I
`
`Cancer—50 Years Later
`
`Taylor SG Ill, Slaughter DP, Smejkal W, Fowler EF, Preston FW. The effect of sex hormones
`on advanced carcinoma of the breast. Canter l948;l:604—l7.
`
`Progress in Endocrine Therapy for Breast Carcinoma
`
`Gabriel N. Hortobagyi, M.D.
`
`Department of Breast Medical Oncology, The Uni-
`verSiiy Of Texas M- D- Anderson Cancer Center.
`Housmn' Texas'
`
`As Cancer commemorates 50 years of continuous
`Publication this anioie is one Of a series 0f sum-
`marks _°" the current §taius 9i some (“The 0""
`cologrc Issues reported In the frrstvolume In 1948.
`
`Address for reprints: Gabriel N. Honobagyi‘ MD”
`Department of Breast Medical Oncology, The Uni—
`verSiiy Of Texas M- D- Anderson Cancer Center.
`Box 56, 1515 Holcombe Blvd., Houston, TX
`77030—4009.
`
`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 h()rmones.1’2 This cascade begins with
`the entry of the hormone into the cell, its binding to the specific
`receptor protein, and the signal transduction pathway that even-
`tually results in the intended hormonal effect, 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 1997.3 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 management of
`metastatic and primary breast carcinoma.4 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.5 Al-
`though other clinical 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,
`was found to be effective in estrogen/progesterone receptor positive
`tumors, and essentially ineffective in those tumors without hormone
`.
`6,10
`.
`receptor express1on.
`Hormone receptor express1on also was found
`
`to be an important prognostic indicator for patients with metastatic
`and primary breast carcinoma.11 Patients with hormone receptor
`positive tumors have a longer survival after the development of me-
`12716
`tastasis than patients with hormone receptor negau've tumors.
`.
`.
`.
`.
`There also is a dlfferent pattern of metastatic spread, w1th hormone
`
`Received March 16‘ 1998; accepted March 28’
`1998.
`
`receptor positive tumors metastasizing preferentially to soft tissues
`and bone, whereas hormone receptor negative tumors spread with
`
`© 1998 American Cancer Society
`
`AstraZeneca Exhibit 2035 p. 1
`InnoPharma Licensing LLC V. AstraZeneca AB IPR2017—00905
`
`

`

`2
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`CANCER July 1, 1998 / Volume 83 / Number 1
`
`greater frequency to deep visceral organs, such as the
`liver, lung, and brain.17
`In primary breast carcinoma patients with estro-
`gen receptor negative tumors tend to have earlier re-
`currences and, at least during the first 5 years, a higher
`incidence of failure than patients with hormone re-
`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 some cases, even inverted.18’21
`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.22 Originally developed for purposes of
`contracepfi'on, tamoxifen and nafoxidine were found
`to have potent antiestrogenic activity.22'23 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.24 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,25 aminoglutethim-
`ide,26 progestins,27’28 and oophorectomyzg”30 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-
`
`maf‘l’33 and to the management of lymph node
`positive‘5’3‘4’35 and lymph node negative‘i’g’s‘s’37 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.24
`A second group of hormonal agents that was de-
`veloped over the last 30 years includes the proges-
`tins.38 Megestrol acetate39’40 and medroxyprogester-
`one acetate‘u'42 are the two principal representafi'ves
`of this group. The mechanism of acu'on of progestins
`is uncertain. Inhibiu'on of gonadotrophin secretion
`and reduced steroid biosynthesis have been proposed;
`others have put forth a direct inhibifion 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 progesu'ns 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 recommended as second-
`]ine hormone therapy after tamoxifen has outlived its
`usefulness.
`
`A dramatic new development is the appearance of
`specific and selective aromatase inhibitors?”45 Ami-
`noglutethimide was the first aromatase inhibitor de-
`veloped, but this compound was not 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 more effective than progestins46 and bet-
`ter tolerated than aminoglutethimide. Therefore, their
`therapeutic ratio appears superior to the progestins
`and aminoglutethimide. Currently, these agents are
`being compared with anu'estrogens in 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 intervenu'ons, such as antiestrogens or gona-
`dotrophin-releasing hormone analogs, will result in
`improved therapeutic efficacy without a substantial
`increase in toxic effects.
`
`The earliest randomized trials 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.“48
`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 rau'os are preferred.1
`The
`luteinizing hormone-releasing hormone
`(LHRH) analogs were developed to inhibit the enu're
`hypothalamic, hypophysiary, and gonadal axis.1’49’51
`These agents have proven to be of major efficacy in
`chemical gonadal ablation in both women and men.
`Therefore, they are used for the management of breast
`and prostate carcinoma with considerable success.
`
`AstraZeneca Exhibit 2035 p. 2
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`

`

`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.52’54 Although the antiestrogenic effect
`is responsible for the antitumor efficacy, the estro-
`gen agonist effect results in maintenance of bone
`mineral content as well as a favorable modification
`
`it has
`of plasma lipid concentrations. However,
`been proposed that the estrogen agonist effect is
`responsible for the development of endometrial car-
`cinoma,55 and most likely for the development of
`antiestrogen-resistant breast carcinoma cells.56 Re-
`cent research in antiestrogens has produced two
`new types of compounds. The first represent pure
`antiestrogens, without any agonist effects.56 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).57’58 These
`agents retain the antiestrogenic effect of tamoxifen
`over breast carcinoma while retaining the estrogen
`agonist effect over bone and plasma lipids. 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.59
`Until the late 1980s, it generally was believed that
`combination hormonal therapy was not more effec-
`tive, but potenfially 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 therapeufi'c efficacy.”51 An
`additional evaluation of combined hormonal therapy,
`both simultaneously and in sequence, clearly is war-
`ranted.60
`
`There are indications that mutations in the p53
`gene, the overexpression of HER-Zlneu oncogene,
`and other well characterized molecular abnormali-
`
`ties might be associated with resistance to hormonal
`intervention.61’63 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.
`
`1-64
`
`represents a classic
`The article by Taylor et a
`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 power of careful 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 was effective 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
`under study. 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
`
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`

`4
`
`CANCER July 1, 1998 / Volume 83 / Number 1
`
`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 of the 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 androgens in this
`group of patients with breast carcinoma. Their list is
`complete enough that more recent controlled trials
`have not added many new items to it.
`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 conduct of 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.
`
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