`
`Cancer-50 Years Later
`
`|
`
`‘Taylor SG III, Slaughter DP, Smejkal W, Fowler EF, Preston FW. Theeffect of sex hormones
`on advanced carcinoma of the breast. Cancer 1948;1:604-17.
`
`Progress in Endocrine Therapy for Breast Carcinoma
`
`Gabriel N. Hortobagyi, mv.
`
`Department of Breast Medical Oncology, The Uni-
`versity of Texas M. D. Anderson Cancer Center,
`Houston, Texas.
`
`ur understanding of the mechanisms of action of hormonal
`agents in normal and pathologic breast tissue has expanded
`dramatically over the last 30 years. The identification of specific
`receptors for estrogens, progestins, androgens, and glucocorticoids
`led to the elucidation of the cascade of events that results in the
`intended effect of steroid hormones.’* This cascade begins with
`the entry of the hormoneinto thecell, its binding to the specific
`receptor protein, and the signal transduction pathway that even-
`tually results in the intended hormonaleffect, such as induction of
`cell proliferation or division, or the production of additional hor-
`monal receptor proteins. The contributions of multiple investiga-
`tors to this process were summarized elegantly by Levenson and
`Jordan in 1997.* The ability to identify and quantitate estrogen and
`progesterone receptor expression in individual tissues soon was
`followed by clinical correlations that established the diagnostic
`and predictive importance of these elements in the managementof
`metastatic and primary breast carcinoma.* Thus it was shown that
`patients with metastatic breast carcinoma whose tumors express a
`high concentration of estrogen receptors have a much higher prob-
`ability of response to hormonal therapy than patients whose tu-
`mors express a low concentration or do not express estrogen
`receptors at all. Subsequent studies demonstrated that the simul-
`taneous expression of estrogen and progesterone receptors further
`increased the probability of response to endocrine therapy, thus
`serving as a marker of an intact hormonal effector pathway.° Al-
`though otherclinical characteristics of the tumor such as extent of
`metastatic spread, patient age, duration of menopause, disease
`free interval, location of tumor, and, more recently, some molec-
`ular markers may influence the probability of response further, by
`far the degree of hormone receptor expression is the most impor-
`tant predictive factor.
`These observations also were reproduced in the context of the
`primary multidisciplinary management of breast carcinoma. Thus,
`adjuvant hormonal therapy, mostly with the antiestrogen tamoxifen,
`As Cancer commemorates 50 years of continuous
`was foundto beeffective in estrogen/progesterone receptor positive
`publication, this article is one of a series of sum-
`tumors, and essentially ineffective in those tumors without hormone
`maries on the current status of some of the on-
`
`
`cologic issues reported in the first volume in 1948. ».6-10 5
`receptor expression.”~~”Hormonereceptor expression also was found
`Addressforreprints: Gabriel N. Hortobagyi, M.D.,
`to be an important prognostic indicator for patients with metastatic
`Department of Breast Medical Oncology, The Uni-
`and primary breast carcinoma."! Patients with hormone receptor
`versity of Texas M. D. Anderson Cancer Center,
`positive tumors have a longer survival after the development of me-
`eon ES,
`(616 Fiolecmiie Tva., Reade, Ti
`tastasis than patients with hormone receptor negative tumors.'?“®
`77030-4009.
`x
`ape
`-
`5
`There also is a different pattern of metastatic spread, with hormone
`receptor positive tumors metastasizing preferentially to soft tissues
`and bone, whereas hormone receptor negative tumors spread with
`
`Received March 16, 1998; accepted March 28,
`1998.
`
`© 1998 American Cancer Society
`
`AstraZeneca Exhibit 2035 p. 1
`InnoPharma Licensing LLC v. AstraZeneca AB IPR2017-00904
`Fresenius-Kabi USA LLCv. AstraZeneca AB IPR2017-01910
`
`
`
`2
`
`CANCER July 1, 1998 / Volume 83 / Number1
`
`greater frequency to deep visceral organs, such as the
`liver, lung, and brain.’”
`In primary breast carcinoma patients with estro-
`gen receptor negative tumors tend to haveearlier re-
`currencesand,at least duringthefirst 5 years, a higher
`incidence of failure than patients with hormonere-
`ceptor positive tumors. Some studies with long fol-
`low-up have suggested that after the initial 3-5 years,
`the prognostic value of estrogen receptor expression
`decreases or even disappears, with the ultimate prob-
`ability of recurrence and death being similar for estro-
`gen receptor positive and estrogen receptor negative
`tumors, or in somecases, even inverted.!?7!
`While our biologic understanding of receptor ac-
`tivity has expanded, a quiet revolution was.
`taking
`place in the development of hormonal agents. Perhaps
`the most influential group of these agents was the
`antiestrogens.** Originally developed for purposes of
`contraception, tamoxifen and nafoxidine were found
`to have potent antiestrogenic activity.*”*° The initial
`clinical trials showed that approximately 33% of pa-
`tients with previously untreated metastatic breast car-
`cinoma, and perhaps a somewhat smaller percentage
`of patients with prior treatment, responded to anties-
`trogen therapy.2* No dose response was identified,
`and from the very early studies it became apparent
`that this agent was better tolerated than all other
`hormonal agents available at the time. The comple-
`tion of several randomized clinical trials that com-
`pared tamoxifen with estrogens,?° aminoglutethim-
`ide,*° progestins,2”*° and oophorectomy?**’ soon
`established the preeminent role of this agent as the
`treatment of choice for hormone-responsive meta-
`static breast carcinoma. Subsequent experience ex-
`tended these observations to male breast carcino-
`ma,*'**? and to the management of lymph node
`positive®**°> and lymph node negative®?*°°" breast
`carcinoma. Today, antiestrogens in general, and ta-
`moxifen in particular, are considered the first-line
`treatment of choice for hormone-responsive meta-
`static breast carcinoma, and hormonal receptor posi-
`tive primary breast carcinoma that requires adjuvant
`systemic treatment.**
`A second group of hormonal agents that was de-
`veloped over the last 30 years includes the proges-
`tins.** Megestrol acetate***° and medroxyprogester-
`one acetate!” are the two principal representatives
`of this group. The mechanism of action of progestins
`is uncertain. Inhibition of gonadotrophin secretion
`and reduced steroid biosynthesis have been proposed;
`others have put forth a direct inhibition of cell growth
`after binding of ligand to the progesterone receptor,
`and down-regulation of estrogen receptor levels, re-
`sulting in reduced sensitivity of tumor cells to estro-
`
`gen. Clinical studies have demonstrated that patients
`with estrogen receptor positive tumors respond better
`to progestins than those with estrogen receptor nega-
`tive tumors. Although controversy regarding the opti-
`mal dose of progestins is ongoing,
`the majority of
`experts would agree that a dose response remains
`unconfirmed. Progestins are well tolerated, but cause
`weight gain, fluid retention, and dyspnea. For this
`reason, this agent usually is recommendedas second-
`line hormone therapy after tamoxifen has outlived its
`usefulness.
`A dramatic new developmentis the appearance of
`specific and selective aromatase inhibitors.47-Ami-
`noglutethimide was the first aromatase inhibitor de-
`veloped, but this compound wasnot selective, result-
`ing in broad inhibition of adrenal steroid production.
`In addition, substantial toxic effects also accompanied
`its use in a significant minority of patients with breast
`carcinoma. Therefore, although its equivalence to
`similar endocrine interventions was established by
`clinical trials, the appearance of better tolerated and
`more selective aromatase inhibitors such as anastro-
`zole and letrozole has completely displaced aminoglu-
`tethimide. Both anastrozole and letrozole have been
`shown to be moreeffective than progestins*® and bet-
`ter tolerated than aminoglutethimide. Therefore, their
`therapeutic ratio appears superior to the progestins
`and aminoglutethimide. Currently, these agents are
`being comparedwith antiestrogensin the treatment of
`metastatic breast carcinoma. Furthermore,
`future
`studies will determine whether the addition of selec-
`tive and potent aromatase inhibitors to other hor-
`monal interventions, such as antiestrogens or gona-
`dotrophin-releasing hormone analogs, will result in
`improved therapeutic efficacy without a substantial
`increase in toxic effects.
`The earliest randomizedtrials of antiestrogens de-
`termined that these compounds were equivalent to
`the major surgical ablative procedures (oophorecto-
`my, adrenalectomy, and hypophysectomy) without
`the irreversible effects of the surgical procedures.*”**®
`These results rapidly transformed the face of hor-
`monal therapy, causing the total displacement of the
`major surgical ablations. Although ovarian ablation
`still is employed in some centers for reasons of cost
`and expediency, hormonal approaches with better
`therapeutic ratios are preferred.'
`The
`luteinizing hormone-releasing hormone
`(LHRH) analogs were developed to inhibit the entire
`hypothalamic, hypophysiary, and gonadal axis.'*°~*!
`These agents have proven to be of major efficacy in
`chemical gonadal ablation in both women and men.
`Therefore, they are used for the managementof breast
`and prostate carcinoma with considerable success.
`
`AstraZeneca Exhibit 2035 p. 2
`
`
`
`They are very well tolerated, with a side effect profile
`that compares favorably with the antiestrogens or the
`new aromatase inhibitors. Although the systems of
`administration still are evolving,
`these agents have
`numerous advantages over surgical or radiant gonadal
`ablation.
`Although high dose estrogens seldom are used,
`synthetic androgens (fluoxymesterone) are used in pa-
`tients with persistently hormone-responsive tumors
`as fourth-line therapy, after antiestrogens, aromatase
`inhibitors, and progestins.
`
`New Directions in Hormonal Therapy
`and
`(tamoxifen
`The
`existing
`antiestrogens
`toremifene) have mixed estrogen agonist and antag-
`onist effects.°*°* Although the antiestrogenic effect
`is responsible for the antitumorefficacy, the estro-
`gen agonist effect results in maintenance of bone
`mineral content as well as a favorable modification
`of plasma lipid concentrations. However,
`it has
`been proposed that the estrogen agonist effect is
`responsible for the development of endometrial car-
`cinoma,’ and most likely for the development of
`antiestrogen-resistant breast carcinoma cells.°° Re-
`cent research in antiestrogens has produced two
`new types of compounds. Thefirst represent pure
`antiestrogens, without any agonist effects.°° Prelim-
`inary reports suggest that these agents might be
`effective in tamoxifen-resistant tumors in vitro and
`in vivo. The long term clinical effects and the ther-
`apeutic ratio of these agents remain under investi-
`gation. The second group of agents is the selective
`estrogen receptor modulators (SERMs).°”°® These
`agents retain the antiestrogenic effect of tamoxifen
`over breast carcinoma while retaining the estrogen
`agonist effect over bone and plasmalipids. At the
`same time, they are deprived of the estrogen agonist
`effect over the endometrium and potentially other
`tissues. The Food and Drug Administration recently
`approved the first SERM for the management of
`osteoporosis. Other indications under investigation
`include the management of metastatic breast carci-
`noma, adjuvant therapy of breast carcinoma, and
`hormone replacement therapy in patients with a
`history of breast or gynecologic malignancies.
`Antiandrogens,
`antiprogestins, and additional
`types of aromatase inhibitors currently are under lab-
`oratory and clinical investigation.*°
`Until the late 1980s, it generally was believed that
`combination hormonal therapy was not more effec-
`tive, but potentially more toxic than single agent hor-
`monal manipulation. The advent of modern hormonal
`agents has shaken this belief. Preliminary results sug-
`gest that the addition of tamoxifen to LHRH analogs
`
`Endocrine Therapy for Breast Carcinoma/Hortobagyi
`
`3
`
`might result in increased therapeutic efficacy.*°*! An
`additional evaluation of combined hormonal therapy,
`both simultaneously and in sequence, clearly is war-
`ranted,
`There are indications that mutations in the p53
`gene, the overexpression of HER-2/neu oncogene,
`and other well characterized molecular abnormali-
`ties might be associated with resistance to hormonal
`intervention.©’-© If these findings are confirmed
`prospectively, they will lead to better selection of
`hormone-responsive and hormone-resistant pa-
`tients for optimal therapy, and might also provide
`novel targets for the prevention or reversal of hor-
`monal resistance.
`1.
`represents a classic
`The article by Taylor et al.°*
`example of enlightened empiricism. At a time when
`modern clinical trial methodology was unknown,
`and when oncology itself was just a nascent disci-
`pline, these pioneers provided an incredible lesson
`in the powerofcareful clinical observation. All their
`critical observations have been confirmed by subse-
`quent studies, including the controlled randomized
`trials initiated several decades later. The authors
`reported that estrogen therapy waseffective in ap-
`proximately 33% of female patients. Furthermore,
`they observed a higher frequency of objective re-
`sponses in older, postmenopausal women com-
`pared with younger women. The observation that
`estrogen therapy was more effective in cutaneous,
`subcutaneous, and lymph node metastases com-
`pared with visceral metastases also has been con-
`firmed repeatedly. Taylor et al. also described the
`lack of radiographic objective responses in osseous
`metastases, which is more an artifact of our ability
`to monitor bone resorption and remodeling than a
`true lack of therapeutic efficacy of the hormones
`understudy. Taylor et al. made similar observations
`regarding androgen therapy. However, with the use
`of androgens, they provided clear evidence of recal-
`cification in bone metastases, a reproducible effect
`with particular relevance to androgen treatment.
`The authors also demonstrated response to andro-
`gens in estrogen receptor-resistant
`tumors, and
`documented the rapid relief of pain in patients with
`bone metastases. The phenomenon of androgen-
`induced tumor flare also was described in this re-
`port. The authors further observed that the duration
`of response to hormonal therapy was dependent on
`the duration of administration of hormones, and
`that when metastatic tumors recurred after discon-
`
`tinuation of hormonal treatment, reinduction was
`possible with the same agent. Taylor et al. reported
`the appearance of mixed responses. Other impor-
`tant observations included the fact that hormonal
`
`AstraZeneca Exhibit 2035 p. 3
`
`
`
`4
`
`CANCER July 1, 1998 / Volume 83 / Number1
`
`therapy could down-stage inoperable locally ad-
`vanced breast carcinoma patients and convert them
`into surgical candidates. The authors also reported a
`single case of male breast carcinoma with a dra-
`matic response to hormonal therapy. Taylor et al.
`presented one ofthe earliest reports of what appears
`to be an objective response to testosterone in a
`patient with brain metastasis. Finally, the authors
`presented a very careful analysis of the side effects
`and toxicity of both estrogens and androgensin this
`group of patients with breast carcinoma. Theirlist is
`complete enough that more recent controlled trials
`have not added many new itemstoit.
`The lesson from this article is that with commit-
`
`ment and dedication, careful clinical observation
`has an extremely important role in furthering our
`understanding of the behavior of a disease, as well
`as the therapeutic interventions under evaluation.
`Today, 50 years after the publication of this article,
`we are fortunate enough to have a much broader
`and deeper understanding of the natural history of
`breast carcinoma, as well as the mechanism of ac-
`tion of hormonal interventions. Furthermore,
`the
`last 50 years have given us an increasingly refined
`methodology for the planning and conductof clin-
`ical trials, whereas a systematic approach to new
`drug development has provided us with novel, ef-
`fective, and well
`tolerated hormonal agents. Al-
`though we stand on the shoulders of giants, we will
`look forward with optimism to additional develop-
`ments in the management of primary and meta-
`static breast carcinoma.
`
`REFERENCES
`1. Hortobagyi GN. Endocrine treatment of breast cancer. In:
`Becker KL, editor. Principles and practice of endocrinology
`and metabolism. Philadelphia: J.B. Lippincott Company,
`1995:1868-75.
`2. Horwitz KB, Costlow ME, McGuire WL. MCEF-7: a human
`breast cancer cell line with estrogen, androgen, progester-
`one, and glucocorticoid receptors. Steroids 1975;26:785-95.
`3. Levenson AS, Jordan VC. MCE-7: the first hormone-respon-
`sive breast cancer cell line. Cancer Res 1997;57:3071-8.
`4. McGuire WL, Carbone PP, Sears ME, Escher GC. Estrogen
`receptors in human breast cancer: an overview. In: McGuire
`WL, Carbone PP, Vollmer EP, editors. Estrogen receptors in
`human breast cancer. New York: Raven, 1975:1-7.
`5. Horwitz KB, McGuire WL. Estrogen and progesterone: their
`relationship in hormone-dependent breast cancer.
`In:
`McGuire WL, Raynaud JP, Baulieu EE, editors. Progesterone
`receptors in normal and neoplastic tissues. New York: Raven
`Press, 1977:103-24.
`6. Nolvadex Adjuvant Trial Organization. Controlled trial of
`tamoxifen as adjuvant agent in management of early
`breast cancer -Interim analysis at four years. Lancet 1983;
`i:257-61.
`
`7. The Ludwig Breast Cancer Study Group. Randomisedtrial of
`chemo-endocrine therapy, endocrine therapy, and mastec-
`
`tomy alone in postmenopausal patients with operable
`breast cancer and axillary node metastasis. Lancet 1984;i:
`1256-60.
`
`Anonymous. Adjuvant tamoxifen in the managementof op-
`erable breast cancer:
`the Scottish Trial. Report from the
`Breast Cancer Trials Committee, Scottish Cancer Trials Of-
`fice (MRC), Edinburgh. Lancet 1987;2:171-5.
`Anonymous. Systemic treatment of early breast cancer by
`hormonal, cytotoxic, or immune therapy. 133 randomised
`trials involving 31,000 recurrences and 24,000 deaths among
`75,000 women. Early Breast Cancer Trialists’ Collaborative
`Group [see comments]. Lancet 1992;339:71-85.
`Anonymous. Systemic treatment of early breast cancer by
`hormonal, cytotoxic, or immune therapy. 133 randomised
`trials involving 31,000 recurrences and 24,000 deaths among
`75,000 women. Early Breast Cancer Trialists’ Collaborative
`Group [review] [see comments]. Lancet 1992;339: 1-15.
`Knight WA, Livingston RB, Gregory EJ, McGuire WL. Es-
`trogen receptor as an independent prognostic factor for
`early recurrence in breast cancer. Cancer Res 1977;37:
`4669-71.
`Howell A, Barnes DM, Harland RN, Redford J, Bramwell VH,
`Wilkinson MJ, et al. Steroid-hormonereceptors and survival
`after first relapse in breast cancer. Lancet 1984;1:588-91.
`McGuire WL. Hormonereceptors: their role in predicting
`prognosis and response to endocrine therapy. Semin Oncol
`1978;5:428-33.
`Samaan NA, Buzdar AU, Aldinger KA, Schultz PN, Yang KP,
`Romsdahl MM, et al. Estrogen receptor: a prognostic factor
`in breast cancer. Cancer 1981;47:554-60.
`Mason BH, Holdaway IM, Mullins PR, Yee LH, Kay RG.
`Progesterone and estrogen receptors as prognostic variables
`in breast cancer. Cancer Res 1983;43:2985-90.
`Clark GM, Osborne CK, McGuire WL. Correlations between
`estrogen receptor, progesterone receptor, and patient char-
`acteristics in human breast cancer. J Clin Oncol 198432:
`1102-9.
`
`Clark GM,Sledge GW Jr., Osborne CK, McGuire WL. Survival
`from first recurrence: relative importance of prognostic fac-
`tors in 1,015 breast cancer patients. J Clin Oncol 1987;5:55—
`61.
`
`the
`Shek LL, Godolphin W. Survival with breast cancer:
`importance of estrogen receptor quantity. Eur J Cancer Clin
`Oncol 1989;25:243-50.
`Raemaekers JM, Beex LV, Koenders AJ, Pieters GF, Smals AG,
`Benraad TJ, et al. Disease-free interval and estrogen recep-
`tor activity in tumor tissue of patients with primary breast
`cancer: analysis after long-term follow-up. Breast Cancer Res
`Treat 1985;6:123-30.
`Andry G, SuciuS, Pratola D, Sylvester R, Leclercq G, da Costa
`PM,etal. Relation between estrogen receptor concentration
`andclinical and histological factors: their relative prognostic
`importance after radical mastectomy for primary breast
`cancer. Eur J Cancer Clin Oncol 1989;25:319-29.
`Crowe JP Jr., Gordon NH, Hubay CA, Shenk RR, Zollinger
`RM,et al. Estrogen receptor determination and long term
`survival of patients with carcinomaof the breast. Surg Gy-
`necol Obstet 1991;173:273-8.
`LeghaSS, Carter SK. Antiestrogens in the treatmentof breast
`cancer. Cancer Treat Rev 1976;3:205-16.
`Legha SS, Slavik M, Carter SK. Nafoxidine—an antiestrogen
`for the treatment of breast cancer. Cancer 1976;38:1535-
`41.
`
`10.
`
`11.
`
`12.
`
`13.
`
`14,
`
`15.
`
`16.
`
`17.
`
`18.
`
`19.
`
`20.
`
`Al.
`
`22.
`
`23.
`
`AstraZeneca Exhibit 2035 p. 4
`
`
`
`24.
`
`DB.
`
`26.
`
`27.
`
`28.
`
`Jaiyesimi IA, Buzdar AU, Decker DA, Hortobagyi GN. Use of
`tamoxifen for breast cancer: twenty-eight years later [re-
`view] [see comments]. J Clin Oncol 1995;13:513-29.
`Matelski H, Greene R, Huberman M, Lokich J, Zipoli T.
`Randomized trial of estrogen vs. tamoxifen therapy for ad-
`vanced breast cancer. Am J Clin Oncol 1985;8:128-33.
`Lipton A, Harvey HA, Santen RJ, Boucher A, White D, Ber-
`nath A, et al. A randomized trial of aminoglutethimide ver-
`sus tamoxifen in metastatic breast cancer. Cancer 1982;50:
`2265-8.
`
`Ettinger DS, Allegra J, Bertino JR, Bonomi P, Browder H,
`Byrne P, et al. Megestrol acetate v tamoxifen in advanced
`breast cancer: correlation of hormone receptors and re-
`sponse. Semin Oncol 1986;13:9-14.
`Muss HB, Wells HB, Paschold EH, Black WR, Cooper MR,
`Capizzi RL, et al. Megestrol acetate versus tamoxifen in
`advanced breast cancer: 5-year analysis—a PhaseLItrial of
`the Piedmont Oncology Association. J Clin Oncol 1988;6:
`1098-106.
`
`ou.
`
`30.
`
`SL
`
`32.
`
`33.
`
`34.
`
`35.
`
`Buchanan RB, Blamey RW, Durrant KR, Howell A, Paterson
`AG, Preece PE,et al. A randomized comparison of tamoxifen
`with surgical oophorectomy in premenopausal patients
`with advanced breast cancer. J Clin Oncol 1986;4:1326-30.
`Ingle JN, Krook JE, Green SJ, Kubista TP, Everson LK, Ah-
`mann DL,et al. Randomizedtrial of bilateral oophorectomy
`versus tamoxifen in premenopausal women with metastatic
`breast cancer. J Clin Oncal 1986;4:178-85.
`Lopez M, Di Lauro L, Lazzaro B, Papaldo P. Hormonal
`treatment of disseminated male breast cancer. Oncology
`(Huntingt) 1985;,42:345-9.
`Hortobagyi GN, DiStefano A, Legha SS, Buzdar AU, Blumen-
`schein GR. Hormonal therapy with tamoxifen in male breast
`cancer. Cancer Treat Rep 1979;63:539-41.
`Kantarjian H, Yap HY, Hortobagyi G, Buzdar A, Blumens-
`chein G. Hormonal therapy for metastatic male breast can-
`cer. Arch Intern Med 1983;143:237—40.
`Fisher B, Redmond C, Brown A, Wolmark N, WittliffJ, Fisher
`ER, et al. Treatment of primary breast cancer with chemo-
`therapy and tamoxifen. N Engl J Med 1981;305:1-6.
`Anonymous. Randomisedtrial of chemo-endocrine therapy,
`endocrine therapy, and mastectomy alone in postmeno-
`pausal patients with operable breast cancer and axillary
`node metastasis. Ludwig Breast Cancer Study Group. Lancet
`19845 1:1256-60.
`. Wallgren A, Baral E, Glas U, Karnstrom L, Nordenskiord B,
`Theve NO, et al. Adjuvant tamoxifen treatment in post-
`menopausal patients with operable breast cancer. J Steroid
`Biochem Mol Biol 1985;23:1161-2.
`. Love RR. Tamoxifen in axillary node-negative breast cancer:
`multisystem benefits and risks [review]. Cancer Invest 1992,
`10:587-93.
`
`38.
`
`39.
`
`40.
`
`Al.
`
`Goldhirsch A, Gelber RD. Endocrinetherapies of breast can-
`cer [review]. Semin Oncol 1996;23:494-505.
`Muss HB, Cruz JM. High-dose progestin therapy for meta-
`static breast cancer [review]. Amn Oncol 1992;3(Suppl 3):
`15-20.
`
`Canetta R, Florentine $5, Hunter H, Lenaz L. Megestrol ace-
`tate. Cancer Treat Rev 1983;10:141-57.
`Muss HB, Case LD, Atkins JN, Bearden J, 3rd, Cooper MR,
`Cruz JM, et al. Tamoxifen versus high-dose oral medroxy-
`progesterone acetate as initial endocrine therapy for pa-
`tients with metastatic breast cancer: a Piedmont Oncology
`Association study [see comments]. J Clin Oncol 1994;12:
`1630-8.
`
`Endocrine Therapy for Breast Carcinoma/Hortobagyi
`
`5
`
`42.
`
`43.
`
`44,
`
`45.
`
`46.
`
`Cavalli F, Goldhirsch A, Jungi F, Martz G, Mermillod B,
`Alberto P. Randomized trial of low- versus high-dose me-
`droxyprogesterone acetate in the induction treatment of
`postmenopausal patients with advanced breast cancer.
`J Clin Oncol 1984;2:414-9.
`Anonymous. New aromatase inhibitors for breast cancer
`[review]. Drug Ther Bull 1997;35:55-6.
`Brodie AM, Njar VC. Aromatase inhibitors and breast cancer
`[review]. Semin Oncol 1996;23:10-20.
`Buzdar AU, Plourde PV, Hortobagyi GN. Aromatase inhibi-
`tors in metastatic breast cancer. Semin Oncol 1996;23:28-32.
`Buzdar AU, Jones SE, Vogel CL, Wolter J, Plourde P, Webster
`A. A phase III trial comparing anastrozole (1 and 10 milli-
`grams), a potent and selective aromatase inhibitor, with
`megestrol acetate in postmenopausal women with ad-
`vanced breast carcinoma. Arimidex Study Group. Cancer
`1997;79:730-9.
`Nemoto T, Patel J, Rosner D, Dao TL. Tamoxifen (Nolvadex)
`versus adrenalectomy in metastatic breast cancer. Cancer
`1984;53:1333-5.
`Wells SA Jr., Santen RJ. Ablative procedures in patients with
`metastatic breast carcinoma. Cancer 1984;53:762-5.
`Nijn JGM, Seynaeve C, Beex L, Mauriac L, van Zijl J,
`Veyret C, et al. Combined treatment With buserelin
`(LHRH-A) and tamoxifen vs single treatment with each
`drug alone in premenopausal metastatic breast cancer:
`preliminary results of EORTC study 10881 [abstract 132].
`Proc Am Soe Clin Oncol 1996;15:117.
`. Taylor CW, Green S, Dalton WS, Martino S, Ingle JN, Robert
`NJ, et al. A multi-center randomized trial of zoladex versus
`surgical ovariectomy in pre-menopausal patients with re-
`ceptor positive metastatic breast cancer [abstract 19]. Breast
`Cancer Res Treat 1996;37:37.
`Boccardo F, Rubagotti A, Perrotta A, Amoroso D,
`Balestrero M, de Matteis A, et al. Ovarian ablation versus
`goserelin with or without tamoxifen in pre-perimeno-
`pausal patients with advanced breast cancer: results of a
`multicentric Italian study. Ann Oncol 1994;5:337-42.
`Jordan VC. Estrogen receptor-mediated direct and indirect
`antitumor effects of tamoxifen. J Natl Cancer Inst 1990;82:
`1662-3.
`. Love RR, Newcomb PA, Wiebe DA, Surawicz TA, Jordan VC,
`CarbonePP, et al. Effects of tamoxifen therapy on lipid and
`lipoprotein levels in postmenopausal patients with node-
`negative breast cancer [see comments]. J Natl Cancer Inst
`1990;82:1327-22.
`. Jordan VC. Molecular mechanismsof antiestrogen action in
`breast cancer [review]. Breast Cancer Res Treat 1994;31:41-
`52.
`. Assikis VJ, Jordan VC. Tamoxifen and endometrial cancer:
`from experiment to patient [review]. Recent Results Cancer
`Res 1996;140:61-71.
`Catherino WH, Jordan VC. A point mutation in the estrogen
`receptor from a tamoxifen-stimulated human breast cancer
`can explain the change of tamoxifen pharmacology from an
`antiestrogen to an estrogen [abstract]. Breast Cancer Res
`Treat 1994;32:32.
`Draper MW,Flowers DE, Huster WJ, Neild JA, Harper KD,
`Arnaud C. A controlled trial of raloxifene (LY139481) HCI:
`impact on bone turnover and serum lipid profile in
`healthy postmenopausal women. J Bone Miner Res 1996;
`11:835-42.
`
`47.
`
`48.
`
`49.
`
`51.
`
`Se.
`
`56.
`
`BF.
`
`AstraZeneca Exhibit 2035 p. 5
`
`
`
`6
`
`58.
`
`5a.
`
`60.
`
`61.
`
`62.
`
`CANCER July 1, 1998 / Volume 83 / Number1
`
`Paech K, Webb P, Kuiper GG, Nilsson S, Gustafsson J, Kushner
`PJ, et al. Differential ligand activation of estrogen receptors
`ERalpha and ERbeta at API sites. Science 1997;277:1508-10.
`Howell A, Downey S, Anderson E. New endocrine therapies
`for breast cancer [review]. Eur J Cancer 1996;32A:576-88.
`Rutqvist LE. Randomized adjuvant breast cancertrials in
`Sweden. Cancer 1994;74(Suppl):1156-9.
`Sluyser M. Nuclear hormone receptor variants: their role in
`malignancy and progression to hormone resistance in can-
`cer. Acta Endocrinol 1991;126:48-53.
`Silvestrini R, Benini E, Veneroni S, Daidone MG, Tomasic G,
`Squicciarini P, et al. p53 and bel-2 expression correlates with
`
`63.
`
`64.
`
`clinical outcome in a series of node-positive breast cancer
`patients. J Clin Oncol 1996;14:1604-10.
`Yamauchi H, O’Neill A, Gelman R, Carney W, HoschS, Kufe
`DW,et al. Elevated circulating HER-2/neu-related protein
`(NRP) is associated with low response rate (RR) to first-line
`hormone therapy (HT)
`in patients with estrogen and/or
`progesteronereceptor positive (ER, PR Pos) advanced breast
`cancer (AdBrCA) [meeting abstract]. Proc Annu Meet Am Soc
`Clin Oncol 1996;15:A116.
`Taylor SG IH, Slaughter DP, Smejkal W, Fowler EF, Pres-
`ton FW. The effect of sex hormones on advanced carci-
`noma of the breast. Cancer 1948;1:604-17.
`
`AstraZeneca Exhibit 2035 p. 6
`
`