Treatment of metastatic breast carcinoma is still controversial. The introduction of new cytotoxic drugs and new chemotherapic regimens has, up to now, not resulted in a significant increase in survival.
Endocrine therapy is the preferred systemic treatment for recurrent or metastatic hormone-receptor-positive post-menopausal breast cancer (Carlson and Henderson, 2003
), since it is well known that breast cancers expressing the oestrogen receptor (ER) and/or progesterone receptor (PgR) are sensitive to an increasingly wide variety of hormonal therapies (Carlson, 2002
). Many patients who have been treated with Tamoxifen (Tam), which is still the standard hormonal treatment for breast carcinoma in the adjuvant setting, need new drugs with antiproliferative effects on oestrogen-dependent breast tumours. The available therapies include Tamoxifen or ovarian ablation (surgical oophorectomy, radiotherapeutic ablation or pharmacologically induced) in pre-menopausal women, Tamoxifen or aromatase inhibitors (AIs) in post-menopausal women, and the progestins, androgens and high-dose oestrogens for both pre- and post-menopausal patients.
Importantly, exposure to endocrine treatment does not seem to hamper later response to chemotherapy (Taylor et al, 1986
). Since the goal of treating metastatic breast cancer is palliative (Hortobagyi, 1998a
), minimally toxic alternatives are needed to improve clinical symptoms, to maintain acceptable performance status and quality of life, and to delay the need for chemotherapy. As endocrine therapies have developed, it has become recognised that a response to one therapy is predictive of a response to further hormonal therapy (Buzdar and Hortobagyi, 1998
; Hortobagyi, 1998b
). The sequential use of endocrine therapy alone offers significant quality-of-life advantages over cytotoxic chemotherapy (Buzdar and Hortobagyi, 1998
), since it offers disease control without the side effects associated with cytotoxic agents. The development of novel endocrine therapies may extend the period of time during which sequential endocrine therapy can be used, thereby postponing the need for cytotoxic chemotherapy. Traditionally, the sequence of endocrine therapies was determined by the relative toxicity of the respective agents, with the least toxic being used first. However, more recently, the relative efficacy of agents has become an increasingly important consideration, particularly since AIs have been shown to represent clinically relevant alternatives to Tamoxifen in women with hormone receptor-positive breast cancer (Carlson et al, 2003
Anastrozole (AN), the first third-generation nonsteroidal AI approved in the USA, acts by reversibly binding to the aromatase enzyme and shows a low toxic profile, because it does not inhibit the production of adrenal steroids, nor does it determine the occurrence of thrombotic events as frequently as with tamoxifen (Bonneterre et al, 1999
). The rationale for the use of this drug as first-line therapy in postmenopausal patients is supported by European (Robertson et al, 1999
) and American (Nabholtz et al, 2000
) phase III studies vs
tamoxifen, which have demonstrated an equivalent efficacy, an increase in time to progression (TTP; 11.1 months for AN and 5.6 months for Tam) and a lower incidence of thrombotic events, indicating the possibility of considering AN as a first-line treatment for patients with advanced breast carcinoma. On the other hand, negative data have also been reported (Nabholtz et al, 2003
Exemestane (Exe) is a second-generation, steroidal AI which irreversibly binds to the enzyme aromatase. The novel aromatase inactivator Exe has been evaluated extensively in phase I and II studies at dosages of up to 600
. It is well tolerated and, as a consequence, a maximum-tolerated dose has not been identified (Di Salle et al, 1994
; Johannessen et al, 1997
). Oral Exe 10–25
suppresses plasma oestrogens to as much as 6–15% of pretreatment levels (Johannessen et al, 1997
). In two phase II uncontrolled studies, objective response (OR) rates with Exe as second-line therapy in postmenopausal women with advanced breast cancer were 22 and 28%, and overall success rates (defined as the proportion of patients with OR or stable disease (SD) for
24 weeks; sometimes described by other authors as ‘clinical benefit' (Buzdar et al, 1998
; Dombernowsky et al, 1998
) were 47 and 48%, respectively (Jones et al, 1998
; Kvinnsland et al, 1998
Phase II studies suggest that there is no cross-resistance between Exe and reversible inhibitors of aromatase and that the tolerability profile is excellent. Therefore, a sequential approach with AN followed by exemestane is worth pursuing, even upon the availability of newer compounds such as fulvestrant and trilostane.
On the basis of these considerations, we performed a phase II study which evaluated the activity of AN, a type II AI, as a first-line drug, and, in the event of disease progression, of exemestane, type I, in patients with metastatic breast carcinoma.