Page 289 - Read Online

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

samples, suggesting that ESR1 amplification may underlie organ-specific metastatic behavior of ER+ breast
[39]
cancers .

Correlation between ESR1 amplification, protein expression, and clinical significance
Many studies show positive correlation between ESR1 amplification and ER protein expression suggesting
that amplification may lead to production of elevated levels of oncogenic ER protein [28,29,34,35] . Interestingly,
studies have shown that ESR1 amplification in a subset of ER+ breast cancers were associated with tamoxifen
resistance and poor prognosis [40,41] . In contrast, contradicting studies have identified ESR1 amplification
as an indicator of longer disease-free survival and increased sensitivity to tamoxifen treatment [35,42] . These
conflicting results suggest that more dedicated studies will be required to fully understand the clinical
implications of ESR1 amplifications. Results from other studies have identified ESR1 amplification in
benign and early-stage breast cancer and is associated with endocrine therapy resistance. Discovery of
ESR1 amplifications in benign papillomas and early-stage breast cancer such as ductal hyperplasias suggests
that ESR1 amplifications may play a role in the tumor initiation process since high expression of ER in
benign breast cells is associated with higher breast cancer risk [29,43,44] , but these findings still require further
validation. The insignificant difference of ESR1 amplification between invasive and non-invasive breast
cancers suggests that ESR1 copy number alteration might not be used as a key predictive marker for invasion
and metastasis, however its enrichment in recurrent disease, especially after endocrine therapy treatment,
suggests that it likely plays a role in intrinsic and/or acquired resistance to endocrine therapy and metastatic
disease progression [45-48] .

Although the use of endocrine agents that block estrogen production (AIs) or block ER function (SERM/
SERD) are front-line therapies to treat metastatic ER+ breast cancer, the use of high-dose estrogens has also
been reported to be effective. This approach was first described over 70 years ago before the discovery of
[49]
anti-estrogens to treat advanced breast cancer . More recently, a study reported a breast cancer patient
harboring an ESR1 amplification showed tumor regression in a liver metastasis after receiving estradiol
[50]
treatment as a primary therapy . Another study using a patient-derived xenograft (PDX) model harboring
an ESR1 amplification derived from a patient with endocrine-refractory disease demonstrated that tumor
[47]
growth was suppressed with estradiol treatment . These results were corroborated in an independent study
using a LTED ER+ MCF7 breast cancer cell model system in which such cells acquire ESR1 amplification
[48]
during long term estrogen deprivation showed an apoptotic response upon estradiol treatment . Collectively,
these studies suggest a role for ESR1 amplification in driving endocrine therapy resistance and metastasis
and that treating ESR1 amplified tumors with intermediate doses of estradiol (6 mg daily) is an option for
some patients.

The presence of ESR1 amplification in some breast cancers is undeniable. However, a clear link between the
presence of ESR1 amplifications in breast tumors and endocrine therapy resistance and metastasis remains
to be shown. Deeper multi-dimensional characterization of relapsed and/or metastatic breast tumors at the
RNA, DNA, and protein levels may aid to better understand its prognostic value. Therefore, more studies
will be required to better understand the functional and therapeutic significance of ESR1 amplifications in
driving endocrine therapy resistance and metastasis.

CYP19A1 amplification
While ESR1 amplification has been an intense area of investigation underlying endocrine therapy resistance
as described above, a study focusing on genomic aberrations of the drug target of AIs, aromatase (CYP19A1),
has deepened our understanding of endocrine-refractory ER+ breast tumors. Copy number alterations
in the gene encoding aromatase, CYP19A1, also has been shown to promote resistance to AIs in patients
with metastatic ER+ breast cancer. While CYP19A1 amplification is very rare in primary untreated ER+
[51]
breast cancers, Magnani et al. found that 21.5% of AI-refractory relapsed tumors to harbor CYP19A1
amplification, suggesting that CYP19A1 amplification is an acquired endocrine therapy resistance