RECENT DEVELOPMENTS IN HORMONAL TREATMENT

A. Advanced Disease
The most extensively investigated SERM other than tamoxifen in the setting of advanced breast cancer is toremifene. At least 5 randomized studies comparing toremifene 40 to 60 mg PO od with tamoxifen 20 to 40 mg PO od in postmenopausal, ER-positive or ER-unknown patients have been conducted, and a metanalysis of these trials has been published (Pyrhonen et al., 1999). This looked at a cohort of 1421 patients, and all results were consistent with the criteria of statistical equivalence between toremifene and tamoxifen as first-line agents in metastatic disease. Toremifene has only limited activity as a second-line agent in patients who have relapsed on tamoxifen and appears to be clinically cross-resistant to tamoxifen (Stenbygaard et al., 1993; Vogel et al., 1993).
Droloxifene has also been investigated in metastatic breast cancer, where there appears to be at least some evidence of activity in tamoxifen-resistant patients (Haarstad et al., 1992). Despite some theoretical advantages over tamoxifen (higher affinity for the estrogen receptor, higher antiestrogenic-to-estrogenic ratio, more effective inhibition of cell growth and division in ER-positive cell lines), efficacy as a first-line hormonal agent appears similar to that of tamoxifen (Rauschning and Pritchard, 1994; Haarstad et al., 1998). Develop¬ment of this agent as a treatment for breast cancer has now been halted.
Raloxifene, too, has been shown to be cross-resistant to tamoxifen in Phase II trials of second-line treatment of advanced breast cancer (Buzdar et al., 1988) and appears to have equal efficacy to existing hormonal agents as first-line treatment for relapsed disease (Gradishar et al., 1997) Idoxifene has been shown to have activity in tamoxifen-resistant patients with advanced breast cancer in both Phase I and Phase II studies (Coombes et al., 1995; Baselga et al., 1999), but further development of this drug as a treatment for breast cancer has recently been halted. A Phase I study of the third-generation SERM, LY 353381-HC1, in tamoxifen-resistant patients showed some evidence of efficacy (Munster et al., 1999), and early data from a Phase II trial of first-line treatment in locally advanced or metastatic breast cancer patients shows promise (Baselga et al., 1999). EM-800 (SCH 57050) appears not to exhibit complete cross-resistance with tamoxifen: clinical benefit was seen in 53% of 32 tamoxifen-resistant patients (Labrie et al., 1997). This compound has also been described as a pure antiestrogen, owing to its lack of agonist activity on breast or endometrium (Couillard et al., 2000). Advantageous agonist effects on bone and lipids do, however, occur in model systems (Picard et al., 2000).
B. Adjuvant Therapy
The use of SERMs (other than tamoxifen) has yet to be investigated in early breast cancer. The initiation of adjuvant trials with SERMs in this area is complicated by the ongoing adjuvant trials with aromatase inhibitors, which are likely to identify a new gold standard for adjuvant therapy. Thus trials versus tamoxifen may not be directly relevant.
C. Primary Therapy
Both raloxifene and idoxifene have been evaluated in short-term presurgical studies examin¬ing changes in the growth fraction as assessed by immunohistological staining, using the mouse monoclonal antibody to Ki67, and the apoptotic index as measured by TUNEL
staining. In both studies, around 2 weeks of the SERM given presurgically significantly decreased the growth fraction in ER-positive tumors only but did not affect apoptosis (Dowsett et al, 1999; Dowsett et al., 2000).
D. Prevention
In the prophylactic setting, the necessity of finding an agent with as few detrimental side effects as possible combined with as many potential added benefits as possible without sacrificing breast cancer prevention efficacy are all of substantial importance. As such, many of the facets of SERMs appear to make them particularly good candidates for prevention. In essence, all of the drugs going forward clinically in this arena must have decreased uterotrophic effects when compared with tamoxifen, with at least as good a profile on lipid and bone metabolism (Haynes and Dowsett, 1999). Raloxifene appears to fill the bill well. Raloxifene has been developed as an alternative to hormone replacement therapy for the treatment of osteoporosis in postmenopausal women. In the MORE (Multiple Outcomes of Raloxifene Evaluation) trial, which randomised 7705 osteoporotic, postmenopausal women to 3 years of raloxifene 60 mg bid, 60 mg od, or placebo, the incidence of invasive breast cancer was 76% lower in the drug-treated groups (Cummings et al., 1999). Com¬bined data from multicenter, double-blind, randomized trials of raloxifene in approxi¬mately 12,000 postmenopausal women with osteoporosis (including those participating in the MORE trial) demonstrated a 58% reduction in breast cancer risk (Jordan et al., 1998). In these trials, no increase in endometrial carcinoma was seen. Breast cancer incidence was a secondary endpoint in these trials. These data have prompted the initiation of a further breast cancer prevention trial by the NSABP, comparing tamoxifen 20 mg PO od to raloxi¬fene 60 mg PO od in women deemed to be at increased breast cancer risk (the STAR trial). This trial aims to randomize 22,000 women.