Clinical Cancer Research 527
`Vol. 4, 527—534, March 1998
`
`Review
`
`Update on Endocrine Therapy for Breast Cancer
`
`Aman U. Buzdarl and Gabriel Hortobagyi
`The University of Texas M. D. Anderson Cancer Center, Houston.
`Texas 77030
`
`Abstract
`
`The choice of endocrine agent for breast cancer de-
`pends on the menopausal status of the patient, the stage of
`disease, prognostic factors, and the toxicity profile of the
`agent. Endocrine therapies are typically given sequentially,
`with the least toxic therapy given first. Tamoxifen is consid-
`ered first-line endocrine therapy for all stages of breast
`cancer. New antiestrogens in development include nonste-
`roidal agents related to tamoxifen and pure steroidal anties-
`trogens. Luteinizing hormone-releasing hormone agonists
`are an effective form of endocrine therapy for premeno-
`pausal women with advanced breast cancer, and aromatase
`inhibitors are effective in postmenopausal women. Newer
`and more selective aromatase inhibitors that are p.o. active
`and have improved side-effect profiles have been developed.
`Recent trials have found these agents to improve survival in
`comparison to the progestins; thus, aromatase inhibitors are
`replacing progestins as second-line therapy for metastatic
`disease. Current trials are examining the potential role of
`aromatase inhibitors as first-line therapy for metastatic dis-
`ease or as adjuvant therapy for early disease. The antipro-
`gestins and antiandrogens studied thus far have had only
`limited success in breast cancer clinical trials.
`
`Introduction
`
`It has been over a century since Beatson demonstrated that
`oophorectomy was effective for treating advanced breast cancer.
`(1) Since then. endocrine therapies have become firmly estab-
`lished for managing all stages of breast cancer.
`In the last few years. many advances have been made in
`endocrine approaches to breast cancer
`therapy. Treatment
`choices have been refined and optimized by the development of
`assays for the presence of estrogen and progesterone receptors
`in tumors. Surgical techniques (i.e.. oophorectomy. hypophy-
`sectomy. and adrenalectomy) have been largely replaced by a
`variety of pharmaceuticals (i.e., antiestrogens, Ll-lRl-l2 agonists.
`aromatase inhibitors. androgens. estrogens. and progestins), and
`
`Received 9/22/97: revised 12/ 16/97: accepted 12/16/97.
`The costs of publication of this article were defrayed in part by the
`payment of page charges. This article must therefore be hereby marked
`advem'semem in accordance with 18 U.S.C. Section 1734 solely to
`indicate this fact.
`
`' To whom requests for reprints should be addressed. at Department of
`Breast Medical Oncology. M. D. Anderson Cancer Center. Box 56.
`1515 Holcombe Boulevard, Houston, TX 77030. Phone:
`(713)792—
`2817: Fax: (713) 794—4385.
`luteininzing honnone-releasing
`2The abbreviations used are: Ll-IRH.
`hormone; ER. estrogen receptor; PR. progesterone receptor: FDA, Food
`and Drug Administration: AG. aminoglutethimide.
`
`research is ongoing to find new agents with greater efficacy and
`improved safety profiles. Certain hormones (estrogens) can have
`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
`improve general health in addition to having antitumor activity
`would be highly desirable both in the breast cancer setting and
`for hormone replacement
`in healthy postmenopausal women
`(2, 3).
`
`The decision to use endocrine therapy for breast cancer is
`based on a number of prognostic factors. Probably the most
`important
`indicator of response to endocrine therapy is the
`presence of HRS and PRs in the tumor. Approximately 30% of
`unselected breast cancer patients respond to endocrine therapy.
`Estrogen receptor and progesterone receptor data help to iden-
`tify patient subgroups who may benefit from endocrine therapy.
`Endocrine therapy response rates in advanced disease average
`33% in tumors positive for one hormone receptor and 50—70%
`in tumors positive for both hormone receptors (4). Furthermore.
`20—30% of patients treated with endocrine therapy have stable
`disease and achieve similar benefits as those patients responding
`to endocrine therapy. Hormone receptor positivity is more com-
`mon in postmenopausal than premenopausal breast cancer pa-
`tients (Fig. 1; Ref. 5). Other predictors of response include prior
`response to endocrine therapy, soft tissue or bony (as opposed to
`visceral) metastases, long disease-free interval, older age. well-
`differentiated tumors, and HER-2/neu negativity.
`Most endocrine agents act by either blocking the produc-
`tion of estrogen (ovarian ablation and aromatase inhibitors) or
`the action of estrogen at the cellular level (antiestrogens); how-
`ever. for some agents (e.g., supraphysiological doses of estro-
`gens, androgens, and progestins). the mechanism of action is
`unknown. The choice of endocrine agent depends on the men-
`opausal status of the patient. because this factor determines the
`source of estrogen: ovarian or adrenal (peripheral; Fig. 2).
`In premenopausal women. the ovary actively produces high
`basal estrogen levels. One treatment option is ovarian ablation,
`which can be accomplished by surgery, radiation, or LHRH
`agonist therapy. Of the surgical techniques, oophorectomy is
`still used in premenopausal women with advanced breast cancer.
`but hypophysectomy and adrenalectomy were abandoned once
`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,
`and estrogen is primarily produced in peripheral tissues such as
`fat and muscle. Endocrine therapies for postmenopausal women
`include antiestrogens. progestins, and aromatase inhibitors.
`Although endocrine therapies operate through different
`mechanisms, they often have similar objective response rates.
`Because breast cancer is a progressive disease and the develop-
`ment of drug resistance is common. endocrine therapies are
`given sequentially. with the least toxic therapy given first.
`In some cases. endocrine therapies have been almost en-
`tirely abandoned on the basis of toxicity. For example. diethyl-
`
`InnoPharma Exhibit 1050.0001
`
`

`

`528 Endocrine Therapy for Breast Cancer
`
`
`
`Premanopausal
`
`Postmenopausal
`
`columns:
`(mum,
`
`Huh-min!
`
`Adm-mutation“:
`homo (mu)
`
`Maul [III
`
`mm
`
`0M
`
`$3‘
`
`Estrogen:
`moat-nun
`
`
`
`Gmtmmu / I. ,3(v
`commas
`
`-.
`
`\
`
`Progesterone
`
`Animus
`
`Peripheral nuns
`(0... muscle. ht. bloat tumors)
`
`1
`
`Estrogen
`
`Fig. 2 Routes of synthesis of estrogen and progesterone in premeno—
`pausal and postmenopausal women.
`
`node-negative breast cancer (10). However. the Eastern Coop-
`erative Oncology Group recently published preliminary results
`(11) of a trial showing prolonged disease-free survival with
`longer than 5 years compared with 5 years in women with
`ER-positive breast cancer.
`Because tamoxifen was found to prevent new tumors from
`developing in the opposite breast, the drug is presently being
`studied in worldwide breast cancer prevention trials in healthy
`women at increased risk for the disease (12). The use of tamox-
`ifen in healthy women has been controversial. Although tamox-
`ifen is generally considered safer than alternative endocrine
`therapies such as androgens, estrogens, and progestins. it is not
`without toxicity. In addition to vasomotor and gynecological
`side-effects (e.g.. hot flashes, vaginal discharge, and irregular
`menses) and an increase in the rate of thromboembolic events
`(1% in the B—14 trial; Ref. 10). the drug has been associated with
`a modest increase in the risk for endometrial cancer (2 cases per
`1000 patients/year; Refs. 13 and 14).
`About 250 cases of tamoxifen-associated endometrial can-
`
`cer have been reported since 1985 (15). It is not known what
`role tamoxifen plays in the etiology of these cancers (13);
`tamoxifen may act as a tumor initiator or promoter or may only
`enhance detection of preexisting endometrial cancer (detection
`bias). Because exposure to unopposed estrogen has been linked
`
`InnoPharma Exhibit 1050.0002
`
`D Premenopausal
`I Postmenopausal
`
`
`
`
`ER+. PR+
`
`ER+. PR-
`
`ER-, PR+
`
`ER—, PR—
`
`Receptor Status
`
`70
`
`en.‘
`
`E
`E 40
`"6
`E 30
`
`oo a
`
`;
`a.
`
`20
`
`10
`
`0
`
`Fig. 1 Breast cancer patients grouped according to their menopausal
`status and the hormone receptor status of their tumors.
`
`stilbestrol was introduced in the 19405 as an endocrine therapy
`for postmenopausal advanced breast cancer (6). Because dieth-
`ylstilbestrol was associated with side effects such as upper
`gastrointestinal distress, thromboembolic risk, fluid retention,
`stress incontinence. and withdrawal bleeding, it all but disap-
`peared from the clinic after the introduction of tamoxifen in the
`19705. Likewise. androgens are associated with virilization.
`nausea. hepatotoxicity with cholestasis.
`increased libido, and
`hypercalcemia; as a consequence. they have been relegated to
`fourth-line therapy for advanced breast cancer in postmeno—
`pausal women.
`
`Current and Future Directions in Endocrine Therapy
`
`Nonsteroidal Antiestrogens
`Tamoxifen. Tamoxifen (Fig. 3) is the first-line endocrine
`therapy for all stages of breast cancer. It was first approved by
`the FDA in 1977 for the treatment of advanced breast cancer in
`
`postmenopausal women and has since been approved for: (a) the
`treatment of advanced breast cancer in premenopausal women;
`(b) use with chemotherapy; (c) adjuvant monotherapy in post—
`menopausal women with node-positive breast cancer; (1!) the
`treatment of node-negative breast cancer; and (e) male breast
`cancer.
`
`In postmenopausal women with advanced breast cancer,
`tamoxifen induces objective responses in about one-third of
`unselected patients; a higher response rate is observed in women
`with ER-positive tumors (7). Adjuvant therapy with tamoxifen
`has reduced recurrence rates, mortality. and the incidence of
`contralateral breast cancer (8). The duration for which to give
`adjuvant tamoxifen therapy is an issue that remains to be re-
`solved. It is clear that 5 years is better than 2 years, (9) but there
`are conflicting data as to whether longer than 5 years would be
`even better (or worse). The National Cancer Institute recom-
`mended limiting adjuvant tamoxifen to 5 years after the Na-
`tional Surgical Adjuvant Breast and Bowel Project B-14 trial
`revealed no additional benefit of longer therapy in patients with
`
`

`

`Clinical Cancer Research 529
`
`O
`
`Tamoxifen
`
`c. O
`
`Toremifene
`
`“0— M92
`0
`
`Droloxifene
`
`Raloxifene
`
`OH
`
`
`
`""icnzigsmcrlzhcacra
`
`“°
`
`ICI 182, 780
`(Faslodex)
`
`Fig. 3 Chemical structures of selected antiestrogens.
`
`to endometrial cancer, the partial estrogenic activity of tamox-
`ifen has been suspect. It is important to note that all of the
`nonsteroidal antiestrogens in clinical development exhibit some
`degree of estrogen agonist activity (2). These new agents will
`require vigorous long-term study before a conclusion can be
`reached regarding the risk of endometrial cancer.
`antiestrogens
`Toremifene. Several new nonsteroidal
`have been developed, and one of these, toremifene, has been
`approved by the FDA for use in advanced breast cancer. In a
`comparative trial involving women with advanced breast cancer
`(16), toremifene (60 and 200 mg) showed similar efficacy and
`safety to tamoxifen (20 mg). The higher dose of toremifene had
`no benefit over the lower dose and was associated with an
`
`thus, 60 mg/day
`function abnormalities;
`liver
`excess of
`approved
`for
`advanced
`breast
`cancer.
`toremifene was
`Toremifene is not yet indicated for adjuvant therapy, and long-
`term data are lacking on the agent. Therefore, it is not yet known
`whether toremifene will have any safety advantage compared
`with tamoxifen. However, it has been shown that toremifene,
`like tamoxifen, has a proliferative (estrogenic) effect on the
`uterus (17). The ultimate place of toremifene in therapy remains
`to be seen. Due to major cross-resistance between the two
`agents, it is unlikely that toremifene will be used as second-line
`therapy after tamoxifen (18, 19).
`is an
`Droloxifene. Droloxifene (3-hydr0xytamoxifen)
`antiestrogen in advanced clinical trials that shows higher bind-
`
`ing affinity for the estrogen receptor than tamoxifen (20). In a
`multicenter Phase II trial
`involving postmenopausal women
`with advanced breast cancer (21), 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 lOO-mg group.
`The median response durations were 12, 15, and 18 months.
`respectively. The most common side effects with droloxifene
`were hot flashes, lassitude, and nausea. Ongoing Phase III trials
`are comparing the safety and efficacy of droloxifene to tamox-
`ifen. Interestingly, because droloxifene is eliminated from the
`body more rapidly than tamoxifen, it may have a role in com-
`bination 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 postmeno-
`pausal osteoporosis (22). In postmenopausal women, raloxifene
`(50 mg/day) was associated with significant reductions in total
`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 pre-
`vention of osteoporosis in healthy postmenopausal women. a
`side benefit may be a reduction in the risk for breast cancer and
`coronary heart disease (3, 24).
`
`Steroidal Antiestrogens
`As discussed,
`the nonsteroidal antiestrogens all possess
`partial estrogenic activity. Steroidal antiestrogens have been
`developed that have no estrogenic activity and are thus less
`likely to have a proliferative effect on the endometrium. These
`compounds were derived from the estradiol molecule. in con—
`trast to the nonsteroidal antiestrogens, which were derived from
`the triphenylethylene structure of tamoxifen. One steroidal an-
`tiestrogen, ICI 182,780 (Faslodex; Fig. 3). has entered clinical
`trials. In vitro, this agent has a high affinity for the estrogen
`receptor and high potency against ER-positive breast cancer cell
`lines (25). In a clinical trial (26), 56 postmenopausal women
`were randomized to ICI 182,780 (6 or 18 mg by injection) or no
`treatment for 7 days before primary breast surgery. ICI 182,780
`significantly reduced expression of ER (P < 0.01), progesterone
`receptor (P < 0.05), and Ki67 (proliferation-associated nuclear
`antigen; P < 0.05) in ER-positive breast tumors. Expression of
`an estrogen-regulated protein (p52) was reduced. irrespective of
`tumor ER status.
`
`In a Phase I trial (27). 19 patients with advanced breast
`cancer who had become resistant to tamoxifen received ICI
`
`182,780 until progression (median, 25 months; Ref. 28). Thir-
`teen patients responded to treatment (7 with a partial response
`and 6 with stable disease), indicating a lack of cross-resistance
`with tamoxifen. ICI 182,780 was well tolerated.
`Although further clinical study of ICI 182.780 is necessary,
`potential advantages include a lack of proliferative effect on the
`endometrium and a lack of cross resistance with tamoxifen. If
`
`the efficacy and safety of ICI 182,780 are established in Phase
`III trials, this agent may have a role as second-line therapy after
`tamoxifen.
`
`LHRH Agom'sts
`In premenopausal women with advanced breast cancer. a
`desirable goal of endocrine therapy is to inhibit ovarian estrogen
`
`InnoPharma Exhibit 1050.0003
`
`

`

`530 Endocrine Therapy for Breast Cancer
`
`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
`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,
`similar to response rates seen with oophorectomy (30). As with
`other endocrine therapies. the frequency of response to LHRH
`agonists is higher in tumors that are hormone receptor positive.
`Side-effects with LHRH agonists consist of injection site reac-
`tions. 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
`adjuvant use of LHRH agonists in premenopausal women are
`under way. In 1992, the Early Breast Cancer Trialists’ Collab-
`orative Group published results of a 15-year follow—up on the
`effects of ovarian ablation (by surgery or radiation) on recur-
`rence and death in women diagnosed with early breast cancer.
`For women <50 years of age at randomization (n = 2102), the
`recurrence-free survival rates were 58.5% versus 48.3% (P =
`0.0004) for patients treated with ovarian ablation versus no
`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
`death. In this same overview, investigators examined the sur-
`vival and recurrence rates in patients treated with chemotherapy
`plus ovarian ablation versus chemotherapy alone. They found a
`20% reduction in the annual odds of recurrence and death with
`
`combination therapy versus chemotherapy alone. It is surmised
`that LHRH agonists as adjuvant
`therapy in premenopausal
`women might offer similar results; this supposition awaits re-
`sults of clinical trials.
`
`Aromatase Inhibitors
`
`In postmenopausal women, the ovary has ceased function-
`ing. However. estrogens are produced in peripheral tissues such
`as muscle, fat. and the breast
`tumor itself, from androgens
`secreted by the adrenal gland (Fig. 2). The final enzyme in this
`synthesis pathway for estrogens is aromatase.
`Inhibition of
`aromatase is an effective therapeutic strategy in postmenopausal
`women with advanced breast cancer.
`
`Nonselective Aromatase Inhibitors
`
`AG. AG (Fig. 4) was the first widely used aromatase
`inhibitor for advanced breast cancer (31). AG is a nonselective
`aromatase inhibitor in that it inhibits other cytochrome P-450
`enzymes. thereby inhibiting the synthesis of other steroid hor-
`
`C2'45
`
`0’
`
`N
`
`‘0
`
`o
`
`0
`
`OH
`
`Aminoglutethimide
`
`Formestane
`
`I“?
`N\’/N
`
`NC
`
`CN
`
`H30
`
`CHa H3C
`
`CH3
`
`N=|
`\I j—<
`
`>—CN
`
`Anastrozole
`
`Fadrozole
`
`FN
`\
`N )
`‘N
`
`NC—<
`
`>—CN
`
`CI—<
`
`F"
`\
`N~ )
`N
`(+)
`
`CH3
`I
`IN
`V”N
`
`Letrozole
`
`Vorozole
`
`Fig. 4 Chemical structures of selected aromatase inhibitors.
`
`mones (Fig. 5). As a consequence, therapy with AG usually
`requires supplemental corticosteroids. This regimen is associ-
`ated with side effects such as skin rash, lethargy, and orthostatic
`hypotension. Therefore, although AG has shown comparable
`efficacy to tamoxifen, its side-effect profile has relegated this
`agent to third-line status (after tamoxifen and progestins). Also,
`the use of AG has rapidly decreased with the availability of
`newer aromatase inhibitors.
`
`Selective Aromatase Inhibitors
`Newer aromatase inhibitors are more selective, have fewer
`side-effects, and do not require coadministration of corticoste-
`roids (31, 32). This structurally diverse group of inhibitors
`includes androstenedione derivatives (formestane),
`imidazole
`derivatives (fadrozole), and triazole derivatives (anastrozole,
`letrozole, and vorozole; Fig. 4).
`Aromatase inhibitors can be divided into two types: suicide
`inhibitors and competitive inhibitors (33). Suicide inhibitors are
`steroidal compounds that form an irreversible covalent bond
`with the aromatase enzyme, and thus have lasting effects in vivo.
`The continued presence of the drug to maintain inhibition is not
`necessary when using suicide inhibitors, and the chance of toxic
`side effects will, therefore, be reduced. Competitive inhibitors
`are mostly nonsteroidal and reversibly bind to the enzyme in
`competition with the natural substrate. Whether the different
`
`InnoPharma Exhibit 1050.0004
`
`

`

`Clinical Cancer Research 531
`
`I Testosterone
`
`
`
`
`
`
`I
`Estradiol
`
`I
`
`Cholesterol
`
`Fig. 5 Simplified diagram depicting steroid hor-
`mone synthesis and the effects of selective versus
`nonselective aromatase inhibitors.
`
`» 'g3.
`
`
`
`
`
`
`Androstenedlone
`
`mt
`
`Selective
`
`-
`
`Nonselectlve
`
`
`
`Estrone
`
`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.
`Formestane. Formestane (4-hydroxyandrostenedione) is
`a selective suicide aromatase inhibitor indicated for advanced
`
`breast cancer in postmenopausal women (outside of the United
`States). In 136 unselected patients with advanced breast cancer.
`formestane (250 mg i.m. every 2 weeks) demonstrated a 26%
`response rate (34). In this study. 13% of patients had injection
`site reactions, and five patients experienced an anaphylactoid
`reaction after inadvertent i.v. administration. Although the high
`selectivity of fonnestane represents a major advance, the need
`for i.m. administration is an impediment to widescale accept-
`ance of this agent in clinical practice.
`Anastrozole. Anastrozole is a selective. nonsteroidal
`
`competitive aromatase inhibitor that was approved by the
`United States FDA in 1996 for the treatment of advanced breast
`
`cancer in postmenopausal women. After once-daily oral dosing
`of 1 mg in postmenopausal women, serum estradiol levels are
`suppressed to assay limits (35). Two Phase III multicenter trials
`have been conducted comparing double-blind anastrozole (1 and
`10 mg/day) with open-label megestrol acetate (40 mg q.i.d.) for
`second-line treatment of advanced breast cancer in 764 post-
`menopausal women (36). About 40% of patients in each group
`benefited from therapy in terms of objective response or stable
`disease (37). There were no significant differences among the
`three treatments with respect to objective response rates or time
`to disease progression (median. 21 weeks). However. a recent
`update with longer follow—up has revealed a significant advan-
`tage in overall survival for the group receiving 1 mg/day anas-
`trozole compared with megestrol (37). Patients treated with 1
`mg of anastrozole had a 22% lower risk of death compared with
`megestrol acetate. Gastrointestinal disturbances were more com~
`mon in patients receiving anastrozole compared with patients
`receiving megestrol acetate. although the difference was not
`significant. In contrast. megestrol acetate was associated with
`significant and progressive weight gain. Ongoing Phase III trials
`are comparing the safety and efficacy of anastrozole with ta-
`moxifen for first-line use in the metastatic setting. In addition.
`anastrozole is being evaluated for use as an adjuvant treatment.
`Fadrozole. Fadrozole (CGS 16949A) is a nonsteroidal,
`p.o. active, competitive aromatase inhibitor that has undergone
`extensive clinical testing in postmenopausal women with ad-
`
`it is available in Japan. Fadrozole exhibits greater potency and
`selectivity than AG (2. 38). but
`it
`is not entirely selective
`because it appears to interfere with adrenal steroidogenesis to
`some extent (39, 40).
`Fadrozole (1 mg b.i.d.) was studied in two double-blind
`Phase III studies in which it was compared to megestrol acetate
`(40 mg q.i.d.) for second-line therapy of advanced breast cancer
`(38). A total of 683 postmenopausal women were enrolled. The
`combined overall response rates were 12.2% for fadrozole and
`14.2% for megestrol acetate. No significant differences between
`treatments were seen in response rates. response durations. time
`to progression. or median survival. Fadrozole was associated
`with a higher incidence of nausea and vomiting. whereas pa-
`tients treated with megestrol acetate were more likely to have
`experienced dyspnea. edema, and weight gain.
`Fadrozole (1 mg b.i.d.) has also been compared with ta-
`moxifen (20 mg/day) for first-line treatment of postmenopausal
`women with advanced breast cancer (41). A total of 212 women
`were enrolled. Prognostic factors were balanced between the
`two treatment groups. with the exception of an excess of visceral
`metastatic disease in the fadrozole group. Response rates were
`20% for fadrozole and 27% for tamoxifen; time to treatment
`failure was 6.1 and 8.5 months. respectively. Fadrozole was
`better tolerated than tamoxifen [WHO grade 2 toxicity 13%
`versus 27% of patients. respectively (P = 0.009)].
`Letrozole. Letrozole (CGS 20267)
`is a nonsteroidal
`competitive aromatase inhibitor that.
`like anastrozole. offers
`high selectivity and once-daily oral dosing (2). Recently. letro-
`2016 was approved for use as second-line treatment
`in post-
`menopausal women with advanced disease. Letrozole has been
`studied in two Phase III
`trials. one comparing letrozole to
`megestrol acetate, the other to aminoglutethimide. Both studies
`involved postmenopausal women with advanced breast cancer
`who had progressed on antiestrogen therapy. The first study (42)
`consisted of three treatment groups: 0.5 mg/day letrozole. 2.5
`mg/day letrozole, and 160 mg/day megestrol acetate. Letrozole
`(2.5 mg) produced a significantly higher response rate (P =
`0.047). with a trend toward a longer time to treatment failure
`than megestrol acetate. The 2.5-mg letrozole dose appeared to
`be significantly more effective than the 0.5—mg dose, although
`the degree of estrogen suppression was similar for the two
`
`InnoPharma Exhibit 1050.0005
`
`

`

`532 Endocrine Therapy for Breast Cancer
`
`Postmenopausal
`
`Tamoxifen
`
`Premenopausal
`
`Tamoxifen or LHRH agonist
`
`Megestrol
`
`Androgen
`
`/ i “mm
`i MN
`LHRH agonist or tamoxifen
`AnastrozoleNV
`No /
`tfresponsc
`L ifresponse
`/ Response \
`Oophorectomy
`Lifresponse
`Anastrozole
`i ifresponse
`Megestrol
`‘tt'response
`Androgen
`
`i ifRSV i
`
`Fig. 6 Endocrine treatment sequences for postm-
`enopausal and premenopausal women.
`
`Cytotoxic
`Chemotherapy
`
`doses. Compared to letrozole. megestrol acetate was associated
`with a higher incidence of serious adverse events (primarily
`cardiovascular and thromboembolic events) and weight gain.
`The second study compared letrozole (0.5 and 2.5 mg/day) with
`AG (250 mg b.i.d.) and was performed with more rigorous
`criteria for response (43). Overall, the objective response rates
`for letrozole were lower (16.7 and 17.7% for 0.5 and 2.5 mg,
`respectively) than in the previous study, probably as a result of
`the more rigorous criteria used. The objective response rate for
`AG was 11.2% (no P given). However, letrozole was signifi-
`cantly better than AG in time to progression (risk ratio. 0.68;
`P < 0.004 for 2.5 mg of letrozole). More patients in the AG arm
`reported adverse events, and letrozole was well tolerated.
`Vorozole. Vorozole is yet another selective nonsteroidal
`competitive aromatase inhibitor that is active when taken p.o.
`Two preliminary reports have appeared describing results from
`Phase [11 trials with vorozole (44, 45). In one of these. vorozole
`(25 mg/day) was compared with megestrol acetate (40 mg
`q.i.d.) in 452 postmenopausal women with advanced breast
`cancer who had failed on tamoxifen (45). In this open-label
`study. vorozole and megestrol acetate had comparable response
`rates (complete response + partial response, 10.5% versus
`7.6%). with vorozole showing a nonsignificant trend toward a
`longer response duration (18.2 versus 12.5 months, P = 0.07).
`Although both treatments were well tolerated, vorozole had a
`lower incidence of weight gain.
`As a group, the selective, nonsteroidal aromatase inhibitors
`(anastrozole, fadrozole.
`letrozole, and vorozole) have similar
`efficacy to megestrol acetate, which had occupied the position
`of second-line therapy for metastatic disease in postmenopausal
`women. However. the new aromatase inhibitors have signifi-
`cantly better side-effect profiles, particularly with regard to
`weight gain. Thus, the selective, nonsteroidal aromatase inhib-
`itors are replacing megestrol acetate for second-line use in this
`group of patients. This relationship is illustrated in Fig. 6 for
`anastrozole.
`the first member of this group of drugs to be
`approved in the United States.
`Aromatase inhibitors are not indicated for premenopausal
`women because compensatory mechanisms can actually cause
`an increase in estrogen production by the ovaries. However,
`
`aromatase inhibitors may be valuable in premenopausal women
`who have progressed after oophorectomy (Fig. 6).
`
`Progestins
`Progestins have been used for treating metastatic breast
`cancer since the 19505, although their mechanism of action
`remains uncertain. Currently, the only progestin indicated for
`postmenopausal advanced breast cancer in the United States is
`megestrol acetate. A second progestin, medroxyprogesterone
`acetate, is available outside the United States for breast cancer
`
`and worldwide in a depot form for contraceptive use. Both of
`these agents are synthetic, p.o. active derivatives of progester-
`one (46).
`Overall response rates for megestrol acetate in metastatic
`disease are about 30% in unselected patients (47). Although the
`efficacy of megestrol acetate appears to be similar to that of
`tamoxifen, the side-effect profile of this progestin has relegated
`it to second-line therapy. Weight gain is the most significant
`side-effect associated with progestin therapy and appears to be
`related to an increase in appetite rather than fluid retention.
`Although weight gain would be desirable in the subset of breast
`cancer patients with cachexia, it has a negative impact on body
`image for the majority of patients. Thromboembolism represents
`a serious side—effect of the progestins and may occur in 4—5% of
`patients.
`
`Antiprogestins
`Because progesterone (as well as estrogen) is believed to
`stimulate proliferation of breast epithelium, it has been hypoth—
`esized that antiprogesterone therapy would be effective in the
`treatment of breast cancer. Mifepristone (RU486) is the first
`clinically available antiprogestin. Currently available overseas
`as an abonifacient, the agent has undergone clinical study for
`the treatment of advanced breast cancer (48).
`In a Phase II trial (49), rnifepristone (200 mg/day) was
`administered to 28 women with previously untreated, PR—
`positive advanced breast cancer. Three patients had a partial
`response for an overall response rate of 10.7%. Toxicity was
`mild to moderate, consisting primarily of nausea,
`lethargy,
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`Clinical Cancer Research 533
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`anorexia. and hot flashes. The investigators concluded that the
`efficacy of mifepristone was minimal. despite an optimal patient
`population.
`A second antiprogestin. onapristone. has undergone early
`clinical evaluation, but its development was discontinued due to
`liver toxicity (2).
`Both rnifepristone and onapristone are nonselective anti-
`progestins; they also bind to glucocorticoid and androgen re—
`ceptors. New antiprogestins are in development that are more
`potent and more selective for the progesterone receptor (50).
`
`Antiandrogens
`in 30—50% of
`Because androgen receptors are present
`primary breast cancers (51). there has been interest in studying
`the use of antiandrogens for this disease.
`Flutamide. a pure nonsteroidal antiandrogen used in the
`treatment of prostate cancer. has been evaluated in Phase II
`clinical trials for metastatic breast cancer. In one such trial (52).
`only one response lasting 8 weeks was observed in 29 evaluable
`patients. leading the investigators to discontinue further evalu—
`ation of flutamide for breast cancer.
`
`A study of metastatic breast cancer in males found that the
`combination of an antiandrogen (cyproterone acetate) with an
`LHRH antagonist (buserelin) induced objective responses in 7
`of 11 patients (53). The side-effects of this treatment were loss
`of libido. impotence. and hot flashes. Further studies are needed
`to define the role of antiandrogens and combinations of antian—
`drogens with LHRH antagonists in male breast cancer.
`
`Discussion
`
`In the last 5 years. a variety of new endocrine agents have
`entered advanced clinical trials. and three of these, anastrozole.
`toremifene. and letrozole, have received marketing approval in
`the United States. Two classes of endocrine agents are the focus
`of much of the research: the antiestrogens and