`
`
`
`977
`
`The Strategic Use of Antiestrogens
`to Control the Development and
`Growth of Breast Cancer
`
`V. Craig Jordan, Ph.D., D.Sc.
`
`TamOXife“ has become the endocrine treatment of choice
`a: all Stages 0f breast cancer. Its low incidence of side
`ad'ects and Proven survival advantage observed during
`n-“fam therapy in postmenopausal women with node-
`frZSIthve disease has encouraged the use of long—term
`d1]? I}?th for Patients to benefit fully from therapy. The
`coulgd as an appropriate level of estrogen-like effects that
`Ev 1 be beneficial to maintain bone densny and prevent
`C111 8 Ppmem 0f coronary heart disease by lowering Cir-
`fmng ChOlesterol. These effects might be useful in all
`[wattlems with 83‘30an receptor-positive breast cancer
`gen:J Currently are receiving no therapy. This antiestro-
`rem:3 agent COuId be effective therapy to deter recur—
`010 -e’ and the estrogen-like side effects support the phySl-
`thtfilc proneSses 0f the patient as hormone-replacement
`Cancapy' I“ the laboratory, a tamoxifen-stimulated breast
`ru er “.‘Odel has been described in vivo. This form of
`indffire.818tance may occur in patients after long-term or
`dru mte adluvant therapy. Novel pure antiestrogemc
`ablegs {lave been discovered that soon Will become avail—
`ildditfls Second'line therapy after tamox1fen failure: In
`in (ion’
`tamoxifen is being evaluated in the United
`velog mm as ChemOSUppressive therapy to prevent the de-
`ar elf-Infant 0f breast cancer in high-risk women. A Slml-
`mica] evaluation is underway in the United States.
`C
`ancer 1992; 70:977—982.
`Ke
`r Words
`eSlStance
`
`.
`tamoxifen breast cancer: Prevention' drug
`’
`
`Enfozlmical development of antiestrogenic drugsl'2 has
`Gian time? a new therapeutic dimenSion for the phy51—
`(Bi
`lreatmg patients with breast cancer. Tamox1fen
`as ii a nDnsteroidal compound,3 is now established
`e gOId Standard” to treat selected patients With all
`
`\—
`0“ szsented at the American Cancer Society National Conference
`Fr Onmlogic Agents, Dallas, Texas, February 61—8, l991.
`'
`CDt‘lsin
`t-he Department of Human Oncology, UniverSIty of Wis-
`A 7 Hum] cancer Center, Madison, Wisconsin.
`of Humidress for reprints: V. Craig Jordan,, Ph.D., D.Sc., Department
`600 Hi ht; Oncologyr UDiVersity of Wisconsin Clinical Cancer Center,
`A8 and Avenue, Madison, W153792.
`ccepted for publication September 15, ‘1991.
`
`stages of this disease.4 The side effects generally are
`limited to symptoms of estrogen blockade. Neverthe—
`less, physicians should remain vigilant to their patients’
`concerns and provide optimal health care during ta-
`moxifen therapy.
`In this article, a treatment strategy is designed for
`the 19905 to maximize the use of antiestrogenic drugs to
`control breast cancer. Long—term adjuvant tamoxifen
`therapy, a concept successfully transferred from the lab—
`oratory to the clinic? provides a survival benefit for
`postmenopausal patients with node—positive disease.6
`This encouraging clinical finding has increased the en—
`thusiasm to extend and broaden the 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 become clear that ta—
`moxifen, an antiestrogenic agent originally introduced
`as a palliative treatment for advanced breast cancer in
`postmenopausal women,7 is effective adjuvant therapy
`in both node-positive and node-negative disease. The
`results of numerous clinical
`trials recently were re—
`viewed.8 Therefore, it is only necessary in this report to
`consider the strategic issues.
`Several clinical trials showed the benefit of at least
`5 years of tamoxifen treatmenth12 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 advantage will 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 pilot clinical evaluation was begun of the
`safety and potential efficacy of long—term adjuvant ta-
`
`AstraZeneca Exhibit 2020 p. 2
`
`
`
`978
`
`CANCER Supplement August 15, 1992, Volume 70, No. 4
`
`,CH3
`OCHZCHZN \
`
`CH3
`
`/
`
`CH3
`
`OCHgCHgN \
`
`
`
`TAMOXIFEN
`
`TOREMIFENE
`
`OH
`
`ow . ‘3
`
`”"(CH2>.ocr\|I(CH2)aCH3
`CH3
`
`HO
`
`Figure 1. Formulas of antiestrogens.
`
`ICI 164,384
`
`moxifen therapy, with initial adjuvant chemotherapy,
`in node-positive breast cancer.‘3'” Not only has the pi-
`lot study provided interesting 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
`younger than 40 years of age, and they maintained their
`menstrual cycles after adjuvant chemotherapy. Long—
`term adjuvant tamoxifen therapy caused an increase in
`Circulating estrogen levels. 15'” Currently, there is no evi-
`dence that the observed increased estrogen levels will
`reverse the action of tamoxifen as an antitumor agent.
`However, it is known that tamoxifen is likely to be more
`effective in a low estrogen environment. Tamoxifen,
`and its metabolites, are competitive inhibitors of estro—
`gen action.17 Two strategies could be considered to re—
`duce estrogen levels: ovariectomy (in node—positive dis—
`ease) or the administration of luteinizing hormone—re—
`leasmg hormone (e.g., depot goserelin). The latter is
`known to inhibit ovarian estrogen synthesis (by sup-
`pressmg luteinizing hormone release),‘8'19 and this may
`be rational therapy for node-negative, estrogen recep—
`tor-pOSitive women who elect not to receive chemother—
`apy because they wish to have a family 5 or more years
`in the future. Clinical trials 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 bone loss. 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 produce an antiest’r’ov
`
`genic effect in the uterus (with some estrogenic actions)!
`but it has estrogenic effects in bone and prevents de.
`creases in density.20 Tamoxifen does not cause any Sig.
`nificant decreases in bone density (compared with con.
`trol) in patients who have received at least a 2-year
`course of adjuvant tamoxifen.“ Similarly, long-term (5.
`year) adjuvant tamoxifen therapy appears to stabilize
`bone loss.22
`It is known that tamoxifen has a mixture of estroc
`
`genic and antiestrogenic actions,‘1 and it is possible that
`the estrogenic actions could cause troublesome side efc
`fects. Estrogens are known to predispose individuals t9
`thromboembolic disorders and endometrial carcinoma
`Tamoxifen causes some decreases in antithrombin 111
`during long-term adjuvant therapy,23 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.24 Unfortunately, only approximately 33% of endo-
`metrial carcinoma is hormone responsive;
`therefore,
`most tumors would be expected to progress. However,
`in one study,25 it was found that a steroid receptor—posL
`tive human endometrial tumor is stimulated to grow in
`athymic mice by either estradiol or tamoxifen. In fact,
`tamoxifen again shows target site specificity. If animals
`are bitransplanted with a human breast tumor (MCF—T)
`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.26 These findings led to an examinatiOn of
`clinical—trial data to determine whether an increase in
`
`endometrial carcinoma occurs during adjuvant tamoxi-
`fen therapy for breast cancer. Currently, only one ran—
`domized clinical trial found an increase in endometrial
`
`carcinoma. This Swedish study27 of approximately
`1900 women, randomized to receive no or tamoxifen
`(20 mg twice a day) treatment, found an increase of 1 l
`endometrial carcinomas in the tamoxifen treatment arm
`
`compared with control. What is 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 ocrult
`endometrial carcinoma that is encouraged to grow by
`tamoxifen. Physicians should, however, remain vigi-
`lant to this possibility and immediately investigate any
`cases of suspicious bleeding.
`
`AstraZeneca Exhibit 2020 p. 3
`
`
`
`Antiestrogens and Breast Cancer /Jordan
`
`Failure of Adjuvant Tamoxifen Therapy
`
`It is unrealistic to believe that indefinite tamoxifen ther—
`
`apy will control disease recurrence indefinitely. Failure
`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 hormone re—
`sponsive. Second—line therapies, like progestins28 and
`aromatase inhibitors,29 can be effective in some pa—
`tients. The new antiestrogenic agent,
`toremifene,3°‘35
`might produce a subsequent response in some patients
`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 model could 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.33'3“ These tumors can be retransplanted but will
`grow only if tamoxifen treatment is maintained?5 It is
`possible that tamoxifen—stimulated growth has been
`described in the clinic.36 However, a withdrawal re—
`sponse may be difficult to define because tamoxifen has
`a long half-life,37 and up to 6 weeks is required to elimi—
`nate all traces of the drug and its metabolites.
`In the laboratory model of tamoxifen—stimulated
`growth, estradiol also stimulated tumor growth.35 This
`suggests that cessation of tamoxifen therapy will not be
`sufficient clinically because the patient’s circulating es—
`trogen ultimately may support tumor growth. For this
`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 cannot be activated. This is achieved by ei—
`ther limiting the amount of endogenous estrogen (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 companies are attempting to de—
`velop a pure antiestrogenic agent
`for clinical use.
`Currently, there is only information available about the
`
`979
`
`efficacy of the lead compounds in various laboratory
`tests. It is therefore possible to formulate an application
`because the pharmacologic principle (i.e., can one syn—
`thesize a compound with pure antiestrogenic proper—
`ties?) has been established.
`The steroidal compound, ICI 164,384 (Fig. 1),38 has
`been evaluated by numerous iiivestigatorsl7'39'40 and
`found to be an effective pure antiestrogen. However, its
`systemic potency is low, and there is significant loss of
`potency if the compound is given to animals orally. ICI
`164,384 probably will not be used clinically, 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.
`How could a pure antiestrogenic drug be used to its
`best advantage in the clinic? The finding that pure an-
`tiestrogens can inhibit tamoxifen—stimulated growth in
`laboratory models34 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 adjuvant ta—
`moxifen therapy.
`It
`is likely that, early in the evolution of breast
`cancer, the disease is significantly more hormonally re—
`sponsive than later. Early treatment of node—negative
`disease with an antiestrogen could provide an advan-
`tage for patients. However, this might not be true if
`therapy with a pure antiestrogenic drug is used early.
`One advantage 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 bone22 and is responsible for lowering
`circulating cholesterol.“ This might be important for
`most postmenopausal women with node-negative dis—
`ease who are denied hormone replacement therapy 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. Ul—
`timately, tamoxifen therapy followed by pure anties_
`trogen therapy at recurrence might be more acceptable
`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
`wider clinical application to prevent breast cancer.
`
`AstraZeneca Exhibit 2020 p. 4
`
`
`
`980
`
`CANCER Supplement August 15, 1992, Volume 70, No. 4
`
`Prevention of Breast Cancer
`
`One of the current goals of laboratory and clinical 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 who to treat. Although we
`know that women who have two or more first-degree
`relatives with breast cancer are at increased risk for the
`
`disease, these women are in a minority (10%) of those
`who subsequently have the disease. Most women have
`breast cancer for apparently arbitrary reasons. Because
`we do not know who will have breast cancer and can
`
`only identify women with an increased risk (e. g., nullip—
`arous women, women bearing a child after age 30
`years, and women who have 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 who will never have breast
`cancer. To prevent the disease, the timing of disease
`initiation should be known. However, we do not know
`
`either the timing or the nature of the carcinogenic insult
`in women. Therefore, currently, precise intervention
`therapy to prevent breast cancer seems unlikely.
`An ovarian influence in the control of breast cancer
`
`growth has been known since the turn of the century.42
`In the laboratory, ovariectomy prevents the develop—
`ment of mammary cancer in high—incidence strains of
`mice43 and mammary carcinogenesis in rats.44L In both
`models, mammary carcinogenesis is 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—age girls 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.45 Recently, one
`study“ suggested the extensive use of luteinizing hor»
`mone—releasing hormone agonists as contraceptives.
`This reversible approach to ovarian suppression would
`reduce, not only the incidence of breast cancer, but also
`that of ovarian and endometrial carcinoma. This inno-
`vative suggestion has merit although there is currently
`little public enthusiasm to sponsor research 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“"27 and prevents mammary tumorigenesis in am'
`mal models.“48 The strategy to use tamoxifen t0 Pre’
`vent breast cancer has a strong scientific rationale for
`further evaluation. However, such a strategy Will 511.0
`ceed only if there is a low incidence of iatrogemic 6115‘
`orders in the women who will never have breast cancer'
`The side effects that occur with tamoxifen recently were
`reviewed.49 Therefore, only the major concerns will b.e
`mentioned in this report. The administration 0f tamoxk
`fen to young women (as yet unidentified) 0f reproduc—
`tive age might be unacceptable because of (1) the pol?
`menopausal symptoms, (2) the risks for teratogenesls’
`and (3) the unknown effects of long—term OVarian hy’
`Perstimulation, i.e., ovarian carcinoma in the PostmenO‘
`pausal years.
`-
`An alternative strategy would be to study the abll;
`ity of tamoxifen to prevent the appearanCe 0f breas-
`cancer in postmenopausal women. However, the Prot
`cess of initiation and promotion of breast canCer almos
`certainly will have occurred before this age, and lama?
`ifen will suppress the growth of malignant cells. Th”;
`concept would be considered Chemosuppression, i.e., tg
`prevent the development of occult disease. Figure 2 dee
`scribes the various strategic approaches to control th
`development of breast cancer.
`
`Chemosuppression
`
`In London/ a Pilot clinical study was begun 0f tamoxlt
`fen therapy in normal women at
`risk for breas
`cancer.5°‘r52 Currently, the only concern of significanc:
`is the declining compliance (80% at 2 years) that Occur
`in both the tamoxifen and control
`treatment arms;
`Close volunteer supervision and support will be 6556“
`ml to achieve success in a major study.
`There is the question of the duration for tam
`therapy. Although tamoxifen is an effective 218?“
`the treatment of breast cancer and long-term adlllva
`therapy iS effective,
`it may be prudent to COI‘SIde‘r/Ve
`5‘Year regimen rather than indefinite treatment
`t;
`have considerable information about 5 years Of treae’
`ment, and additional long—term studies will prodime Int
`sults during the next few years. An analysis of adluva
`
`()Xifen
`t for
`{it
`
`TUMOR
`DETECTION
`
`INITIATION
`{
`
`PROMOTION
`
`MALIGNANT CELL
`REPLICATION
`
`NT
`< PREVENTION >< CHEMOSUPPRESSION > <TREATMEl
`fro
`Figure 2. Concepts for the strategic use of antiestl'Qgens to can
`the development of breast cancer.
`
`AstraZeneca Exhibit 2020 p. 5
`
`
`
`Antiestrogens and Breast Cancer /I0rdun
`
`981
`
`therapy trials 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 women are 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 now to reduce the death
`rate from breast cancer? There are hundreds of thou—
`
`sands of women at risk 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 but is
`now postmenopausal. Delayed tamoxifen treatment as
`maintenance therapy could benefit those who have es~
`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—
`vantage to 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
`prevent the development of these tumors. The potential
`value of tamoxifen as hormone—replacement therapy 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
`approach to determine the value in lives saved. How<
`ever, most women during the next decade will receive
`adjuvant tamoxifen immediately after mastectomy. The
`women who are 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 on all clinical information, the
`
`medical community is already in a position to choose a
`therapy of benefit to treat appropriate patients.
`
`Concluding Remarks
`
`The unexpected success of tamoxifen as adjuvant ther—
`apy has led to the use of extended treatment regimens
`and interest in the development of antiestrogenic drugs
`with different pharmacologic properties. The pure an-
`tie-strogens may be useful second—line therapy after ta—
`moxifen failure. However, most of the current interest
`in antiestrogenic agents is in their use as a preventative
`for women with a high risk for breast cancer. Although
`the situation is not optimal (we do not know who to
`treat), tamoxifen currently is the “best bet” as an agent
`to prevent this disease. There is little doubt it is effec—
`tive, and it has been examined extensively by clinicians.
`
`However, the absolute benefit to women is still a cause
`
`for concern. Treating large populations to benefit only a
`few persons is 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 who to treat should be pursued rigor—
`ously. The last decade has seen an explosion of knowl—
`edge that may provide many new clues to identifying
`high—risk women. If laboratory research can categorize
`women at 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 done for the
`patient. This will not occur with breast cancer because
`parallel research ventures in the laboratory and clinic
`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
`Trrat 1988; 11:197—209.
`2. Lerner L], Jordan VC. Development of antiestrogens and their
`use in breast cancer: eighth Cain Memorial Award lecture
`szr'rr Res 1990; 50:4177—89.
`3. Harper MIK, Walpole AL. A new derivative of triphenylethyp
`ene effect on implantation and mode of action in rats. I Row-0,41
`Fertil1967; 13:101—19.
`Jordan VC, Murphy CS. Endocrine pharmacology of antiestio
`gens as antitumor agents. Endocr Rev 1990; 11:578—610
`Jordan VC. Laboratory studies to develop general principles for
`the adjuvant
`treatment of breast cancer with antiestrogeng;
`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 I Mud 1988; 319:1681—92_
`7. Cole MP, lones CTA, Todd lDH. A new antioestrogenic agent in
`late breast cancer. Br ] Cancer 1971; 25:270~5.
`jordan VC, Long-term adjuvant tamoxifen therapy from breast
`cancer: the prelude to prevention. Cancer Treat Rep 1990; 17;15_
`36.
`9. Breast Cancer Trials Committee, Scottish Trials Office~ Adj“.
`vant tamoxifen in the management of operable breast cancer:
`the Scottish trial. Lancet 1987; 2:171«5.
`10. Fisher B, Costantino J, Redmond C, Poisson R, Bowman D, Cou.
`ture ], et al. A randomized clinical trial evaluating tamoxifen in
`the treatment of patients with node negative breast cancer who
`have estrogen receptor positive tumors. N Engl I Med 1989;
`320:479—84.
`‘11. Falkson HC, Cray R, Wolberg WH, CilChrist KW, Harris IE, Tor—
`mey DC, et a1. Adjuvant trial of 12 cycles of CMFPT, followed
`by observation or continuous tamoxifen versus 4 cycles of
`CMFI’T in postmenopausal women with breast cancer: an
`ECOG Phase III study. I Clin Oncol 1990; 8:599—607.
`12. Boccardo F, Rubagotti A, Bruzzi P, Capellini M, lsola G, Nenci 1,
`et al. Chemotherapy versus tamoxifen versus chemotherapy
`plus tamoxifen in node positive, estrogen receptor~positive
`
`4.
`
`5.
`
`8.
`
`AstraZeneca Exhibit 2020 p. 6
`
`
`
`982
`
`13.
`
`14.
`
`15.
`
`16.
`
`17.
`
`18.
`
`19.
`
`20.
`
`21.
`
`breast cancer patients: results of a multicentric Italian study. I
`Clin Oncol 1990; 821310—20.
`Tormey DC, Iordan VC, Long—term adjuvant therapy in node
`positive breast cancer: a metabolic and pilot clinical study. Breast
`Cancer Res Treat 1984; 42297—302.
`Tormey DC, Rasmussen P, Jordan VC. Update on long—term
`tamoxifen study [letter], Breast Cancer Res Treat 1987; 9:157—8.
`Iordan VC, Fritz NF, Tormey DC. Endocrine effects of adjuvant
`chemotherapy and long—term tamoxifen administration on node
`positive patients with breast cancer. Cancer Res 1987; 47:624-
`30.
`Ravcljn PM, Fritz NF, Tormey DC, Jordan VC. Endocrine status
`of premenopausal node positive breast cancer patients follow—
`ing adjuvant chemotherapy and long-term tamoxifen. Cancer
`Res 1987; 48:1026—9.
`Pasqualini IR, Gelly C. Biological response of the antiestrogen
`lCl 164,384 in human hormone-dependent and hormone—inde—
`pendent mammary cancer cell lines. Cancer Lett 1990; 50:133—9.
`Nicholson RI, Walker KI. Use of LH-RH agonists in the treat—
`ment of breast disease. Proc R Soc Edinburgh [Biol Sci] 1989;
`95bz271-9.
`Robertson IFR, Walker K], Nicholson RI, Blarney RW, Combined
`endocrine effects of LH-RH agonists (Zoladex9) and tamoxifen
`(Nolvadex‘g)
`therapy in premenopausal women with breast
`cancer. Br] 31th 1989; 76:1262—9.
`Jordan VC, Phelps E, Lindgren IU. Effects of antiestrogens on
`bone in castrated and intact female rats. Breast Cancer Res Treat
`1987;10:31~5.
`Love RR, Mazess RB, Tormey DC, Barden HS, Newcomb PA,
`Jordan VC. Bone mineral density in women with breast cancer
`treated with adjuvant tamoxifen for at least two years. Breast
`Cancer Res Treat 1988; 12:297—301.
`Fornander T, Rutqvist LE, Sioberg HE, Blomqvist L, Mattsson A,
`Glas U. Long—term adjuvant tamoxifen in early breast cancer:
`effect on bone mineral density in postmenopausal women. I Clin
`Oncol 1990; 8:1019—26.
`Iordan VC, Fritz NF, Tormey DC. Long-term adjuvant therapy
`with tamoxifen: effect on sex hormone binding globulin and
`antithrombin [11. Cancer Res 1987; 47:4517—9.
`Killackey MA, Hakes TB, Pierce VK. Endometrial adenocarci—
`noma in breast cancer patients receiving tamoxifen. Cancer Treat
`Rep 1985; 69:237—8.
`Satyaswaroop PG, Zaino R], Mortel R. Estrogen—like effects of
`tamoxifen on human endometrial carcinoma transplanted into
`nude mice. Cancer Res 1984; 44:4006—10.
`Gottardis MM, Robinson SP, Satyaswaroop PG, Iordan VC.
`Contrasting actions of tamoxifen on endometrial and breast tu-
`mor growth in the athymic mouse. Cancer Res 1988; 48:812—5,
`Fornander T, Rutqvist IC, Cedermark B, Glas U, Mattsson A,
`Silfversward C, et a1. Adjuvant tamoxifen in early breast cancer:
`occurrence of new primary cancers. Lancet 1989; 1:117~20.
`Muss HB, Wells HB, Paschold EH, Black WR, Cooper MR, Ca—
`pizzi RL, et al. Megestrol acetate versus tamoxifen in advanced
`breast cancer five-year analysis: a phase III trial of the Piedmont
`Oncology Association. I Clin Oncol 1988; 621098—104.
`Smith lE, Harris AL, Morgan M, Ford HT, Gazet IC, Harmer CL,
`et a1. Tamoxifen versus aminoglutethimide in advanced breast
`carcinoma: a randomized crossover
`trial. Br Med I 1981;
`283:1432—5.
`
`22.
`
`23.
`
`24.
`
`25.
`
`26.
`
`27.
`
`28.
`
`29.
`
`30.
`
`31.
`
`Kangas L, Nieminen AL, Blaco C, Gronroos M, Kallio S, Karja—
`lainen A, et al. A new triphenylethylene compared Fc<1157a: 11,
`Antitumor effects. Cancer Chemother Pharmacol 1986; 17:109—
`13.
`
`Valavaara R, Pyrhonen S, Heikkinen M, Rissanen P, Blanco C,
`Tholix E, et a1. Toremifene, a new antiestrogenic compound for
`treatment of advanced breast cancer: phase III study. Eur]
`Cancer 1988; 242785—90.
`
`CANCER Supplement August 15, 1992, Volume 70, No. 4
`
`32.
`
`33.
`
`34.
`
`35.
`
`36.
`
`37.
`
`38.
`
`39.
`
`40.
`
`41.
`
`42.
`
`43.
`
`44.
`
`45.
`
`46.
`
`47.
`
`48.
`
`49.
`
`50.
`
`52.
`
`Pythonen S. Phase III studies of toremifene in metastatic breasr
`cancer. Breast Cancer Res Treat 1990; 16(SUPPI):41 86'
`er
`Osborne CK, Coronado EB, Robinson IP. Human breaSt caqzs.
`in the athymic nude mouse: cytostatic effect of long-term an“
`stimu’
`trogen therapy. Eur I Cancer 1987; 23:1189—94.
`Gottardis MM, Iordan VC. Development Of tamoxifen— rm
`lated growth of MCF—7 tumors in athymic mice after long"'fe
`antiestrogen administration. Cancer Res 1988; 4815183771 t ta—
`Gottardis MM, Iiang SY, Ieng MH, Jordan VC. Inhibltloin 0th .
`moxifen-stimulated growth of an MCF-7 tumor Variant 1“ 2198);.
`mic mice by novel steroidal antiestrogens- Cam” RES 1
`’
`nd
`49:4090—3.
`~
`Ba
`Legault—Poisson S, Iolivet I, Poisson R, Beretta—Piccoli M,
`1 re.
`PR. Tamoxifen induced tumor stimulation and Withdrawa
`cen—
`sponse. Cancer Treat Rep 1979; 63:1839—41-
`Patterson IS, Settatree RS, Adam HK, Kemp JV' Serum conterm
`trations of tamoxifen and major metabolites during long’urid.
`Nolvadex therapy, correlated with clinical response In: MO! and
`sen HT, Palshoff T, editors. Breast cancer: experimenta ‘
`clinical aspects. Oxford, UK: Pergamon, 1980:89—92'
`Enda—
`Wakeling AE, Bowler J. Steroidal pure antiestrogens' I
`15f
`crinol 1987; 112:R7—10.
`Cormier EM, Jordan VC. Contrasting ability 0f antieStr9§1611m3
`inhibit MCFv7 growth stimulated by EStYadiol or epl 8
`growth factor. Eur] Cancer 1989; 24:57—63-
`Thompson 13w, Katz D, Shima TB, Wakelins AE' Lip
`Dickson RB. lCI 164,384, a pure antagonist 0‘ estrog
`lated MCF—7 cell proliferation and invasion. C‘mccr Res
`vCi
`49:6929—33.
`Love RR, Newcomb PA, Wiebe DA, Surawrcz TS, 10951911 and
`Carbone PP, et al. Effects of tamoxifen therapy in 11Pld ega‘
`lipoprotein levels in postmenopausal patients With node—n
`tive breast cancer. I Natl Cancer Inst 1990; 823132741-
`1119001
`Boyd 5. On oophorectomy in cancer of the breast BrMe‘
`s of
`-
`-
`2:1161—7.
`Lathrop AE, Loeb L. Further investigations 0" “19.011512.
`9
`tumors in mice III or the part played by intern?ll secretioni-lk 6'
`spontaneous development of tumors. I Cancer R35 1919;
`' ction
`Dao TL. The role of ovarian hormones in initiating the indu
`1
`of mammary cancer in rats by polynuClear hydrOC
`Res 1962; 22:973—81.
`Kelsey IL. A review of the epidemiology of human breast canc
`Epidemiol Rev 1979; 1:74—96.
`cert
`Pike MC, Ross RK, Lobo RA, Key TI, Potts M, Idenfiersoiii
`LHRH agonists and the prevention of breast and Ovarian Ct
`c
`BrICancer 1989; 60:142—6.
`‘1le
`lordan VC. Effect of tamoxifen (1C1 46,474) on 11111121110115“),
`I
`growth of DMBA—induced rat mammary carcinoma”
`and
`Cancer 1976; 12:4