of ESR1 LBD point mutations were identified in metastatic tumors that were extensively treated
[53]
with AIs, suggesting that such mutations may be enriched in breast tumors upon AI treatment . ESR1-
Y537S and ESR1-D538G are partially sensitive to fulvestrant [37,47,63] , and newer oral SERDs that have better
bioavailability compared to fulvestrant, such as AZD9496, have shown promising results in treating
[66]
tumor growth driven by ESR1 LBD point mutants in experimental models . Although fulvestrant is used
exclusively in the metastatic setting for ER+ disease, treating primary breast tumors upfront with fulvestrant
or more potent SERDs like AZD9496 may reduce the incidence of disease driven by ESR1 LBD point
mutations.

Despite the potential effectiveness of fulvestrant in targeting ER proteins with point mutations in the LBD, it
is completely ineffective against ER fusion proteins generated from in-frame ESR1 fusion transcripts arising
[75]
from ESR1 translocations . These ESR1 fusions transcripts, ESR1-e6>YAP1 and ESR1-e6>PCDH11X, were
[75]
identified in patients with metastatic ER+ breast tumors that were pan-endocrine therapy resistant . Both
fusions retain the first 6 exons of ESR1 fused in-frame to C-terminal sequences of the partner gene but lack
exons encoding the LBD, rendering these fusions insensitive to all endocrine therapies that target the LBD,
including fulvestrant and most likely AZD9496. These ESR1 fusions were found to generate hyperactive
ESR1 fusion proteins that not only drive endocrine therapy resistant growth, but also play a role in the
[75]
metastatic process, reprogramming the ER cistrome to drive EMT and metastasis to lung . Despite the
lack of an ESR1 LBD, blocking signaling downstream of ESR1 fusions with a CDK4/6 inhibitor, palbociclib,
[75]
suppressed ESR1 fusion-driven growth at primary and metastatic sites in experimental models . Similar
to ESR1 point mutations, ESR1 fusion formation is likely a mechanism of acquired endocrine therapy
resistance. To date, ESR1 fusion transcripts that produce stable ESR1 fusion proteins have only been detected
in metastatic breast tumors resistant to multiple lines of endocrine therapies. This suggests that ESR1 fusions
may be enriched in tumors from the selective pressure of endocrine treatment. Since the ESR1-e6>YAP1 and
ESR1-e6>PCDH11X fusions were identified from a small cohort of late-stage ER+ patients, more RNA-seq
data from primary and late-stage, treatment-refractory tumors are clearly required, particularly with longer
sequencing reads, which increase fusion gene detection sensitivity to better understand the incidence of
ESR1 fusions in both primary and metastatic breast cancer.