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Endocrine Therapeutic Strategies for Patients with Hormone Receptor-positive Advanced Breast Cancer

European Oncology & Haematology, 2017;13(2):127–33 DOI: https://doi.org/10.17925/EOH.2017.13.02.127

Abstract:

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.
Keywords: Hormone receptor-positive advanced breast cancer, selective oestrogen receptor modulators, aromatase inhibitors, selective oestrogen receptor degrader, endocrine resistance, endocrine sensitivity
Disclosure: Peter Schmid declares personal fees from Pfizer, Boehringer, Bayer, Puma, Eisai, Celgene and Roche/Genetech.
Acknowledgments: 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.
Authorship: 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.
Open Access: 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.
Received: August 07, 2017 Accepted: September 20, 2017 Published Online: October 18, 2017
Correspondence: 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: p.schmid@qmul.ac.uk
Support: 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

Endocrine resistance
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.

Endocrine therapy
Tamoxifen
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
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 favouring fulvestrant.19

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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Keywords: Hormone receptor-positive advanced breast cancer, selective oestrogen receptor modulators, aromatase inhibitors, selective oestrogen receptor degrader, endocrine resistance, endocrine sensitivity