Breast cancer, the most common neoplasm in American women, will result in approximately 46,000 deaths in 1995 and is second only to lung cancer as a cause of cancer-related mortality in women . At diagnosis, approximately 5% of women have metastatic disease, and current treatment for these women is only palliative. Consequently, it is important to define new therapeutic modalities and refine the therapeutic index of those already being used.
This paper reviews (1) the basis of endocrine therapy, a well-accepted treatment for metastatic breast cancer, (2) currently available and newer hormonal agents, (3) areas now under investigation, and (4) mechanisms of hormonal resistance.
Endocrine therapy generally is well tolerated by women with metastatic breast cancer and elicits a response in approximately one-third of unselected patients and in at least 50% of patients whose tumors are estrogen-receptor (ER) positive. Well-defined factors associated with a greater likelihood of response to endocrine therapy include:
- ER- and progesterone(Drug information on progesterone)-receptor (PR) positivity
- Late premenopausal or late post-menopausal status
- Older age
- Long interval from diagnosis to first recurrence (disease-free interval)
- Disease limited to sites outside the viscera, such as bone and soft tissue
- Previous response to endocrine therapy .
Because of their favorable therapeutic index, hormonal agents are the treatment of choice for asymptomatic patients with metastatic breast cancer, especially those who are older. Randomized trials show no adverse effect on survival for patients initially treated with endocrine therapy rather than chemotherapy, although initial rates of response to chemotherapy tend to be somewhat higher [2-4]. Tamoxifen(Drug information on tamoxifen) has been the drug of choice for first-line treatment of advanced disease because of its low toxicity. Second-line therapy now includes progestins and aromatase inhibitors, which have response rates similar to tamoxifen but more side effects (Tables 1 and 2).
Breast cancer cells have steroid receptors for estrogens(Drug information on estrogens), progestins, glucocorticoids, and androgens. Treatment of breast cancer in premenopausal women traditionally has involved removal of the ovaries, the source of estrogen, and, in postmenopausal patients, administration of pharmacologic doses of estrogen. (In postmenopausal women, large doses of estrogen can cause tumor regression.) The exact mechanism of these treatment modalities and the effects of estrogens and antiestrogens on the breast cancer cell are not fully defined. Our current understanding is that estrogen downregulates ERs and thereby decreases the hormone's effects .
Heat Shock Proteins--One speculative mechanism involves heat-shock proteins (hsps). When an estrogen antagonist (E) interacts with the ER, the ER-hsp complex dissociates. The DNA-binding domain then attaches to the estrogen-binding site on the DNA, initiating transcription of estrogen-regulated genes. Conversely, binding of an antiestrogen (AE) to the ER stabilizes the DNA-hsp, which prevents the ER-DNA interaction and thereby inhibits transcription (Figure 1).
Growth Factors--Breast cancer cells also secrete other growth factors that are autostimulatory (autocrine) and/or are stimulated by substances secreted by surrounding cells (paracrine; see Figure 2). Receptors for epidermal growth factor (EGFRs) and a closely related gene product, c-erbB2 (Her-2/neu), are found on breast cancer cells. Epidermal growth factor and transforming growth factor-alpha (TGF-alpha) interact with the EGFR and activate tyrosine kinase, a signal transduction pathway shown to induce proliferation of breast cancer cell lines in nude mice .
Transforming growth factor-alpha can act as an autocrine or paracrine growth factor. Receptors for TGF-beta also are present on breast cancer cells (primarily those that are ER-negative), and some breast cancer cells produce TGF-alpha in response to estrogens. Using antibodies against TGF-alpha or EGFR to block the effects of TGF-alpha can inhibit some breast cancer cells.
Insulin-like growth factor (IGF) also is produced by breast cancer cells in vitro and may result in both autocrine and paracrine mitogenic effects . Factors that increase IGF production include estrogen, TGF-alpha, EGF, and insulin. Antiestrogens, TGF-beta, and glucocorticoids inhibit its secretion .
Currently Available Hormonal Therapies
Currently available additive therapies include androgens, progestins, gonadotropin-releasing hormone (GnRH) agonists, corticosteroids, and, paradoxically, estrogens. Androgens, which were discovered to be effective in the 1940s, cause breast cancers to regress in approximately 20% of patients but are poorly tolerated because of virilization and other major toxicities.
Physiologic doses of estrogen (hormone replacement therapy) are generally avoided in women with breast cancer because of theoretical concerns that they might stimulate breast cancer cell growth. Higher doses yield response rates in postmenopausal women similar to those produced by other available agents, but estrogen therapy is frequently associated with nausea, vomiting, and other toxic effects [17,18]. During the 1950s, progestins were found to yield response rates of 30% in unselected patients with breast cancer .
Response rates of 20% to 25% also were reported for corticosteroid therapy alone . For example, in elderly patients in whom endocrine therapy has failed, 15 mg of prednisolone(Drug information on prednisolone) administered daily caused tumor regression in 14% of patients and tumor stabilization lasting 6 months or longer in 21% . Corticosteroids also can improve sense of well being, appetite, and functional status in seriously ill cancer patients . However, because of their long-term undesirable toxicities, corticosteroids typically are reserved for reducing inflammation and swelling in patients with intracranial metastases or the superior vena cava syndrome.
Gonadotropin-releasing hormone agonists have proven effective in pre-menopausal patients with metastatic breast cancer, but their role in standard practice has not yet been defined.
Tamoxifen, the prototypic hormonal agent used in breast cancer, is one of several antiestrogens now available and falls into the broad category of hormone antagonists. Other groups of hormone antagonists only recently introduced into the breast cancer treatment armamentarium include antiprogestins, antiandrogens, and aromatase inhibitors.