Breast cancer Session 1
`
`288
`
`AND
`HORMONO-
`SEQUENTIAL
`OR
`CONCURRENT
`CHEMOTHERAPY IN ADVANCED BREAST CANCER: LONG TERM
`SURVIVAL ANALYSIS OF A RANDOMIZED TRIAL
`
`F Cavalli‘, A. Goidhirsch‘, S. Pampallonaz, M. Ghielminili3
`‘ DiVision of Oncology, Ospedale San Giovanni, BelEnzona, Switzerland
`2 SAKK Coordinating Centre, Bern. Swrtzeriand
`3 Medizinische Klinik, lnselspital, Bern, Switzerland
`
`From 1975 to 1980, 466 patients Wllh advanced breast cancer were entered a
`tnal designed to compare concurrent versus
`sequential hormone and
`chemotherapy After
`randomization, patients
`received hormonal
`treatment
`(oophorectomy for premenopausal and Tamoxifen for postmenopausal women)
`and a chemotherapy either at the same time (arm A concurrent) or at the
`moment of hormonal treatment failure (mm B: sequential). At randomization
`patients were also a55igned to one of three different chemotherapy regimens
`representing minimal
`(only
`oral),
`convemional
`or
`intensive
`(including
`Arithracyclines) cytotoxic treatmem A first analysis reported a tendency of dung
`better for premenopausal women treated conwrrently and postmenopausal
`patients treated sequentially (BMJ 286: 5-8, 1983).
`The final analy5is, at more than 12 years median follow-up, demonstrates no
`difference in survrval between patients in arm A and B (136 % at 5 years,
`median 23 months). For each treatment arm no significant SUI'VNal driterence is
`seen between the three chemotherapy schedules. Mapr predictors of survrval ‘n
`the multivariate regression analysis are performance status, the presence of
`metastasis in the liver and the risk category (high vs.
`low, detennined
`prospectively according to extension of
`tumor and free
`interval
`since
`mastectomy). Menopausal status does not influence survival.
`We conclude that the timing of chemotherapy (immediately or at the moment of
`hormonal treatment
`failure) does not
`influence the survival of women with
`umreated advanced breast cancer. Reasons for the different outcome of the
`preliminary results as compared wnh the final analysis will be discussed.
`
`289
`
`Phase 1 study of a new oral aromatase
`lnhlbltor:CGS
`20267
`lveson TJ,"2 Smith iE,1 Ahem J,‘ Smithers DA? Trunet P,3
`Dowsett M?
`Dept of Medicine‘ and Academic Biochemistry? Royal Marsden
`Hospital, London. Ciba-Geigy Basel, Switzerland?
`An open between patient phase 1 study of CGS 20267 a non-
`steroidal aromatase inhibitor comparing 0.1, 0.5 & 2.5 mg po Od
`has been performed in 3 successive groups of 7 postmenopausal
`patients wrth metastatic breast cancer (total = 21). No toxicity was
`seen at any of the three doses. Endocrine data are available on
`all 21 patients. There was a statistically significant suppression of
`oestrone (E1) and oestradiol
`(E2)
`levels
`in all patients
`(p<0.0001). E2 and E1 fell from mean pre-treatment levels of
`22pM and 69pM to below the detection limits of the assays (3pM
`and 10pM) in 8 and 16 patients respectively. There was a trend
`towards more efticient E1 suppression With the higher doses.
`CGS 20267 had no significant effect on follicle stimulating
`hormone,
`luteinising hormone,
`thyroid stimulating hormone,
`cortisol, aldosterone, 17-hydroxyprogesterone, or androstene-
`dione. So far of 21 assessable patients 6 have responded to
`treatment (1 CR and 5 PR according to UICC criteria) giving an
`overall response rate Of 28.6% (95% CI 11.3-52.2%) in addition a
`further 6 have had stable disease for greater than 3 months.
`These results suggest that CGS 20267 is a very potent and
`specific oral aromatase inhibitor and phase II studies are now
`required to determine its clinical efficacy.
`
`290
`
`SEQUENTIAL ESTROGEN RECEPTOR DETERMINATIONS FROM
`PRIMARY BREAST CANCER AND AT RELAPSE: PROGNOSTIC
`AND THERAPEUTIC RELEVANCE
`v, Spataro‘, A. Goidhirschl. F. Cavalli‘, M. Cast'iglionez and R D. Gamera
`‘ Division of Oncology, Ospedale San Giovanni, Bellinzona, Switzerland
`2 institute of Medical Oncology, Inselspital. Unrversrty of Bern, Bern, Swrtzeriand
`3 Harvard Medical School, Harvard School of Public Health, Boston, MA, USA
`For the intemationai Breast Cancer Study Group (formerly Ludwig Group)
`
`We retrospectively evaluated 401 patients who had estrogen receptor (ER)
`assays both at primary surgery and at relapse. The median time between ER
`assessments was 27 months (range' 212 months). The median follow—up time
`from diagnosrs was 6 years (range. 2—1 2 years). For patients with ER+ tumors at
`primary diagnosis. 29% (767261) had EFl- tumors at relapse, while for ER-
`prtrnan'es. the conversion rate was 33% (46/140). Conversions from EFl+ to ER—
`occurred more often when the time interval between assays was less than one
`year (p - 0.004), while conversions from ER- to ER+ tended to occur late
`(beyond 3 years; p - 0 0003). Treatments received between assays (usually
`adjuvant therapy) had only a slight Influence on ER status conversion. Post-
`relapse survrval was poor for patients who md the biopsy accessflile recurrence
`within one year. Among patients whose accessible relapse was beyond one
`year, those wrth ER- primaries who convened to ER+ had a longer survival than
`those whose recurrence was classified again as ER- (p - 0.006). This group of
`patients with ER- primaries who recurred beyond one year with and ER+ tumor
`in an accessbie site represented 29% (40/140) of all patients with ER-
`pnmaries, and had an estimated overall survival rate of more than 60% at 6
`years from theaccessbie relapse.
`We conclude that reassessrnent of ER status upon relapse is of little clinical
`value for patients who recur within one year, but is important for patients who
`recur later especially for those with EFi- primaries.
`
`291
`
`SECOND LIN E ENDOCRINE TREATMENT OF ADVANCED
`BREAST CANCER - A RANDOMJSED CROSS-OVER
`STUDY OF MEDROXYPROGFSTERONE ACETATE AND
`AMINOGLUTE’I‘HIMIDE
`R Hultbom, I Terje, E Holmberg, U-B Wallgren, J Ranstam, J Bergh, U
`01215, L Hallsten, T Hatschek, K Idestrdm, B Nordberg, M Soderberg
`Depts of Oncology, Gothenburg, Lund, Uppsala, Stockholm, Malmd.
`Linkdping, Umca and Karlstad, Sweden
`
`Females with advanced breast cancer, progressing after an initial response
`to tamoxifen frequently respond upon further endocrine treatment.
`Presently progestins and aromatase inhibitors are used for such therapy.
`Which is most effective and least toxic has been investigated by randomis-
`ing 200 patients in a prospective study where half were first given
`modroxyprogestcrone acetate (Farlutal®), the other half aminoglutethimidc
`(Orimetenc®). Upon progression patients crossed over to the other drug.
`The main issue was which sequence resulted in the longest total period of
`time with tumor control and best quality of life.
`Mm; Patients progressing on tamoxifen were randomised to (MPA) T.
`Farlutal 500 mg bid. and upon failure to (AG+C) T. Orimctcne 250 mg
`bid. and cortisone acetate 37.5 mg daily or the reversed sequence. Accrual
`of
`tients were made at 13 hospitals in Sweden May 1986 through January
`19$. Follow-up with objective response classification according to UICC
`and quality of life estimate according to Nottingham Health Profile (NHP)
`were made every three months for up to 18 months.
`Emits; Median duration in the sequence AG+C-v MPA was 11.7
`months, while time in the sequence MPA -' AG+C was 9.8 months, not
`significantly different. No difference in median survival (21 months) were
`seen. NHP estimate disclosed a wellbcing at least as good for AG+C as for
`MPA reflecting pain relief, physical mobility and capability of household
`work Side effects were unexpectedly small for AG+C.
`mm Significant differences concerning efficacy and quality of life
`was not found. Toxicity profiles were different but acceptable for both regi-
`anS.
`
`Annals of Oncology 3 (Suppl. 5): 1992.
`© 1992 Kluwer Academic Publishers. Primed in the Netherlands.
`
`75
`
`AstraZeneca Exhibit 2143 p. 1
`InnoPharma Licensing LLC V. AstraZeneca AB IPR2017-00900
`Fresenius-Kabi USA LLC V. AstraZeneca AB IPR2017-01913
`
`

`

`76 Breast cancer Session I
`
`292
`
`LOW DOSE AMINOGLUTETHIMIDE WITHOUT HYDROCOR—
`TiSONE AS SECOND-LINE TREATMENT IN ADVANCED
`BREAST CANCER.
`A.Farris, G.Sanna, G.Sarobba, V.Mllia, B.Massidda*.
`Chair of Clinical Oncology, University of Sassari and 1"‘Cagliari.
`
`53 postmenopausal pts (in age > 70 years) with metastatic
`breast cancer were submited to second—line treatment with
`aminoglutethimide
`at
`dose
`of
`250 mgs/day without
`hydrocortisone. All patients were previously treated with
`tamoxifene.
`Prior treatment with tamoxifene showed objective responses
`in 63% of patients.
`by
`remission
`oblective
`had
`(30.2%)
`16/53
`patients
`(2 complete and H1 partial),
`aminoglutethimide treatment
`10/53
`(26.11%)
`a
`stable disease
`and
`23/53 (43.4%)
`a
`progression .
`(87.5%) had osseous or soft
`0f 16 responder patients 111
`(75.0%)
`positive
`hormonal
`tissue metastases
`and
`12
`receptors in the primary breast tumor.
`Time to progression was 187 +/— 58 days in the group of
`patients with remission and 135 +/— 114 days In that with
`stable disease. All patients responders to aminoglutethimide
`responded to first line therapy with tamoxifene.
`in
`and,
`No
`significant
`side-effects were
`observed
`particular, plasma cortisol
`levels were unchanged during
`the treatment.
`In conclusion,
`low doses aminoglutethlmide
`without hydrocortisone replacement
`is effective, without
`toxicity, as second line in advanced breast cancer.
`
`294
`
`FADROZOLE HYDROCHLORIDE (CGS 16 949 A), A DOUBLE-
`BLIND DOSE—FINDING STUDY IN POSTMENOPAUSAL PATIENTS
`WITH ADVANCED BREAST CANCER.
`
`K. Hoffken. Essen, Germany, Fl Chacon, P. Dombernowsky, P. Goes.
`P. Wllemee. T. Engan, J. Bonte, M. Tublana-Hulln, J.J. Lopez- Ldpez,
`I. Elomaa. H. Cheudrl, P. Trunet
`for the AVBCZ INTERNATIONAL STUDY GROUP
`
`To daterrrine the optimal dafly dose of fadrozole, a new potent oral nonstaroldal
`sromatase Inhibitor, a mullcentre, randomised. downs-bind, dose-hiding study was
`performed In poesnenopausal patients with advanced breast cancer after failure of
`tamoxifen. ThedaeestestedwereO51and2mgtwicedaiiy. UlCCcriterlawere used
`toaeseestumourreeponse.
`'I'hestud'ywasepprovedbylocelEthbalConmitteee and
`lnlotmed Consent was obtahed from all patients (pts). Records of pts with CR, PR or
`NO were peer reviewed.
`From June '88 to Jan.
`'90, 423 pts were enrolled In 49
`centres, h Argentina, Belgium, Canada, Denmark, Finland, France, Gemiany,
`Netherlands, Norway and Spain. Patient characteristics (intent-to—treat) were: nedlan
`apeBSyrs,PSO:159pts,1:165pts,2:95pts,3:2pts;mediantimesh1ce
`menopause: 14yrs; median DFI: 26 mths. Receptor status was posllve in 56% of pie,
`unimown h 43.3%, negative in 0.7%. Ninety-five percent of pts had had treatment with
`tamidenfaadvanceddseaeeand4.7%mdhsdprogresslonddseaseunder
`adiwam tamoxien. Shay-six pts (15.8%) had had additional treatment for advanced
`disease. Seventy~three pts were not evaluable (or tumour response because of non-
`evaiuablafmeaaumble lesions (16).
`lack of documentation (37). stopping treatment
`before assessment
`(17) or concomitant anti-cancer therapy (3).
`The oblective
`response rate (CR+PR) of the remaining 350 pts was: 17.5% for 1rng/d (95% CI: 10.9 -
`24.1%), 13.2% for Zing/d (11 - 25.4%) and 13.1% for 4mg/d (6.9 - 19.3%)(NS). NC
`was 333%, 30% and28.3%, and PD was 49.2%, 51.8% and 60.5% Ior 1, 2 and 4mg
`daily. The median overall duration of obiectlve response was 15.4, 10 and 15.4 mtha
`(NS) and TI'F was 5, 5 end 34 mths, respectively (pu0.04). The rmh adverse events
`reported, hdependent oi causal relatiomhlp. were (Intem-to-treat) nauseaNomltlng:
`11.3% 0! pts, hot flushes 5.4%. fatigue 4.5%, dyspnea 31%, dyspepsia 3.1%,
`diarri'unea 3.1%, comdpatlon 2.8%, headache 2.4%, skin rash 1.9%, anorexia 1.7%,
`dlzfiness 1.7%, hyperhldroeis 1.7%, coughing 1.7%, vertigo 12%, log crarrps 12%,
`lethargy 1%.
`In conclusim, the overall objective response rate was 16.1% (122-2096)
`with no difference between dam, and Iadrozole appeared wel tolerated
`
`Annals of Oncology 3 (Suppl. 5): 1992.
`© 1992 Kluwer Academic Publishers. Printed in the Netherlands.
`
`II
`
`293
`
`SOMAI‘ULIHE PLUS IAHJXIFEN IN POST ENOPAUSAL BREAST CANCER PATIENTS.
`D. Cannsta,
`F. Boccardo, L. Csnobbio, F. Penss, D. Amoroao. Dept.
`Medical Oncology 2, Nat. Institute Cancer Research, Genoa, Italy.
`Thirty previously untreated post. menopausal breast cancer peCLEnts (pee) were
`given
`Tamoxifen
`(10 mg t.i.d.) and a long acting Somatoatstine
`analogue
`(Somatuline,
`Ipsen) 20 mg s.c. weekly for almost six months or until disease
`progression. Main pts characteristics were: median age 77.5 yrs, range:
`(68-
`83), median initial H'HO PS 0(0-1) and median DFI 13 yrs (0-15). Disease sites
`were skin:
`9 pts,
`nodes:
`3 pts,
`bone:
`7 pt 1, breast: 1.3 pt, pleura: 1 pt,
`lung
`3 pta. All pts were evaluable for toxicity and
`for
`response
`(UICC
`criteria). Median duration of treatment was 6.5 months
`(2-32).
`Objective
`response rate was 36* (3 RC and 9 RP); median response duration was 1.3 months
`(9-32). Treatment was well tolerated; without:
`inducing major effects. The
`behaviour of serum CH and IGF-1 levels during treatment is shown below.
`
`SERUM CH AND IGF-l LEVELS (ii-7 PIS)
`Time 0
`IA days
`
`1 month
`
`3 months
`
`6 months
`
`IGF-l 7o(51.8-113.L.) u9(45.2-53.2)
`GH
`0.61(0.1-5.83)
`o.2(o.2-3.7)
`
`39.2(37.B-72.8) A5.5(A2—119) A3.h(43.b)*
`0.6(0.2-6.8)
`1 2(o.1-9.1)
`h.b(0.l—16)
`
`Median value in ins/I11; *p<0.05 (Mann-Whitney U Test)
`
`a
`Overall
`in IGF-l levels was
`significant decrease
`produced
`by
`combined
`treatment,
`while an opposite trend was observed with respect: to GH levels.
`In
`addition Gil behaviour was extremely variable among pts and in the
`same pts
`following each Somstuline administration.
`Our preliminary findings
`suggest
`that
`the
`combination of Tamoxifen and Somstuline is a
`safe
`and effective
`which is able
`regimen
`for breast
`cancer pts,
`to achieve
`a
`significant
`reduction in circulating IG'F-l levels.
`
`295 ALTERATIONS IN PIASMA AND URINE ESTROGENS
`IN BREAST CANCER PATIENTS TREATED WITH
`AMINOGUJTEi'i-DWDE OR 4—HYDROXY-
`ANDROSI‘E‘IEDIONE.
`
`RE Leaningl, H. Adicrueutzz, D.C. Jotnmncascn', T. Fotsis2 sni D. Ekeel
`I Department ofOnooiogy, Haskeisnd University Hosp'asi. Bergen, Norway,
`ZWoraimalammMeamwnennaW
`
`(4—OHA,Lenaron)iltht
`'
`Auinogimethiuidc(AO)and4—hydmx
`twmhahifiaxumamuivdymcdformmdbmanm.
`Traccrotuiiulnveshowubuhdrugstoinhibitinvlwmisakmof
`W(A)hmcsuwc(El)by>m.Onlheuhertnnd.sevcmlsmfiu
`haven: Mmtobeminedatlcvdswmofufirmd
`vsilu bubrthisfindhgnnybeflctotecbnicaimflaflsorilmggcsu
`sitcrmfivocstmgenunocsisnahnwnToamdythis
`mmnnasurei
`mimesuogenmhoiiteexcretbnusingsspedfic
`-MSrmtindbcoupare
`ahamiominplssmandmimryeauogcnsinlnfimtsueatedmthAGorMHA.
`Themesnvaiuuoftualcamgem(taE).nnprminmycsuugcumhofiwsard
`phsnmestmgemdunngtreamuncxpreaacdas‘lzofthchmrolvalnuwue
`Phsrm
`Urine
`
`Treatman
`
`Ez
`
`E1
`
`515
`
`U E]
`
`E)
`
`E;
`
`E3
`
`lGOHE] ”H.541
`
`(11:7) 21% 36% 30%
`AG
`4OHA (11:9) 36% 30% 33%
`
`39% 36% 29% 52% 33%
`36% 32% 25% 75% 21%
`
`37%
`24%
`
`C(ndlnimKOmrcsuhsstnwanintcrmlmincncyhctwecntherdafive
`dehsnncstmgcnammsmedbyamwcbniqucundtherehfive
`summdmimryeumgcumbdilcsinlnicmauoatedwithAGmOHA.
`Tlrfmdingspwidcindimaupfimwthchymhahfluflmennybcaimhc
`estmgcuaotloesinpstiemsuuiodwithanmtmeinhjbim.
`
`_.._...-
`
`AstraZeneca Exhibit 2143 p. 2
`
`

`

`Breast cancer Session I
`
`77
`
`297 TAHOXIFEN AND INTERFERON BETA IN THE mamtmr or META-
`STATIC BREAST CANCER: A PHASE II STUDY.
`“L.Repatto,G.Gardin,E.Campora,c,uaso,s,Giudict’LHm-nni,
`P.Pronzato,P.F.Conte,P.G.Giannessi,P.Bruzzi,R.Rosso for the
`G.0.N.0. Coup. Istituto Nazionale per la Ricarca sul Cancro,
`V.1e Benedetto XV/lO 16132 Genova;Div. di Oncol. Hedica, 05p.
`S.Chiara,Pisa;Sarvizio di Oncol. Medina, 03p. S.Andraa,l.a Spezia
`In vitro studies indicate that Interferon (IFN) Beta has direct
`antiprolifarative activity and can determine an increase in ER
`content in breast cancer cell lines (Golstain, Cancer Rea.49,
`2698,1989).A phase II study was conducted in 26 metastatic brea-
`st cancer patients (pts) to evaluate the efficacy and ttoxicity
`of a combination of IFN Beta 6x10 IU im every 2 days for 2 weeks
`followed by Tamoxifen 20 mg/die plus IFN Beta 3x10 UI
`im every
`2 days untill progression. Patient characteristics were: medi-
`an age 60 (range 42-73); PS 0 (range 0-1); ER status: positive
`6 pts, unknown 20; prior adjuvant treatment 15 pts (chemotherapy
`13; Hormonotharapy 2); prior palliative chemotherapy 8 pta.
`Sites of metastases were: bone 8,
`soft tissue 10, viscera 2,
`bone-soft tissue 3, viscera-soft tissue 1, bone-viscera 1, bone-
`viacara-aoft tissue 1. One complete response and 5 partial res-
`ponse were observed (response rate 232), stable disease in A6.3z
`and progression in 30.72. Median duration of response was 3 mon-
`ths (range 1-7) and median time to progression was 2 months (ra-
`nge l-Z). Toxicities were mild: grade 1-2 fever plus grade 1-2
`fatigue in 13 pts, flu-like syndrome in 3 pts. The study is on-
`going and a randomized comparison with Tamoxifen is planned.
`
`296
`
`MODULATION OF ESTROGEN AND PROCESTERONE RECEPTORS
`BE§¥)RE AJID AFTER TTULAThflBWT “HTH BVTIHUHBRODLAquiA 2A
`GFN)HQPATH3§TSVVTTH BREASTCJUVCER
`Passalacqua R, Savoldi L., Mmli R., Manotti L. Guazzi A., Cocconl G.
`Medical Oncology Department, University Hospital of Panna. Italy.
`Whether interferons induce a positive or negative effect on the expression of
`hormonal receptors inbreastcancer isstill adebamdquestlon. Twelve breastcancer
`patients with local recurrence or accessible soft tissue metastasis. without any
`concurrent treatment, were included in our study. Using an immunocytochemical
`assay (ICA) with monoclonal antibodies to estrogen (ER) and progesterone (PgR)
`receptors,wehaveevaluatedhonnonereceptorsstamsonfineneedle aspiration
`performed before and after administration of IFN at the dose of 3.0 MU/IM, three
`times a week for two weeks.
`The aspirated cells were immediately suspended in a buffered saline solution.
`CficceflfugedontoglasssfidwandpromsedforlCAstainingawordingwdr
`Abbott ER-ICA and PgR-ICA kit Smears were randomly evaluated by two
`observers, without any information about patients and sample succession. Results of
`ICA were expremed as percentage of stained cells calculamd on a minimum 400
`cancer cells. A calculation of the mean percentages of positive cells before and alter
`IFN and a t-tcst for paired data were performed. The results are presented below:
`
`Before IFN
`mean +/- SE
`
`After IFN
`mean +/- SE
`
`p—value
`
`ER-ICA
`
`PgR~ICA
`
`72.4:l:8.9
`
`50.3:t12.9
`
`51.4i11.7
`
`48.6:t12.4
`
`0.05
`
`0.60
`
`The pemntage ofER-ICA positive cells decreases after IFN treatment and the value
`of the t-test is of borderline significance (P=0.05). The expression of PgR is not
`significantly influenced by the IFN administration
`Our results suggest that IFN-ALPHA 2A decreases the expression of ER in breast
`cancer patients. Whether this phcmmenon is the result ofa biologic modulation or
`not. will be further investigated.
`
`298
`
`CHANGES IN SERUM LIPIDS LEVEL AND LIPOPROTEIN
`PROFILE IN BREAST CANCER WOMEN TREATED WITH
`TAMOXIFEN.
`
`299
`
`DROLOXIFBlE, A NEW ANTIESTFIOGEN IN ADVANCED BREAST
`CANCER, A DOUBLE BLIND DOSE FINDING PHASE II TRIAL
`
`A.Dziewulska-Bokiniec, J.Hojtacki'
`University Medical School of Gdansk, Gdansk, Poland.
`Estrogens play a significant role in the regulation
`of lipid metabolism and have a protective function in
`coronary heart disease development.The aim of
`this
`study was
`to evaluate the influence of antiestrogen
`therapy with tamoxifen on lipid metabolism.
`The serum lipids: total, free cholesterol,HDL,LDL,
`triacyloglicerols and lipoprotein profile were esti—
`mated in a group of patients and in a control group.
`The former
`included 43 postmenopausal breast cancer
`women,the mean age 68,3 years,treated with tamoxifen
`from 6
`to 54 months.The control group comprised 43
`healthy women,the mean age 65,5 years.
`We observed statistically significant difference
`between patients'
`total cholesterol mean value 237,3
`mg/dl and control
`total cholesterol
`- 268,8 mg/dl
`(p<0,05) as well as LDL 156,0 mg/dl vs 190,4 mg/dl
`(p<0,05l,also LDL:HDL ratio 2,89 vs 3,53
`(p<0,05).
`Dysproteinenia was more frequent in the control group
`55,9% vs 37,23 (p(0,05).In neither group statistically
`significant difference was noticed in triacyloglice-
`role and HDL levels.
`Significant differences in serum lipids levels in
`breast cancer women show that tamoxifen therapy is a
`protective factor against coronary heart disease. We
`conclude that it is due to an estrogen-like activity
`of
`the drug.Tamoxifen is a mixed agonist/antagoniat
`drug.
`
`N. Vlfilldng, Oncologlc Contra, Karollnaka Hospital, Stockholm, for the DRL 002
`Inlamational Study Group
`
`Droloxilana (3—OH-tamoxifen) Is a new antiestrogen with intareatlng preclinical
`and clinical charactcrlsfics:
`- High affinity to estrogen-receptors (more than ten-fold higher than tamoxifen)
`- Higher amlcotrogen/estrogan ratio than tamoxifen
`- Lack of carcinogenicity ln animal models and In vitro testing
`
`‘
`
`achieves peak serum concantmtlons within hours
`and steady-state serum concentrations within days
`' cleared rapidly: serum allmlnation half life of less than 24 hours
`The objectrva of the study was to determine the optimal daily dose of droloxllana
`in the treatment of postmenopausal patients with advanced breast cancer.
`Between June 15, 1988 and March 31, 1991, 389 woman with horrnona receptor
`positive or unknown metastatic or locally unraaactable breast cancer were
`entered In 42 Canadian, Brazilian and European Centers Droloxifane was
`administered In a double-blind randomized daalgn with oral doses of either 20, 40
`or 100 mg once a day as first-line systemic therapy with the exception of
`adjuvant chemotherapy rt laminated at least one year before recruitment. An
`Interim analysis of the 331 patients included until Oct. 30, 1990 is presented The
`records of all patients were peer ravrewed at adjustifioation meetings. Twontylwo
`patients were inaligfiale because they had surgically operable breast canoar, 40
`patients were Ineligible because of violation at various allgblli‘ty criteria, while 20
`were lnevaluabla because of protocol violations. Fourteen patlents remained
`open. The overall response rate (CR + PR) was 23/74 (31 96) for 20 mg, 33/74
`(45 $6) for 40 mg and 38/83 (42 96) for 100 mg, Median time to disease
`prograsalonwas5+months (rangaotoa1 +), 8+ months (rangaot028+),and
`5 + months (range 0 to 28 +) for 20, 40 and 100 mg respectively. Toxicity was
`minimal at all doses and drolordfena appears to be well tolerated.
`
`Annals of Oncology 3 (Suppl. 5): 1992.
`© 1992 Kluwer Academic Publishers. Printed in the Netherlands.
`
`AstraZencca Exhibit 2143 p. 3
`
`

`

`78 Breast cancer Session I
`
`N.A.Malamus, Evangelia
`acostas.
`edicine Oncology Unit,
`
`300 TOXICITY OF LONG-TERM TREATMENT WITH TAMOXIFEN IN
`BREAST CANCER PATIENTS.
`S.F.Samelis, G.P.Stathopoulos
`Kondili N.P.Moscho oulos, P.Pa
`Universit
`of Athens
`2nd
`ivision of
`Hippokration Hospital Athens, Greece.
`ne-
`Toxicity of Tamoxifen is generally considered more or less
`gligible. This permits long-term administration of this drug,
`with positive effect in a good percentage of advanced breast
`cancer patietns as well as an adjuvant treatment of post—meno-
`pausal patients in particular.
`In the present study we reviewed
`the side effects of a longer than two years treatment of Tamo-
`xifen in breast cancer patients. 246 patients were reviewed.
`Their characteristics were: median age 54 (34-88), women 243 pa~
`tients, men 3, premenopausal 64, post menopausal 179. 216
`pa-
`tients got Tamoxifen as adjuvant and 30 as treatment of metasta-
`tic disease. The dose of Tamoxifen was 20-40 mgs per day and the
`duration was from 2 to 13 years with a median of 4 years.
`The
`follow-up of the patients was 2 to 19 years with a median of
`4.8 years. No patient ceased the treatment because of serious
`side effects. Several minor reactions were observed. The toxi-
`city was grouped as follow: Myelotoxicity: Anaemia,
`leukopenia,
`thrombocytopenia in total 17 patients (6.9%). Metabolic side
`a-
`effects: Hypercalcemia 8 patients (3.25%), Hypocalcemia 3
`tients (1.
`), serum cholesterol decrease in 5 patients (2%?
`and in 3 increase. Uric acid increase in 2 patients, blood urea
`and serum creatinine increase in 3 patients. Liver toxicity by
`increase of y-Glutamic transpeptidase in 3 patients. Face
`la-
`shing, headaches and skin rash in 18 patients (7 32%). Decrea-
`se 0
`sight (1 patient) decrease of nail growth (2 atients).
`One patient had metrorhagia, another 3 years after Tamoxifen
`presented with TBC lymphodenopathy, 7 patients (2.8%) presented
`second malignancy 2-8 years after they started treatmetn. Two
`ovarian cancers,
`1 endometrial,
`1 cervical,
`1 bladder and gas-
`tric, one carcinoma, and one lyngohoma.
`Conclusion: Tamoxifen long term treatment two-thirteen years
`is well
`tolerated.
`7 second malignancies that were observed in
`different sites can not be, necessarity attributed to Tamoxifen.
`
`301
`
`Prognostic value of positive Tamoxifen response in
`subsequent hormonal manipulation in patients with
`advanced breast cancer.
`
`0. Clinton, H. Earl, T. Latief, P. Wainwright, T.J.Priestman.
`CRC Trials Unit, Birmingham. UK.
`
`Twenty six patients with advanced breast cancer were started on
`Mcdroxyprogestcrone acetate (MPA). Group A included 14
`patients who were ER/PgR positive and Group B included 12
`patients- ER/PgR negative.
`Histological grades were
`comparable but only 21% of receptor positive patients while
`50% of receptor negative patients were Grade III.
`The pattern of metastatic disease,
`local recurrence/axillary
`nodes, metastatic nodes, bone metastases and soft tissue/visceral
`metastases were similar in both groups.
`Prior tamoxifen responses were not dissimilar, 78% in group A
`and 67% in group B but the average duration of response was
`25 months in group A and 12 months in group B.
`Positive MPA response was 50% in both groups but the average
`duration of response was 1 1 months in group A and 6 months in
`group B.
`In conclusion although the presence of hormone receptors in
`breast cancer patients is predictive for a positive tamoxifen
`response neither hormone receptor positivity or previous
`positive tamoxifen response is predictive for subsequent
`response to MPA. The duration of response to both tamoxifen
`and MPA is significantly longer in those patients with ER and
`PgR receptors.
`
`302
`
`one moxie-rm We: (Doonpeptyln) as A
`”new use exoocnme marma- IN
`PRENENOPAUBAL mono Banner canon
`mums
`
`z.Neékovié-Konstatinovié, L.Vuletié,
`Lj.Nikolié, S.§u§njar, S.Jelié,
`S.Radulovié, H.3rankovié
`immute of analogy end Idiology, Belgrede, “noel-vie
`
`of
`treec-nt
`the
`in
`been unloved
`Endocrine miwletion have
`15401. Twelve
`rete of
`netutetic breeet cercinlm with reepor—e
`ml petimtflptl) with m breeet cuter were uttered
`into pilot we“ ii trlel to man efficacy, toxicity end influence on
`the pte hml etetue
`of
`eynthetic ail melt-town D-‘I’rpé-Grmi
`(Decepeptyl). The pte, eyed from 33-50 yre, with newly dimmed etege
`Iv breeet career (3 pt.) or with recurrent dieeeee (9 on), were not
`previously treetod by my kind of harm-l them.
`lteroid receptor
`etetu
`(El
`led Pl)
`Ins Imam in 9/12 pte. Decepeptyl m ensued
`unthly et e deuce of 3.75 In La. mtil progrmicn. ten- Lll,
`rsu
`end eetrediol
`levele were deter-ined prior
`eeoh echlnietretion of
`WI. The therapeutic responee In mlmtod in 11/12 pte. Five
`pte achieved pertiel
`r-iuione leetim 73,90,643“,
`3 pte showed
`etebiliutian of
`their dieeeee end 3 pte M progressive dieeeee.
`dejective renieeion nae em in 3H pte with pletkowlml, no in 5/6
`pa with soft
`tissue involv-ent, mile the optinl
`reeporwe of bt'l'I
`-toetuu wee etdailiutiom‘lo pte).The beet the-mic response
`wee
`found in pte eyed fro- ki-LS yre, evm in pte with immlete
`overien with end regerdleu of eteroid receptor etetue. The
`significant upon-union of ween un- LII
`end eetrediol
`levele,
`and
`pertiel mien of -n FSI
`levele, were fella-ted by wrhoee in
`ell
`treated pte. The Uterus-y wee free of my aide effect, except hot
`filth-d in 7 pte. The mdeet elde effects of
`this treatment
`locality
`nku Decqteptyl ettrectlve elternetive to oofluorectcny in treetim
`ml at with mantis breeet tuner.
`
`TREATMENT OF THE ADVANCED BREAST CANCER IN PREHENUPAU—
`303
`SAL WOMEN WITH LHRH AGDNISTS AND HEGESTROL ACETATE
`
`Lopez Clemente P.H., Gonzalez Lerriba J.L., Alonso H.C
`Cesado A., Dominguez S., Adrover E., Velverde J.J.,
`Ldpez
`
`Martin J.A., Rodriguez Lescure A., and Diez—Rubio E.
`We have treated thirty premenopeusel women with advanced
`low rlsk breast cancer
`(bone metastasesz20 pts., ekins8 pts.,
`nodes:8 pts. and lung-pleural 3 pts) with an hormonal associa-
`tion of Leuprolide Acetate and Hegestrol Acetate continously.
`Patiens characteristics: median age 40,5 y(33-49).Initlel
`cliniEra—l—stagezulv-Z,
`IIA S,‘ HE S,
`IIIA 7, IIIB 3,1v 6. Pre—
`vious treatment: none 2, surgery 5, surgery+radiotherepy 2,
`surgery+chemotherepy 16, chemotherepy+surgery+rediotherepy 3,
`eurgery+rediotherepy+hormonotherapy 2. Hormonal receptors :
`negatives 7 pts., positives 3pts., unknows 20 pts.. Relapse
`free survival median: 10,5 m(O—SO).
`Results: overall objetive response 9/30(30%),complet res—
`ponstfif7fC§T3%), partial responses 8/30(26.6%); etabilitetion
`14/30(46.6%) with subjetive response in 10 caees(33,3%); pro-
`gresion 7/30(23,3%). ObJetive response site: skin 5, bone 3,
`nodes 2,
`lung 1. pleural 1. The median of the duration of ob—
`jetive responses was 19 m(7—42+) with a time for the response
`of 3 m(1-9) median; for the subjetive response was of 7 m
`(2—23+) and 1 m(1-4) respectively. The treatment duration me—
`dian was 7 m(1—42+). The median of the overall survival was
`65 m(1—96+). The most important toxicitys were emenorrea
`(16/30), gain of body weight (7/30) and initial pain incre-
`ment (6/30).
`Conclusionscin premenopeusel women with low risk advanced
`breast cancer the efficec1ty of LHRH—egonists is similar to
`the surgical or phisical castration with m1nor toxicity. The
`hormonal association with Hegestrol Acetate induce a medical
`estrogenic complete blockade that may improve the therapeutic
`benefits.
`
`Annals ofOncology 3 (Suppl. 5): 1992.
`© 1992 Kluwer Academic Publishers. Printed in the Netherlands.
`
`ll
`
`AstraZeneca Exhibit 2143 p. 4
`
`

`

`304
`
`A PILOT STUDY OF r-ALPHA-INTERFERON-ZB (IFN) PLUS
`HEDOXYPROGESTERONACETATE (MFA)
`IN HORMONAL REFRACTORY
`METASTATIC BREAST CANCER
`
`T. Wildfang, O. Grflndsl.
`H.—J. SFhmfilI
`Medirinische Hochschule Hannover. Konstantv—Gutschow-—Str. R
`2000 Hannnver 61. Germanv
`
`0. Schnalke, R. Rendel, H. Kiihnle,
`v
`
`investigations showed that r~alpha~TFN-2b may
`Preclinical
`have an influence on cell differentiation and steroid recep-
`tor expression in human mammarian carcinoma cells. Based on
`these results we designed a phase-TT-tria] with a combination
`of HPA + TFN in patients (pts) with ER/PR—positive advanced
`breast cancer and progression under hormonal
`treatment.
`
`from day 1S HPA 1000 mg/day p.o., while TPN was continued
`ix/wk. Response was evaluated after 12 wks.
`in case of
`CR/PR/NR/NC the therapy was continued until progression. Ste-
`roid receptor expression was
`investigated in punctahle skin
`or lvmph node lesions before and 2 wka after the TFN treat—
`ment. Patient charagtegistigsg 9 pts are at present eva—
`luable. median age 70 (51—79), mastectomy 9/9, all pts with
`irradiation and ) 2 hormonal
`treatments. documented progres—
`sion. Metastatic sites:
`lncoresinna] lymph nodes (5). hone
`(5).
`lunR (3). skin (1). other sites (1). Results: The median
`treatment duration was 28 wks
`(8—48 wks). 1/9 CR (111), for
`An wkq. PR 2 (222)
`(24/52+ wks), HR b. PD 2: Determination of
`steroid receptors showed significant increase in oestrogen
`and particularly ER receptor expression after TFN treatment
`
`pression under TF'N in breast cancer is an highly interesting
`concept for the.
`improvement of hormonal
`treatment
`in hormone
`receptor positive breast cancer. The reinatitution of hormo-
`nal
`treatment modulated by TF‘N seems to he interesting in
`terms of particularly low toxicity.
`
`Breast cancer Session I
`
`79
`
`305
`
`SERUM LEVEL ADAPTED HIGH-DOSE NEDROXYPROGESTERONE
`ACETATE (MPA) THERAPY FUR ADVANCED BREAST CANCER.
`K. Pollow' and R. Kreienberg
`Department of Obstetrics and Gynecology and *Dspartmsnt of
`Experimental
`Endocrinology,
`Johannes Gutenberg—Universtét
`Heinz, F.R.G.
`an HPA (Farlutal) effective level service was
`5 years
`ago,
`instituted in the Federal Republic of Germany in order to be
`able to perform an effective level adapted high-dose progestin
`therapy in advanced breast cancer with the help of MPA serum
`level measurements. The objectives of the trial were to opti—
`mise MPA therapy by ensuring effective levels of a minimum of
`100 ng/ml. Up to now more than 2000 patients with histologi-
`cally provsn advanced breast cancer entered this study, but up
`to now 846 of all patients have been evaluated. Treatment
`schedule:
`initially 1,500 mg HPA were given per as as a los-
`ding dose for a period of at least 6 weeks and then the daily
`dosis was
`reduced down to 1,000 mg. Serum