Endocrine approaches to the treatment of metastatic breast cancer were first suggested in the late 1800s by Beatson. At about the same time, Schinzinger suggested the use of irradiation to the ovaries as perhaps the first form of adjuvant systemic therapy. Surgical removal of the ovaries and/or ovarian ablation by irradiation arose from these original ideas and became standard therapy in the 1950s and 60s both for metastatic breast cancer and in the adjuvant setting. As the human endocrine system became better understood, it seemed clear that these treatments worked by reducing estrogen levels. It was also observed that women who underwent surgical ovarian removal without hormone replacement were at a greatly reduced risk of developing breast cancer. This was perhaps the first demonstration of endocrine prevention.
During the 1950s and 60s, a variety of other endocrine approaches were developed, but these were mainly surgical. They included the use of adrenalectomy and hypophysectomy as second-line endocrine therapies for premenopausal women who initially had positive responses to ovarian ablation. Unfortunately, these procedures were accompanied by both immediate complications and the long-term requirement for various types of endocrine replacement. Nevertheless, these ablative therapies were used with considerable success into the 1970s.
With the development of modern endocrine agents, including the antiestrogens, progestational agents, and first, second-, and third-generation aromatase inhibitors, a wide variety of more palatable endocrine approaches are now available. These newer endocrine therapies continue to supplement and rival chemotherapeutic and radiation approaches in the management of breast cancer.
The most appropriate hormonal therapy for a patient with metastatic breast cancer depends, in large part, on the patients menopausal status.
As mentioned above, the role of ovarian ablation as a treatment for premenopausal women with metastatic disease has long been appreciated. First introduced around the turn of the 20th century,[1,2] this therapy was used, without any ability to select patients, for many decades.
With the discovery of the estrogen receptor by Jensen et al in the 1950s, it became apparent that women who have measurable estrogen receptors and, subsequently, progesterone(Drug information on progesterone) receptors in their tumors were more likely to respond to endocrine maneuvers than were those who have only one or neither receptor measurable. Levels of estrogen and progesterone receptors were also found to predict response to hormonal therapy.
About 30% of women with tumors positive for either estrogen or proges-terone receptors and about 60% of women with tumors positive for both receptors will respond to endocrine maneuvers. Women with higher levels of estrogen and/or progesterone receptors are more likely to respond than are those with lower but still positive levels. The use of ovarian ablation remained limited in the 1960s, 70s, and early 80s however, by the requirement for either a course of pelvic irradiation or a major surgical procedure.
A further development during the 1990s was the widespread availability of ovarian ablation by laparoscopic means. This relatively simple procedure can be carried out in the outpatient setting in most women requiring surgical ovarian ablation, and has made ovarian ablation a more acceptable therapy.
Early in the development of tamoxifen(Drug information on tamoxifen) (Nolvadex), small, comparative studies[6-8] showed that tamoxifen was equally effective to ovarian ablation in the metastatic setting. A subsequent meta-analysis, although still containing a relatively small number of patients randomized between these two treatments, further clarified the approximate equivalence of these two therapies. Because tamoxifen could be administered orally, had few side effects, and did not result in permanent ovarian ablation, it became the drug of choice in many situations for the treatment of premenopausal women with metastatic disease.
In the 1970s, the luteinizing hormonereleasing hormone (LHRH) analog were developed. These agents, particularly goserelin(Drug information on goserelin) (Zoladex), were explored in metastatic breast cancer, and numerous phase II studies showed activity in this setting. Subsequently, the results of a large randomized study confirmed the equivalence of goserelin to ovarian ablation.
More recently, four small studies comparing tamoxifen plus an LHRH analog to an LHRH analog alone have suggested that the combination may be superior in terms of time to progression and overall survival. Once again, meta-analysis of these four trials has been helpful in suggesting that there may be a benefit to the combination in comparison to an LHRH analog alone.
Because tamoxifen is generally used as first-line therapy in this setting, however, the more germane question remains whether tamoxifen plus an LHRH analog is superior to tamoxifen alone. Randomized trials to answer this question should be considered.
Treatment RecommendationsIn the meantime, it seems clear that premenopausal women who are estrogen receptor and progesterone receptor positive and/or have suitable clinical characteristics (eg, long disease-free interval, soft-tissue and/or bone involvement, pleural effusion, slow pace of disease) remain candidates for endocrine approaches to the treatment of breast cancer. These women can receive either tamoxifen or ovarian ablation by medical, surgical, or radiotherapeutic means as first-line endocrine therapy. The combination of an LHRH analog and tamoxifen could also be considered for first-line treatment.
For women whose disease responds to initial ovarian ablation but subsequently progresses, tamoxifen should be considered as second-line therapy. For women who begin therapy with tamoxifen, ovarian ablation by medical, surgical, or radiotherapeutic means should be considered as a second-line treatment.
It should be remembered that such drugs as the aromastase inhibitors and the progestational agents have not been shown to be effective in women who are still premenopausal. Thus, some form of ovarian ablation should precede the use of these drugs.
Diethylstilbestrol(Drug information on diethylstilbestrol) (DES) was once considered the first-line treatment for all postmenopausal women. With the advent of tamoxifen, however, this much less toxic drug was quickly adopted, perhaps even before the results of randomized trials showing its equivalence were available.
Until a few years ago, second-line therapy was probably best delivered by medroxyprogesterone(Drug information on medroxyprogesterone) acetate or megestrol(Drug information on megestrol) acetate (Megace), both of which have been shown to be equivalent to tamoxifen in a variety of randomized clinical trials. However, these progestational agents have an unpleasant side effect profile that includes dyspnea, weight gain, and an increased risk of deep-vein thrombosis and pulmonary emboli.
Over 15 years ago, aminoglutethimide (Cytadren), the prototype of the aromatase inhibitors, became available. In postmenopausal women, virtually all estrogen is produced by aromatase, an enzyme found in brain, muscle, and peripheral fat that converts androgenic hormones produced by the female adrenal gland to estrogens(Drug information on estrogens).
Unfortunately, aminoglutethimide was nonspecific, in that it also blocked 11-, 17-, and 21-hydroxylation in the adrenal pathway of steroidogenesis, resulting in reduced production of the mineralocorticoids and glucocorticoids required for life. Thus, aminoglutethimide, in daily doses higher than 500 mg, required concurrent hydrocortisone(Drug information on hydrocortisone) replacement. Aminoglutethimide tended to cause drowsiness, and maculopapular rashes were also common side effects of this agent. The accompanying cortisone(Drug information on cortisone) had its own set of side effects.
The development of the second-generation aromatase inhibitors, such as formestane(Drug information on formestane) (Lentaron), was not terribly helpful, since these were injectable and thus harder to use. Now, however, a wide variety of third-generation aromatase inhibitors, including anastrozole(Drug information on anastrozole) (Arimidex), letrozole(Drug information on letrozole) (Femara), and exemestane(Drug information on exemestane) (Aromasin), have been developed. Each of these drugs has been compared against aminoglutethimide or megestrol acetate in randomized clinical studies.[13-15]
All three third-generation aromatase inhitors have been shown to be superior to megestrol acetate to some degree. Randomized trials of anastrazole have shown improved overall survival, while randomized trials of letrozole have shown improved time to treatment failure and improved overall survival in comparison to megestrol acetate. Similarly, randomized trials comparing exemestane to megestrol acetate have shown improvements in time to treatment failure, time to progression, and overall survival. In addition, comparisons of letrozole to aminoglutethimide (500 mg) used without hydrocortisone have demonstrated the superiority of the third-generation aromatase inhibitor.
Two trials comparing anastrozole to tamoxifen as first-line therapy for metastatic disease were presented at the 1999 European Cancer Conference (ECCO). One large European study randomized over 650 women to receive either tamoxifen or anastrozole. This study showed almost identical response rates, time to treatment failure, and time to progression for the two drugs. However, less than half of the patients were known to be estrogen receptor positive; estrogen receptor status in the remaining patients was unknown. A similarly designed North American study of about 350 women randomized to tamoxifen or anastrozole, of whom about 90% were positive for estrogen or progesterone receptors, showed a statistically significant benefit, with respect to both time to treatment failure and time to progression, in favor of an astrozole.
The somewhat different results of these two trials seem problematic, and further examination of the data is underway. These preliminary results suggest, however, that this particular aromatase inhibitor may be at least equivalent, if not superior to, tamoxifen in the first-line setting. Further follow-up will be required to confirm these results and to assess survival. Certainly, these data have generated great interest in the upcoming results of a randomized study in which anastrozole (A) is being compared to tamoxifen (T) and to the combination of the two drugs (AT) as adjuvant therapy for receptor positive or unknown postmenopausal women (the so-called ATAC trial).
Treatment RecommendationsBased on currently available data, postmenopausal women with metastatic disease should be treated first with tamoxifen, followed by a second-generation aromatase inhibitor (anastrozole, letrozole, or exemestane) and then, probably, by megestrol acetate. Drugs with a more problematic side effect profile, such as fluoxymesterone(Drug information on fluoxymesterone) and danazol(Drug information on danazol), can be reserved for fourth-line therapy when required. The rapid development of the aromatase inhibitors and the suggestion that at least one of them, anastrozole, may be equivalent to if not better than tamoxifen in the first-line metastatic setting, suggest that the sequence of hormonal therapies may change over the next few years as more data become available.