Br. J. Cancer (1984), 50, 199-205
`
`A comparison of two doses of tamoxifen (Nolvadex*) in
`postmenopausal women with advanced breast cancer: 10mg
`bd versus 20 mg bd
`D.G. Bratherton!, C.H. Brown!, R. Buchanan?, V. Hall?, E.M. Kingsley Pillers?,
`T.K. Wheeler! & C.J. Williams?
`
`' Addenbrooke’s Hospital, Hills Road, Cambridge, CB2 20Q; *Royal South Hants Hospital, Fanshawe Street,
`Southampton SO9 4PE UK.
`
`In a comparative double-blind trial involving 263 postmenopausal women with advanced breast
`Summary
`cancer treated with tamoxifen,
`the mean objective tumour response rate and duration was 32% and 15
`monthsrespectively. No significant difference was foundin clinical response and adverse effects between those
`randomised to 10mg and those to 20 mg twice daily. Although the mean serum concentration of tamoxifen in
`the 20mg bd group wassignificantly higher no correlation between serum level and clinical benefit was
`demonstrated.
`
`Patients and methods
`Tamoxifen (Nolvadex*) is widely used asafirst line
`therapy in the management of breast cancer. Early
`two separate centres
`The trial was carried out at
`clinical
`results
`indicated that
`the
`threshold of
`(Cambridge and Southampton).
`consistent therapeutic activity lay between 10 and
`Postmenopausal women with primary inoperable,
`20mg daily. Ward (1973),
`in a small randomised
`locally recurrent or metastatic breast cancer with
`comparison of 10mg bd and 20mg bd, reported a
`measurable or evaluable disease were
`assessed.
`greater tumour response rate at
`the higher dose,
`Patients previously treated with tamoxifen and
`although
`the
`difference was
`not
`statistically
`those receiving other endocrine therapies within the
`significant. The only other direct comparison of
`previous 6-weeks were excluded. During the trial,
`two dosages was a non-randomised study (Lerneret
`concomitant
`anticancer medication was
`not
`al., 1976)
`in which the results were considered
`permitted, with
`the
`exception
`of
`palliative
`inconclusive. A review of 19 major clinical
`trials
`radiotherapy for painful bone metastases, which
`(Mouridsen ef al., 1978) suggested that a dose of
`were then excluded as evaluable lesions.
`40mg daily was associated with a higher overall
`to receive
`Patients were allocated, double blind,
`response than 20mg daily (39% versus 28%) but
`tamoxifen either 10mg or 20mg twice daily in the
`this conclusion needs confirming in a prospective
`randomised trial.
`form of matching tablets by the hospital pharmacist
`using a computer-generated randomisation code.
`Recently a method for analysing concentrations
`Because the supply of matching 20mg tablets was
`of tamoxifen in serum has become available (Adam
`limited, only 4 months’ treatment was provided for
`et al,
`1980a). No correlation between serum
`each patient. After 4 months’ therapy the code for
`concentrations and clinical response was found in
`
`individual and_furtherpatients was broken
`
`
`39 patients but it was recommended that a further
`tamoxifen was prescribed using conventional sales
`study in a larger number of patients was required
`material (““Nolvadex”’ 10 mg).
`(Patterson et al., 1980).
`Generalclinical status, side effects and soft tissue
`The purpose of this trial was to compare tumour
`disease were evaluated monthly for
`the first 4
`response rate and duration between the two most
`months. Bone and lung lesions were
`assessed
`commonly used dosage regimens of tamoxifen, viz
`radiologically on entry and at 3 months. Hepatic
`t0mg bd and 20mgbd,and to attempt to correlate
`involvement was judged clinically by measuring
`clinical response with serum tamoxifen level
`in a
`liver size below the costal margin. Tumour response
`large numberofpatients.
`
`to therapy was assessed according to the U.LC.C.
`criteria (Hayward ef al., 1977, 1978). Briefly,
`the
`four response categories were defined as follows:
`
`*“Nolvadex” is a Trade Mark, the property of Imperial
`Chemica! Industries PLC.
`Correspondence: D.G. Bratherton.
`Received 24 April 1984; accepted 22 May 1984.
`
`all
`(CR) disappearance of
`response
`Complete
`knownlesions, determined by two observations not
`
`© The Macmillan Press Ltd., 1984
`
`AstraZeneca Exhibit 2050 p. 1
`InnoPharma Licensing LLC v. AstraZeneca AB IPR2017-00904
`Fresenius-Kabi USA LLC v. AstraZeneca AB IPR2017-01910
`
`

`

`200
`
`D.G. BRATHERTONet ai.
`
`less than 4 weeks apart. In the case of lytic bone
`metastases,
`these must be shown radiologically to
`have calcified.
`
`disclosed to the
`complete.
`
`clinician until
`
`the
`
`trial was
`
`response (PR) Firty percent decrease in
`Partial
`measurable lesions and objective improvement
`in
`evaluable bur non-measurable lesions, determined
`by two observations not less than 4 weeks apart.
`No new lesions should have appeared. It
`is not
`necessary for every lesion to have regressed to
`qualify for partial response, but no lesion should
`have progressed.
`
`lesions unchanged (i.e. 50%
`(NC)
`change
`No
`decrease or 25% increase in the size of measurable
`lesions).
`If non-measurable but evaluable lesions
`represent the bulk of disease and these clearly do
`not respond even though measurable lesions have
`improved, then this is considered as no change and
`not partial response.
`
`Results
`
`Of 263 patients recruited, 26 (15 on 10mg bd; 11 on
`20mg bd) were excluded from the analysis on the
`grounds of protocol
`ineligibility or inadequacy of
`data recording. A further 16 (11 on 10mgbd; 5 on
`20mgbd) were withdrawn from the trial within
`four weeks of starting treatment for the reasons
`shown in Table I and these were classified as
`treatmentfailures.
`Distribution of the 237 assessable patients by
`dose according to baseline characteristics is shown
`in Table II. The two groups were well matched
`except
`for
`a preponderance of bone-dominant
`disease (25 versus 14) and correspondingly fewer
`patients with soft tissue dominant disease (70 versus
`75) in the higher dose group. However the logistic
`regression method of analysis used takes
`into
`account
`any imbalance in prognostic variables
`(Armitage & Gehan, 1974). Most patients (96%)
`had not
`received any previous systemic additive
`treatmentfor their disease.
`With 237 evaluable patients there is an 80%
`chance of obtaining a statistically significant result
`at the 5% level (two-tailed) if the true difference in
`response rates wasat least 18% (30-48%).
`
`Table I Reasons for withdrawal from trial
`within 4 weeks
`
`No. ofpatients
`
`Death
`Withdrawndueto side
`effects
`Defaulted
`Rapid deterioration
`Other
`
`4
`
`1
`4
`1
`1
`11
`
`1
`
`1
`3
`_
`—_
`5
`
`percent
`(PD) Twenty-five
`disease
`Progressive
`increase in the size of any lesion or the appearance
`of new lesions.
`for any
`Patients withdrawing from the trial
`reason during the first 4 weeks were considered to
`be “treatmentfailures’.
`Initial
`response was assessed at 3 months and
`confirmed at 4 months. Tamoxifen treatment was
`continucd in patients achieving CR or PR or NC
`with stable/improving performance status at
`the
`discretion
`of
`the
`physician. Tamoxifen was
`discontinued after 3 months if patients showed PD
`or NC with deteriorating performance status and
`was also withdrawn at any time when rapid disease
`progression or intolerable side effects occurred.
`The duration of response was taken as the length
`l10mgbd=20mgbd
`of time between the start of tamoxifen therapy and
`documentation
`of
`progressive
`disease,
`the
`introduction of additional or alternative anticancer
`medication or the withdrawal of tamoxifen.
`Tumour response data were audited by exchange
`of record forms between the principal investigators
`of the two centres.
`The proportion of responders has been analysed
`using logistic regression. The terms fitted were dose,
`age,
`disease-free
`interval,
`presence/absence
`of
`primary tumour and dominantsite. Duration of
`response has been compared between the two dose
`groups using the logrank test (Peto etal., 1977).
`Where possible two 10ml samples of blood were
`taken from each patient at least one month apart
`between the 8th and 16th week of treatment by
`which time steady state kinetics were assumed to
`have been reached (Patterson et al/., 1980). Serum
`was
`analysed
`for
`tamoxifen
`and
`desmethyl
`metabolite
`concentrations
`using
`the method
`described by Adam et al. (19805). Results were not
`
`Tumour response rates
`(CR+PR) are
`Objective tumour
`response rates
`shown in Table III. Thirty-four percent (39/116) of
`patients in the 10mgbd group achieved more than
`50% tumour
`regression
`compared with
`31%
`(37/121)
`in
`the 20mgbd group.
`Inclusion of
`patients achieving disease stabilisation (NC) gives
`response rates of 50% (58/116) and 57% (69/121)
`respectively. None of these differencesis statistically
`significant.
`
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`
`

`

`TAMOXIFEN DOSAGEIN BREAST CANCER
`
`201
`
`Table II Patient demography
`
`Table IV Tumour response to tamoxifen by
`dominantsite regardless of dose
`
`Dose of tamoxifen
`— Dominantsite
`10mgbd
`20mgbd
`Tumour
`response
`
`Soft tissue
`
`Bone
`
`Visceral
`
`116
`
`121
`
`No. of patients
`2
`7
`8
`38
`PR
`Age (yt)
`8
`9
`34
`NC
`Mean
`%6
`18
`50
`PD
`Range
`8
`3
`3
`Failures
`Disease free interval:
`lyr 63—_—SS62
`
`
`1-5 yrs
`38
`40
`CR+PR
`58/145
`9/39
`9/51
`> Syrs
`15
`17
`(40.0%)
`(23.1%)
`(17.6%)
`Not documented
`1
`1 ——_—_—
`Previous treatment:
`None
`Surgery
`Radiotherapy
`Other
`
`69.3
`45-91
`
`67.4
`38-89
`
`41
`37
`56
`4
`
`42
`Table V Tumourresponse to tamoxifen
`69
`by primary tumourregardless of dose
`45
`5 $F
`
`54
`61
`1
`
`Primary tumour:
`Present
`Absent
`Not documented
`:
`:
`Dominantsite:
`70
`75
`Soft tissue
`25
`14
`Bone
`Visceral
`26
`25
`Not documented
`1
`1
`
`
`50
`70
`1
`
`Primary tumour
`Tumour TT
`response
`Present
`Absent
`
`CR
`PR
`NC
`PD
`Failures
`
`CR+PR
`
`2
`24
`28
`44
`6
`
`21
`29
`3
`50
`8
`
`26/104
`(25.0%)
`
`50/131
`(38.2%)
`
`Table IIT Tumour response to tamoxifen by dose level
`
`Tamoxifen
`
`Tumour response
`CR
`PR
`NC
`PD
`Failure
`
`10mgbd
`14
`25
`19
`47
`11
`
`20 mg bd
`9
`28
`32
`47
`5
`
`37/121 (30.6%)
`39/116 (33.6%)
`CR+PR
`
`CR+PR+NC
`58/116 (50.0%)
`69/121 (57.0%)
`
`.
`:
`.
`2
`With respect to prognostic variables, a significant
`correlation between both the dominant
`site of
`disease and presence/absence of primary tumour
`and tumour response to therapy was found. In the
`case of dominant site (Table IV), the response rate
`was significantly higher for soft
`tissue dominant
`disease than either bone dominant (P=0.037) or
`visceral dominant (P=0.003) disease. in the case of
`presence/absence of primary tumour
`(Table V),
`those patients with a primary tumourirrespective of
`other
`lesions
`showed a statistically significantly
`
`lower (P=0.035) response rate than those without a
`primary tumour.
`Response with respect
`to age and disease free
`interval (DFI) are shown in Tables VI and VII. The
`differences in response rates between the various
`strata
`did not
`achieve
`statistical
`significance,
`although
`some
`trend
`towards
`an_
`increasing
`response rate with age up to 80 years and length of
`DFIis evident.
`
`Table VI Tumour response to tamoxifen by age
`regardless of dose
`
`
`A
`ge range (years)
`>80
`60-69
`70-79
`jeapunne
`<60
`
`3
`CR
`4
`5
`11
`8
`PR
`8
`18
`19
`14
`NC
`8
`15
`14
`PD
`25
`35
`27
`7
`
`6
`2
`3
`2
`Failures
`CR+PR
`12/51
`23/75
`30/74
`11/34
`(23.5%) (32.4%) (30.7%) (40.5%)
`
`
`
`
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`
`

`

`202
`
`D.G. BRATHERTONetail.
`
`Table VII Tumour response by disease
`free interval regardless of dose
`
`Disease free interval (y)
`
`Tumour
`response
`<ly
`I-Sy
`>Sy
`
`
`progressive disease after 4 months on the lower
`dose became a complete responder when the dose
`was increased to 20 mg bd.
`
`Adverse reactions
`
`A total of 31 adverse effects were reported by 24
`(9%) of the patients entered but
`there was no
`consistent
`indication that
`these were dose-related
`(Table IX). Three patients (1%) were withdrawn
`due to treatment intolerance: paroxysmal nocturnal
`dyspnoea (1 patient at 20mg bd), vaginal discharge
`CR+PR 34/125=30/78 12/32
`
`(1 patient at 20mgbd), oedema (1 patient at
`(27.2%)
`(38.5%)
`(37.5%)
`10mgbd). Against
`the spontaneous background
`incidence of symptoms in women with advanced
`malignancy and in the absence of a control group
`however,
`it
`is
`impossible
`to
`ascertain what
`proportion of these symptoms wasdefinitely drug-
`related.
`
`CR
`PR
`NC
`PD
`Failures
`
`4
`30
`33
`52
`6
`
`13
`17
`10
`32
`6
`
`6
`6
`8
`10
`2
`
`Duration of response
`
`The median durations of objective response for the
`10mgbd and 20mgbd groups were 18 and 12
`months
`respectively.
`This
`difference
`is
`not
`statistically significant (P<0.10). At the time when
`data was
`analysed 20 patients
`(51%)
`in the
`10mgbd and 14 (38%) in the 20mgbd group were
`still in remission.
`Both groups of patients were
`followed up
`Side effect 10mgbd=20mgbd
`identically,
`to either the date of withdrawal from
`the trial or if response was continuing, to the date
`of analysis. In both groups, the median duration of
`follow-up was 4 months.
`
`
`
`Improvement of response category after the trial
`Although tumour response to treatment was only
`assessed double-blind for four months and response
`rates quoted above refer to the situation during
`that period,
`10 patients
`subsequently
`showed
`improvement in response category and the majority
`of these eventually achieved complete remission of
`their
`disease
`(Table VIID. One patient with
`
`Improval of tumour response category
`Table VIII
`after the initial four month treatment period
`Initial
`classification
`Best
`
`Dosage group
`(4 month)
`response
`
`10mg bd
`
`PD* — CR
`NC — PR
`PR — CR
`PR — CR
`PD — PR
`PR — CR
`PR — CR
`NC
`—>
`PR
`NC
`—_—
`CR
`20 mg bd
`PR — CReee
`
`*Dose changed to 20 mg bd.
`
`Table IX Side effects associated with tamoxifen
`therapy
`
`Numberofpatients
`
`Nausea
`Vomiting
`Hotflushes
`Vaginal discharge
`Vaginal bleeding
`Pruritis
`Cardiac failure
`Dyspnoea
`Anorexia
`Abdominal pain
`Constipation/diarrhoea
`Dysphagia
`Tiredness
`Depression
`Vertigo
`Bone pain
`
`
`
`SrOCONOGOPNOORHKKew
`
`RSOrBREOHRaneHKVPHOw
`
`Total
`
`_ nN
`
`— oO
`
`Serum tamoxifen analysis
`Serum samples for drug analysis were obtained
`from 152 subjects (64% of evaluable cases). In 59
`patients only a single sample was available. In the
`remaining 93 cases the mean value of the two
`determinations was
`used. Concentrations
`of
`tamoxifen and desmethyltamoxifen were within
`20% of each other
`in
`60
`and 58
`instances
`respectively
`and
`in
`45
`instances
`for
`both
`compounds. Hence in this subgroup steady state
`kinetics were
`unequivocally
`demonstrated
`but
`attempts
`to correlate
`the
`steady state
`serum
`
`AstraZeneca Exhibit 2050 p. 4
`
`

`

`TAMOXIFEN DOSAGE IN BREAST CANCER
`
`203
`
`°.
`
`e ee
`
`ee
`
`se°°
`
`&..
`Ste
`$3e
`
`ee
`3
`°°
`3
`f
`i
`e
`°
`
`3
`:
`.
`
`°
`:
`
`.
`
`.
`.
`°
`e
`*
`:
`i
`°°
`:
`e
`*e
`#
`093°
`.
`i
`e,%,
`
`3 oe
`3°
`;
`
`were
`results
`clinical
`with
`concentrations
`unsuccessful. The ratio of metabolite to parent
`compound was reasonably constant
`thus allowing
`the ratio to be used as an indication of patient
`compliance; poor compliance would result in higher
`metabolite concentrations because of the longer half
`life of the latter compound leading to an increased
`metabolite/parent compoundratio.
`Table X showsthe results of analysis of variance
`of serum concentrations allowing for dose and
`response (CR+PR) and the interaction between
`these
`parameters. There were
`no
`significant
`differences between responders and non-responders
`either within a dose group or on combining dose
`groups. The mean
`serum concentrations
`of
`159ngml~' and 273ngml~! for 10 and 20mgbd
`respectively were markedly different
`(P<0.0001).
`Figure
`1
`shows
`the
`scattergram of
`serum
`concentrations of
`tamoxifen in the
`two dose
`groups.
`In the group in which steady state kinetics were
`proven, the mean ratio of metabolite to unchanged
`drug concentration was 1.79+0.01 (n=25) for the
`10mgbd group and 1.87+0.08 (n=20)
`for
`the
`20mg bd dose group. These were not significantly
`different. This suggests there was no difference in
`compliance between the two groupsofpatients.
`
`all
`for
`Table X Serum tamoxifen concentrations
`patients
`
`4
`
`500
`
`400/-
`
`
`
`=
`
`2 300+
`c
`2
`pans
`3
`5
`8
`§
`s 200
`3
`E
`o
`Ee
`
`Dose of tamoxifen
`
`100
`
`10mgbd 20mgbd Overall Response
`
`Responders Mean
`8.€.
`n
`
`158.6
`11.1
`36
`
`289.6
`20.2
`28
`
`224,1°
`11.4
`64
`
`
`Non-responders Mean_160.0 256.8 208.4?
`
`
`s.e.
`11.3
`15.7
`9.6
`n
`41
`47
`88
`20 mg b.d.
`10 mg b.d.
`Nolvadex dose
`
`273.28
`159.3"
`Overall® Mean
`10.8
`10.3
`$e.
`
`
`77n 75
`
`*These means have been adjusted to allow for the
`unequal numbersin thecells.
`*Overall difference between dose levels significant
`(P <0.0001).
`*Overall difference between responders and non-
`responders notsignificant (P > 0.05).
`
`Discussion
`
`involving 237 evaluable
`The results of this trial
`postmenopausal patients with advanced breast
`cancer have failed to detect a significant therapeutic
`
`Figure 1
`
`tamoxifen dose of 20mgbd
`a
`advantage for
`compared with !0mgbd.
`In a previous smaller
`comparison between 20 and 40mg daily (Ortiz de
`Taranco ef al., 1979),
`the objective response rates
`were
`also not
`significantly different. However,
`consideration of the NC group brought the total
`response rates (CR+PR+NC) to 51% for 20mg
`daily and 79% for 40mg daily thus demonstrating
`a statistically significant advantage for the higher
`dose. The corresponding overall response rates in
`our trial were 50% and 57% which concurs with
`
`AstraZeneca Exhibit 2050 p. 5
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`€
`

`

`204
`
`D.G. BRATHERTONetal.
`
`this previous finding although our beneficial trend
`was not marked.
`Inclusion of patients obtaining
`disease stabilisation should be considered to be
`worthwhile, however, because survival in this group
`of patients may be as long as in those experiencing
`partial tumour remissions (Henningsen & Amerger,
`1977; Cavalli et al., 1983).
`Premenopausal patients were excluded from this
`trial. The efficacy of doses as low as 10mgbd in
`such patients has been questioned on the grounds
`that this dose may not completely antagonise their
`high endogenous levels of oestrogens (Manni &
`Pearson, 1980; Santen et al., 1981). The results of
`this study should not therefore be extrapolated to
`the premenopausal age group. This study also does
`not exclude the possibility of a response to higher
`doses after failure at lower doses; 23% (7/30) of
`patients with documented progressive disease on
`20mg
`tamoxifen
`daily
`have
`previously
`been
`reported to have achieved disease stabilisation for
`up to 15 months when the dose was increased to
`40mg daily although no objective responses were
`observed (Stewart er al.,
`1982). We have now
`described one complete remission in a patient given
`20 mg bd when previously unresponsive to 10mg bd.
`However, one patient with progressive disease
`developed a partial
`response with no change in
`therapy.
`the overall response rate,
`It
`is interesting that
`side effect profile and prognostic trends emerging
`from the trial
`(ie. correlation of
`response to
`dominant site, age, disease free interval etc.) are
`similar to those reported in reviews of published
`clinical
`trials (Mouridsen et al., 1978; Patterson,
`1981)
`suggesting that our patient
`sample was
`representative of the population normally treated.
`The lower response rate in patients with primary
`tumours,
`irrespective of dose,
`is probably a
`function of the size of the lesion (5cm by definition
`of “inoperable”), making the criterion for partial
`response (more than 50% decrease in the product
`of perpendicular diameters) more
`difficult
`to
`achieve because of the increased tumour burden.
`This is supported by the fact that addition of the
`NC category obliterates the significant difference in
`response
`rates
`for patients with and without
`primary tumour (52% and 56% respectively).
`
`References
`
`(1980a).
`ADAM, H.K., GAY, M.A. & MOORE, R.H.
`Measurement of Tamoxifen in serum by thin-layer
`densitometry. J. Endocrinol., 84, 35.
`(19805).
`J.V.
`ADAM, H.K., PATTERSON,
`J.S. & KEMP,
`Studies on the metabolism and pharmacokinetics of
`tamoxifen in normal volunteers. Cancer Treat. Rep.,
`64, 761.
`
`than 4
`Some patients clearly required longer
`months to achieve an optimal therapeutic response.
`Indeed,
`two patients who had actually been
`classified as having progressive disease at 4 months
`subsequently responded (one CR and one PR). This
`observation has previously been reported by Glick
`et al.
`(1980) who recommended that
`tamoxifen
`should not be discontinued unless progressive
`disease is documented or significant symptomatic
`deterioration occurs.
`serum
`the
`patients
`of
`In
`both
`groups
`concentration of tamoxifen varied widely. This
`probably
`results
`from a
`combination
`of
`a
`population spread
`in
`half-life
`and
`presumed
`invariable, but unknown degrees of incomplete
`compliance. However,
`the spread was similar
`in
`both groups and the mean serum concentration in
`the 20mgbd group was approximately double that
`for the lower dose. Despite this difference in serum
`concentrations, there was no identifiable difference
`in clinical response. One possible explanation might
`be that
`the circulating tamoxifen levels may not
`necessarily reflect cytoplasmic concentrations
`in
`target cells, particularly in tumours with abnormal
`vasculature. Furthermore, oestrogen receptor status,
`which may be an important factor in determining
`response to endocrine therapy, was not measured in
`patients in this study and hence receptor imbalance
`. between the patient groups cannot be excluded.
`In conclusion, tamoxifen has been confirmed to
`be a safe and effective therapy for postmenopausal
`women with advanced breast cancer,
`the mean
`objective response rate being 32% with less than
`1% of patients stopping treatment because of side
`effects. However,
`no
`statistically
`significant
`advantage for 40mg daily over 20mg daily has
`been found, neither was there any evidence of a
`correlation between tumour response and serum
`tamoxifen level.
`
`to H.K. Adam and J.V. Kemp for
`We are grateful
`analysing serum samples and S.H. Ellis for performing the
`statistical analyses. The advice of L. Battersby and H. de
`Haan was much appreciated. Weare also grateful to Mrs
`P.C. Williams and Mrs I.K. Bell
`for supervising the
`accurate collection ofclinical data.
`
`(1983).
`CAVALLI, F., BEER, M., MARTZ, G. & 5 others.
`Concurrent
`or
`sequential
`use
`of
`cytotoxic
`chemotherapy and hormone treatment
`in advanced
`breast cancer. Br. Med. J., 286, 5.
`
`AstraZeneca Exhibit 2050 p. 6
`
`

`

`TAMOXIFEN DOSAGEIN BREAST CANCER
`
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`(1980). Tamoxifen plus sequential CMF chemotherapy
`anti-cancer
`agent
`in
`humans.
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`versus tamoxifen alone in postmenopausal patients
`Antioestrogens.
`(Eds. Sutherland & Jordan), Sydney:
`with advanced breast cancer:
`a
`randomised trial.
`Academic Press, p. 453.
`PATTERSON,J.S., SETTATREE, R.S., ADAM, H.K. & KEMP,
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`HAYWARD,
`J.L., CARBONE, P.P., HEUSON,
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`PETO, R., PIKE, M.C., ARMITAGE, P. & 7 others. (1977).
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`B. & AMBERGER, H.
`(1977).
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`A.
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`(1980). Antioestrogen-
`MANNI, A. & PEARSON, O.H.
`disease progression during tamoxifen therapy at a dose
`induced remissions
`in premenopausal women with
`stage IV breast cancer: Effects on ovarian function.
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`ORTIZ DE TARANCO, A.V., DONNAY CANDIL, O. &
`BAENA HERRERA,L. (1979). Treatment of Stage IV
`breast cancer with antioestrogens (nolvadex)
`in 78
`postmenopausal patients. Oncologia 80,8.
`
`AstraZeneca Exhibit 2050 p. 7
`
`