E22. Fulvestrant in 2004: current and future indications
for breast cancer
Anthony Howell
*
CRUK Department of Medical Oncology, University of Manchester, Christie Hospital, Wilmslow Road, Manchester M20 4BX, England, UK
Fulvestrant is an oestrogen analogue. A bulky side-
chain in the 7 a position of the parent oestrogen molecule
inhibits activation of the oestrogen receptor (ER) and
increases receptor turnover, thus markedly reducing the
number of ERs per cancer cell. This mechanism of action
differs from the selective oestrogen receptor modulators
(SERMs) such that tamoxifen-bound ERs are not
downregulated and are available to bind to endocrine
response elements of target genes. This difference in
mechanism of action between fulvestrant and SERMs is
presumably why fulvestrant is highly active after ta-
moxifen failure. In the original phase II trial of 19 pa-
tients, approximately two thirds of patients had clinical
benefit (CB) [1]. Subsequent trials where fulvestrant was
compared with anastrozole after tamoxifen failure, in-
dicated CB rates for fulvestrant of 44.6% [2] and 42.2%
[3], respectively. In these trials, there were no significant
differences between the activity of fulvestrant and anas-
trozole in tamoxifen failures. However, the proportion of
patients who had CB for one year was 19.2% for ful-
vestrant and 13.9% for anastrozole (P = 0.07). A further
randomised trial indicated that fulvestrant was equiva-
lent to tamoxifen as first-line therapy for advanced dis-
ease in patients with hormone receptor +ve tumours [4].
Fulvestrant is therefore active after failure of tamoxifen
or when used as first-line endocrine therapy for advanced
breast cancer. Several groups have produced non-
randomised data. In a study where fulvestrant was given
after first-, second- or third-line endocrine therapy with a
variety of agents (n = 67), the CB rate was 59.7%, with a
median duration of response of six months. Responses
were seen in patients with HER2+/ER+ tumours [5]. In
another study of 44 previously endocrine-treated pa-
tients with advanced disease, the CB rate was 52% (L
Petruzelka, Prague, University Karlovy). Endocrine
therapy is effective when given after fulvestrant. In 35
patients who had CB on fulvestrant, the CB rate to
subsequent endocrine therapy was 57%. In the same
study, the CB rate was 43% (n = 35) in patients who had
not responded to fulvestrant [6]. Another study showed
that treatment with predominantly aromatase inhibitors
(AI) after second-line fulvestrant produced CB in 25 out
of 54 (46%) patients [7].
The studies outlined above indicate that fulvestrant is
effective in some patients after one, two or three endo-
crine therapies. In addition, other endocrine therapies
are effective after fulvestrant failure. Additional studies
are required to evaluate precisely the position of fulve-
strant in the sequence we use to treat advanced breast
cancer. New phase II and III trials (n P 8) in over 3000
patients are either planned or are currently in progress
(summarised in [8]). These are mainly evaluating fulve-
strant versus a steroidal AI after failure on non-steroidal
AIs or further phase II studies in advanced disease or as
neoadjuvant therapy. At present, the available data in-
dicate that, because there is a relative lack of cross-re-
sistance between tamoxifen/aromatase inhibitors and
fulvestrant, this agent should be regarded as an addi-
tional endocrine therapy to add to our sequence of
treatments for advanced breast cancer.
References
1. Howell A, DeFriend D, Robertson J, Blamey R, Walton P.
Response to a specific antioestrogen (ICI 182780) in tamoxifen-
resistant breast cancer. Lancet 1995, 345, 29–30.
2. Howell A, Robertson JF, Quaresma Albano J et al. Fulvestrant,
formerly ICI 182,780, is as effective as anastrozole in postmen-
opausal women with advanced breast cancer progressing after
prior endocrine treatment. J Clin Oncol 2002 Aug 15, 20(16),
3396–3403.
3. Osborne CK, Pippen J, Jones SE et al. Double-blind randomised
trial comparing the efficacy and tolerability of fulvestrant versus
EJC Supplements Vol 2 No. 9 (2004) 65–66
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*
Tel.: +44 161 446 8037; fax: +44 161 446 8000.
E-mail address: anthony.howell@christie-tr.nwest.nhs.uk.
1359-6349/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.ejcsup.2004.08.021