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Review Breast Cancer Therapeutic Place of Fulvestrant in the Management of Hormone-receptor Positive Breast Cancer Yogesh R Belagali, 1 Hanmant V Barkate, 1 Jaykumar J Sejpal 1 and Bhavesh B Parekh 2 1. Department of Medical Affairs and Clinical Research, Intas Pharmaceuticals Limited, Ahmedabad, India; 2. HCG Hospital, Ahmedabad, India Abstract Fulvestrant is an oestrogen-receptor antagonist that exerts selective oestrogen receptor downregulation, antiproliferative activity and induction of apoptosis. It is indicated for the treatment of postmenopausal women with locally advanced or metastatic breast cancer for disease relapse or progression on or after adjuvant anti-oestrogen therapy. Fulvestrant was initially approved at a dose of 250 mg, however, the results of the CONFIRM trial led to approval of 500 mg dose (i.e. 500 mg on days 0, 14 and 28, then 500 mg every 28 days). Fulvestrant has also shown superiority over anastrozole as first-line therapy in the phase II trial. There are contrasting data for its efficacy when used in combination with anastrozole. It is well tolerated, with no significant difference with respect to the toxicity profile of other hormonal therapies. Treatment with fulvestrant is not associated with any clinically significant effects on sex hormone levels, bone-specific turnover markers or endometrial thickening. Fulvestrant has been recommended by the National Comprehensive Cancer Network and the European School of Oncology guidelines as a treatment option in first- and second-line management of hormone-receptor positive breast cancer. Keywords Fulvestrant, metastatic breast cancer, CONFIRM trial, EFECT trial, FIRST trial, FACT trial, SWOG trial Disclosure: Yogesh R Belagali, Hanmant V Barkate and Jaykumar J Sejpal are employees of Intas Pharmaceuticals Limited. Bhavesh B Parekh is an employee of HCG Hospital, Ahmedabad. No funding was received in support of the publication of this article. 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: 25 February 2016 Accepted: 14 April 2016 Citation: European Oncology & Haematology, 2016;12(1):44–50 Correspondence: Hanmant V Barkate, Intas Pharmaceuticals Limited, Ahmedabad, 380054, India. E: drbarkate@intaspharma.com Globally, breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death in women. 1 More than 1.67 million cases of breast cancer were recorded in 2012, accounting for around 11.9% of all new cancer cases and 25.1% in women. 2 Oestrogen receptor- (ER)-positive breast cancer accounts for 75% of breast cancers in postmenopausal women. 3 Aromatase inhibitors (AIs) and anti-oestrogens are used in the adjuvant endocrine therapy of postmenopausal women with ER-positive breast cancer. AIs constitute the standard of care in the first-line management of patients with hormone-receptor positive breast cancer. 4 Both anastrozole and letrozole have proven superior to tamoxifen as five years’ primary adjuvant therapy in early breast cancer, in addition to providing a number of tolerability benefits compared with the tamoxifen. 5 The selective oestrogen receptor modulator Selective oestrogen receptor downreglators (SERDs) is a novel class of anti-oestrogens that differ from SERMs in being a full or ‘pure’ receptor antagonist. Fulvestrant is a SERD that competitively binds to oestrogen receptors (ER), with approximately 100-times greater binding affinity than that of tamoxifen. 8 Following binding to ER, fulvestrant blocks dimerisation of the receptor and limits its nuclear translocation. The fulvestrant-bound ER complex is unstable and more susceptible to degradation, resulting in downregulation of receptor expression. Fulvestrant also blocks the recruitment of both transcriptional activating factors (AF-1 and AF-2) to ER, which are needed for full activation of the transcription of ER- regulated genes. In contrast, tamoxifen blocks recruitment of AF-2 only. Hence, fulvestrant exhibits full ER antagonist activity, while showing no known oestrogen agonist activity. 9 It does not show cross-resistance (SERM) tamoxifen is also used widely to treat both premenopausal and postmenopausal patients with advanced breast cancer as first- line treatment. 6 Other endocrine therapies include the progestins, such as megestrol acetate, high-dose oestrogens and androgens. However, these treatment options are being used less frequently as newer, more effective and better-tolerated therapies become available. Although adjuvant endocrine therapy is an effective treatment for breast cancer, most patients with advanced disease will eventually exhibit resistance to individual therapies. Nonetheless, an initial response to endocrine treatment is generally indicative of a positive response to further alternative endocrine agents. 7 with tamoxifen, or the oestrogen receptor agonist activity associated with tamoxifen. Fulvestrant has been shown to be active in patients with breast cancer previously treated with a SERM such as tamoxifen or with a non-steroidal anti-inflammatory (AI) such as anastrozole. 10 44 Effect of fulvestrant on tumour receptors Robertson et al. conducted a randomised study in postmenopausal women with primary breast cancer (T1–T3, ER+ or ER status unknown). Fulvestrant was administered as a single intramuscular (IM) dose of either 50 mg (n=39), 125 mg (n=38) or 250 mg (n=44), 14–21 days prior to tumour resection, or continuous oral tamoxifen (20 mg daily; n=36) TOU C H ME D ICA L ME D IA