Effects of fulvestrant 750 mg in premenopausal women with oestrogen-receptor-positive primary breast cancer

doi:10.1016/j.ejca.2007.11.007

European Journal of Cancer

Volume 44, Issue 3, February 2008, Pages 391-399

https://doi.org/10.1016/j.ejca.2007.11.007 Get rights and content

Abstract

Fulvestrant (Faslodex™) is a pure anti-oestrogen that reduces markers of hormone sensitivity and proliferation in postmenopausal women with oestrogen-receptor (ER)-positive breast cancer. This randomised trial compared the effects on the tumours of a single dose of 750 mg fulvestrant to those of daily tamoxifen (20 mg) taken 14–16 days prior to surgery in 60 premenopausal women with ER-positive primary breast cancer. There were statistically significant falls in the expression of ER and Ki67 levels compared to the baseline with both drugs. Both drugs caused a decrease in PgR expression from baseline but this was only statistically significant with fulvestrant. No statistically significant differences were seen between the two treatment groups. Fulvestrant caused an increase in circulating levels of oestradiol, irrespective of the stage of the menstrual cycle at which patients commenced treatment. No major changes were seen in LH, FSH and progesterone levels with either drug. The most common adverse events with fulvestrant were headaches, hot flushes, nausea and disturbance of menses. Contrary to previous studies with fulvestrant 250 mg, these findings suggest that at a dose of 750 mg fulvestrant is effective at reducing the effects of oestrogen on ER-positive breast cancer in premenopausal women.

Introduction

The inhibition of oestrogen production and its binding to oestrogen receptors (ER) is the basis by which hormone-sensitive breast cancers are treated.¹ Fulvestrant (Faslodex™) is an ER antagonist that reduces cellular expression (down-regulation) of both ER and progesterone receptors (PgR).2, 3, 4 Fulvestrant is a steroidal 7α-alkylsulphinyl analogue of oestradiol. Because it is structurally different to the selective oestrogen receptor modulators (SERMs), it has a very strong affinity for the ER leading to a more complete blockade of the effects of oestrogen.² Currently, tamoxifen (with or without luteinising hormone-releasing hormone (LHRH) agonists) is the drug of choice for premenopausal women with ER-positive breast cancer. Fulvestrant lacks cross-resistance with many of the currently used drugs including tamoxifen and therefore potentially offers an alternative strategy in the treatment of premenopausal women.

Fulvestrant is at least as effective as the third-generation aromatase inhibitor anastrozole in the treatment of postmenopausal women with advanced oestrogen-sensitive cancers that have progressed on prior therapy.5, 6, 7 The effects of fulvestrant in premenopausal women have yet to be fully evaluated. A previous study by Robertson et al. showed that at a dose of 250 mg, fulvestrant was ineffective in terms of reduction in ER, PgR and Ki67 expression.⁸

The main objective of this study was to compare the effects of intramuscular fulvestrant at a dose of 750 mg with tamoxifen on ER, PgR and Ki67 levels in the tumours of premenopausal women with ER-positive primary breast cancer. The study also assessed the safety and tolerability of this dose of fulvestrant in premenopausal women.

Section snippets

Study design and patients

This was a Phase II, randomised (randomised permuted blocks; the allocation was made using randomised permuted blocks with the block length randomly being 6 or 8) open-label single-centre study that aimed to recruit 60 premenopausal women with ER-positive breast cancer (30 per treatment arm). The study included premenopausal women with histologically confirmed primary ER-positive breast cancer (T1–T3).

Sixty patients, 30 in each group, gives an 80% chance of showing a 25% difference in the two

Patients

Sixty two patients were randomised for the study. One patient withdrew from the study following randomisation but before receiving any drug treatment and another was ruled ineligible following randomisation due to an abnormal electrocardiogram. Of the 60 who received drug, 30 patients had tamoxifen and 30 fulvestrant. Mean age and age distribution were similar for the two groups (Table 1).

Tumour markers

Baseline levels of expression of ER and PgR were the same (Allred score of 7) for both treatment arms and

Discussion

This study was designed to investigate the effects of fulvestrant at a dose of 750 mg on hormone receptor expression and proliferation in premenopausal women with ER-positive early breast cancer; 750 mg was chosen because a previous study investigating the effect of a single intramuscular injection of 250 mg fulvestrant had shown no significant effect on ER or PgR or Ki67 levels in premenopausal women.⁹ In contrast to the lack of effect of a 250 mg dose, fulvestrant 750 mg significantly

Conflict of interest statement

None declared for the authors O.E. Young, L. Renshaw, E.J. Macaskill, S. White, D. Faratian, J.St.J. Thomas. For J.M. Dixon unrestricted educational grant received from AstraZeneca to perform this study. Mr. Dixon is also in receipt of unrestricted educational grants from Novartis and Pfizer.

Acknowledgements

Thanks to all the patients who participated in this study. The study was supported by an unrestricted educational grant from AstraZeneca although the study was developed, written and originated from the Edinburgh Breast Unit.

References (11)

V.C. Jordan et al.
Development and evolution of therapies targeted to the estrogen receptor for the treatment and prevention of breast cancer
Steroids
(2007)
J.F. Robertson et al.
For the Study 41 Investigators. Effects of fulvestrant 250 mg in premenopausal women with oestrogen receptor-positive primary breast cancer
Eur J Cancer
(2007)
A.E. Wakeling et al.
A potent specific pure antiestrogen with clinical potential
Cancer Res
(1991)
A. Howell et al.
ICI 182,780 (Faslodex): development of a novel, ‘pure’ antiestrogen
Cancer
(2000)
J.F. Robertson et al.
Comparison of the short-term biological effects of 7alpha-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-nonyl]estra-1,3,5, (10)-triene-3,17beta-diol (Faslodex) versus tamoxifen in postmenopausal women with primary breast cancer
Cancer Res
(2001)

There are more references available in the full text version of this article.

Cited by (56)

Efficacy of a novel orally active SERD AZD9496 against hormone dependent post-menopausal breast cancer depends on inhibition of cellular aromatase activity
2020, Journal of Steroid Biochemistry and Molecular Biology
Citation Excerpt :
Administration of fulvestrant has been shown to be painful for patients [10] that may affect adherence. Other injection site related events including sciatica, neuralgia, neuropathic pain, and peripheral neuropathy etc. have also been reported [11]. These drawbacks of fulvestrant administration make further dose escalation challenging, which could be responsible for fulvestrant not achieving higher efficacy than currently observed.
Treatment of hormone sensitive breast cancer tumors with endocrine therapy such as antiestrogens or aromatase inhibitors has improved the outcome significantly. Studies including our own have shown that downregulation of ERα with pure antiestrogen fulvestrant in combination with aromatase inhibitors may prolong responsiveness of the tumors to endocrine therapy. Fulvestrant has been studied as second line or first line treatment for post-menopausal hormone receptor positive breast cancers as a single agent or in combination with AIs. Studies have also suggested that further escalation of dose may improve benefit. However, dose escalation of fulvestrant, which is administered via intramuscular injection, is difficult due to its poor solubility. To overcome this shortcoming of an injectable drug, a novel orally active antiestrogen, AZD9496 was developed. In addition to being orally active, AZD9496 is designed as a selective ERα downregulator (SERD). In the current study, we compared the effect of AZD9496 and fulvestrant on the growth of MCF-7Ca (human estrogen receptor positive MCF-7 cells stably transfected with human placental aromatase gene) xenografts grown in ovariectomized athymic nude mice. AZD9496 was also compared to fulvestrant in vitro as a single agent or in combination with anastrozole. Our current study shows that AZD9496 is equally effective as fulvestrant at controlling the growth of hormone sensitive human breast cancer tumors. Similar to fulvestrant, AZD9496 inhibits cellular aromatase activity through ERα mediated signaling. However, unlike fulvestrant, combination of AZD9496 with anastrozole did not produce increased tumor inhibition. Our results show that AZD9496 was significantly better at inhibiting cellular aromatase which contributed to its anticancer activity. Next, we measured the effect of AZD9496 on the mouse uterus. Uterine weight of mice treated with AZD9496 was significantly lower than that for mice treated with androstenedione. This reduction in uterine weight was due to AZD9496 mediated inhibition of aromatase activity and not a direct effect on uterine ERα expression. We also observed that anti-cancer efficacy of AZD9496 depended on its ability to inhibit cellular aromatase. These results suggest that AZD9496 may be a better alternative to fulvestrant due to its selectivity for mammary ER and ability to inhibit aromatase in addition of downregulating ERα that can be obtained upon oral administration. As such, AZD9496 may prove to be a better option than fulvestrant for the treatment of hormone sensitive human breast cancer.
Selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs) in cancer treatment
2018, Pharmacology and Therapeutics
Citation Excerpt :
Collectively, these data resulted in the 500 mg dose becoming the clinically-approved dose of fulvestrant going forward. A neoadjuvant study evaluating an even higher 750 mg dose of fulvestrant in premenopausal women, demonstrated fulvestrant can significantly reduce ER, PgR and Ki67 in ER+ tumors compared to baseline (Young et al., 2008), however, comparisons were not done against the 500 mg dose, making it difficult to assess the increase in efficacy with the higher 750 mg dose. The 500 mg dose of fulvestrant was then compared to anastrozole in the phase II FIRST (Fulvestrant First-Line Study Comparing Endocrine Treatments) study in postmenopausal patients that had not received any prior endocrine therapy.
Breast cancer is the most frequently diagnosed cancer in women, with estrogen receptor positive (ER+) breast cancer making up approximately 75% of all breast cancers diagnosed. Given the dependence on active ER signaling in these tumors, the predominant treatment strategy has been to inhibit various aspects of this pathway including directly antagonizing ER with the use of selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs). Interestingly, the dependence on ER for breast cancer growth is often retained even after progression through several lines of antiestrogen therapy, making ER a bonafide biomarker for this cancer subtype and driving the continued research and development of novel ER-targeted therapeutics to treat this patient population. This, combined with the continuous discovery of mechanisms underlying endocrine resistance, is resulting in a continually evolving treatment landscape for ER+ breast cancer. This review discusses various ER antagonists investigated for the treatment of breast cancer, outlining their pharmacological and tissue-specific mechanisms of action as well as their specified use within the ER+ breast cancer setting. In addition, mechanisms of resistance to SERMs and SERDs, the use of ER antagonists in combination therapy strategies, and the ongoing development of novel drugs are also reviewed in the context of the changing clinical landscape of ER+ breast cancer. Lastly, the role of SERMs and SERDs in non-breast cancer indications is also discussed.
Novel flexible heteroarotinoid, SL-1-18, promotes ERα degradation to inhibit breast cancer cell growth
2017, Cancer Letters
Citation Excerpt :
SERDs like fulvestrant do not display tamoxifen-like agonistic effects, nor do they induce any cross-resistance to tamoxifen and/or aromatase inhibitors [13,14]. While several studies have suggested that fulvestrant is effective in the treatment of advanced breast cancer that has progressed after adjuvant tamoxifen therapy [15–19], its clinical outcome has been hampered by its poor bioavailability [15,20], underscoring the need to develop new drugs with improved pharmacological properties. Previous studies have suggested that flexible heteroarotinoids (Flex-Hets)— compounds derived from retinoic acid— could have promising therapeutic potential [21–27].
SL-1-18 (1-(chrysen-6-yl)-3-(4-nitrophenyl)thiourea) is new flexible heteroarotinoid (Flex-Het) analog derived from the parent compound, SHetA2, and our previous study showed comparable activity to SHetA2 in terms of inhibiting ER+ breast cancer cell growth. This current study aims to determine the molecular mechanism underlying SL-1-18's effect on breast cancer cell growth. Our results indicate that SL-1-18 inhibits cell proliferation of ER+ breast cancer cells (MCF-7 and T-47D) by preventing cell cycle progression. SL-1-18 treatment correlated positively with decreased expression of key cell-cycle regulators, such as cyclin D1, as well as other ERα-target genes at both the transcript and protein levels. Interestingly, decreased expression of ERα was also observed, with a significant reduction at the protein level within 2 h of SL-1-18 treatment, while the decrease in mRNA occurred at a later time point. ERα degradation was shown to be mediated by the ubiquitination-proteasome pathway. In summary, this is the first study to show that a Flex-Het— SL-1-18— can promote the degradation of ERα via the ubiquitin-proteasome pathway and should be further developed as a therapeutic option for ER+ breast cancer.
Mechanisms of resistance to selective estrogen receptor down-regulator in metastatic breast cancer
2017, Biochimica et Biophysica Acta - Reviews on Cancer
Based on the prominent role estrogen receptor (ER) plays in breast cancer, endocrine therapy has been developed to block the ER pathway and has shown great effectiveness. Fulvestrant, the first selective ER down-regulator (SERD), was demonstrated to completely suppress ERα and notably efficient. However, resistance to fulvestrant occurs, either intrinsic or acquired during the treatment. Several potential mechanisms inducing fulvestrant resistance have been proposed, composed of activated ERα-independent compensatory growth factor signaling, stimulated downstream kinases, altered cell cycle mediators, etcetera. Experimentally, combinations of fulvestrant with targeted treatments were reported to eliminate the resistance and improve the effect of fulvestrant. Meanwhile, some clinical trials associated with the targeted combination therapies are in progress. This review focuses on the underlying mechanisms that contribute to fulvestrant resistance in ER-positive breast cancer and provides an overview of combined fulvestrant with targeted agents to shed light on optimal therapies for patients with ER-positive breast cancer.
Clinical predictors of benefit from fulvestrant in advanced breast cancer: A Meta-analysis of randomized controlled trials
2016, Cancer Treatment Reviews
Data on the comparative efficacy of fulvestrant and other endocrine treatments are inconsistent. Clinical markers predictive of greater benefit from fulvestrant compared to the alternate endocrine agents have not been identified.
We searched the literature from inception to May 2015, using MEDLINE, EMBASE, and major conference proceedings. We included randomized controlled trials (RCTs) that compared fulvestrant containing arm to either tamoxifen or an aromatase inhibitors (AI) and presented results for subgroup analyses as Hazard Ratios (HR) for Time to Progression (TTP) or Progression Free Survival (PFS). Subgroup analyses reported in at least two RCTs were included. Data were then weighted using generic inverse variance approach and pooled in meta-analysis using RevMan 5.3 software. Difference between sub-groups was tested with chi² statistics.
Analysis included 4 RCTs comparing fulvestrant-based therapy to AI alone and comprising 2382 patients (1190 on fulvestrant and 1192 on control arms). TTP/PFS was the primary endpoint in all included studies. Four sub-groups fulfilled our criteria. Fulvestrant was associated with greater benefit in patients with visceral metastasis (HR 0.85 vs 1.02 for no visceral disease, p for difference = 0.05) and in those patients with a time to recurrence >5 years (HR 0.80 vs 1.09 for recurrence ⩽5 years, p for difference = 0.02). There was no apparent difference in benefit based on age >65 years (HR 0.86 vs 0.96, p for difference = 0.32) or HER2/neu status (HR 0.36 vs 0.92, p for difference = 0.09).
Patients with advanced breast cancer with visceral involvement and longer time from diagnosis to recurrence had significantly better TTP/PFS with the use of fulvestrant. These results may have implications for selection of patients in the design of future clinical trials and to inform treatment decisions in clinical practice.
A good drug made better: The fulvestrant dose-response story
2014, Clinical Breast Cancer
Citation Excerpt :
Furthermore, the residual ER that remains detectable after treatment with fulvestrant 500 mg in NEWEST and Trial 5727,28 raises the possibility that greater reductions in ER expression and improved efficacy could be achieved using an even higher fulvestrant dose. Fulvestrant 750 mg, although requiring 3 separate 5-mL IM injections, has been shown to be well tolerated and is effective in reducing ER expression in premenopausal women.37 However, to our knowledge, no studies using a dose more than fulvestrant 500 mg for postmenopausal breast cancer have been reported, and 3 or more 5-mL injections per dose, as required by the current formulation, may present practical impediments.
Sequential use of endocrine therapies remains the cornerstone of treatment for hormone receptor-positive advanced breast cancer, before the use of cytotoxic chemotherapy for unresponsive disease. Fulvestrant is an estrogen receptor (ER) antagonist approved for the treatment of postmenopausal women with ER+ advanced breast cancer after failure of prior antiestrogen therapy. Initially approved at a monthly dose of 250 mg, the recommended fulvestrant dose was revised to 500 mg (500 mg/mo plus 500 mg on day 14 of month 1) after demonstration of improved progression-free survival versus fulvestrant 250 mg. We have reviewed the dose-dependent effects of fulvestrant, both from a retrospective combined analysis of dose-dependent reduction of tumor biomarkers in the presurgical setting (3 previously reported studies: Study 18, Neoadjuvant Endocrine Therapy for Women with Estrogen-Sensitive Tumors, and Trial 57) and from a review of clinical studies for advanced breast cancer in postmenopausal women. Analysis of presurgical data revealed a consistent dose-dependent effect for fulvestrant on tumor biomarkers, with increasing fulvestrant dose resulting in greater reductions in ER, progesterone receptor, and Ki67 labeling index. The dose-dependent biological effect corresponds with the dose-dependent clinical efficacy observed in the treatment of advanced breast cancer after failure of prior antiestrogen therapy. Although it remains to be determined in a phase III trial, cross-trial comparisons suggest a dose-dependent relationship for fulvestrant as first-line treatment for advanced breast cancer. Overall, biological and clinical data demonstrate a strong dose-dependent relationship for fulvestrant, supporting the efficacy benefit seen with fulvestrant 500 mg over the 250 mg dose.

View all citing articles on Scopus

View full text

Effects of fulvestrant 750 mg in premenopausal women with oestrogen-receptor-positive primary breast cancer

Abstract

Introduction

Section snippets

Study design and patients

Patients

Tumour markers

Discussion

Conflict of interest statement

Acknowledgements

Steroids

Eur J Cancer

A potent specific pure antiestrogen with clinical potential

Cancer Res

ICI 182,780 (Faslodex): development of a novel, ‘pure’ antiestrogen

Cancer

Comparison of the short-term biological effects of 7alpha-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-nonyl]estra-1,3,5, (10)-triene-3,17beta-diol (Faslodex) versus tamoxifen in postmenopausal women with primary breast cancer

Cancer Res