teaser
Ignace Vergote
MD PhD
Department of Gynaecologic Oncology
University Hospitals Leuven Gasthuisberg
Belgium
E:[email protected]
Endocrine therapy is the established treatment of choice for women with advanced, oestrogen receptor (ER)-positive breast cancer, with the selective oestrogen receptor modulator (SERM) tamoxifen having been the preferred treatment for over 20 years. Recently, nonsteroidal aromatase inhibitors (AIs), such as anastrozole and letrozole, have shown superiority over tamoxifen with respect to both efficacy and tolerability. These drugs are becoming the preferred options in this setting. The steroidal AI exemestane is still under evaluation.
Unfortunately, many patients with advanced disease will eventually undergo disease progression on tamoxifen or AIs, necessitating the use of an alternative therapy. While cytotoxic chemotherapy is an option in this setting, these women are predominantly elderly and so may be less able to tolerate the acute side-effects associated with cytotoxic agents. However, patients who respond to an initial endocrine therapy frequently exhibit responses to subsequent endocrine interventions, an approach that offers marked quality-of-life advantages over cytotoxic therapies.
The sequential use of endocrine therapies depends on the availability of agents with different mechanisms of action, thus circumventing the problem of cross-resistance. As a result, it is important that newer endocrine therapies are effectively and rationally incorporated into sequential treatment schedules, to ensure that the most effective and better-tolerated agents are used earlier. This way, endocrine therapies may be used for an extended period of time, thus delaying the decision to use cytotoxic chemotherapy.
Fulvestrant, a new oestrogen receptor antagonist
Fulvestrant (Faslodex) is a new type of ER antagonist which, unlike tamoxifen, does not have any oestrogen agonist effects. Fulvestrant binds to the ER with a much greater affinity than tamoxifen. The binding of fulvestrant to the ER leads to the dissociation of receptor-associated proteins, prevents dimerisation of the ER and inhibits binding of the ER to DNA.(1) The fulvestrant-ER complex is promptly degraded, leading to the rapid loss of cellular ER, an effect that results in reduced levels of progesterone receptor (PgR) expression and clearly differentiates fulvestrant from tamoxifen and other SERMs that increase PgR expression. In postmenopausal women with primary breast cancer, data from preclinical mechanistic studies have been confirmed in neoadjuvant clinical studies with fulvestrant. Here, preoperative administration with fulvestrant before surgery produced dose-dependent reductions in cellular ER and PgR, which were associated with significantly greater reductions in cell turnover compared with tamoxifen.(2)
Use of fulvestrant in the endocrine sequence
Over recent decades, the majority of postmenopausal women with hormone-receptor-positive advanced breast cancer have received tamoxifen as the initial treatment. However, newer agents offer efficacy and tolerability advantages for the first-line treatment of this patient group, including the nonsteroidal AIs anastrozole and letrozole. After progression on tamoxifen, fulvestrant is at least as effective as anastrozole for time-to-progression, objective response (OR; complete response [CR] + partial response [PR]) and clinical benefit (CB; CR + PR + stable disease >-24 weeks) rates. In these patients, fulvestrant led to a median duration of response of 16.7 months, compared with 13.7 months for anastrozole,(3) and a recent analysis has shown that fulvestrant is not significantly different from anastrozole for overall survival (hazard ratio: 0.98; 95% confidence intervals: 0.84, 1.15; p=0.81).(4) Importantly, fulvestrant was as well tolerated as anastrozole, but was associated with significantly fewer joint disorders (5.4% vs 10.6%; p=0.0036).
Further evidence of the efficacy of fulvestrant in the endocrine sequence has been demonstrated in patients who had received prior therapy with tamoxifen and AIs, in whom fulvestrant produced CB in seven of 17 patients (41%).(5) Fulvestrant has also shown activity in compassionate use and named patient programmes. Some of these included heavily pretreated patients who had experienced CB on fulvestrant, with one patient having received eight prior endocrine therapies and eight prior chemotherapies.(6,7) However, an important principle when determining where newer endocrine agents are to be incorporated into the treatment schedule is that well-tolerated agents such as fulvestrant should be used earlier, before reliance on less well-tolerated therapies is necessary.
Endocrine therapies are effective after progression on fulvestrant
A central consideration when establishing optimal endocrine sequences is whether tumours continue to exhibit further endocrine sensitivity after progression on a given agent. Two retrospective studies in postmenopausal women with advanced breast cancer have examined responses to subsequent hormonal treatments after progression on fulvestrant. Both studies were questionnaire-based and are important to establish whether progression on fulvestrant leads to cross-resistance.
One study evaluated responses to further endocrine treatment following progression on firstline fulvestrant.(8) Follow-up data were available for patients who derived CB with fulvestrant. These patients went on to receive second-line endocrine treatment with anastrozole, letrozole, tamoxifen and megestrol acetate, leading to further OR (three of 35 patients) or CB (20 of 35 patients).
A second retrospective study examined subsequent responses in patients progressing after first-line tamoxifen and second-line fulvestrant.(9) Follow-up data for patients who had derived CB from fulvestrant and received further endocrine therapy indicated that further therapy produced an OR in four of 54 patients and CB in 25 of 54 patients.
Although data in these studies are somewhat limited by the nature of their collection, they clearly suggest that progression following treatment with fulvestrant does not lead to cross-resistance with endocrine therapies such as AIs, tamoxifen or megestrol acetate. Fulvestrant can therefore be effectively incorporated anywhere into the endocrine sequence without prejudicing the use of further endocrine agents after progression.
Conclusion
Fulvestrant represents a new type of ER antagonist: an effective, well-tolerated treatment option that prolongs disease control while maintaining quality of life. Fulvestrant is the only ER antagonist to have demonstrated efficacy in tamoxifen-resistant disease; it is at least as effective as the AI anastrozole after progression on tamoxifen. Disease progression on fulvestrant does not result in cross-resistance to other endocrine therapies, with many patients going on to derive further benefit from subsequent treatment with AIs and other agents. As a result, although the future profile of endocrine treatments for advanced, hormone-sensitive, postmenopausal breast cancer is continually being reassessed and redefined, it is likely that fulvestrant will play an important role in this group of patients. Continuing efforts to identify the optimal sequences of endocrine agents will be necessary and are being addressed in a number of studies, including the Study Of Faslodex vs Exemestane with/without Arimidex (SOFEA) and the Evaluation of Faslodex vs Exemestane Clinical Trial (EFECT). The outcomes of these trials will help ensure that patients derive maximum benefit from well-tolerated therapies.
References
- Wakeling AE. Similarities and distinctions in the mode of action of different classes of antioestrogens. Endocr Relat Cancer 2000;7:17-28.
- Bundred NJ, Anderson E, Nicholson RI, et al. Fulvestrant, an estrogen receptor downregulator, reduces cell turnover index more effectively than tamoxifen. Anticancer Res 2002;22:2317-9.
- Robertson JF, Osborne CK, Howell A, et al. Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma in postmenopausal women – a prospective combined analysis of two multicenter trials. Cancer 2003;98:229-38.
- Pippen J, Osborne CK, Howell A, et al. Fulvestrant (faslodex) versus anastrozole (arimidex) for the treatment of advanced breast cancer: a prospective combined survival analysis of two multicenter trials. Breast Cancer Res Treat 2003;82 Suppl 1:S101.
- Perey L, Thürlimann B, Hawle H, et al. Fulvestrant (‘faslodex’) as hormonal treatment in postmenopausal patients with advanced breast cancer progressing after treatment with tamoxifen and aromatase inhibitors. Breast Cancer Res Treat 2002; 6 Suppl 1:S72 Abstract 249.
- Franco S, Perez A, Tan-Chiu E, et al. Fulvestrant (Faslodex®) demonstrates clinical benefit in heavily pretreated postmenopausal women with advanced breast cancer: a single-center experience. Breast Cancer Res Treat 2003;82:S105.
- Steger G, Bartsch R, Wenzel C, et al. Fulvestrant (Faslodex®) in metastatic breast cancer. Breast Cancer Res Treat 2003;82 Suppl 1:S104.
- Howell A. Postmenopausal women with advanced breast cancer who progress on fulvestrant or tamoxifen retain sensitivity to further endocrine therapies. Breast Cancer Res Treat 2002;76 Suppl 1:S72 Abstract 251.
- Vergote I, Robertson JF, Kleeberg U, et al. Postmenopausal women who progress on fulvestrant (‘Faslodex’) remain sensitive to further endocrine therapy. Breast Cancer Res Treat 2003;79:207-11.
