Current breast cancer clinical trials

Numerous phase III randomized clinical trials have demonstrated the efficacy of selective estrogen receptor modulators (SERMs) in women at increased risk for breast cancer, DCIS and invasive disease in the adjuvant and metastatic setting. Until recently, antiestrogens had minimal impact on patients progressing on tamoxifen, but Faslodex® (fulvestrant), a novel agent with a mechanism distinct from SERMs, has now demonstrated efficacy at least equivalent to anastrozole in tamoxifen-resistant patients. Faslodex is being compared to tamoxifen for advanced disease, and a new generation of trials will evaluate neoadjuvant and adjuvant therapy with this unique endocrine agent.

 


Mode of Action

Mode of action of estradiol (E)
1.E binds with high affinity to the estrogen receptor (ER) to form an E-ER complex.
2.The E-ER complex pairs with another E-ER complex
(dimerizes) and localizes in the cell nucleus. The two
transcription activation functions of ER, called AF1 and AF2, are both active.
3.The E-ER dimer binds to estrogen-sensitive genes at the estrogen response element (ERE).
4.The dimer activates transcription of the estrogen-sensitive gene. (AF1 and AF2 interact with coactivators to stimulate the transcription enzyme RNA polymerase II [RNA POL II].)

Mode of action of tamoxifen (T)
1.T binds to ER with low affinity compared with E.
2.The T-ER complex dimerizes and localizes in the cell nucleus, and AF1 (but not AF2) is active.
3.The T-ER dimer binds to the gene DNA at the ERE.
4.Transcription of the estrogen-sensitive gene is lessened because AF2 is inactive and coactivator binding is likewise attenuated. AF1 activity results in the partial agonist activity of T.

Mode of action of Faslodex (F)
1.F binds to ER with affinity similar to E.
2.F triggers rapid degradation of ER.
3.The F-ER complex results in reduced rate of dimerization and nuclear localization.
4.There is reduced binding of F-ER to ERE on the gene resulting in blocked trascription.

 

 

SELECT PUBLICATIONS

Bundred N et al. ICI 182,780 (Faslodex) an estrogen receptor downregulator reduces cell turnover index more effectively than tamoxifen. Proc ASCO 2001;Abstract 1660.

Curran M, Wiseman L. Fulvestrant. Drugs 2001;61:807-13; discussion 814. Abstract

Erikstein B et al. ICI 182,780 ('Faslodex') 250 mg monthly intramuscular (i.m.) injection shows consistent pk profile when given as either 1 x 5ml or 2 x 2.5 ml injections in postmenopausal women with advanced breast cancer (ABC). Proc ASCO 2001;Abstract 2025.

Gradishar WJ, Jordan VC. Clinical potential of new antiestrogens. J Clin Oncol 1997;15:840-52. Abstract

Howell A. Faslodex (ICI 182780). An oestrogen receptor downregulator. Eur J Cancer 2000;36 Suppl 4:S87-8. Abstract

Howell A et al. Comparison of efficacy and tolerability of fulvestrant (Faslodex) with anastrozole (Arimidex) in post-menopausal women with advanced breast cancer. Breast Ca Res Treat 2000;64(1):Abstract 6.

Howell A et al. ICI 182,780 (Faslodex): Development of a novel, "pure" antiestrogen. Cancer 2000;89(4):817-825. Abstract

Osborne CK. A double-blind randomized trial comparing the efficacy and tolerability of Faslodex™ (fulvestrant) with Arimidex™ (anastrozole) in post-menopausal (PM) women with advanced breast cancer (ABC). Breast Ca Res Treat 2000;64(1):Abstract 7.

Osborne CK et al. Selective estrogen receptor modulators: Structure, function and clinical use. J Clin Oncol 2000;18(17):3172-3186. Abstract

 

 

 

 

 

 

 

 

Posters:

Home

 

MECHANISM OF ACTION
If you look at drugs that interact with the estrogen receptor, estrogen is on one end of the spectrum, stimulating most genes under its control after binding to the estrogen receptor. Drugs like tamoxifen stimulate some genes and inhibit others, depending on the tissue and gene. At the far other end of the spectrum, drugs like Faslodex seem to have a pure antiestrogenic profile on all genes with none of the agonist qualities of tamoxifen.

—C Kent Osborne, MD

SECOND-LINE METASTATIC TRIALS OF FASLODEX VERSUS ARIMIDEX
In terms of efficacy, Faslodex was at least equal to treatment with a third-generation aromatase inhibitor, which currently is our best endocrine therapy for postmenopausal patients.
There were also some hints that Faslodex might be a bit better, mainly in the North American trial 21, where the overall rates of objective response and clinical benefit were slightly higher for Faslodex, though not statistically significant.
The duration of response in Trial 0021 was significantly better for Faslodex and was of a magnitude that is clinically and humanly worthwhile in the metastatic setting. These results suggest that perhaps this agent also might give an extra boost as adjuvant therapy which will be tested in clinical trials.

—Richard Elledge, MD

TRIAL DESIGN
The European trial and the American trial are a little bit different in their structure and results. The American trial — which I think has a better design — was a double-blind study. Patients assigned to Arimidex received placebo injections. So, it’s clearly blinded. Also, because the patients in both groups had to come to the clinic once a month, there was consistency with regard to the patient being seen.
The European trial was not double-blinded. The patients on Arimidex were seen every three months, while the patients on Faslodex were seen by someone every month. This design has the potential to have some bias in terms of identifying when the patient progresses. Patients in the Faslodex group of the European trial were seen more often, and conceivably progression would be identified a little earlier than in an Arimidex patient.
Having said that, the results show similar response rates between the two drugs, but in the American trial, the response duration is about twice as long for Faslodex compared to Arimidex. We have to keep it in mind that aromatase inhibitors are very good agents in and of themselves, and in one of these new trials, Faslodex is at least as good as Arimidex, and in the other we see an advantage at least in one important parameter.

—C Kent Osborne, MD

PATIENTS’ REACTIONS TO FASLODEX
The monthly intramuscular injection doesn’t seem to be much of a deterrent. For older patients where there may be a compliance question, the injection may be a plus. Also there are some patients where reimbursement may be more favorable for an injectable agent. Other patients may not like the idea of an injection or coming to the doctor’s office once a month — they prefer a pill. Efficacy will be the key determining factor though, particularly if we move to the adjuvant setting.

— William Gradishar, MD

EORTC STUDY 10963
The preoperative EORTC trial evaluates one injection of Faslodex after the diagnosis of breast cancer has been made but before surgery. The idea is for the Faslodex injection to cover the operative period as a potent antiestrogen that will lower estrogen receptor levels. We want to test the hypothesis of Bernie Fisher and others that adverse events related to metastases occur during the perioperative period, and hopefully we can alter that with Faslodex. The aim is to put more than 3,000 women into this study.

—Professor Anthony Howell, FRCP

PROPOSED NEOADJUVANT TRIAL
We are looking for a trial to replace ATAC and are considering evaluating conventionally timed versus perioperative endocrine therapy. Faslodex lends itself to that because of its rapid effects on the tumor in situ, and you can measure surrogate markers. We would like to take the best arm of ATAC and compare that with Faslodex in a factorial way — looking at drug against drug and timing against timing. Hopefully, we’ll have a pilot protocol ready to go next year. This type of trial — where you’re looking at the tumor intact — can be a gold mine in the search for the valuable surrogate markers of response.

—Michael Baum, ChM, FRCS
Home · Contact us
Terms of use and general disclaimer