The likelihood of response to initial hormonal therapy is similar for several classes of drugs, and so initial treatment can often be selected based on their side-effect profiles. In previously untreated patients, or for those several years removed from adjuvant hormonal therapy, competitive inhibitors of estrogen binding are usually the first choice.
The oldest and most widely prescribed estrogen antagonist is tamoxifen,52 but toremifene has also been approved for this indication. Raloxifene is currently marketed for prevention of osteoporosis and may also have some efficacy against metastatic breast cancer, although further study is clearly required.53 Tamoxifen appears to be effective for both pre- and post-menopausal women with advanced, receptor-positive disease.54 Common side effects of tamoxifen include hot flashes (particularly in perimenopausal women), disruption of menstrual cycles, and vaginal dryness or discharge.55 In addition, weight gain and mild fluid retention are frequent, with nocturnal leg cramps not uncommonly reported. Patients with bone metastasis may suffer a syndrome of "tumor flare," typically 7 to 10 days after initiation of tamoxifen. This is seen in 1 to 3 percent of patients and consists of increased pain at sites of metastases; it may lead to hypercalcemia. As this is predictive of subsequent response to tamoxifen, therapy should be continued, with supportive measures as needed. Approximately 1 percent of healthy patients on tamoxifen will develop deep-vein thrombosis, although women with metastatic breast cancer also have an increased incidence of thromboembolic disease.56 Other, rare complications such as cataract formation or an increased incidence of endometrial cancer are seldom of concern to women with metastatic disease.
The average duration of response to initial hormone therapy is approximately 1 year. Women whose disease stabilizes on tamoxifen appear to do as well as those achieving objective remissions. While responses lasting for years are not uncommon (particularly if there has been a long disease-free interval), eventually most tumors will develop resistance to tamoxifen, leading to clinical progression. This may occur due to outgrowth of receptor-negative clones within a heterogenous population or to acquired, specific resistance to estrogen antagonists. Once a responding tumor progresses on tamoxifen, other agents in this class have little activity. Indeed, a fraction of such patients will briefly improve when tamox-ifen is withdrawn, suggesting that changes in the receptor or the cellular estrogen-response machinery has led to the drug behaving as an estrogen agonist.57
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