977
`
`The Strategic Use of Antiestrogens
`to Control the Development and
`Growth of Breast Cancer
`
`V. Craig Iardan, Ph.D., D.Sc.
`
`Eamoxifen has become the endocrine treatment ofchoice
`or all Stages of breast cancer. Its low incidence of side
`efffmts and proven survival advantage observed during
`adllfvant therapy in postmenopausal women with node-
`imsltlve disease has encouraged the use of long't91‘m
`dreatment for patients to benefit fully from therapy. The
`rug has an appropriate level of estrogen-like effects that
`Could be beneficial to maintain bone density and prevent
`devehlpment of coronary heart disease by lowering Cir‘
`(Mating Cholesterol These effects might be useful in all
`Patients with estrogen receptor-positive breast cancer
`who currently are receiving no therapy. This antiestro-
`genic agent could be effective therapy to deter recur-
`0?:°_ea and the estrogen-like side effects support the physi'
`th 3"? processes of the patient as hormone-replacement
`e"‘PY- In the laboratory, at tamoxifen-stimulated breast
`dancer "10del has been described in vivo. This form 0f
`i rug resistance may occur in patients after long-term OT
`dndefinite adjuvant therapy. Novel pure antiestrogenic
`aalgs have been discovered that soon will become avail-
`adde.
`€13 5eC0nd-line therapy after tamoxifen failure. In
`.
`"1011.
`tamoxifen is being evaluated in the United
`mgdom as chemosuppressive therapy to prevent the de-
`velopment of breast cancer in high-risk women. A simi-
`ar C1i“iCfll evaluation is underway in the United States.
`Ca
`"°e’ 1992; 70:977-982.
`
`Ke
`
`3.’ w°TdS:
`Feslstance
`
`.
`tamoxifen breast cancer, PT9V3““°“' drug
`y
`
`Pie Clinical development of antiestrogenic drugs” has
`n
`.
`~
`Ci mduced a new therapeutic dimension for the phyS1-
`(Film treating patients with breast cancer. Tamoxifen
`18' llr 3 nonsteroidal compound? is NOW established
`as the "gold standard" to treat selected patients with all
`
`\\m
`on Nplesented at the American Cancer Society National Conference
`EW Oncologic Agents, Dallas, Texas, February 6~3. 1991-
`mnsi Ton} the Department of Human Oncology, University of Wis-
`“ Clmical CCTDCGF Center, Madison, Wisconsin.
`Address for reprints: V. Craig ]ordan,, Ph.D., D.Sc-/ D9?-'=‘1‘tme“t
`Oncology, University of Wisconsin Clinical Cancer Center.
`A: land Avenue, Madison, WI 53792.
`F-‘pted for publication September 15, 1991.
`
`600
`
`stages of this disease.‘’ 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,5 provides a survival benefit for
`postmenopausal patients with node—positive disease.“
`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.“ 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 treatment;9‘” 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: ls 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 Ex. 2020 p. 2
`
`

`
`978
`
`CANCER Supplement August 15, 1992, Volume 70, No. 4
`
`/
`
`CH3
`
`CH3
`
`OCH2CH2N \
`
`
`
`/
`
`CH3
`
`OCHZCHZN \
`
`CH3
`
`
`
`TAMOXIFEN
`
`TOREMIFENE
`
`OH
`
`ow’ t
`
`(CH2)1oCl\i|(CH2)3CH3
`CH3
`
`HO
`
`Figure 1. Formulas of antiestrogens.
`
`ICI 164,384
`
`moxifen therapy, with initial adjuvant chemotherapy,
`in node—positive breast cancer.”'”' 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.‘5'”’ 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 aCt10I1.17 Two strategies could be considered to re-
`duce estrogen levels: ovariectomy (in node—positive dis—
`lease) or the administration of luteinizing hormone—re—
`keasmg h0fm0_r1e (e.g., depot goserelin). The latter is
`f10W_n to inhibit ovarian estrogen synthesis (by sup-
`Pressltlg luteinizing hormone release),“"” and this may
`1:6 _rat10nal therapy for node—negative, estrogen recep-
`OT P051t1Ve women who elect not to receive chemother-
`f3PY because they wish to have a family 5 or more years
`in the future. Clinical trials are ongoing to address both
`the 5-3_1f€t}_' and efficacy of tamoxifen—depot goserelin
`combinations.
`th One natural concern about indefinite tamoxifen
`_eraPY was the probability that an antiestrogenic drug
`tnlght cause serious bone loss. Ultimately, this would
`llmlt the use of the agent in women with either node-
`negatwe disease or those surviving long term. We
`found (in the laboratory) that tamoxifen has a target—
`Site Specificity, i.e., tamoxifen will produce an antiestrov
`
`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 corn
`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.”
`It is known that tamoxifen has a mixture of estrot
`
`genic and antiestrogenic actions,‘ and it is possible that
`the estrogenic actions could cause troublesome side ef.
`fects. Estrogens are known to predispose individuals ts)
`thromboembolic disorders and endometrial carcinoma‘
`Tamoxifen causes some decreases in antithrombin II1
`during long—term adjuvant therapy,” 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.
`TaInoxifen—induced endometrial carcinoma is
`
`at
`
`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 found that a steroid receptor—posi-
`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— '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 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 study” of approximately
`1900 women, randomized to receive no or tamoxifen
`(20 mg twice a day) treatment, found an increase of 1 1
`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 fromall 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 grow by
`tamoxifen. Physicians should, however, I'eITla11"l vigi-
`lant to this possibility and immediately investigate any
`cases of suspicious bleeding.
`
`Astrazeneca Ex. 2020 p. 3
`
`

`
`Antiestrogens and Breast Cancer /Iordmz
`
`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 progestins" and
`aromatase inhibitors,” 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.35 It is
`possible that tamoxifen—stimulated growth has been
`described in the clinic.“ 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.” 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-
`rnatase 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 investigators‘7'3°"‘° 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 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 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 bone” 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. U]-
`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 Ex. 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.“
`In the laboratory, ovariectomy prevents the develop-
`ment of mammary cancer in high-incidence strains of
`mice“ and mammary carcinogenesis in rats.“ 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.“ 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 the?’
`apy‘°'z7 and prevents mammary tumorigenesis in am’
`mal models.‘7'48 The strategy to use tamoxifen t0 PIE’
`vent breast cancer has a strong scientific rationale for
`further evaluation. However, such a strategy will sue’
`ceed only if there is a low incidence of iatrogenic 0115‘
`orders in the women who will never have breast Carlee“
`The side effects that occur with tamoxifen recentll’ were
`reviewed.” Therefore, only the major concerns will b.e
`mentioned in this report. The administration of tame”
`fen to young women (as yet unidentified) of repf0d“C'
`“V9 age might be unacceptable because of (1) the Posft’
`menopausal symptoms, (2) the risks for teratogenesls’
`and (3) the unknown effects of long-term ovarian by’
`PeTSti1'nulation,i.e., ovarian carcinoma in the postmeno’
`pausal years.
`,
`An alternative strategy would be to study the aw;
`it)’ Of tamoxifen to prevent the appearance Of breasg
`cancer in postmenopausal women. However, the Prot
`cess of initiation and promotion of breast cancer almos
`certainly will have occurred before this age, and tame)?’
`ifen will suppress the growth of malignant Cells; Thls
`concept would be considered Chemosuppression, 1-e-I Ki
`PreVeht 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 of tamoxi;
`fen therapy in normal women at
`risk f0T breas
`cancer.5°‘52 Currently, the only concern of significance
`is the declining compliance (80% at 2 years) that Occurs
`in both the tamoxifen and control
`treatment arms‘
`Close volunteer supervision and support will be 955611’
`tial to achieve success in a major study.
`.f 11
`There is the question of the duration for tam0><1 e r
`therapy. Although tamoxifen is an effective agent fot
`the treatment of breast cancer and long-term edlllvan
`therapy is effective, it may be prudent to C011-Sldeéve
`5‘Year regimen rather than indefinite treatment‘
`t,
`have considerable information about 5 years Of treae-
`ment, and additional long-term studies will pI‘0d‘}Ce rm
`sults during the next few years. An analysis of adluva
`
`TUMOR
`DETECTION
`
`INITIATION
`{
`
`PROMOTION
`
`MALIGNANT CELL
`REPLICATION
`
`< PREVENTION >< cmsmosuppnessnon > JREATMEN
`Figure 2. Concepts for the strategic use of antiestrogens *0 C°“fl’
`the development of breast cancer,
`
`1
`
`Astrazeneca Ex. 2020 p. 5
`
`

`
`Antiestrogens and Breast Cancer /Iordan
`
`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—
`Inary 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-
`tiestrogens 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
`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.
`
`4.
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`5,
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`3. Harper MJK, Walpole AL. A new derivative of triphenylethyl—
`ene effect on implantation and mode of action in rats. ] Reprod
`FrrtiI1967; 132101-19.
`Jordan VC. Murphy CS. Endocrine pharmacology of antiestro~
`gens as antitumor agents. Endocr Rev 1990; 11:578-610.
`Jordan VC. Laboratory studies to develop general principles for
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`treatment of breast cancer with antiestrogens;
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`Cancer Res Treat 1983; 3(Suppl):73—86.
`I
`6_ Early Breast Cancer Trialists' Collaborative Group. Effects of
`adjuvant tamoxifen and of cytotoxic therapy on mortality in
`early breast cancer. N Eng] J Med 1988; 319:1681—92.
`7. Cole MP, Jones CTA, Todd IDH. A new antioestrogenic agent in
`late breast cancer. Br [ Cancer 1971; 2512705-
`Jordan VC, Long—te1‘m adjuvant tamoxifen therapy from breast
`Cancer; the prelude to 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. Lamar 1987; 2:l71~5.
`1()_ Fisher B, Custantino J, Redmond C, Poisson R, Bowman D, Cou-
`ture J, et al. A randomized clinical trial evaluating tamoxifen in
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`have estrogen receptor positive tumors. N Engl J Med 1989;
`320:479~84.
`11. Falkson HC, Cray R, Wolberg Wl-l, Gilchrist KW, Harris J13, Tor-
`mey DC, et al. Adjuvant trial of 1?. cycles of CMFPT, followed
`by observation or continuous tamoxifen versus 4 cycles of
`CMFPT in postmenopausal women with breast cancer: an
`ECOG Phase lll study. ] Clin Oncol 1990; 8599-607.
`12. Boccarclo 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
`
`3,
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`AstraZeneca Ex. 2020 p. 6
`
`

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`CANCER Supplement August 15, 1992, Volume 70, No. 4
`
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`breast cancer patients: results of a multicentric Italian study. I
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`Tormey DC, Jordan VC. Long—term adjuvant therapy in node
`positive breast cancer: a metabolic and pilot clinical study. Breast
`Cancer Res Treat 1984; 4:297—302.
`Tormey DC, Rasmussen P, Jordan VC. Update on long—term
`tamoxifen study [letter]. Breast Cancer Res Treat 1987; 9:157-8.
`Jordan 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-
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`Ravdin PM, Fritz NF, Tormey DC, Jordan VC. Endocrine status
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`ing adjuvant chemotherapy and long-term tamoxifen. Cancer
`Res 1987; 48:1026-9.
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