[CANCER RESEARCH 46, 4823—4826, September 1986]
`
`Treatment of Advanced Postmenopausal Breast Cancer with an Aromatase
`Inhibitor, 4-Hydroxyandrostenedione: Phase 11 Report1
`
`Paul E. Goss, Trevor J. Powles, Mitchell Dowsett, Gillian Hutchison, Angela M. H. Brodie, Jean-Claud Gazet, and
`R. Charles Coombes2
`
`Cancer Resth Campaign Laboratory (P. E. 6.], Royal Marsden Hospital (7'. J. P., R. C. C.], Sutton, Surrey, SM2 5PX, United Kingdom; Department ofEndocrinology,
`Chelsea Hospital for Women, London, SW3 6LT, IM. 0.], United Kingdom; Department of Pharmacology and Experimental Therapeutim, University ofMaryland,
`School ofMedicine, Baltimore, Maryland 2120! IA. 8.]; Ludwig Institutefor Cancer Research (London Branch) IR. C. C.] and St. George’s Hospital [J—C. C., G. H.],
`London, SW1 7, United Kingdom
`
`ABSTRACT
`
`PATIENTS AND METHODS
`
`4-Hydroxyandrostenedione (4-OHA), a potent new aromatase inhibi-
`tor, was given i.m. (500—1000 mg) to 58 patients with advanced postmen-
`opausal breast cancer. 0f 52 assessable patients 14 responded (27%), in
`10 (19%) the disease stabilized, and in 28 (54%) the disease progessed.
`Sterile abscesses occurred at the injection site in 6 patients and painful
`lumps were found in a further 3 patients. Two patients developed allergic-
`type reactions and 4 developed lethargy, suspected to be treatment
`induced. Plasma estradiol levels were suppressed from a mean of 7.2 t
`0.8 (SE) pg/ml before treatment to 2.6 2 0.2, 2.7 t 0.2, and 2.8 t 0.3
`pg/ml after 1, 2, and >4 months, respectively, of treatment and remained
`suppressed in patients whose disease relapsed. No significant fall in
`estrone levels was seen. Similarly, dehydroepiandrosterone sulfate, sex
`hormone binding globulin, and gonadotrophin levels were unaltered after
`6 months of treatment. Plasma 4-OHA levels were measured in a
`radioimmunoassay for androstenedione after chromatographic separation
`of 4-0HA from androstenedione. Drug concentrations ranged from 0.7
`to 23.2 (7.8 1 1.1) ng/ml after 2 months on treatment.
`4—0HA is an effective drug in the management of postmenopausal
`patients with breast cancer and does not produce notable systemic side
`effects.
`
`INTRODUCTION
`
`Estrogen deprivation is thought to be a major mechanism of
`the endocrine treatment of breast cancer. Approximately 30%
`of postmenopausal patients with advanced breast cancer re-
`spond to current modes of endocrine therapy. The source of
`estrogen in these patients is from conversion of circulating
`androgens by the estrogen synthetase enzyme complex, aro-
`matase, in peripheral tissues (1). Our approach is to deprive
`tumors of estrogen with compounds which selectively inhibit
`this enzyme. Since our first report in 1973 we have identified a
`number of aromatase inhibitors of which 4-OHA3 (The material
`used in this study was supplied by Ciba-Geigy, Basle, Switzer-
`land; 4-OI-IA; CGP 32349.) is the most potent inhibitor of
`human placental aromatase (2, 3) (Ki 0.15 pM). 4-0HA treat-
`ment inhibits peripheral aromatization in rhesus monkeys (4),
`suppresses ovarian estrogen secretion in rats (3), and causes
`regression comparable to ovariectomy of carcinogen-induced
`mammary tumors in these animals (5).
`Our preliminary communication on the first use of this drug
`in humans documented response in 4 of 11 postmenopausal
`women with advanced breast cancer (6). We report here a larger
`Phase II study confirming the biological activity of 4-0HA in
`advanced postmenopausal breast cancer, and toxicity findings
`are discussed. The endocrine effects and plasma drug levels of
`4-OHA are also described.
`
`Received 3/24/86; accepted 6/10/86.
`The costs of publication of this article were defrayed in part by the payment
`of page charges. This article must therefore be hereby marked advertisement in
`accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
`' Supported in part by a Cancer Research Campaign Clinical Fellowship for
`P. E. G. and NIH Grant CA-27440 to A. B.
`’ To whom request for reprints should be addressed.
`’ The abbreviations used are: 4-OHA. 4-hydroxyandrostcnedione; ER, estrogen
`receptor; LH, leuteinizing hormone; FSH. follicle stimulating hormone: DHAS,
`dehydroepiandrosterone sulfate; SHBG, sex hormone binding globulin; AG,
`aminoglutethimide; 17/30HSDH, I7fi-hydroxysteroid dehydrogenase.
`
`Patient Selection. All patients selected were postmenopausal or sur-
`gically ovariectomiud women who had been shown to have primary
`breast cancer and assessable (by International Union Against Cancer
`criteria) progressive metastatic disease (7). Patients were included ir-
`respective of the ER status of their primary or metastatic tumors. “ER
`positive” tumors were designated to be those which bound more than
`15 fmol estradiol per mg cytosol protein as measured by a previously
`described method (8). No patient had received endocrine or chemo-
`therapy within 4 weeks of the start of treatment. Exclusion criteria
`included a second primary tumor; significant renal (blood urea nitrogen,
`>12 mM), hepatic (bilirubin, >17 uM), or cardiac disease; rapidly
`progressive life threatening metastases; a life expectancy of <6 weeks;
`adverse psychological factors or refusal to give written infomed con-
`sent. Informed consent was obtained from all patients, and the study
`was approved by the Royal Marsden Hospital Ethics Committee; the
`Office for Protection from Research Risks, NIH; and Human Volun-
`teers Research Committee, University of Maryland School of Medicine,
`Baltimore, MD. Patients were free to withdraw from the trial at any
`time.
`
`Clinical Protocol. All patients were fully staged by previously pub-
`lished methods (9) at the beginning of treatment and again at 2, 6, and
`12 months and 6 monthly intervals thereafter. They were seen on an
`outpatient basis weekly for the first 8 weeks and then once a month.
`Investigations included a history, full clinical examination by at least 2
`physicians with bidimensional measurement of all lesions, full blood
`count, urea, electrolytes, calcium, phosphate, liver function tests, 1-
`glutamyl transferase on each visit and chest X-ray, bone scan, limited
`skeletal survey, liver ultrasound, and photography every 2 months.
`Response to treatment was measured according to the standard criteria
`of the International Union Against Cancer (7). In the case of bidimen-
`sional lesions response was defined as either disappearance of all lesions
`or a decrease by 50% or more in the sum of the products of the
`diameters of individual lesions with no lesion increasing in size. In each
`case no new lesions should have appeared. Progression was defined as
`either the appearance of new lesions or an increase of 25% or more in
`the sum of the products of the diameters of individual lesions or if an
`increase of less than 25% made additional treatment necessary. In
`situations such as infiltration of the breast, liver involvement, or me»
`diastinal lymphadenopathy objective regression was classified as a 50%
`or greater decrease in that measurement which was regarded as being
`in excess of that usual for the site under consideration.
`Initially patients received 4-OHA at a dose of 500 mg once weekly
`in alternate buttocks by i.m. injection. The dose chosen was approxi-
`mately 0.2% of the acute 10% lethal dose obtained in mice during
`preclinical toxicity studies. Later in 11 patients, mainly nonresponders,
`the dose was increased to 1000 mg (500 mg in each buttock weekly).
`The drug, supplied as a sterile microcrystalline powder and stored at
`4‘C, was suspended in physiological saline (500 mg/4 ml) immediately
`prior to administration. Injection sites were varied to avoid local side
`effects. Where these became severe, treatment was decreased in fre-
`quency or stopped. In the event of disease progression, treatment was
`immediately discontinued, the patient was restaged (as above), and
`alternative treatment was considered. Patients who died or whose
`treatment was discontinued before 4 weeks of treatment were excluded
`from analysis. Patients on treatment for less than 8 weeks were not
`assessable.
`
`Toxicity and side effects were assessed by routine blood tests, clinical
`examination when visiting the hospital, and a standard questionnaire
`4823
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`

`LHYDROXYANDROSTENEDIONE [N BREAST CANCER
`
`completed each week by the patient and a district nurse. Particular
`attention was paid to the development of local toxicity and to symptoms
`or signs suggestive of hormonal side effects.
`Hormone Measurement. Estradiol, estrone. LH, FSH. and DHAS
`were measured by radioimmunoassay according to previously descn‘bed
`methods with minor modifications (6, 10—12). Cross-reaction of 4-
`OHA in the estradiol assay was <1 x l0“% and was avoided in the
`estrone assay by the chromatography of ether extracts on Lipidex 5000
`(Packard) using chlorofonnzhexanezmethanol
`(50:50:1) as eluent.
`SHBG binding capacity was measured by the two-tier column method
`as described previously (13).
`Blood was taken from patients before therapy was instituted and
`during treatment, shortly before each injection of 4-OHA, and at a
`similar time of day for each patient. Plasma was stored at —20‘C until
`analysis. All samples from the same patient were analyzed in the same
`assay batch.
`Drug Measurement. Ether extracts of plasma were subjected to
`chromatography on Lipidex 5000 in trimethylpentanezisopropyl alco-
`hol (1:5) which separated androstenedione from 4-OHA. The levels of
`4-OHA were then measured, utilizing its 25% cross-reaction in a
`previously described androstenedione assay (14). Full details of this
`methodology are to be published elsewhere.
`
`RESULTS
`
`Response to Therapy. Six of the 58 patients entered into the
`trial were not assessable because +0HA was administered for
`less than 3 weeks. Table 1 gives the pretreatment characteristics
`of all the patients entered. Most patients were heavily pre-
`treated, 29 (50%) having received at least 2 previous endocrine
`therapies. Only 8 patients had not received any previous endo-
`crine therapy.
`Overall evaluation of 52 assessable patients (Table 2) revealed
`that 14 (27%) had objective complete (4 patients) or partial (10
`patients) responses to treatment. In 10 (19%) patients the
`disease stabilized for at least 8 weeks on therapy and in 28
`(54%) patients the disease progressed. Of the 22 ER positive
`patients, 6 responded to 4-OHA, 3 had static disease, and in
`13 the disease progressed. Of the 3 patients with ER negative
`tumors I responded and 2 had progressive disease. Twenty-
`four patients had previously responded to endocrine therapy,
`
`Table l Pretreatment characteristic: ofpatients treated with
`4-hydroxyandmrtenedione
`The majority of 58 treated patients had soft tissue disease either locally or as
`skin metastases or lymph nodes. In association with these bone metastases were
`the most common distant site of involvement. Fifty % of the patients had had
`two or more endocrine therapies.
`No. of patients entered
`58
`Age (yr?
`Median
`Range
`BR status
`Positive
`Negative
`Unknown
`
`64
`37-84
`
`24
`3
`31
`
`Table 2 Response to l-hydroxyandrostenedione according to estrogen receptor
`status and previous response to endocrine therapy
`Fourteen patients responded to 4-OHA. Only one responder was known to
`have an ER negative tumor. Four patients who had failed to respond to other
`therapies (tamoxifen in all cases) responded to 4-OHA.
`Response to 4—0HA
`PR
`NC
`PD
`10
`lo
`28
`
`CR‘
`4
`
`14
`
`NA
`6
`
`Overall response
`
`ER status
`Positive
`Negative
`Unknown
`
`Previous response to endocrine
`therapy
`Responders
`Nonresponders
`No previous therapy or re-
`sponse not assessable
`
`1
`0
`3
`
`2
`2
`0
`
`5
`l
`4
`
`5
`2
`3
`
`3
`0
`7
`
`3
`3
`4
`
`13
`2
`13
`
`l4
`9
`S
`
`2
`0
`4
`
`3
`0
`3
`
`‘ CR, complete response; PR, partial response; NC, no change; PD, progressive
`disease; NA, not assessable.
`
`Table 3 Response to l—hydmryandrostenedione according to sites ofdisease
`Soft tissue sites were the commonest to respond to therapy. Although bone
`pain was relieved in 63% only a minority of patients showed a healing of bone
`metastases sufficient to qualify as a partial response.
`No. having
`disease
`
`No. responding
`to 4-0HA
`
`Site of disease'
`
`Local disease
`Skin other than chest wall
`Lymph nodes
`Bone
`Bone pain
`Lung parenchyma
`Pleural effusion
`Liver
`Central nervous system
`
`31
`20
`26
`35
`8
`8
`3
`I l
`2
`
`ll (35%)
`5 (25%)
`8 (31%)
`4 (l 1%)
`5 (63%)
`l (l3%)
`0
`0
`0
`
`and 7 of these responded to 4-OHA, while in 3 the disease
`stabilized. There was no difference (P = 0.4) in disease free
`interval (i.e., the time from primary diagnosis to fust relapse)
`between responders and nonresponders. Response by site of
`disease is shown in Table 3. The responses seemed to occur
`most often in soft tissue and lymph nodes affected by breast
`cancer, with only 1 response in a visceral site. There were no
`responses in liver metastases (n = 11). Only 4 of 35 (11%)
`patients’ skeletal metastases responded although bone pain was
`alleviated in 5 of 8 patients with this symptom. Of the 14
`patients who responded to 4-0HA, 4 have since relapsed at 3,
`4, 4, and 13 months. Ten patients remain in remission for
`periods between 2 and 18 months. Mean duration of response
`and response to subsequent therapy cannot yet be adequately
`evaluated.
`
`Toxicity. Sterile abscesses occurred at the injection site in 6
`patients (in 4 only after the dose had been increased to 1000
`mg) and moderately painful lumps occurred in a further 3
`patients. The severity of the abmesses caused treatment to be
`discontinued in 2 patients and the frequency of injections was
`decreased in 2 others. Four patients experienced transient, mild
`lethargy which appeared to be treatment related. One patient
`who had been on treatment for 6 months developed an anaphy-
`lactoid reaction immediately after an injection. Perioral edema
`which resolved within 24-48 h occurred in 1 patient. No other
`systemic toxicity was noted.
`Endocrine Effects. Plasma estradiol levels were suppressed
`from 7.2 1- 0.8 (SE) pg/ml before treatment to 2.6 i- 0.2 pg/ml
`after 1 month of treatment. There was no further change in
`estradiol levels after 2 or 24 months of treatment (Fig. 1).
`There was no significant difference between responders and
`4824
`
`Pretreatment sites of disease (no.)
`Local disease
`Skin. other than chest wall
`Lymph nodes
`Bone
`Bone pain
`Lung parenchyma
`Pleural effusion
`Liver
`Central nervous system
`No. of patients who had 2 or more pre-
`vious endocrine therapies
`Objective response to prior endocrine ther-
`193'
`
`31
`20
`26
`35
`8
`8
`3
`11
`2
`29 (50%)
`
`27 (47%)
`
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`#HYDROXYANDROSTENEDIONE IN BREAST CANCER
`
`n- 14
`
`leEI(pg/ml) b
`
`u
`
`e
`
`e
`
`Pretrmlv
`
`Mann treetmefl
`
`Fig. 1. Mean plasma levels of estradiol (5;) in patients before and during
`treatment with 4—OHA (500 mg i.m. weekly). Bars, SE.
`‘1’ < 0.001 versus
`pretreatment.
`
`its earlier steps in the steroid biosynthetic pathway (19), de—
`pleting corticosteroids, and requiring their replacement (20). In
`addition, AG causes substantial drowsiness in approximately
`40% of patients and a morbilliform, maculopapular skin rash
`in approximately one-third of patients (16). Our study ad-
`dressed the question of whether a more powerful and selective
`aromatase inhibitor than AG could produce improved response
`rates without adverse side effects.
`The observed overall response rate of 27% is similar to other
`major forms of endocrine treatment although there was a bias
`in favor of ER positive tumors in our study (ER positive, 22;
`ER negative, 3; unknown, 27) which might have favored higher
`response rates (21). However, most patients had advanced
`metastatic disease (average, 2.5 metastatic sites per patient) and
`one-half had already received several endocrine therapies prior
`to receiving 4-OHA. A number of these patients had been
`resistant to their previous therapy which would reduce the
`likelihood of their response to subsequent endocrine treatment
`(15). In addition the optimum dose, route of administration,
`and dose scheduling have not yet been determined. A compar-
`ison of 4-0HA to other forms of endocrine therapy is now
`needed to define its exact role in breast cancer management.
`As regards toxicity, the most frequent side effect was devel-
`opment of local sterile abscesses and moderately painful lumps
`at the injection sites. The incidence of painful lump decreased
`as the technique of administration was modified. A slow rate
`of injection through a narrow bore needle together with careful
`selection of the injection site, tended to alleviate this problem.
`This is in keeping with the experience of other investigators
`using parenteral medroxyprogesterone acetate, another steroid
`used in patients with advanced breast cancer (22). Local toler-
`ability is not a problem with the lower dosage regimens now
`being investigated. Lethargy is a common symptom in patients
`with malignant disease and its occurrence in four of our patients
`is difficult to evaluate. The two allergic-type reactions noted
`both occurred in patients with known previous drug allergies.
`The possibility that the cause of these was an excipient used in
`the formulation is being investigated.
`We have reported previously (6) that plasma estradiol levels
`were suppressed by greater than 50% by a single 500-mg i.m.
`injection of 4-OHA and that this suppression was maintained
`for at least 1 week. In the present study this marked suppression
`was confirmed and it was demonstrated that there is no escape
`from suppression as treatment is continued. Since similar sup-
`pression of estradiol was seen in responders and nonresponders
`it is likely that any lack of tumor response is due to differences
`in estrogen dependence in the tumors and not to ineffective
`suppression of estradiol.
`The failure of 4—OHA to suppress estrone was an unexpected
`finding since both estradiol and estrone are formed from the
`conversion of androgenic precursors (testosterone and andro-
`stenedione, respectively) and the two estrogens are interconver-
`tible by l7BOHSDH. 4-OHA inhibits conversion of both an-
`drogen precursors to their respective estrogens with equal effi-
`ciency in human placental microsomes. Aminoglutethimide
`which is an aromatase inhibitor by virtue of its interaction with
`cytochrome P—450 (18) reduces plasma estradiol and estrone in
`a parallel manner (23). The lack of estrone suppression in this
`study is unlikely to be due to cross-reaction of 4—OHA in the
`Approximately 30—40% of postmenopausal patients with
`advanced breast cancer respond to hormonal manipulation if
`assay since the column chromatography system used prior to
`the estrone assay was designed specifiwa to avoid this poten-
`selected randomly without regard to the ER status of their
`tial problem. 4—Hydroxyestrone is a minor metabolite of 4-
`tumors (15). AG is an example of an agent in current clinical
`use (16, 17). It
`is thought to exert its antitumor effect by
`OHA in vitro (24) and is converted very rapidly to 4-methox-
`yestrone (25) which does not coelute with estrone from the
`suppressing circulating estrogens through its inhibitory action
`on the enzyme complex aromatase (18). However, it also inhib-
`Lipidex columns and is therefore unlikely to interfere in the
`4825
`
`ISO
`
`125
`
`100
`
`75
`
`w
`
`25
`
`0
`
`
`
`96atPretreatmentlevels
`
`0
`
`e
`
`i
`
`rsn
`LH
`sues
`was
`E.
`Elm
`5.00
`Fig. 2. Endocrine effects of chronic 4—0HA (500 mg i.m. weekly; >l month)
`in patients. 51, estradiol; 5., estrone; (R), responders; (NR), nonresponders. ', P
`< 0.001 versus pretreatment.
`
`nonresponders in the suppression of estradiol levels (P > 0.1)
`(Fig. 2).
`Plasma levels of estrone, DHAS, SHBG binding capacity,
`LH, and FSH after at least 1 month of treatment are shown in
`Fig. 2. Mean pretreatment levels were; estrone, 26.5 1 4.2 pg/
`ml; DHAS, 0.82 1 0.19 jig/ml; SHBG, 12.2 1- 1.6 ng testoster-
`one/ml; LH, 47.6 i 6.2 IU/liter; and FSH, 49.8 i 4.3 IU/liter.
`There was no significant fall or rise in any of these hormones
`(paired t tests). The mean estrone level fell to 88.2% of base-
`line values but this fall was not statistically significantly differ-
`ent from pretreatment levels (P > 0.1).
`Drug Levels. Drug concentrations in plasma taken from 22
`patients after 2 months of therapy and 1 week after their
`previous injection, ranged from 0.7 to 23.2 (7.8 :t 1.1) ng/ml.
`
`DISCUSSION
`
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`LHYDROXYANDROSTENEDIONE IN BREAST CANCER
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`13'
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`14
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`'
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`15‘
`16.
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`17.
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`18'
`19.
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`3,17-dione, an aromatase inhibitor, and its metabolism in vim and in vivo in
`the rat. Biochem. Pharmacol.. 31: 701-705. I98I.
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`estrogens and catecholamines and other catechols by the catcchol—O-meth—
`yltransfcrase of human liver. J. Clin. Endocrinol. Metab., 34: 736-746, I972.
`Brodie, A. M. H., Marsh, D. A., and Brodie, H. J. Aromataae inhibitors.
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`acetoxy-androstene-3,I7-dione. J. Steroid. Biochem., 10: 423-429, I979.
`Brodie, A. M. H., Romanoff, L. P., and Williams, K. I. H. Metabolism of
`the aromatase inhibitor 4-hydroxyandrostenedione by male rhesus monkeys.
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`Brodie, A. M. H., Brodie, H. J., Romanoff. L., Williams. J. G., Williams, K.
`I. H., and Wu, J. T. Inhibition of estrogen biosynthesis and regression of
`mammary tumors by aromatase inhibitors. Hormones Cancer. Adv. Exp.
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`Brodie, A. M. H., Garrett, W. M., Hendrikson, J. R., Marcotte, P. A., and
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`
`analysis. The validity of the result is supported by previous
`observations in rats where suppression of estradiol synthesis by
`4-OHA was markedly greater than that of estrone (3, 26). This
`nonparallel suppression of the estrogens by 4-0HA might be
`expected to occur if the drug caused inhibition of I7BOHSDH.
`Although the drug appears to interact with that enzyme [4-
`hydroxytestosterone is a metabolite of 4-OHA in rhesus mon-
`keys (27)], the inhibition of 17BOHSDH by 4-OHA in vitro is
`about loo-fold less effective than that of aromatase (28). Al-
`though the explanation for the result remains unknown, these
`results indicate that inhibition of estradiol but not estrone
`synthesis is important for successful endocrine treatment of
`postmenopausal breast cancer.
`Plasma DHAS levels are a relatively stable marker of adrenal
`activity and are closely related to urinary free cortisol levels
`(20). Since 4-0HA therapy did not affect DHAS it is unlikely
`that it has a significant effect on adrenal function.
`Gonadotrophin levels were unaffected by 4-OHA treatment
`in patients although in ovariectomized rats levels of LH and
`FSH were suppressed after administration of 4-OHA (26) which
`was probably due to the slight androgenic activity of the com-
`pound (3). Higher doses of 4-0HA in patients may suppress
`gonadotrophins; however, peripheral aromatase is not under
`gonadotrophin control in postmenopausal women. These re-
`sults indicate that at the dose used in this study this is unlikely
`to be a significant mechanism of action in these patients. Lack
`of significant androgenic activity is confirmed by our observa-
`tion that therapy does not alter SHBG binding capacity.
`Measurable 4~OHA plasma concentrations 1 week after the
`previous injection suggest that a depot of drug is formed at the
`injection site. Slow release of the compound from this site
`together with its rapid metabolism and clearance rate (27) may
`account for the l0w levels found. We have previously reported
`(29) that 4-OHA is both a competitive, reversible inhibitor of
`aromatase as well as a slower irreversible suicide inhibitor. This
`latter effect together with the depot formed at the injection site
`may account for the sustained suppression of estradiol despite
`low drug levels.
`In conclusion, 4-OHA, a potent new aromatase inhibitor, is
`capable of markedly reducing plasma estradiol levels and pro-
`ducing tumor regression in postmenopausal patients with ad-
`vanced breast cancer. This is the first direct evidence that
`selective inhibition of estradiol synthesis is important in the
`endocrine treatment of postmenopausal breast cancer. A major
`22-
`advantage of its use over other forms of endocrine therapy is
`the apparent absence of significant systemic toxicity. Optimum 23.
`dose, route of administration, and dose scheduling are now
`being investigated.
`
`20,
`
`21.
`
`24_
`
`ACKNOWLEDGMENTS
`
`We thank Dr. Sue Ashley for computer analysis, Anthony Murphy
`for dispensing assistance, and Marion Hill for estradiol, estrone, and
`drug level measurements. We also thank Dr. M. Jarman and Professor
`S. L. Jeffcoate for helpful discussions and Ciba-Geigy for their assist-
`ance and supply of 4»hydroxyandrostenedione. We also thank the
`Cancer Research Campaign, Phase I committee, for funding the toxi-
`cology studies and providing a clinical fellowship to P. G.
`
`REFERENCES
`l. Grodin, H. M., Siiteri, P. K., and MacDonald. P. C. Source of estrogen
`produc9ti7t3n in postmenopausal women. J. Clin. Endocrinol. Metab., 36: 207—
`2. 12313.11; A: M. H., Schwarzel, w. C., and Brodie, H.
`.1. Studies on the
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`25'
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`26-
`
`27'
`
`28
`
`29.
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`4826
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`AstraZencca Exhibit 2152 p. 4
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`

`Cancer Research
`
`TheJournalofCancerResearcM 1916-1930))1 TheAmencanJournal ofCancer (1931-1940)
`
`AAC-R QTEZEZQASSESEEE“
`
`Treatment of Advanced Postmenopausal Breast Cancer with an
`Aromatase Inhibitor, 4-Hydroxyandrostenedione: Phase II
`Report
`
`Paul E. Goss, Trevor J. Powles, Mitchell Dowsett, et al.
`
`Cancer Res 1986;46:4823-4826.
`
`Updated version
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