`
`“Univ. of Minn.
`Bio-Metlical
`Lihrary
`<_< August 15, 1992
`& 20 92
`Volume 70
`Number4
`ISSN 0008-543X CANCAR
`
`:
`
`
`
`
`UdCCL
`
`An rerceniitigy |
`International Journal of the
`American Cancer Society
`
`American Cancer Society
`National Conference on New
`Oncologic Agents
`Dallas, Texas
`February 6-8, yey
`
`Published for the American Cancer Reaa
`by J.B. Lippincott Company, Peas
`
`
`
`InnoPharma Licensing LLC v. AstraZeneca AB IPR2017-00905
`
`AstraZeneca Exhibit 2020p. 1
`
`
`
`V. Craig Jordan, Ph.D., D.Sc.
`
`Tamoxifen has becomethe endocrine treatmentof choice
`eff all stages of breast cancer. Its low incidenceof side
`an and proven survival advantage observed during
`vant therapy in postmenopausal women with node-
`ce disease has encouraged the use of long-term
`~ ment for patients to benefit fully from therapy. The
`cone an appropriatelevelofestrogen-like effects that
`deve] be beneficial to maintain bone density and prevent
`cul
`‘Opment of coronary heart disease by lowering cir-
`ating cholesterol. These effects might be usefulin all
`patients with estrogen receptor-positive breast cancer
`Sent Currently are receiving no therapy. This antiestro-
`rence agent could be effective therapy to deter recur-
`0
`e, and the estrogen-like side effects support the physi-
`°8IC processes of the patient as hormone-replacement
`Gana In the laboratory, a tamoxifen-stimulated breast
`tne2 model has been described in vivo. This form of
`ind aianad mayoccurin patients after long-term or
`r nite adjuvant therapy. Novel pure antiestrogemic
`"8s have been discovered that soon will become avail-
`additic second-line therapy after tamoxifen failure. In
`in See tamoxifen is being evaluated in the United
`Valor om as chemosuppressive therapy to prevent the de-
`ar ee of breast cancer in high-risk women. A simi-
`‘an ‘ical evaluation is underwayin the United States.
`Cer 1992; 70:977-982.
`Ke
`i
`r a Words;
`tamoxifen, breast cancer, prevention, drug
`®sistance,
`ieclinical developmentof antiestrogenic drugs’? has
`Cian a a new therapeutic dimension for the physi-
`i ye patients with breast cancer. Tamoxifen
`as fh ), a nonsteroidal compound,’ is now established
`© “gold standard”to treat selected patients withall
`
`Ni
`Presented at the American Cancer Society National Conference
`a Oncologic Agents, Dallas, Texas, February 6-8, 1991.
`Onsin Cth ane Department of Human Oncology, University of Wis-
`Ad Inical Cancer Center, Madison, Wisconsin.
`ofte for reprints: V, Craig Jordan, Ph.D., D.Sc., Department
`600 Hj "e Oncology, University of Wisconsin Clinical Cancer Center,
`abiland Avenue, Madison, WI53792.
`‘cepted for publication September 15, 1991.
`
`stages of this disease.* The side effects generally are
`limited to symptoms of estrogen blockade. Neverthe-
`less, physicians should remainvigilantto their patients’
`concerns and provide optimal health care during ta-
`moxifen therapy.
`In this article, a treatmentstrategy is designed for
`the 1990s to maximize the use of antiestrogenic drugs to
`control breast cancer. Long-term adjuvant tamoxifen
`therapy, aconcept successfully transferred from the lab-
`oratory to theclinic,’ provides a survival benefit for
`postmenopausal patients with node-positive disease.°
`This encouraging clinical finding has increased the en-
`thusiasm to extend and broadenthe use of antiestrogen
`therapy. This article addresses some of the issues in-
`volved and considers the potential benefits of a broader
`application of tamoxifen therapy.
`
`Long-Term Adjuvant Tamoxifen Therapy
`
`During the past 3-4 years, it has becomeclearthat ta-
`moxifen, an antiestrogenic agent originally introduced
`as a palliative treatment for advanced breast cancer in
`postmenopausal women,’is effective adjuvant therapy
`in both node-positive and node-negative disease. The
`results of numerous clinical
`trials recently were re-
`viewed.® Therefore,it is only necessary in this report to
`considerthe strategic issues.
`Severalclinical trials showed the benefit of at least
`5 years of tamoxifen treatment;””” however, there is
`currently a trend toward evaluating indefinite adjuvant
`tamoxifen therapy. There are two major concerns about
`this strategy. First, will the patient benefit from continu-
`ous therapy? It is hoped that an advantagewill be ob-
`served in the analysis of current clinical trials because
`the prospects for patient survival are not good after
`there is recurrence. Any strategy to suppress the process
`of recurrence would be a valuable advance. However,
`this raises a second issue: Is indefinite tamoxifen ther-
`apy safe?
`In 1977, a pilotclinical evaluation was begunof the
`safety and potential efficacy of long-term adjuvant ta-
`
`AstraZeneca Exhibit 2020 p. 2
`
`
`
`978
`
`CANCER Supplement
`
`August 15, 1992, Volume70, No. 4
`
`/CHg
`OCH2CH2N|
`
`CHg
`
`2CHs
`OCH2CHeN |
`
`CHs
`
`TAMOXIFEN
`
`TOREMIFENE
`
`OH
`
`ao ~ 9
`
`™(CHe)10CN(CHa)gCHg
`Hs
`
`HO
`
`IC] 164,384
`Figure 1. Formulas of antiestrogens.
`
`moxifen therapy, with initial adjuvant chemotherapy,
`in node-positive breast cancer.'*"* Not only hasthe pi-
`lot study providedinteresting therapeutic data, but also
`the findings in the patients treated have proved to be an
`invaluable resource to monitor the acceptability and
`safety of tamoxifen. Many of these patients were
`youngerthan 40 years of age, and they maintained their
`menstrual cycles after adjuvant chemotherapy. Long-
`term adjuvant tamoxifen therapy caused an increase in
`circulating estrogenlevels.">"® Currently, there is no evi-
`dence that the observed increased estrogen levels will
`reverse the action of tamoxifen as an antitumor agent.
`However, itis knownthat tamoxifenis likely to be more
`effective in a low estrogen environment. Tamoxifen,
`andits metabolites, are competitive inhibitors of estro-
`gen action.!”? Two strategies could be consideredto re-
`duce estrogen levels: ovariectomy(in node-positive dis-
`ease) or the administration of luteinizing hormone-re-
`leasing hormone (e.g., depot goserelin). The latter is
`known to inhibit ovarian estrogen synthesis (by sup-
`Pressing luteinizing hormonerelease),'®° and this may
`be rational therapy for node-negative, estrogen recep-
`tor-positive women whoelect not to receive chemother-
`apy because they wish to have a family 5 or more years
`in the future. Clinicaltrials are ongoing to address both
`the safety and efficacy of tamoxifen—depot goserelin
`combinations.
`One natural concern about indefinite tamoxifen
`therapy was the probability that an antiestrogenic drug
`might cause serious boneloss. Ultimately, this would
`limit the use of the agent in women with either node-
`negative disease or those surviving long term. We
`found (in the laboratory) that tamoxifen has a target-
`site specificity, i.e., tamoxifen will producean antiestro-
`
`genic effect in the uterus (with some estrogenic actions)
`but it has estrogenic effects in bone and prevents de.
`creases in density.”° Tamoxifen does not cause any sig.
`nificant decreases in bone density (compared with con.
`trol) in patients who have received at least a 2-yea,
`course of adjuvant tamoxifen.”! Similarly, long-term (5.
`year) adjuvant tamoxifen therapy appears to stabilize
`boneloss.”
`It is known that tamoxifen has a mixture of estro.
`genic and antiestrogenic actions,‘ andit is possible that
`the estrogenic actions could cause troublesomeside ef.
`fects. Estrogens are knownto predispose individuals ty
`thromboembolic disorders and endometrial carcinoma,
`Tamoxifen causes some decreases in antithrombin Il]
`during long-term adjuvanttherapy,” but the decreases
`are within the clinically acceptable range. However,
`women with a prior history of thromboembolic dis-
`order should not receive long-term tamoxifen therapy
`unless the risks are outweighed by the severity of the
`disease.
`Tamoxifen-induced endometrial carcinoma is a
`much more complicated issue, and the findings deserve
`to be placed into perspective. As might be expected,
`endometrial carcinoma has been detected in patients
`who are being treated for breast cancer with tamoxi-
`fen.** Unfortunately, only approximately 33% of endo-
`metrial carcinoma is hormone responsive;
`therefore,
`most tumors would be expected to progress. However,
`in one study,”it was foundthat a steroid receptor-posi-
`tive human endometrial tumoris stimulated to grow in
`athymic mice by either estradiol or tamoxifen. In fact,
`tamoxifen again showstarget site specificity. If animals
`are bitransplanted with a humanbreast tumor (MCF-7)
`and a human endometrial carcinoma (EnCa 101), ta-
`moxifen will inhibit estradiol-stimulated growth of the
`breast tumor but encourage the growth of the endome-
`trial tumor.”* These findings led to an examination of
`clinical-trial data to determine whether an increase in
`endometrial carcinomaoccurs during adjuvant tamoxi-
`fen therapy for breast cancer. Currently, only one ran-
`domizedclinical trial found an increase in endometrial
`carcinoma. This Swedish study*” of approximately
`1900 women, randomized to receive no or tamoxifen
`(20 mg twice a day) treatment, found an increase of 11
`endometrial carcinomasin the tamoxifen treatment arm
`compared with control. Whatis particularly interesting
`is the association of an increased risk for endometrial
`carcinoma with increased duration of tamoxifen ther-
`apy. Nevertheless,it is clear from all clinical results that
`no patient should be denied adjuvant tamoxifen ther-
`apy for breast cancer because she might have an occult
`endometrial carcinoma that is encouraged to growby
`tamoxifen. Physicians should, however, remain vigi-
`lant to this possibility and immediately investigate any
`cases of suspicious bleeding.
`
`AstraZeneca Exhibit 2020 p. 3
`
`
`
`of tamoxifen therapy usually is associated with estro-
`gen receptor-negative clone emergence. However,
`based on experience with advanced disease, a signifi-
`cant proportion of disease will remain hormonere-
`sponsive. Second-line therapies, like progestins”® and
`aromatase inhibitors,”’ can be effective in some pa-
`tients. The new antiestrogenic agent, toremifene,*”°
`might produce a subsequentresponse in somepatients
`in whom tamoxifen therapy fails after an initial re-
`sponse. Toremifene currently is being evaluated in
`Phase III trials against tamoxifen in postmenopausal
`patients with advanced disease. The next step will be to
`evaluate this antiestrogenic drug as adjuvant therapy.
`Several forms of drug resistance to antiestrogens
`have been described in the laboratory.* However, the
`observation that tamoxifen can encourage the growth
`of endometrial carcinoma in athymic mice naturally
`raised the question of whether a modelcould be devel-
`oped for tamoxifen-stimulated breast cancer growth.
`Long-term tamoxifen therapy eventually can cause
`the growth of MCF-7 breast
`tumors in athymic
`mice.**** These tumors can be retransplanted but will
`grow only if tamoxifen treatment is maintained.”It is
`possible that tamoxifen-stimulated growth has been
`described in the clinic.*° However, a withdrawal re-
`sponse maybedifficult to define because tamoxifen has
`a long half-life,” and up to 6 weeksis required to elimi-
`nate all traces of the drug andits metabolites.
`In the laboratory model of tamoxifen-stimulated
`growth,estradiol also stimulated tumor growth.This
`suggests that cessation of tamoxifen therapy will not be
`sufficient clinically because the patient's circulating es-
`trogen ultimately may support tumor growth. Forthis
`reason, significant numbers of patients may respond to
`second endocrine treatment after the failure of success-
`ful tamoxifen treatment. The tumor has a withdrawal
`response to tamoxifen, and the existing estrogen recep-
`tor system cannotbe activated. This is achieved by ei-
`ther limiting the amount of endogenousestrogen (aro-
`matase inhibitors) or perturbing the regulation of the
`estrogen receptor system (progestins). An alternate ther-
`apeutic strategy would be to develop antiestrogenic
`drugs that do not have the estrogen-like properties of
`tamoxifen,
`
`Pure Antiestrogens
`
`Several pharmaceutical companiesare attempting to de-
`velop a pure antiestrogenic agent
`for clinical use.
`Currently, there is only information available about the
`
`ties?) has been established.
`Thesteroidal compound,ICI 164,384 (Fig. 1),°* has
`been evaluated by numerous investigators!”°?*° and
`foundto be an effective pure antiestrogen. However,its
`systemic potency is low, andthereis significant loss of
`potency if the compoundis given to animals orally. ICI
`164,384 probably will not be usedclinically, but nonste-
`roidal agents with a higher potency could be targeted
`for development. An orally active agent should be an
`essential component of any strategy to introduce a new
`antiestrogen. Oral tamoxifen is so well tolerated that
`patients would be reluctant to consider injections or
`sustained-release implants as an alternative.
`Howcould a pure antiestrogenic drug be used toits
`best advantagein the clinic? The finding that pure an-
`tiestrogens can inhibit tamoxifen-stimulated growth in
`laboratory models* identifies their use as second-line
`therapy in advanced disease or at first recurrence in
`patients with node-positive or node-negative breast
`cancer who do not respond to long-term adjuvantta-
`moxifen therapy.
`It
`is likely that, early in the evolution of breast
`cancer, the diseaseis significantly more hormonallyre-
`sponsive thanlater. Early treatment of node-negative
`disease with an antiestrogen could provide an advan-
`tage for patients. However, this might not be trueif
`therapy with a pure antiestrogenic drug is used early.
`Oneadvantage of long-term adjuvant tamoxifen ther-
`apy is that the drug appears to have an appropriate
`level of estrogenic side effects.* Its estrogenicity might
`be beneficial to bone” and is responsible for lowering
`circulating cholesterol.*? This might be important for
`most postmenopausal women with node-negative dis-
`ease who are denied hormonereplacementtherapy be-
`cause only a minority will have a recurrence. A pure
`antiestrogenic drug might produce deleterious effects
`on the physiologic actions of estrogen in such patients
`that might preclude early evaluation in these women.
`By contrast, it might be advisable to evaluate adjuvant
`therapy in women with extensive nodal metastases, U]-
`timately, tamoxifen therapy followed by pure anties-
`trogen therapy at recurrence might be moreacceptable
`to patients if orally active pure antiestrogenic drugs are
`not available.
`It is likely that the next decade will see the evalua-
`tion of several new agents that should provide clini-
`cians with other valuable antiestrogenic agents with
`different properties. Nevertheless, the success of ta-
`moxifen, and its balance of estrogenic and antiestro-
`genic actions, has encouraged a consideration of its
`widerclinical application to prevent breast cancer.
`
`AstraZeneca Exhibit 2020 p. 4
`
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`
`980
`
`CANCER Supplement August 15, 1992, Volume 70, No. 4
`
`Prevention of Breast Cancer
`
`Oneof the current goals of laboratory andclinical re-
`search is to devise a strategy to prevent the develop-
`ment of breast cancer. An effective plan ultimately
`could prevent more than 40,000 deaths annually. A suc-
`cessful strategy would intervene in those women in
`whom the disease could develop. Such an intervention
`must have significantly less risk to the patient than
`death from breast cancer and preferably be given pre-
`cisely and for a short period. Regrettably, we cannot
`identity unequivocally the population of women in
`whom breast cancer will develop. Therefore, there is
`the immediate problem of whoto treat. Although we
`know that women who have two or morefirst-degree
`relatives with breast cancerare at increasedrisk for the
`disease, these women are in a minority (10%) of those
`whosubsequently have the disease. Most women have
`breast cancer for apparently arbitrary reasons. Because
`we do not know whowill have breast cancer and can
`only identify women withanincreasedrisk (e.g., nullip-
`arous women, women bearing a child after age 30
`years, and women whohave multiple breast biopsies
`for suspicious lesions), the application of an interven-
`tion to prevent the disease must have negligible risk for
`the vast majority of women whowill never have breast
`cancer. To prevent the disease, the timing of disease
`initiation should be known. However, we do not know
`either the timing orthe natureof the carcinogenicinsult
`in women. Therefore, currently, precise intervention
`therapy to prevent breast cancer seemsunlikely.
`An ovarianinfluence in the control of breast cancer
`growth has been knownsincetheturn ofthe century.*?
`In the laboratory, ovariectomy prevents the develop-
`ment of mammary cancer in high-incidencestrains of
`mice*? and mammary carcinogenesis in rats.** In both
`models, mammary carcinogenesisis initiated in young
`pubescent females, but all animals will have tumors
`unless prophylactic ovariectomy is done. It would be
`clearly unacceptable to do indiscriminate oophorecto-
`mies on teen-agegirls to avoid the possibility of breast
`cancer! Nevertheless,
`there is epidemiologic data to
`support the view that early oophorectomy dramatically
`reduces the incidence of breast cancer.*° Recently, one
`study*® suggested the extensive use ofluteinizing hor-
`mone-releasing hormone agonists as contraceptives.
`This reversible approach to ovarian suppression would
`reduce,not only the incidenceof breast cancer, but also
`that of ovarian and endometrial carcinoma. This inno-
`vative suggestion has merit although there is currently
`little public enthusiasm to sponsorresearch in repro-
`ductive endocrinology.
`An alternative approach would be to administer
`antiestrogenic drugs to block estrogen action. Tamoxi-
`fen reduces the incidence of second primary breast
`
`cancers that develop during adjuvant tamoxifen ther-
`apy’°’” and prevents mammary tumorigenesis in an
`mal models.*”“* The strategy to use tamoxifen to Pre
`vent breast cancer has a strongscientific rationale for
`further evaluation. However, such a strategy will suc
`ceed onlyif there is a low incidenceofiatrogenic dis”
`orders in the women whowill never have breast cance
`Thesideeffects that occur with tamoxifen recently wer®
`reviewed.” Therefore, only the major concerns will be
`mentionedin this report. The administration of tamon”
`fen to young women(asyet unidentified) of reproduc:
`tive age might be unacceptable becauseof (1) the per
`menopausal symptoms, (2) the risks for teratogenes>
`and (3) the unknowneffects of long-term ovarian hy-
`perstimulation,i.e., ovarian carcinomain the postmen”
`pausal years.
`:
`An alternative strategy wouldbe to study the ra
`ity of tamoxifen to prevent the appearance of ee
`cancer in postmenopausal women. However, the pro
`cess ofinitiation and promotion of breast cancer almos
`certainly will have occurred before this age, and tamo””
`ifen will suppress the growth of malignant cells. This
`concept would be considered chemosuppression, 1& -
`prevent the developmentofoccult disease. Figure 2 -
`scribes the various strategic approaches to control th
`developmentof breast cancer.
`
`Chemosuppression
`In London,a pilot clinical study was begun of et
`fen therapy in normal women at
`risk for brea
`cancer.*”-? Currently, the only concern of significane’
`is the declining compliance (80%at 2 years) that occurs
`in both the tamoxifen and control
`treatment _
`Close volunteer supervision and support will be eset
`tial to achieve success in a major study.
`ifen
`Thereis the question of the duration for tamox"” i
`therapy. Although tamoxifen is an effective age" at
`the treatment of breast cancer and long-term adjuyen
`therapy is effective,
`it may be prudent to consid
`5-year regimen rather than indefinite treatment
`-
`have considerable information about 5 years of ee
`ment, and additional long-term studies will produce a
`sults during the next few years. An analysis of adjuv*
`
`INITIATION
`
`PROMOTION
`
`MALIGNANT CELL
`REPLICATION
`
`TUMOR
`DETECTION
`
`< PREVENTION >< CHEMOSUPPRESSION > < TREATME
`Figure 2. Conceptsforthestrategic use of antiestrogenst ae
`the developmentof breast cancer.
`
`NT
`
`AstraZeneca Exhibit 2020 p. 5
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`
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`Antiestrogens and Breast Cancer/Jordan
`
`981
`
`therapytrials indicates that the survival advantage of
`tamoxifen persists for one decade; therefore, interven-
`tion in normal women may blunt the appearance of
`primary disease significantly.
`Trials to establish the value of tamoxifen as a pre-
`ventative in womenare being started by the National
`Cancer Institute. We hope an evaluation of the results
`of tamoxifen therapy by the. end of the century will
`provide the medical community with valuable informa-
`tion for clinical practice. In the meantime,is there any
`contribution that can be made nowto reduce the death
`rate from breast cancer? There are hundreds of thou-
`sands of womenatrisk for dying of breast cancer who
`currently receive no therapy. This is a forgotten patient
`population that has received either no adjuvant therapy
`for node-negative disease or has had adjuvant chemo-
`therapy for premenopausal node-positive disease butis
`now postmenopausal. Delayed tamoxifen treatment as
`maintenance therapy could benefit those who havees-
`trogen-receptor positive disease because this drug
`usually would be prescribed if there was a recurrence.
`Tamoxifen is essentially safe therapy. Why not delay
`recurrence by prescribing tamoxifen now? Another ad-
`vantageto this strategy is that women with a history of
`breast cancer are at the highest risk for a second pri-
`mary tumor. This drug could be effective therapy to
`preventthe developmentof these tumors. The potential
`value of tamoxifen as hormone-replacementtherapy to
`support bone density and reduce the risk of coronary
`heart disease may be an added advantage. We might
`take the position that a clinical trial would be the best
`approachto determine the value in lives saved. How-
`ever, most women during the next decade will receive
`adjuvant tamoxifen immediately after mastectomy. The
`women whoare currently at risk for either a second
`primary breast cancer or a recurrence of their initial
`disease will confront the rigors of chemotherapy for
`advanced disease. Based onall clinical information, the
`medical communityis already in a position to choose a
`therapy of benefit to treat appropriate patients.
`
`Concluding Remarks
`
`The unexpected success of tamoxifen as adjuvantther-
`apy hasled to the use of extended treatment regimens
`andinterest in the developmentof antiestrogenic drugs
`with different pharmacologic properties. The pure an-
`tiestrogens may be useful second-line therapy after ta-
`moxifen failure. However, most of the current interest
`in antiestrogenic agentsis in their use as a preventative
`for womenwith a high risk for breast cancer. Although
`the situation is not optimal (we do not know whoto
`treat), tamoxifen currently is the “best bet” as an agent
`to preventthis disease. Thereis little doubtit is effec-
`tive, andit has been examined extensively by clinicians.
`
`However, the absolute benefit to womenisstill a cause
`for concern. Treating large populationsto benefit only a
`few personsis not standard practice, and there are no
`parallels that can be drawn with earlier clinical re-
`search.
`The advantages of tamoxifen are that it has few
`side effects and is effective. The drug will be evaluated
`rigorously during this decade and may provide the
`physician with a useful preventative intervention. How-
`ever, the issue of whototreat should be pursuedrigor-
`ously. The last decade has seen an explosion of knowl-
`edge that may provide many newcluesto identifying
`high-risk women. If laboratory research can categorize
`womenat risk, then the physician will be able to pre-
`scribe a drug that has been evaluated properly in the
`clinic. Too often the laboratory scientist is able to pre-
`dict genetic disorders when nothing can be donefor the
`patient. This will not occur with breast cancer because
`parallel research ventures in the laboratory andclinic
`are destined to converge in the near future.
`
`References
`
`1.
`
`Jordan VC. The development of tamoxifen for breast cancer ther-
`apy: a tribute to the late Arthur L. Walpole. Breast Cancer Res
`Treat 1988; 11:197-209.
`2. Lerner LJ, Jordan VC. Development of antiestrogens and their
`use in breast cancer: eighth Cain Memorial Award lecture.
`Cancer Res 1990; 50:4177-89.
`3, Harper MJK, Walpole AL. A new derivative of triphenylethyl-
`ene effect on implantation and mode of action in rats. ] Reprod
`Fertil 1967; 13:101-19.
`Jordan VC, Murphy CS. Endocrine pharmacologyof antiestro-
`gens as antitumor agents. Endocr Rev 1990; 11:578-610,
`Jordan VC. Laboratory studies to develop generalprinciples for
`the adjuvant
`treatment of breast cancer with antiestrogens:
`problems and potential for future clinical applications. Breast
`Cancer Res Treat 1983; 3(Suppl):73-86.
`6. Early Breast Cancer Trialists’ Collaborative Group. Effects of
`adjuvant tamoxifen and of cytotoxic therapy on mortality in
`early breast cancer. N Engl ] Med 1988; 319:1681-92.
`7. Cole MP, Jones CTA, Todd IDH. A new antioestrogenic agent in
`late breast cancer. Br J Cancer 1971; 25:270-5.
`Jordan VC. Long-term adjuvant tamoxifen therapy frombreast
`cancer:the preludeto prevention. Cancer Treat Rev 1990; 17:15-
`36.
`9. Breast Cancer Trials Committee, Scottish Trials Office. Adju-
`vant tamoxifen in the management of operable breast cancer:
`the Scottish trial. Lancet 1987; 2:171-5.
`10, Fisher B, Costantino J, RedmondC, Poisson R, BowmanD, Cou-
`ture J, et al. A randomized clinical trial evaluating tamoxifen in
`the treatmentof patients with node negative breast cancer who
`have estrogen receptor positive tumors. N Engl J Med 1989;
`320:479-84.
`11. Falkson HC, Gray R, Wolberg WH, Gilchrist KW, Harris JE, Tor-
`mey DC,et al. Adjuvant trial of 12 cycles of CMFPT, followed
`by observation or continuous tamoxifen versus 4 cycles of
`CMFPTin postmenopausal women with breast cancer: an
`ECOG PhaseIII study. J Clin Oncol 1990; 8:599-607.
`12. Boccardo F, Rubagotti A, Bruzzi P, Capellini M,Isola G, Nenci I,
`et al. Chemotherapy versus tamoxifen versus chemotherapy
`plus tamoxifen in node positive, estrogen receptor-positive
`
`4.
`
`5.
`
`8.
`
`AstraZeneca Exhibit 2020 p. 6
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`982
`
`18.
`
`14.
`
`15.
`
`17.
`
`18.
`
`19.
`
`20.
`
`21.
`
`22.
`
`29.
`
`24.
`
`28.
`
`26.
`
`20.
`
`28,
`
`29.
`
`30.
`
`31.
`
`32.
`
`33:
`
`34,
`
`30.
`
`37.
`
`38.
`
`39}
`
`40,
`
`41,
`
`42.
`
`43.
`
`44,
`
`45,
`
`46.
`
`47.
`
`48.
`
`49.
`
`50.
`
`52.
`
`CANCER Supplement August 15, 1992, Volume 70, No. 4
`PyrhonenS. PhaseIII studies of toremifene in metastatic breast
`breast cancerpatients: results of a multicentric Italian study. J
`cancer. Breast Cancer Res Treat 1990; 16(Suppl):41-6-
`er
`Clin Oncol 1990; 8:1310-20.
`Osborne CK, Coronado EB, Robinson JP. Human breast ee
`Tormey DC, Jordan VC. Long-term adjuvant therapy in node
`in the athymic nude mouse:cytostatic effect of long-term aes
`positive breast cancer: a metabolic andpilot clinical study. Breast
`trogen therapy. Eur J Cancer 1987; 23:1189-94.
`Cancer Res Treat 1984; 4:297-302.
`gtimu-
`Gottardis MM, Jordan VC. Development of tamoxifen-
`rm
`Tormey DC, Rasmussen P, Jordan VC. Update on long-term
`lated growth of MCF-7 tumorsin athymic mice after longte
`tamoxifen study[letter]. Breast Cancer Res Treat 1987; 9:157-8.
`antiestrogen administration. Cancer Res 1988; 48:51s f ta-
`Jordan VC,Fritz NF, Tormey DC.Endocrineeffects of adjuvant
`Gottardis MM,Jiang SY, Jeng MH,Jordan VC. Inhibition a @
`chemotherapy and long-term tamoxifen administration on node
`moxifen-stimulated growth of an MCF-7 tumor variant in 3
`positive patients with breast cancer. Cancer Res 1987; 47:624-
`mic mice by novel steroidal antiestrogens. Cancer _
`30.
`16.
`Ravdin PM,Fritz NF, Tormey DC,Jordan VC. Endocrine status
`
`49:4090-3, .M,Band
`Legault-Poisson S, Jolivet J, Poisson R, Beretta-Piccoli M,
`ie
`36.
`of premenopausal nodepositive breast cancer patients follow-
`PR. Tamoxifen induced tumor stimulation and withdraw@
`ing adjuvant chemotherapy and long-term tamoxifen. Cancer
`Res 1987; 48:1026-9.
`cen-
`sponse. Cancer Treat Rep 1979; 63:1839-41.
`Patterson JS, Settatree RS, Adam HK, Kemp JV, Serum Onert
`Pasqualini JR, Gelly C. Biological response of the antiestrogen
`trations of tamoxifen and major metabolites during nete
`ICI 164,384 in human hormone-dependent and hormone-inde-
`Nolvadextherapy, correlated with clinical response. we
`an
`pendent mammary cancer cell lines. Cancer Lett 1990; 50:133-9,
`sen HT, Palshoff T, editors. Breast cancer: experimenta °
`Nicholson RI, Walker KJ. Use of LH-RH agonists in the treat-
`clinical aspects. Oxford, UK: Pergamon, 1980:89-92.
`Endo-
`ment of breast disease. Proc R Soc Edinburgh [Biol Sci] 1989;
`Wakeling AE, BowlerJ. Steroidal pure antiestrogen® J
`95b:271-9.
`Robertson JFR, WalkerKJ, Nicholson RI, Blamey RW. Combined
`crinol 1987; 112:R7-10.
`g tO
`Cormier EM, Jordan VC. Contrasting ability of antiestOB
`endocrine effects of LH-RH agonists (Zoladex®) and tamoxifen
`inhibit MCF-7 growth stimulated by estradiol or ep
`(Nolvadex®)
`therapy in premenopausal women with breast
`cancer. Br J Surg 1989; 76:1262-9.
`growth factor. Eur J Cancer 1989; 24:57-63.
`pman ME,
`Thompson EW,Katz D, Shima TB, Wakeling AE,Lip
`Jordan VC, Phelps E, Lindgren JU. Effects of antiestrogens on
`en stimu,
`Dickson RB. ICI 164,384, a pure antagonist of estros
`bonein castrated and intact female rats. Breast Cancer Res Treat
`lated MCF-7cell proliferation and invasion. Cancer —
`1987; 10:31-5.
`49:6929-33,
`Love RR, Mazess RB, Tormey DC, Barden HS, Newcomb PA,
`rdan ve,
`Love RR, Newcomb PA, Wiebe DA, Surawicz TS, Jo sid
`an
`Jordan VC. Bone mineral density in women with breast cancer
`Carbone PP, et al. Effects of tamoxifen therapy in lipid ega-
`treated with adjuvant tamoxifen for at least two years. Breast
`lipoprotein levels in postmenopausal patients with noden
`Cancer Res Treat 1988; 12:297-301.
`tive breast cancer. J Natl Cancer Inst 1990; 82:1327-31.
`Fornander T, Rutqvist LE, Sjéberg HE, Blomqvist L, Mattsson A,
`411900;
`iey On oophorectomyin cancerof the breast. BrMes
`Glas U. Long-term adjuvant tamoxifen in early breast cancer;
`:1161-7.
`igins
`©
`effect on bone mineral density in postmenopausal women.J Clin
`Lathrop AE, Loeb L. Further investigations on the nae
`Oncol 1990; 8:1019-26.
`tumorsin miceIII or the part played by internal secretory
`Jordan VC,Fritz NF, Tormey DC. Long-term adjuvant therapy
`spontaneous development of tumors. J Cancer Res 1916; ction
`with tamoxifen: effect on sex hormone binding globulin and
`Dao TL. Therole of ovarian hormonesin initiating the int
`antithrombin III. Cancer Res 1987; 47:4517-9.
`of mammarycancerin rats by polynuclear hydrocarbons:
`Killackey MA, Hakes TB, Pierce VK. Endometrial adenocarci-
`nomain breast cancerpatients receiving tamoxifen. Cancer Treat
`Res 1962; 22:973-81.
`breast cance”
`Kelsey JL. A review of the epidemiology of human
`Rep 1985; 69:237-8.
`Satyaswaroop PG, Zaino RJ, Mortel R. Estrogen-like effects of
`Epidemiol Rev 1979; 1:74-96.
`BE:
`Pike MC, Ross RK, Lobo RA, Key TJ, Potts M, Henders0”ot
`tamoxifen on human endometrial carcinomatransplantedinto
`LHRHagonists and the prevention of breast and ovarian ©
`nude mice. Cancer Res 1984; 44:4006-10.
`Cottardis MM, Robinson SP, Satyaswaroop PG, Jordan VC.
`iation andur
`Br J Cancer 1989; 60:142-6.
`Contrasting actions of tamoxifen on endometrial and breast tu-
`Jordan VC. Effect of tamoxifen (ICI 46,474) on ist
`morgrowth in the athymic mouse. Cancer Res 1988; 48:812-5.
`growth of DMBA-induced rat mammary carcinomara:
`Fornander T, Rutqvist JC, Cedermark B, Glas U, Mattsson A,
`Cancer 1976; 12:419-23.
`en and
`Silfversward C,et al. Adjuvant tamoxifenin early breast cancer:
`Jordan VC, Lababidi MK, Mirecki DM. The antioestto®
`c3H/
`occurrence of new primary cancers. Lancet 1989; 1:117-20.
`antitumourproperties of prolonged tamoxifen therapy m
`Muss HB, Wells HB, Paschold EH, Black WR, Cooper MR, Ca-
`OUJ mice. Eur J Cancer 1990; 26:718-21.
`pizzi RL,et al. Megestrol acetate versus tamoxifen in advanced
`Jordan VC. Tamoxifen for the prevention of breast cance
`breast cancerfive-year analysis: a phaseIII trial of the Piedmont
`DeVita VT, Hellman S, Rosenberg SA, editors. Cancer PM
`Oncology Association. J Clin Oncol 1988; 6:1098-104.
`tion. Philadelphia: JB Lippincott, 1990:1-12.
`Smith IE, Harris AL, Morgan M, Ford HT, Gazet JC, Harmer CL,
`PowlesTJ, Hardy JR, Ashley SE, Cosgrove D, Davey JB, °
`et al. Tamoxifen versus aminoglutethimide in advanced breast
`M,et al. Chemoprevention of breast cancer. Breast Care
`carcinoma: a randomized crossover
`trial. Br Med J 1981;
`283:1432-5.
`Treat 1989; 14:23-31.
`ve Dr
`Powles TJ, Hardy JR, Ashley SE, Farrington GM, Contail
`Kangas L, Nieminen AL, Blaco G, GronroosM,Kallio S, Karja-
`DaveyJB, et al. A pilottrial to evaluate acute toxicity 2m
`lainen A, et al. A new triphenylethylene compared Fe-1157a: II,
`ity of tamoxifen for prevention of breast cancer
`Antitumoreffects. Cancer Chemother Pharmacol 1986; 17:109-
`13.
`G, D®
`1989; 60:126-31.
`Powles T], Tillyer CR,Jones AL, Ashley SE, Treleaver 7ay
`Valavaara R, Pyrhonen S, Heikkinen M,Rissanen P