Fulvestrant in the treatment of postmenopausal women with advanced hormone-sensitive breast cancer

Review question

We reviewed the evidence concerning the effectiveness and safety of fulvestrant in prolonging time without further progression of cancer in women with advanced hormone-sensitive breast cancer. We found nine studies testing whether or not fulvestrant is superior to other treatment options.


Seventy percent of breast cancers are sensitive to hormones, and there are a variety of endocrine therapies that lower or block female hormones to treat these cancers. Fulvestrant is one such endocrine therapy that can be used to treat hormone-sensitive breast cancers by blocking oestrogen. It is administered by monthly injection for women with advanced disease. The definition of advanced disease is when the primary cancer in the breast has either spread to heavily involve the lymph nodes or grown to a considerably large size (stage III) or when the cancer has spread beyond the breast and the lymph nodes to other tissues or organs, or both (stage IV). The goal of treatment in these settings is to improve quality of life, reduce symptoms caused by the cancer, and extend length of life. It is noteworthy that the studies examined in this review predominantly used a lower dose of fulvestrant (250 mg) as compared to the now standard, more effective, and approved dose of 500 mg.

Study characteristics

The evidence is current to 7 July 2015. Our review identified nine clinical trials that compared the effectiveness and safety of fulvestrant against other standard treatments for advanced hormone-sensitive breast cancer and pooled the data from these trials to analyse all the data together. Three different endocrine therapies were analysed as comparator drugs against fulvestrant. Two of these drugs were the aromatase inhibitors anastrozole and exemestane, which lower oestrogen levels in postmenopausal women, and the third was tamoxifen, which works by blocking oestrogen. Four of the studies were in the first-line setting, meaning that fulvestrant was tested against these endocrine therapies as the initial treatment for advanced disease. Five of the studies tested fulvestrant in the second-line or more setting, meaning after the women had progressed on a prior initial treatment for advanced disease. Two studies examined fulvestrant in combination with anastrozole against anastrozole alone, and the other seven studies compared fulvestrant alone with other comparator drugs.

Key results

We found that fulvestrant was at least as effective as the other three standard endocrine therapies used in the treatment of advanced hormone-sensitive breast cancer and is possibly more effective at the new standard dose of 500 mg, rather than the lower dose of 250 mg, which was previously used and tested in all but one of the included studies. We also found that combining fulvestrant with an aromatase inhibitor did not improve effectiveness, and neither was effectiveness influenced by whether fulvestrant was used as the first treatment upon diagnosis of advanced disease or after another endocrine therapy. This was evident in the pooled data analysis for both survival time without progression of cancer and the rate of tumour shrinkage or stabilisation due to fulvestrant as compared with the other endocrine therapies. In addition, fulvestrant-treated women did not experience worse side effects than those receiving the comparator endocrine therapies, and quality of life was equivalent in both fulvestrant-treated women and women treated with the other endocrine therapies.

Fulvestrant can therefore be considered an effective and safe treatment for postmenopausal women with advanced hormone-sensitive breast cancer, when treatment with endocrine therapy is indicated.

Quality of the evidence

All studies were of high quality.

Authors' conclusions: 

For postmenopausal women with advanced hormone-sensitive breast cancer, fulvestrant is at least as effective and safe as the comparator endocrine therapies in the included studies. However, fulvestrant may be potentially more effective than current therapies when given at 500 mg, though this higher dosage was used in only one of the nine studies included in the review. We saw no advantage with combination therapy, and fulvestrant was equally as effective as control therapies in both the first- and second-line setting. Our review demonstrates that fulvestrant is a safe and effective systemic therapy and can be considered as a valid option in the sequence of treatments for postmenopausal women with hormone-sensitive advanced breast cancer.

Read the full abstract...

Fulvestrant is a selective oestrogen receptor down-regulator (SERD), which by blocking proliferation of breast cancer cells, is an effective endocrine treatment for women with hormone-sensitive advanced breast cancer. The goal of such systemic therapy in this setting is to reduce symptoms, improve quality of life, and increase survival time.


To assess the efficacy and safety of fulvestrant for hormone-sensitive locally advanced or metastatic breast cancer in postmenopausal women, as compared to other standard endocrine agents.

Search strategy: 

We searched the Cochrane Breast Cancer Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), and ClinicalTrials.gov on 7 July 2015. We also searched major conference proceedings (American Society of Clinical Oncology (ASCO) and San Antonio Breast Cancer Symposium) and practice guidelines from major oncology groups (ASCO, European Society for Medical Oncology (ESMO), National Comprehensive Cancer Network, and Cancer Care Ontario). We handsearched reference lists from relevant studies.

Selection criteria: 

We included for analyses randomised controlled trials that enrolled postmenopausal women with hormone-sensitive advanced breast cancer (TNM classifications: stages IIIA, IIIB, and IIIC) or metastatic breast cancer (TNM classification: stage IV) with an intervention group treated with fulvestrant with or without other standard anticancer therapy.

Data collection and analysis: 

Two review authors independently extracted data from trials identified in the searches, conducted 'Risk of bias' assessments of the included studies, and assessed the overall quality of the evidence using the GRADE approach. Outcome data extracted from these trials for our analyses and review included progression-free survival (PFS) or time to progression (TTP) or time to treatment failure, overall survival, clinical benefit rate, toxicity, and quality of life. We used the fixed-effect model for meta-analysis where possible.

Main results: 

We included nine studies randomising 4514 women for meta-analysis and review. Overall results for the primary endpoint of PFS indicated that women receiving fulvestrant did at least as well as the control groups (hazard ratio (HR) 0.95, 95% confidence interval (CI) 0.89 to 1.02; P = 0.18, I2= 56%, 4258 women, 9 studies, high-quality evidence). In the one high-quality study that tested fulvestrant at the currently approved and now standard dose of 500 mg against anastrozole, women treated with fulvestrant 500 mg did better than anastrozole, with a HR for TTP of 0.66 (95% CI 0.47 to 0.93; 205 women) and a HR for overall survival of 0.70 (95% CI 0.50 to 0.98; 205 women). There was no difference in PFS whether fulvestrant was used in combination with another endocrine therapy or in the first- or second-line setting, when compared to control treatments: for monotherapy HR 0.97 (95% CI 0.90 to 1.04) versus HR 0.87 (95% CI 0.77 to 0.99) for combination therapy when compared to control, and HR 0.93 (95% CI 0.84 to 1.03) in the first-line setting and HR 0.96 (95% CI 0.88 to 1.04) in the second-line setting.

Overall, there was no difference between fulvestrant and control treatments in clinical benefit rate (risk ratio (RR) 1.03, 95% CI 0.97 to 1.10; P = 0.29, I2 = 24%, 4105 women, 9 studies, high-quality evidence) or overall survival (HR 0.97, 95% CI 0.87 to 1.09, P = 0.62, I2 = 66%, 2480 women, 5 studies, high-quality evidence). There was no significant difference in vasomotor toxicity (RR 1.02, 95% CI 0.89 to 1.18, 3544 women, 8 studies, high-quality evidence), arthralgia (RR 0.96, 95% CI 0.86 to 1.09, 3244 women, 7 studies, high-quality evidence), and gynaecological toxicities (RR 1.22, 95% CI 0.94 to 1.57, 2848 women, 6 studies, high-quality evidence). Four studies reported quality of life, none of which reported a difference between the fulvestrant and control arms, though specific data were not presented.

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