527.Full.Pdf

Vol. 4, 52 7-534, Marc/i 1998 Clinical Cancer Research 527

Review

Update on Endocrine Therapy for Breast Cancer

Aman U. Buzdar’ and Gabriel Hortobagyi research is ongoing to find new agents with greater efficacy and The University of Texas M. D. Anderson Cancer Center, Houston, improved safety profiles. Certain hormones (estrogens) can have Texas 77030 a major positive impact on the general health of women (i.e., preventing osteoporosis, lowering serum lipid levels, and reduc- ing menopausal symptoms). Thus, new endocrine agents that Abstract improve general health in addition to having antitumor activity The choice of endocrine agent for breast cancer de- would be highly desirable both in the breast cancer setting and pends on the menopausal status of the patient, the stage of for hormone replacement in healthy postmenopausal women disease, prognostic factors, and the toxicity profile of the (2, 3). agent. Endocrine therapies are typically given sequentially, The decision to use endocrine therapy for breast cancer is with the least toxic therapy given first. Tamoxifen is consid- based on a number of prognostic factors. Probably the most ered first-line endocrine therapy for all stages of breast important indicator of response to endocrine therapy is the cancer. New antiestrogens in development include nonste- presence of ERs and PRs in the tumor. Approximately 30% of roidal agents related to tamoxifen and pure steroidal anties- unselected breast cancer patients respond to endocrine therapy. trogens Luteinizing hormone-releasing hormone agonists Estrogen receptor and progesterone receptor data help to iden- are an effective form of endocrine therapy for premeno- tify patient subgroups who may benefit from endocrine therapy. pausal women with advanced breast cancer, and aromatase Endocrine therapy response rates in advanced disease average inhibitors are effective in postmenopausal women. Newer 33% in tumors positive for one hormone receptor and 50-70% and more selective aromatase inhibitors that are p.o. active in tumors positive for both hormone receptors (4). Furthermore, and have improved side-effect profiles have been developed. 20-30% of patients treated with endocrine therapy have stable Recent trials have found these agents to improve survival in disease and achieve similar benefits as those patients responding comparison to the progestins; thus, aromatase inhibitors are to endocrine therapy. Hormone receptor positivity is more com- replacing progestins as second-line therapy for metastatic mon in postmenopausal than premenopausal breast cancer pa- disease. Current trials are examining the potential role of tients (Fig. 1 ; Ref. 5). Other predictors of response include prior aromatase inhibitors as first-line therapy for metastatic dis- response to endocrine therapy, soft tissue or bony (as opposed to ease or as adjuvant therapy for early disease. The antipro- visceral) metastases, long disease-free interval, older age, well- gestins and antiandrogens studied thus far have had only differentiated tumors, and HER-2/neu negativity. limited success in breast cancer clinical trials. Most endocrine agents act by either blocking the production of estrogen (ovarian ablation and aromatase inhibitors) or Introduction the action of estrogen at the cellular level (antiestrogens); how-

It has been over a century since Beatson demonstrated that ever, for some agents (e.g. , supraphysiological doses of estro- oophorectomy was effective for treating advanced breast cancer. gens, androgens, and progestins), the mechanism of action is ( 1) Since then, endocrine therapies have become firmly estab- unknown. The choice of endocrine agent depends on the men- lished for managing all stages of breast cancer. opausal status of the patient, because this factor determines the In the last few years, many advances have been made in source of estrogen: ovarian or adrenal (peripheral; Fig. 2). endocrine approaches to breast cancer therapy. Treatment In premenopausal women, the ovary actively produces high choices have been refined and optimized by the development of basal estrogen levels. One treatment option is ovarian ablation, assays for the presence of estrogen and progesterone receptors which can be accomplished by surgery, radiation, or LHRH in tumors. Surgical techniques (i.e., oophorectomy, hypophy- agonist therapy. Of the surgical techniques, oophorectomy is sectomy, and adrenalectomy) have been largely replaced by a still used in premenopausal women with advanced breast cancer, variety of pharmaceuticals (i.e., antiestrogens, LHRH2 agonists, but hypophysectomy and adrenalectomy were abandoned once aromatase inhibitors, androgens. estrogens, and progestins), and pharmacological approaches became available (6). Antiestrogen therapy (i.e., tamoxifen) has proven effective in premenopausal patients as well. In postmenopausal women, ovarian function has ceased, Received 9/22/97: revised 12/16/97: accepted 12/16/97. and estrogen is primarily produced in peripheral tissues such as The costs of publication of this article were defrayed in part by the fat and muscle. Endocrine therapies for postmenopausal women payment of page charges. This article must therefore be hereby marked include antiestrogens, progestins, and aromatase inhibitors. advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Although endocrine therapies operate through different ‘To whom requests for reprints should be addressed, at Department of mechanisms, they often have similar objective response rates. Breast Medical Oncology, M. D. Anderson Cancer Center, Box 56, Because breast cancer is a progressive disease and the develop- 1515 Holcombe Boulevard, Houston, TX 77030. Phone: (713) 792- ment of drug resistance is common, endocrine therapies are 2817; Fax: (713) 794-4385. given sequentially, with the least toxic therapy given first. 2 The abbreviations used are: LHRH, luteininzing hormonereleasing hormone: ER, estrogen receptor; PR, progesterone receptor; FDA, Food In some cases, endocrine therapies have been almost en- and Drug Administration: AG. aminoglutethimide. tirely abandoned on the basis of toxicity. For example, diethyl-

50 Hypothalamus 0 o Premenopausal

0 #{149}Postmenopausal 0 40 47 ‘4- 0 Premenopausal Postmenopausal 30 0 U 0 20 a- (FSH7/’

10 Gonadotrophins Adrenal gland 0 irJ1 Ovary ER+, PR+ ER+, PR- ER-, PR+ ER-, PR- Prolactin Receptor Status Growth hormone

Fig. 1 Breast cancer patients grouped according to their menopausal Corticosterolds status and the hormone receptor status of their tumors. Progesterone

ProgesteroneI Androgens

stilbestrol was introduced in the 1940s as an endocrine therapy for postmenopausal advanced breast cancer (6). Because dieth- 1 ylstilbestrol was associated with side effects such as upper Peripheral 1ssues gastrointestinal distress, thromboembolic risk, fluid retention, (e.g. muscle, fat, breast tumors) stress incontinence, and withdrawal bleeding, it all but disap- peared from the clinic after the introduction of tamoxifen in the 1970s. Likewise, androgens are associated with virilization, 1 nausea, hepatotoxicity with cholestasis, increased libido, and Estrogens hypercalcemia; as a consequence. they have been relegated to Fig. 2 Routes of synthesis of estrogen and progesterone in premeno- fourth-line therapy for advanced breast cancer in postmenopausal and postmenopausal women. pausal women.

Current and Future Directions in Endocrine Therapy node-negative breast cancer (10). However, the Eastern Coop- Nonsteroidal Antiestrogens erative Oncology Group recently published preliminary results Tamoxifen Tamoxifen (Fig. 3) is the first-line endocrine (1 1) of a trial showing prolonged disease-free survival with therapy for all stages of breast cancer. It was first approved by longer than 5 years compared with 5 years in women with the FDA in 1977 for the treatment of advanced breast cancer in ER-positive breast cancer. postmenopausal women and has since been approved for: (a) the Because tamoxifen was found to prevent new tumors from treatment of advanced breast cancer in premenopausal women; developing in the opposite breast, the drug is presently being (b) use with chemotherapy; (c) adjuvant monotherapy in post- studied in worldwide breast cancer prevention trials in healthy menopausal women with node-positive breast cancer; (d) the women at increased risk for the disease ( 12). The use of tamox- treatment of node-negative breast cancer; and (e) male breast ifen in healthy women has been controversial. Although tamox- cancer. ifen is generally considered safer than alternative endocrine In postmenopausal women with advanced breast cancer, therapies such as androgens, estrogens, and progestins, it is not tamoxifen induces objective responses in about one-third of without toxicity. In addition to vasomotor and gynecological unselected patients; a higher response rate is observed in women side-effects (e.g., hot flashes, vaginal discharge, and irregular with ER-positive tumors (7). Adjuvant therapy with tamoxifen menses) and an increase in the rate of thromboembolic events has reduced recurrence rates, mortality, and the incidence of (1% in the B-14 trial; Ref. 10), the drug has been associated with contralateral breast cancer (8). The duration for which to give a modest increase in the risk for endometrial cancer (2 cases per adjuvant tamoxifen therapy is an issue that remains to be re- 1000 patients/year; Refs. 13 and 14). solved. It is clear that 5 years is better than 2 years, (9) but there About 250 cases of tamoxifen-associated endometrial can- are conflicting data as to whether longer than 5 years would be cer have been reported since 1985 (15). It is not known what even better (or worse). The National Cancer Institute recom- role tamoxifen plays in the etiology of these cancers (13); mended limiting adjuvant tamoxifen to 5 years after the Na- tamoxifen may act as a tumor initiator or promoter or may only tional Surgical Adjuvant Breast and Bowel Project B-l4 trial enhance detection of preexisting endometrial cancer (detection revealed no additional benefit of longer therapy in patients with bias). Because exposure to unopposed estrogen has been linked

ing affinity for the estrogen receptor than tamoxifen (20). In a 9,,,,,g”s__NMe2 Ct multicenter Phase II trial involving postmenopausal women with advanced breast cancer (2 1), objective responses were seen in 30% of patients receiving 20 mg of droloxifene, compared with 47% of the 40-mg group and 44% of the 100-mg group. The median response durations were 12, 15, and 18 months, respectively. The most common side effects with droloxifene Tamoxifen Toremifene were hot flashes, lassitude, and nausea. Ongoing Phase III trials are comparing the safety and efficacy of droloxifene to tamoxifen. Interestingly, because droloxifene is eliminated from the body more rapidly than tamoxifen, it may have a role in combination chemohormonal therapy (6). Raloxifene. Raloxifene is a benzothiophene antiestrogen that was being developed for breast cancer therapy but now is in clinical trials for the prevention and treatment of postmenopausal osteoporosis (22). In postmenopausal women, raloxifene (50 mg/day) was associated with significant reductions in total Droloxifene Raloxifene serum and low-density lipoprotein cholesterol as well as serum markers of bone turnover (i.e., osteocalcin and alkaline phos- phatase; Ref. 23). If raloxifene becomes available for the prevention of osteoporosis in healthy postmenopausal women, a OH side benefit may be a reduction in the risk for breast cancer and coronary heart disease (3, 24).

Steroidal Antiestrogens HO cH2,SO(CH2)3CF2CF3 As discussed, the nonsteroidal antiestrogens all possess partial estrogenic activity. Steroidal antiestrogens have been ICI 182, 780 developed that have no estrogenic activity and are thus less (Faslodex) likely to have a proliferative effect on the endometrium. These Fig. 3 Chemical structures of selected antiestrogens. compounds were derived from the estradiol molecule, in contrast to the nonsteroidal antiestrogens, which were derived from the triphenylethylene structure of tamoxifen. One steroidal antiestrogen, ICI 182,780 (Faslodex; Fig. 3), has entered clinical to endometrial cancer, the partial estrogenic activity of tamox- trials. In vitro, this agent has a high affinity for the estrogen ifen has been suspect. It is important to note that all of the receptor and high potency against ER-positive breast cancer cell nonsteroidal antiestrogens in clinical development exhibit some lines (25). In a clinical trial (26), 56 postmenopausal women degree of estrogen agonist activity (2). These new agents will were randomized to ICI 182,780 (6 or 18 mg by injection) or no require vigorous long-term study before a conclusion can be treatment for 7 days before primary breast surgery. ICI I 82,780 reached regarding the risk of endometrial cancer. significantly reduced expression of ER (P < 0.01 ), progesterone Toremifene. Several new nonsteroidal antiestrogens receptor (P < 0.05), and Ki67 (proliferation-associated nuclear have been developed, and one of these, toremifene, has been antigen; P < 0.05) in ER-positive breast tumors. Expression of approved by the FDA for use in advanced breast cancer. In a an estrogen-regulated protein (p52) was reduced, irrespective of comparative trial involving women with advanced breast cancer tumor ER status. (16), toremifene (60 and 200 mg) showed similar efficacy and In a Phase I trial (27), 19 patients with advanced breast safety to tamoxifen (20 mg). The higher dose of toremifene had cancer who had become resistant to tamoxifen received ICI no benefit over the lower dose and was associated with an 182,780 until progression (median, 25 months; Ref. 28). Thir- excess of liver function abnormalities; thus, 60 mg/day teen patients responded to treatment (7 with a partial response toremifene was approved for advanced breast cancer. and 6 with stable disease), indicating a lack of cross-resistance Toremifene is not yet indicated for adjuvant therapy, and long- with tamoxifen. IC! 182,780 was well tolerated. term data are lacking on the agent. Therefore, it is not yet known Although further clinical study of IC! I 82,780 is necessary, whether toremifene will have any safety advantage compared potential advantages include a lack of proliferative effect on the with tamoxifen. However, it has been shown that toremifene, endometrium and a lack of cross resistance with tamoxifen. If like tamoxifen, has a proliferative (estrogenic) effect on the the efficacy and safety of IC! 182,780 are established in Phase uterus (17). The ultimate place of toremifene in therapy remains III trials, this agent may have a role as second-line therapy after to be seen. Due to major cross-resistance between the two tamoxifen. agents, it is unlikely that toremifene will be used as second-line therapy after tamoxifen (18, 19). LHRH Agonists Droloxifene. Droloxifene (3-hydroxytamoxifen) is an In premenopausal women with advanced breast cancer, a antiestrogen in advanced clinical trials that shows higher bind- desirable goal of endocrine therapy is to inhibit ovarian estrogen

production, which is under the control of circulating gonado- tropins produced by the pituitary. Gonadotropin production is under the control of hypothalamic LHRH, which is normally released in a pulsatile fashion. Continuous treatment with LHRH agonists dramatically reduces levels of serum gonado- tropins. and hence estradiol; in premenopausal women, this is essentially a medical (and reversible) form of castration (29). LHRH agonists may also have a direct cytotoxic effect on Aminoglutethimide Formestane cancer cells (30). Although a number of LHRH agonists have been evaluated

for the treatment of breast cancer (e.g. , goserelin, buserelin, leuprolide, and triptorelin), only goserelin acetate implant is indicated (FDA approved) for breast cancer in the United States. Objective response rates to LHRH agonists have ranged from 31-63% in premenopausal women with advanced breast cancer, NC)(.)(CN similar to response rates seen with oophorectomy (30). As with H3C CH3 H3C CH3 other endocrine therapies, the frequency of response to LHRH agonists is higher in tumors that are hormone receptor positive. Anastrozole Fadrozole Side-effects with LHRH agonists consist of injection site reactions, tumor flare, and menopausal symptoms. Recent results from the Early Breast Cancer Trialists’ Collaborative Group have contributed to a renewed interest in ovarian ablation as adjuvant therapy (8), and studies of the ffN adjuvant use of LHRH agonists in premenopausal women are N,,)\ CH3 under way. In 1992, the Early Breast Cancer Trialists’ Collab-

orative Group published results of a 15-year follow-up on the NCH-&-CN ClGJHjN; effects of ovarian ablation (by surgery or radiation) on recurrence and death in women diagnosed with early breast cancer. For women <50 years of age at randomization (n 2102), the Letrozole Vorozole recurrence-free survival rates were 58.5% versus 48.3% (P 0.0004) for patients treated with ovarian ablation versus no Fig. 4 Chemical structures of selected aromatase inhibitors. therapy, respectively. The overall survival rates were 52.9 and

42.3%, respectively (P = 0.00007). The conclusion of this overview was that ovarian ablation was associated with an approximate 25% reduction in the annual odds of recurrence and mones (Fig. 5). As a consequence, therapy with AG usually death. In this same overview, investigators examined the sur- requires supplemental corticosteroids. This regimen is associ- vival and recurrence rates in patients treated with chemotherapy ated with side effects such as skin rash, lethargy, and orthostatic plus ovarian ablation versus chemotherapy alone. They found a hypotension. Therefore, although AG has shown comparable 20% reduction in the annual odds of recurrence and death with efficacy to tamoxifen, its side-effect profile has relegated this combination therapy versus chemotherapy alone. It is surmised agent to third-line status (after tamoxifen and progestins). Also, that LHRH agonists as adjuvant therapy in premenopausal the use of AG has rapidly decreased with the availability of women might offer similar results; this supposition awaits re- newer aromatase inhibitors. suIts of clinical trials. Selective Aromatase Inhibitors Newer aromatase inhibitors are more selective, have fewer Aromatase Inhibitors side-effects, and do not require coadministration of corticoste- In postmenopausal women, the ovary has ceased function- roids (31, 32). This structurally diverse group of inhibitors ing. However, estrogens are produced in peripheral tissues such includes androstenedione derivatives (formestane), imidazole as muscle, fat, and the breast tumor itself, from androgens derivatives (fadrozole), and triazole derivatives (anastrozole, secreted by the adrenal gland (Fig. 2). The final enzyme in this letrozole, and vorozole; Fig. 4). synthesis pathway for estrogens is aromatase. Inhibition of Aromatase inhibitors can be divided into two types: suicide aromatase is an effective therapeutic strategy in postmenopausal inhibitors and competitive inhibitors (33). Suicide inhibitors are women with advanced breast cancer. steroidal compounds that form an irreversible covalent bond with the aromatase enzyme, and thus have lasting effects in vivo. Nonselective Aromatase Inhibitors The continued presence of the drug to maintain inhibition is not AG. AG (Fig. 4) was the first widely used aromatase necessary when using suicide inhibitors, and the chance of toxic inhibitor for advanced breast cancer (31). AG is a nonselective side effects will, therefore, be reduced. Competitive inhibitors aromatase inhibitor in that it inhibits other cytochrome P-450 are mostly nonsteroidal and reversibly bind to the enzyme in enzymes, thereby inhibiting the synthesis of other steroid hor- competition with the natural substrate. Whether the different

Fig. 5 Simplified diagram depicting steroid hormone synthesis and the effects of selective versus 1r;r;taiiiii nonselective aromatase inhibitors. I

lll - 111* Selective 111*1

Nonselective

mechanisms of interaction with aromatase results in clinical vanced breast cancer. It is not available in the United States, but differences among these agents is yet to be determined. it is available in Japan. Fadrozole exhibits greater potency and Formestane. Formestane (4-hydroxyandrostenedione) is selectivity than AG (2, 38), but it is not entirely selective a selective suicide aromatase inhibitor indicated for advanced because it appears to interfere with adrenal steroidogenesis to breast cancer in postmenopausal women (outside of the United some extent (39, 40). States). In 136 unselected patients with advanced breast cancer, Fadrozole (I mg bid.) was studied in two double-blind formestane (250 mg i.m. every 2 weeks) demonstrated a 26% Phase III studies in which it was compared to megestrol acetate response rate (34). In this study, 13% of patients had injection (40 mg q.i.d.) for second-line therapy of advanced breast cancer site reactions, and five patients experienced an anaphylactoid (38). A total of 683 postmenopausal women were enrolled. The reaction after inadvertent iv. administration. Although the high combined overall response rates were 12.2% for fadrozole and selectivity of formestane represents a major advance, the need 14.2% for megestrol acetate. No significant differences between for i.m. administration is an impediment to widescale accept- treatments were seen in response rates, response durations, time ance of this agent in clinical practice. to progression, or median survival. Fadrozole was associated Anastrozole Anastrozole is a selective, nonsteroidal with a higher incidence of nausea and vomiting, whereas pa- competitive aromatase inhibitor that was approved by the tients treated with megestrol acetate were more likely to have United States FDA in 1996 for the treatment of advanced breast experienced dyspnea, edema, and weight gain. cancer in postmenopausal women. After once-daily oral dosing Fadrozole (1 mg b.i.d.) has also been compared with ta- of I mg in postmenopausal women, serum estradiol levels are moxifen (20 mg/day) for first-line treatment of postmenopausal suppressed to assay limits (35). Two Phase III multicenter trials women with advanced breast cancer (4 1 ). A total of 2 12 women have been conducted comparing double-blind anastrozole ( 1 and were enrolled. Prognostic factors were balanced between the 10 mg/day) with open-label megestrol acetate (40 mg q.i.d.) for two treatment groups, with the exception of an excess of visceral second-line treatment of advanced breast cancer in 764 post- metastatic disease in the fadrozole group. Response rates were menopausal women (36). About 40% of patients in each group 20% for fadrozole and 27% for tamoxifen; time to treatment benefited from therapy in terms of objective response or stable failure was 6. 1 and 8.5 months, respectively. Fadrozole was disease (37). There were no significant differences among the better tolerated than tamoxifen [WHO grade 2 toxicity 13% three treatments with respect to objective response rates or time versus 27% of patients, respectively (P 0.009)]. to disease progression (median, 21 weeks). However, a recent Letrozole. Letrozole (CGS 20267) is a nonsteroidal update with longer follow-up has revealed a significant advan- competitive aromatase inhibitor that, like anastrozole, offers tage in overall survival for the group receiving I mg/day anas- high selectivity and once-daily oral dosing (2). Recently. letro- trozole compared with megestrol (37). Patients treated with I zole was approved for use as second-line treatment in post- mg of anastrozole had a 22% lower risk of death compared with menopausal women with advanced disease. Letrozole has been megestrol acetate. Gastrointestinal disturbances were more com- studied in two Phase III trials, one comparing letrozole to mon in patients receiving anastrozole compared with patients megestrol acetate, the other to aminoglutethimide. Both studies receiving megestrol acetate, although the difference was not involved postmenopausal women with advanced breast cancer significant. In contrast, megestrol acetate was associated with who had progressed on antiestrogen therapy. The first study (42) significant and progressive weight gain. Ongoing Phase III trials consisted of three treatment groups: 0.5 mg/day letrozole, 2.5 are comparing the safety and efficacy of anastrozole with ta- mg/day letrozole, and 160 mg/day megestrol acetate. Letrozole moxifen for first-line use in the metastatic setting. In addition, (2.5 mg) produced a significantly higher response rate (P = anastrozole is being evaluated for use as an adjuvant treatment. 0.047), with a trend toward a longer time to treatment failure Fadrozole Fadrozole (CGS 16949A) is a nonsteroidal, than megestrol acetate. The 2.5-mg letrozole dose appeared to p.o. active, competitive aromatase inhibitor that has undergone be significantly more effective than the 0.5-mg dose, although extensive clinical testing in postmenopausal women with ad- the degree of estrogen suppression was similar for the two

Postmenopausal Premenopausal

Tamoxifen Tamoxifen or LHRH agonist

if respo”””-._,, ““‘ if response

Anastrozole LHRH agonist or tamoxifen

, if response No Megestrol Response if response Oophorectomy Fig. 6 Endocrine treatment sequences for postmenopausal and premenopausal women. 4if I if response Androgen Antstrozole Cytotoxic

Chemotherapy if response Megestrol

if response

Androgen

doses. Compared to letrozole, megestrol acetate was associated aromatase inhibitors may be valuable in premenopausal women with a higher incidence of serious adverse events (primarily who have progressed after oophorectomy (Fig. 6). cardiovascular and thromboembolic events) and weight gain. The second study compared letrozole (0.5 and 2.5 mg/day) with Progestins AG (250 mg bid.) and was performed with more rigorous Progestins have been used for treating metastatic breast criteria for response (43). Overall, the objective response rates cancer since the 1950s, although their mechanism of action for letrozole were lower (16.7 and 17.7% for 0.5 and 2.5 mg, remains uncertain. Currently, the only progestin indicated for respectively) than in the previous study, probably as a result of postmenopausal advanced breast cancer in the United States is the more rigorous criteria used. The objective response rate for megestrol acetate. A second progestin, medroxyprogesterone AG was 1 1 .2% (no P given). However, letrozole was signifi- acetate, is available outside the United States for breast cancer candy better than AG in time to progression (risk ratio, 0.68; and worldwide in a depot form for contraceptive use. Both of P < 0.004 for 2.5 mg of letrozole). More patients in the AG arm these agents are synthetic, p.o. active derivatives of progester- reported adverse events, and letrozole was well tolerated. one (46). Vorozole. Vorozole is yet another selective nonsteroidal Overall response rates for megestrol acetate in metastatic competitive aromatase inhibitor that is active when taken p.o. disease are about 30% in unselected patients (47). Although the Two preliminary reports have appeared describing results from efficacy of megestrol acetate appears to be similar to that of Phase III trials with vorozole (44, 45). In one of these, vorozole tamoxifen, the side-effect profile of this progestin has relegated (2.5 mg/day) was compared with megestrol acetate (40 mg it to second-line therapy. Weight gain is the most significant q.i.d.) in 452 postmenopausal women with advanced breast side-effect associated with progestin therapy and appears to be cancer who had failed on tamoxifen (45). In this open-label related to an increase in appetite rather than fluid retention. study. vorozole and megestrol acetate had comparable response Although weight gain would be desirable in the subset of breast rates (complete response + partial response, 10.5% versus cancer patients with cachexia, it has a negative impact on body 7.6%), with vorozole showing a nonsignificant trend toward a image for the majority of patients. Thromboembolism represents longer response duration (18.2 versus 12.5 months, P = 0.07). a serious side-effect of the progestins and may occur in 4-5% of Although both treatments were well tolerated, vorozole had a patients. lower incidence of weight gain. As a group, the selective, nonsteroidal aromatase inhibitors (anastrozole, fadrozole, letrozole, and vorozole) have similar Antiprogestins efficacy to megestrol acetate, which had occupied the position Because progesterone (as well as estrogen) is believed to of second-line therapy for metastatic disease in postmenopausal stimulate proliferation of breast epithelium, it has been hypoth- women. However, the new aromatase inhibitors have signifi- esized that antiprogesterone therapy would be effective in the cantly better side-effect profiles, particularly with regard to treatment of breast cancer. Mifepristone (RU486) is the first weight gain. Thus, the selective, nonsteroidal aromatase inhib- clinically available antiprogestin. Currently available overseas itors are replacing megestrol acetate for second-line use in this as an abortifacient, the agent has undergone clinical study for group of patients. This relationship is illustrated in Fig. 6 for the treatment of advanced breast cancer (48). anastrozole. the first member of this group of drugs to be In a Phase II trial (49), mifepristone (200 mg/day) was approved in the United States. administered to 28 women with previously untreated, PR- Aromatase inhibitors are not indicated for premenopausal positive advanced breast cancer. Three patients had a partial women because compensatory mechanisms can actually cause response for an overall response rate of 10.7%. Toxicity was an increase in estrogen production by the ovaries. However, mild to moderate, consisting primarily of nausea, lethargy,

anorexia, and hot flashes. The investigators concluded that the are expected to replace progestins as second-line therapy after efficacy of mifepristone was minimal, despite an optimal patient tamoxifen. Whether the new selective aromatase inhibitors will population. have a role in the adjuvant setting remains to be tested in clinical A second antiprogestin, onapristone, has undergone early trials. One rationale for using aromatase inhibitors as adjuvant clinical evaluation, but its development was discontinued due to therapy is their good tolerability profile in combination with liver toxicity (2). efficacy rates comparable with other endocrine therapies for Both mifepristone and onapristone are nonselective anti- treatment of postmenopausal advanced breast cancer; again, the progestins; they also bind to glucocorticoid and androgen re- possible effects of long-term estrogen deprivation in aggravat- ceptors. New antiprogestins are in development that are more ing osteoporosis and cardiovascular disease would need to be potent and more selective for the progesterone receptor (50). taken into account. The hope is that the newer endocrine therapies discussed in

Antiandrogens this report will offer clinicians the ability to treat patients with Because androgen receptors are present in 30-50% of hormone-responsive breast cancer better (i.e. , with less primary breast cancers (5 1 ), there has been interest in studying toxicity). the use of antiandrogens for this disease. Flutamide, a pure nonsteroidal antiandrogen used in the References treatment of prostate cancer, has been evaluated in Phase II I . Beatson, G. T. On the treatment of inoperable cases of carcinoma of clinical trials for metastatic breast cancer. In one such trial (52), the mamma. Suggestion for a new method of treatment, with illustrative only one response lasting 8 weeks was observed in 29 evaluable cases. Lancet, 2: 104-107, 1896. patients, leading the investigators to discontinue further evalu- 2. Howell, A., Downey, S.. and Anderson, E. New endocrine therapies ation of flutamide for breast cancer. for breast cancer. Eur. J. Cancer, 32A: 576-588, 1996. A study of metastatic breast cancer in males found that the 3. Tonetti, D. A., and Jordan, V. C. Targeted anti-estrogens to treat and combination of an antiandrogen (cyproterone acetate) with an prevent diseases in women. Mol. Med. Today, 2: 218-223, 1996. 4. Sedlacek, S. M., and Horowitz, K. B. The role of progestins and LHRH antagonist (buserelin) induced objective responses in 7 progesterone receptors in the treatment of breast cancer. Steroids, 44: of 1 1 patients (53). The side-effects of this treatment were loss 467-484, 1984. of libido, impotence, and hot flashes. Further studies are needed 5. Beck, W. W. Obstetrics and gynecology, pp. 126. Baltimore, MD: to define the role of antiandrogens and combinations of antian- Williams & Wilkins, 1989. drogens with LHRH antagonists in male breast cancer. 6. Goldhirsch, A., and Gelber, R. D. Endocrine therapies of breast cancer. Semin Oncol., 23: 494-505, 1996. 7. Jaiyesimi, I. A., Buzdar, A. U., Decker, D. A., and Hortobagyi, G. N. Discussion Use of tamoxifen for breast cancer: twenty-eight years later. J. Clin. In the last 5 years, a variety of new endocrine agents have Oncol., 13: 513-529, 1995. entered advanced clinical trials, and three of these, anastrozole, 8. Early Breast Cancer Trialists’ Collaborative Group Systemic treat- toremifene, and letrozole, have received marketing approval in ment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomized trials involving 3 1,000 recurrences and 24,000 deaths the United States. Two classes of endocrine agents are the focus among 75,000 women. Lancet, 339: 1-15, 71-85, 1992. of much of the research: the antiestrogens and the aromatase 9. Swedish Breast Cancer Cooperative Group Randomized trial of two inhibitors. versus five years of adjuvant tamoxifen for postmenopausal early stage Because tamoxifen has been so successful in the adjuvant breast cancer. J. Natl. 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A U Buzdar and G Hortobagyi

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