`© 1994 Kluwer Academic Publishers. Printed in the Netherlands.
`
`New agents in breast cancer —— minisymposium
`
`Aromatase inhibitor development for treatment of breast cancer
`
`Shigeru Masamural, Herman Adlercreutzz, Harold Harvey3, Allan Lipton3, Laurence M. Demers4, Richard
`J. Santenl, and Steven J. Santnerl
`2Department of Clinical
`1Department of Internal Medicine, Wayne State University, Detroit, MI;
`Chemistry, University of Helsinki, Helsinki, Finland; 3Department of Medicine and 4Departments of
`Pathology and Medicine, The Milton S. Hershey Medical Center, The Pennsylvania State University,
`Hershey, PA, USA
`
`Key words: breast cancer, aromatase, estradiol, hormonal therapy, CGS 20267
`
`Summary
`
`Inhibition of estrogen production provides effective therapy for patients with horrnone-dependent breast
`cancer. The source of estrogens in premenopausal women is predominantly the ovary, but after the
`menopause, estradiol
`is synthesized in peripheral
`tissues through the aromatization of androgens to
`estrogens. Uptake from plasma is the primary mechanism for maintenance of estradiol concentrations in
`breast cancer tissue in premenopausal women, whereas several steps may be operant in postmenopausal
`women. These include enzymatic synthesis of estradiol via sulfatase, aromatase, and 17B-hydroxysteroid
`dehydrogenase in the tumor itself. Aromatization of androgens secreted by the adrenal to estrogens in
`peripheral tissues and transport to the tumor via circulation in the plasma provides another means of
`maintaining breast tumor estradiol levels in postmenopausal women. These various sources contribute to
`the high tissue estrogen levels measured in breast tumor tissue.
`To effectively suppress tissue concentrations of estrogens and circulating estradiol in postmenopausal
`patients, various aromatase inhibitors have been developed recently. These include steroidal inhibitors such
`as 4-hydroxy—androstenedione as well as non-steroidal compounds with imidazole and triazole structures.
`The most potent of these, CGS 20267, is reported to suppress levels of active estrogens (i.e., estrone,
`estrone sulfatase, and estradiol) by more than 95%. This compound can suppress both serum and 24-hr
`urine estrogens to a greater extent than produced by the second generation inhibitor, CGS 16949A. CGS
`20267 is highly specific since it does not affect cortisol and aldosterone serum levels during ACTH
`stimulation tests nor sodium and potassium balance in 24-hr urine samples. These data suggest that CGS
`20267 can be expected to bring improved response rates in the treatment of metastatic hormone—dependent
`breast cancer without substantial side effects.
`
`Introduction
`
`pendent upon estradiol for cellular proliferation.
`Studies to elucidate the mechanism of estradiol
`
`A subpopulation of human breast cancers are de-
`
`stimulated growth have been ongoing for two
`
`Presented by R.J. Santen at the 16th Annual San Antonio Breast Cancer Symposium, San Antonio TX, November 4, 1993;
`Mini-symposium on New Agents in Breast Cancer (supported by an educational grant from Rhone-Poulenc Rorer).
`Address for correspondence and ofiprints: Richard J. Santen, M.D., Department of Internal Medicine, Wayne State University,
`Harper Hospital, 1 Webber S, Detroit, MI 48201, USA; Tel: 313-745-8244; Fax: 313-993-0645.
`
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`20
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`S Masamura et al
`
`decades. Several hormonally related strategies
`have been developed for treatment of human
`breast cancer which are based upon the principle
`that estrogens are mitogenic for these tumor cells.
`Initial methods involved surgical ablative ther-
`apies such as oophorectomy, adrenalectomy, and
`hypophysectomy.
`These procedures eliminate
`ovarian
`estrogen
`synthesis,
`adrenal
`steroid
`synthesis, and the stimulatory effects of the
`gonadotropins on estrogen production in the
`ovaries, respectively. The rates of response to
`these
`therapies
`range
`from 30-40% [1].
`Adrenalectomy and hypophysectomy, because
`they involve major surgery, are infrequently
`employed currently, whereas oophorectomy con-
`tinues to be selected. Pharmacologic methods to
`alter the hormonal milieu eliminate the need for
`
`major surgery and have generally replaced sur-
`gical ablative therapies. Agents currently used
`are the antiestrogen tamoxifen,
`the progestins
`medroxyprogesterone
`acetate
`and megestrol
`acetate, gonadotropin releasing hormone analogs
`such as goserelin, and inhibitors of estrogen
`biosynthesis such as the aromatase inhibitors.
`Surprisingly,
`inhibition of aromatase, which
`blocks the conversion of androgens to estrogens,
`is effective therapy in patients with breast cancer
`even after they relapse from responses to anties-
`trogen or progestin (medroxyprogesterone acetate
`or megestrol acetate) therapy. Several second-
`and third-generation aromatase inhibitors are now
`available which are highly potent and associated
`with few side effects. Their role in the therapy of
`breast cancer will probably become increasingly
`important.
`In this review, the current status of
`aromatase inhibitors will be discussed.
`
`General role of aromatase
`
`Fat, liver, muscle, and hair follicles contain the
`
`aromatase enzyme which catalyzes the conversion
`of androgens to estrogens [2,3].
`In postmeno-
`pausal women,
`the major source of circulating
`estrogens is the peripheral conversion from andro-
`gens in fat tissue and in muscle [2]. Androstene-
`
`dione, the major precursor androgen, and testos-
`terone, a minor substrate, are secreted primarily
`from the adrenal glands and are converted in
`peripheral
`tissues
`to estrone
`and estradiol,
`respectively, through the catalytic action of the
`enzyme aromatase. The major aromatized pro-
`duct, estrone,
`is then enzymatically reduced to
`estradiol by the enzyme 17B-hydroxysteroid de-
`hydrogenase. These enzymatic activities result in
`measurable amounts of circulating estrogen in the
`range of 10-20 pg/ml in the plasma of postmeno-
`pausal women.
`Despite relatively low serum concentrations,
`the levels of estradiol in breast tumors of post-
`menopausal women are almost equivalent to those
`in premenopausal women [4]. The tumor tissue
`levels are much higher than the values predicted
`from calculations of serum concentrations and the
`
`affinity (Kd) of tissue receptors for estradiol. One
`of the explanations for maintenance of high tissue
`estradiol concentrations is the in situ synthesis of
`estradiol catalyzed by the various enzymatic activ-
`ities present in breast tumor tissue itself. These
`include sulfatase which catalyzes the conversion
`of estrone sulfate to estrone, aromatase which
`
`mediates androgen to estrogen conversation, and
`17B-hydroxysteroid dehydrogenase which allows
`formation of estradiol from estrone. The absolute
`
`levels of aromatase activity in human breast
`cancer tissues are low (5-100 pg/gm tissue/hr)
`when compared to those of sulfatase and 17].’)-
`hydroxysteroid dehydrogenase [5]. However, it is
`difficult to quantitate experimentally the amount
`of estradiol synthesized locally by each enzymatic
`pathway and the amount concentrated in tissue via
`uptake from plasma. Nonetheless, tissue enzymes
`such as sulfatase, 17B—hydroxysteroid dehydrogen-
`ase, and aromatase are likely to be involved in the
`production of at least some of the estrogen pre-
`sent in situ in tumor tissue. As another possible
`source of estrogens in breast
`tumors,
`lipoidal
`estradiol is reported to accumulate in estrogen
`receptor (ER) positive as well as ER negative
`breast cancer cells and can be hydrolyzed to free
`estradiol by esterase or lipase in tissues [6,7].
`Androstenedione is
`the major circulating
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`
`Aromatase inhibition for breast cancer therapy
`
`21
`
`Table 1. Partial list of aromatase inhibitors [20].
`
`Type of
`inhibition
`
`Mechanism
`based
`
`Competitive
`
`Type of
`compound
`
`Steroid
`Steroid
`
`Steroid
`Steroid
`
`Steroid
`Steroid
`Steroid
`Steroid
`Steroid
`Non-steroid
`Non-steroid
`lmidazole
`Imidazole
`
`Imidazole
`
`Imidazole
`
`Name of compound
`
`Ki“
`
`K intactb
`
`l. lx l 0’3 S'1
`4.5xl0'3S‘1
`
`4.O3xl0'3S'1
`5.5x l O'4S'1
`
`l.1lxl0'_3S'1
`8.4xl0’3S'1
`1.8x10'4S'1
`
`l,4,6—androsta—triene—3 , l 7—dione
`4-OH-androstenedione
`
`4-androstene-3,6,l7- trione
`Testolactone
`
`10B-propargylestr-4-ene-3,17-dione
`70t(4’-amino)phenylthio-1,4—androstadiene—3,17-dione
`l-methyl-androsta-1,4-diene-3,17-dione
`60:-bromo-androstene-dione
`70L(4 ’-amino)phenylthio-4-androstene-3,17-dione
`Aminoglutethimide
`Pyridoglutethimide
`CGS l6949A
`R-767 l 3
`
`CGS 20267
`
`Econazole
`
`3.4nM
`18nM
`540nM
`l l00nM
`0.l9nM
`0.70nM
`
`—
`
`0.06uM°
`
`3 Ki —— inhibitory constant
`h K inact — rate constant for inactivation of the enzyme (S=seconds)
`° IC50
`
`substrate for estrogens in the plasma of post-
`menopausal women and aromatase is the rate-
`limiting enzyme that regulates the conversion of
`androstenedione to estrone. Thus, the control of
`
`aromatase activity in tumors and in peripheral
`tissues can be a critical factor for regulation of
`postmenopausal breast cancer growth. Conse-
`quently, this enzyme provides a unique target for
`inhibition of tumor estradiol concentrations.
`
`Development of aromatase inhibitors
`
`The first aromatase inhibitor used in clinical
`
`studies was aminoglutethimide [8—lO]. The rates
`of objective (complete or partial) tumor regression
`with this agent were equal to those induced by
`surgical ablative therapies, antiestrogens, or high
`doses of progestin [ll]. Aminoglutethimide was
`also active in a substantial number of patients
`with breast cancer who exhibited total resistance
`
`In spite of the clinical effec-
`to tamoxifen [12].
`tiveness and partial non-cross resistance with anti-
`estrogens, aminoglutethimide is not an ideal aro-
`
`matase inhibitor because of its non-specificity and
`side effects.
`
`To overcome these drawbacks, more potent
`and specific aromatase inhibitors have been under
`development. As a class, these inhibitors can be
`divided into those which are steroidal and com-
`
`pete for the active site of the enzyme, and non-
`steroidal compounds which structurally fit into or
`near the enzyme active site. Further, some inhibi-
`tors are altered by the aromatase enzyme to make
`sites available which bind covalently to and per-
`manently inactive the enzyme. Agents of this
`type are called mechanism-based or "suicide" in-
`hibitors.
`
`Pyridoglutethimide is one of the non-steroidal
`compounds developed through modification of the
`structure of aminoglutethimide to bring greater
`specificity and lesser side effects. While lacking
`the drawbacks of aminoglutethimide such as inhi-
`bition of cholesterol side-chain cleavage and
`sedative properties on the CNS [l3,l4], this com-
`pound is considerably less potent than its parent.
`Another non—steroidal competitive inhibitor, R-
`767l3,
`is also highly potent and specific as an
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`22
`
`S Masamura et al
`
`100 - AG 1000 mg/day
`
` CGS 2 mg/day
`
`‘CV93
`0.9.9‘
`355:2
`»:o:o:o::‘
`:o:o:o:o‘
`0»
`‘
`
`C.‘
`
`UU
`
`) 75
`U
`.0
`"4-
`O
`
`‘E 50
`(D
`
`UL0
`
`) Q
`
`\./
`_ 25
`Q)
`>
`Q)
`A
`
`NS
`
`’
`
`mu
`
`'
`
`1
`
`9O0.9;
`.~.1:3:3:OO.O.§
`C.O0
`'9Q
`ooI.‘.09’‘Io
`0:0,o
`0.0‘O
`
`
`
`O
`
`Estrone
`
`|___
`
`Estrone
`Sulfate
`Plasma
`
`Estrodiol
`
`Estrone
`
`Estrodiol
`
`___Jl.__
`
`Urine
`
`__l
`
`Figure 1. Estrogen levels in plasma and urine (mean i SE), expressed as percent suppression from basal values (before
`treatment).
`In this study, postmenopausal breast cancer women are treated either with 1000 mg aminoglutethimide (AG) and
`40 mg cortisol for 2-12 weeks or with 2 mg CGS 16949A. The numbers over the bars represent the number of patients
`analyzed.
`(**, P<0.01; ***, P<0.001; by paired comparison of basal and treatment values.)
`
`aromatase inhibitor. R-76713 has the potency to
`suppress circulating estradiol
`to undetectable
`levels in normal men and to achieve 64% inhibi-
`
`tion in premenopausal women [15,16]. While the
`racemic form was initially studied,
`the stereo-
`isomer R83842 is more potent and is currently
`under clinical study [17].
`4-hydroxyandrostenedione is one of the mech-
`anism—based ("suicide") class of inhibitors. This
`
`compound effectively suppresses estrogen syn-
`thesis while associated with no estrogenic, anti-
`estrogenic, or antiandrogenic properties
`[18].
`Metabolism to 4-hydroxytestosterone renders it
`slightly androgenic but this does not appear to be
`associated with clinical sequelae. A large clinical
`trial conducted by Hoffken et al. [19] utilized 500
`mg of 4-hydroxyandrostenedione administered in-
`tramuscularly every two weeks for six weeks, and
`then 250 mg every two weeks thereafter. This
`compound reduced plasma estradiol of postmeno-
`pausal patients from 10-11 pg/ml to 4 pg/ml for
`up to 7 months. 24% of women experienced an
`
`objective tumor responses while 11% noted minor
`side effects such as hot flashes or constipation.
`Other studies reported sterile abscesses due to the
`intramuscular injection required for administration
`of this compound [14]. However, this effect is
`apparently reduced by improved. formulation.
`While oral administration of this agent might be
`considered preferable, this route is limited by the
`marked first—pass effect on metabolism in the liver
`and rapid production of glucuronidated deriva-
`tives.
`
`Other non-steroidal aromatase inhibitors are
`
`being developed as well. CGS 16949A(fadrazo1e
`hydrochloride) and CGS 20267 represent two of
`these agents (Table 1) [13]. Our studies demon-
`strated that fadrazole is 500-fold more potent than
`aminoglutethimide, but not completely specific for
`aromatase (Figure 1). Fadrazole hydrochloride
`also blocks cortisol and aldosterone synthesis
`through inhibiting 11B—hydroxylase activity and
`corticosterone methyl oxidase [21]. While basal
`levels of circulating cortisol and aldosterone are
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`
`Aromatase inhibition for breast cancer therapy
`
`23
`
`and other estrogens were measured by the method
`of Fotsis and Adlercreutz [24]. A total of 13
`
`postmenopausal breast cancer patients received
`CGS 20267 for 6 weeks in initial doses of 0.1-2.5
`
`mg/day followed over a 6-week period by an
`increasing amount of the compound to 0.25-5
`mg/day.
`Since
`there were no statistically
`significant differences in levels of suppression
`
`
`
`.
`
`O
`
`10
`5
`Weeks of therapy
`
`15
`
`‘ ces 20267
`
`Estradiol
`
`O
`
`10
`5
`Weeks of therapy
`
`15
`
` O
`
`CGS 20267
`
`Estrone sulfate
`
`$
`
`10
`5
`Weeks of therapy
`
`1 5
`
`10
`
`E 8
`Ba
`3 6
`'5
`E 4
`
`E 2
`
`O
`
`30
`
`E3
`
`:20
`E:
`(D
`
`c g
`
`U)
`lJ.J
`
`10
`
`O
`
`E so
`if
`
`Q) 60
`
`*5
`"E": 40
`(I)
`(1)
`
`§ 20
`‘:73
`L“
`
`o
`
`2. Effects of CGS 20267 on plasma estradiol,
`Figure
`estrone, and estrone sulfate in 8 patients at doses of 0.1
`mg/day (first 6 weeks) and 0.25 mg/day (second 6 weeks)
`over 12 weeks of therapy. Results represent mean i SD.
`Data reproduced from ref. [22].
`
`Astrazeneca Ex. 2025 p. 5
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`not significantly influenced, ACTH-stimulated
`cortisol and aldosterone responses are blunted,
`even when low doses (i.e., 1.8, 2.0, and 4.0
`
`mg/day) of fadrazole hydrochloride are used.
`Blockade of llB—hydroxylation by CGS l6949A
`also increases levels of precursor steroids such as
`l7ot-hydroxyprogesterone and androstenedione in
`some patients.
`We have recently directed our attention toward
`CGS 20267, an even more potent and specific
`aromatase inhibitor. CGS 20267 (letrozole) is a
`
`compound of the benzonitrile class which is
`approximately 1,000- to 10,000-fold more potent
`than aminoglutethimide and approximately 8-fold
`more potent than fadrazole hydrochloride. We
`initially studied 8 postmenopausal patients with
`advanced breast cancer who received 0.1 mg/day
`of CGS 20267 for 6 weeks, followed by 0.25
`mg/day for an additional 6 weeks. Greater than
`90% suppression of estradiol, estrone, and estrone
`sulfate were achieved over a 2-week period and
`the patients reached over 97% suppression by 6
`weeks of therapy with the dose of 0.1 mg/ml
`(Figure 2)
`[22].
`Since very low levels of
`circulating estrogens are present in these patients,
`standard radioimmunoassays are not sufficiently
`sensitive
`for
`the
`assessment of
`aromatase
`
`inhibition under these circumstances [23]. For
`this reason, in our studies estradiol was measured
`
`with a highly sensitive assay combining a high
`specific
`activity trace with a high affinity
`antiserum obtained from Baker Clinical Assays
`(Germany). This radioimmunoassay provides a
`sensitivity of 0.1 pg/ml with a direct non—chro-
`matographic method involving diethyl ether ex-
`traction of plasma [22]. The radioiinmunoassay
`utilized for estrone measurements is also sensitive
`
`enough to detect levels as low as 1 pg/ml. To
`further
`substantiate
`the degree of estrogen
`suppression achieved with CGS 20267, we also
`utilized a highly sensitive technique involving gas
`liquid chromatography-mass spectrometry (GLC/
`MS) analysis of 24—hr urine specimens. Before
`and 12 weeks after treatment with three different
`
`doses of CGS 20267, 24—hr urines were collected
`
`and estrone, estradiol, estriol, catecholestrogens,
`
`
`
`24
`
`S Masamura et al
`
`Table 2. Effects of CGS 20267 on 24-h urinary excretion of estrogens.
`
`Catechol estrogens
`
`Estriol“
`
`Total
`
`2—hydroxy-
`estrone
`6.50:i:2.38
`
`4-hydroxy-
`estrone
`l.36:l:0.51
`
`2-hydroxy-
`estradiol
`l.27i0.39
`
`2-methoxy-
`estrone
`1.78:t0.49
`
`Total catechol
`estrogens
`10.9l:t3.68
`
`7.64i2.68
`
`unnarya b
`estmgens '
`37.02i9.55
`
`0.62120. 10
`
`00610.02
`
`0.90i0.27
`
`02310.05
`
`1.8 1i0.36
`
`0.47i0.09
`
`4. l0i0.59
`
`90
`
`96
`
`39
`
`87
`
`83
`
`94
`
`89
`
`Before
`treatment°’d’°
`
`d f
`After
`treatmentc’ '
`
`% inhibition
`
`3 Since enzymatic hydrolysis was used to free conjugated steroids for estrone, estradiol, and estriol, the results reflect quantities
`of conjugated steroids, but are expressed as nanomoles of free steroid excreted per 24 h.
`b Numerical total of all estrogens measured, including catechol estrogens, estrone, estradiol, estriol, 17-epiestriol, 16-epiestriol,
`16ot-hydroxy-estrone, 15oz-hydroxy-estrone, 160-hydroxy-estrone, and l6-keto-estradiol.
`° Mean i:SE, nmol/24h.
`d Postmenopausal breast cancer patients (n=13).
`" Blood taken before administration of CGS 20267.
`f Blood taken after 12 week administration of cos 20267.
`
`Table 3. Effects of CGS l6949A on 24-h urinary excretion of estrogens.
`
`2-hydroxy—
`estrone
`4.90i1.23
`
`4-hydroxy-
`estrone
`0.4li0.06
`
`Catechol estrogens
`2-hydroxy-
`estradiol
`l.50i0.26
`
`2-methoxy-
`estrone
`l.37i0.3l
`
`Total catechol
`estrogens
`8.l7i1.83
`
`Estriol“
`
`5.53:l:0.77
`
`Total
`urinarya b
`estrogens '
`27.2i3.5
`
`l.40:t0.28
`
`02210.07
`
`0.32i0.04
`
`0.38:l:0.l2
`
`2.3l:l:0.46
`
`2.l9i0.37
`
`8.84il.47
`
`Normal
`women°’d
`
`CGS l6949A-
`treated women”
`
`% inhibition
`
`71
`
`50
`
`79
`
`72
`
`72
`
`60
`
`67
`
`3 Since enzymatic hydrolysis was used to free conjugated steroids for estrone, estradiol, and estriol, the results reflect quantities
`of conjugated steroids, but are expressed as nanomoles of free steroid excreted per 24 h.
`b Numerical total of all estrogens measured, including catechol estrogens, estrone, estradiol, estriol, 17—epiestriol, 16-epiestriol,
`16ot-hydroxy-estrone, 15a-hydroxy-estrone, 16B—hydroxy-estrone, and 16-keto-estradiol.
`° Mean iSE, nmol/24h.
`d Normal postmenopausal women, aged 48-64 yr (n=10, mean 57).
`5 All treated women (n=9) had metastatic breast carcinoma previously treated with hormonal agents. They continued to take
`4mg CGS l6949A 4-8 weeks after the dose escalation phase of the study (0.3-16mg).
`(Reproduced from Ref. [25].)
`
`between these three dosage groups, the data from
`the 13 patients were pooled and analyzed. As
`shown in Table 2, the sums of the excretion of
`
`free and conjugated estrogens decreased to 10-
`20% of basal
`levels during therapy, and total
`urinary estrogens fell
`to levels reflecting 89%
`inhibition.
`
`The plasma radioimmunoassay and urinary
`GLC/MS data in patients receiving CGS 20267
`
`suggested that this compound is a highly potent
`aromatase inhibitor. While different
`radio-
`
`immunoassays were used, the degree of suppres-
`sion with CGS 20267 appeared greater than that
`observed previously in patients receiving CGS
`l6949A (fadrazole hydrochloride)
`[25].
`For
`example, our data from studies using CGS
`l6949A revealed 58-71% inhibition of serum
`
`estrone, 68-73% for estrone sulfate, 23-33% for
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`
`
`estradiol, 74-79% for 24-hr urinary estrone, and
`52-66% for 24-hr urinary estradiol. This degree
`of suppression was substantially less than that
`(i.e., >95% suppression) observed in patients
`receiving CGS 20267. Measurement of total
`urinary estrogens with GLC/MS provided more
`direct means of comparing these two aromatase
`inhibitors since identical methodology was used to
`assess estrogen suppression in patients receiving
`either compound. Total urinary estrogen levels
`were suppressed by 67% with CGS 16949A and
`by 89% with CGS 20267 (Table 2,3).
`With respect to specificity, CGS 20267 did not
`block cortisol or aldosterone production. Sodium
`and potassium balance in 24-hr urine specimens
`was
`unaffected.
`Cortisol
`and
`aldosterone
`
`measured in serum during ACTH stimulation tests
`responded similarly under control conditions and
`during drug administration [22]. As more than
`95% suppression of estrogens can be achieved
`with CGS 20267, we expect that tumor regression
`can be expected in clinical studies of antitumor
`efficacy. Phase II trials are currently ongoing to
`determine the precise percentages of patients with
`tumor regression in response to this agent.
`side
`CGS 20267 produced only nominal
`effects
`in the
`23 patients
`treated at The
`Pennsylvania State University trial. Hot flashes
`were observed in 10 patients, hair thinning in 3,
`nausea in 4, diarrhea in 2, and dyspepsia in 2.
`All toxicity was ECOG Grade 1 and not substan-
`tial. Hot flashes have been observed with all
`aromatase inhibitors.
`It is not clear whether the
`
`Aromatase inhibition for breast cancer therapy
`
`25
`
`side effects suggest that this compound may have
`great therapeutic benefit.
`Its current role will
`probably be in patients
`relapsing following
`adjuvant therapy with tamoxifen. The mechan-
`isms whereby aromatase inhibitors are active
`following antiestrogen therapy are,
`as yet,
`incompletely understood. A working hypothesis
`is that tumor cells deprived of estrogen develop
`enhanced sensitivity to
`estradiol.
`If
`this
`hypothesis is proven in ongoing studies, aro-
`matase inhibitors which can completely inhibit
`estrogen biosynthesis would provide additional
`benefit
`to patients whose tumor cells have
`enhanced sensitivity to estradiol. Further studies
`are required to assess the actual clinical advan-
`tages of CGS 20267 and to test the concept of
`complete estrogen inhibition. Phase II studies to
`assess these aspects are currently ongoing.
`
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