Endocrine treatment constitutes the therapeutic backbone for patients with oestrogen and/or progesterone receptor-positive breast cancer unless there is visceral crisis or suspected or known endocrine resistance. Whether all patients who are suitable for endocrine therapy should receive combination therapy or whether there remains a role for single-agent endocrine therapy is yet to be determined. Cancer biology (ESR1 mutational status) and disease pattern determine the choice of single-agent endocrine treatment. Possibly, patients with low disease burden, slow progression and presumed endocrine sensitivity might still be considered for single-agent endocrine therapy, whereas patients with more aggressive disease including visceral metastases might benefit from combination therapy. Improved guidance on selection and sequencing of treatments should become available once overall survival (OS) and progression-free survival (PFS) data have been reported from the ongoing trials in breast cancer, principally, FALCON (NCT01602380), PALOMA-2 (NCT01740427) and MONALEESA-2 (NCT01958021), which include different patient groups and, probably, different endocrine sensitivity.
Hormone receptor-positive advanced breast cancer, selective oestrogen receptor modulators, aromatase inhibitors, selective oestrogen receptor degrader, endocrine resistance, endocrine sensitivity
Peter Schmid declares personal fees from Pfizer, Boehringer, Bayer, Puma, Eisai, Celgene and Roche/Genetech.
Medical writing support, including preparation of the drafts under the guidance of the author, was provided by Catherine Amey and Janet Manson, Touch Medical Media.
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.
This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.
August 07, 2017 Accepted
September 20, 2017 Published Online:
October 18, 2017
Peter Schmid, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London Charterhouse Square, London EC1M 6BQ, UK. E: firstname.lastname@example.org
The publication of this article was supported by AstraZeneca. The views and opinions expressed in the article are those of the authors and not necessarily those of AstraZeneca.
The majority (60–75%) of all breast cancers have oestrogen and/or progesterone receptors.1
Endocrine treatment constitutes the therapeutic backbone for patients with this cancer subtype
unless there is a visceral crisis or concern/proof of endocrine resistance,2 as recommended by
the third European School of Oncology (ESO)/European Society for Medical Oncology (ESMO)
international consensus guidelines for Advanced Breast Cancer (ABC 3)3 and the National
Comprehensive Cancer Network (NCCN) guidelines.4 Current endocrine therapy includes: selective
oestrogen receptor modulators, aromatase inhibitors, and selective oestrogen-receptor degraders
(Table 1), and the modes of action of these therapies are outlined in Figure 1. Not all patients have
a response to first-line endocrine therapy (primary or de novo resistance). Such resistance occurs
in approximately 40% of patients with hormone receptor (HR)-positive breast cancer, and even
patients who do respond eventually exhibit acquired resistance.5 Cytotoxic chemotherapy is also
considered a first-line treatment option in patients diagnosed with HR-positive breast cancer. The
decision for chemotherapy or endocrine therapy depends on a number of factors, outlined below,
and there is a wide variation in the use of these treatments.6
Several molecular mechanisms have been proposed to underlie endocrine resistance, including:
loss of oestrogen receptor expression; altered activity of oestrogen-receptor co-regulators;
deregulation of apoptosis and cell cycle signalling; hyperactive receptor tyrosine kinase; and
stress/cell kinase pathways.7 The oestrogen receptor may be activated in a ligand-independent
manner via intracellular signal transduction pathways mediated either by the phosphatidylinositol-
3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway,
(Figure 1) or the mitogen-activated protein kinase (MAPK) pathway which promotes oestrogen
receptor phosphorylation and subsequently, activation.8,9 In addition, mutations in the ESR1
gene have recently attracted attention as an important mechanism for endocrine resistance
in metastatic breast cancer (MBC). These mutations occur in approximately 20–40% of patients
with metastatic oestrogen receptor-positive disease who received endocrine therapies, with the
higher occurrence in more advanced patients.10 Clustered in a ‘hotspot’ within the ligand-binding
domain (LBD) of the oestrogen receptor, these mutations lead to ligand-independent oestrogen
receptor activity that promotes tumour growth, and partial resistance to endocrine therapy, and
potentially enhanced metastatic capacity.10 The purpose of this article is to provide a concise
overview of endocrine therapeutic strategies for MBC, including studies with cohorts in first-line
therapy, second-line and beyond.
Tamoxifen, first described in the treatment of advanced breast cancer
in 1971,11 is the oldest selective oestrogen receptor modulator in clinical
use. In the 1990s, tamoxifen became standard first-line treatment based
on randomised, controlled trials, demonstrating comparable efficacy to
megestrol acetate or aminoglutethimide, but with superior tolerability.
Subsequently, tamoxifen was replaced by third-generation aromatase
inhibitors (letrozole, anastrozole, exemestane), which have demonstrated
3–4 months improvement in progression-free survival (PFS) in a range of
randomised, controlled trials, for example, in postmenopausal women
with oestrogen synthesis occurring mainly in peripheral tissues, but do
not benefit in overall survival (OS) (Table 1).12-16
Fulvestrant is a selective oestrogen receptor degrader that blocks
oestrogen receptor dimerisation and DNA binding, inhibiting nuclear
translocation while increasing turnover of the oestrogen receptor
(Figure 1). This leads to inhibition of oestrogen signalling via a reduction
of oestrogen receptor expression and accelerated oestrogen receptor
degradation.17 A multicentre, double-blind, randomised trial, in patients
with metastatic/locally advanced breast cancer comparing treatment
with fulvestrant (250 mg/month) versus tamoxifen (20 mg/day) found no
significant difference between fulvestrant and tamoxifen for the primary
end point of time to progression (TTP).18 Similarly, in a double-blind,
randomised trial comparing the efficacy and tolerability of fulvestrant
versus anastrozole in postmenopausal women with advanced breast
cancer progressing on prior endocrine therapy, fulvestrant was found to
be at least as effective as anastrozole, with efficacy endpoints slightly
Initial investigation of fulvestrant in breast cancer used a dose of 250 mg,
which the latest evidence suggests is suboptimal. Whereas fulvestrant
250 mg is sufficient to competitively inhibit binding of oestradiol to
the oestrogen receptor, oestrogen receptor downregulation is a dosedependent
process.20 At this dose, inhibition of oestrogen receptor
transcription may occur but with incomplete oestrogen receptor
degradation, i.e., so that both mechanisms of action of fulvestrant are
not being utilised fully. This might explain why initial trials investigating fulvestrant at the 250 mg dose showed only comparable efficacy to
anastrozole or tamoxifen.18,19 The open-label, randomised, phase III
Fulvestrant and Anastrozole Combination Therapy (FACT) trial found
no clinical advantage with the combination of fulvestrant 250 mg plus
anastrozole versus anastrozole alone.21 In contrast, the Southwest
Oncology Group (SWOG), in another open-label, randomised, phase
III trial, reported results favouring this combination approach over
anastrozole alone (Table 2).22 In this study, among women who had not
received prior tamoxifen therapy, the median PFS was 12.6 months with
anastrozole alone versus 17.0 months with fulvestrant plus anastrozole
(hazard ratio, 0.74; 95% confidence interval [CI], 0.59–0.92; p=0.006),
suggesting an increased clinical benefit in patients who were endocrine
therapy-naïve. A potential drug interaction has also been reported with
fulvestrant plus anastrozole, resulting in a decrease in trough anastrozole
concentration in patients in this study.23
Further supporting the effect of fulvestrant dose on efficacy, fulvestrant
500 mg/month versus 250 mg/month was compared in the Comparison
of Faslodex in Recurrent or MBC (CONFIRM), a randomised, doubleblind,
phase III trial.24 Fulvestrant 500 mg was associated with a 19%
reduction in the risk of death and a 4.1 month difference in median
OS compared with fulvestrant 250 mg (Median OS 26.4 months versus
22.3 months, respectively; hazard ratio, 0.81; 95% CI, 0.69–0.96; nominal
p=0.02). Fulvestrant 500 mg regimens therefore offer the possibility of greater antitumour activity than the 250 mg regimen.25,26 Comparison
of the fulvestrant high-dose 500 mg regimen versus anastrozole in the
Fulvestrant fIRst-line Study comparing endocrine Treatments (FIRST) trial
showed a 34% reduction in the risk of progression in patients treated
with fulvestrant (hazard ratio, 0.66; 95% CI, 0.47–0.92; p=0.01).27
To investigate further the potential benefits of fulvestrant 500 mg/
month, and expand upon earlier data suggesting an increased clinical
benefit for fulvestrant in patients who were endocrine therapy naïve,22
the Fulvestrant and AnastrozoLe COmpared in hormonal therapy-
Naïve advanced breast cancer (FALCON) first-line therapy cohort only
randomised, double-blind, multicentre phase III trial was initiated.28 In
this study, there was a statistically significant 21% reduction in the risk
of disease progression or death in women with HR-positive advanced
breast cancer who had been treated with fulvestrant 500 mg (n=230)
compared with those who had received anastrozole 1 mg/day (n=232).
The median PFS was 16.6 months with fulvestrant versus 13.8 months
with anastrozole (hazard ratio, 0.797; 95% CI, 0.637–0.999; p=0.0486).29
Subgroup analysis showed improved PFS in fulvestrant-treated patients
whose disease had not spread to the liver or lungs at baseline, indicating
that fulvestrant would be a particularly advantageous option for patients
with non-visceral disease whereas, for patients with visceral disease,
outcomes were similar.
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