`
`Fulvestrant: Pharmacologic Profile Versus Existing Endocrine
`
`Agents for the Treatment of Breast Cancer
`
`Aman U Buzdar and John FR Robertson
`
`OBJECTIVE: To compare the pharmacologic profile of fulvestrant with that of tamoxifen and the aromatase inhibitors with respect to
`the choice of treatment for advanced breast cancer (ABC).
`DATA SOURCES: Principal literature and review articles were obtained from MEDLINE (1991—March 2006). Key search terms
`included fulvestrant, tamoxifen, aromatase inhibitors, pharmacology, and breast cancer. Further data sources were identified from
`the bibliographies of selected articles.
`STUDY SELECTION AND DATA EXTRACTION: Eng|ish—language preclinical and clinical research and review articles reporting
`pharmacologic and safety data for fulvestrant, tamoxifen, and the aromatase inhibitors were evaluated to identify relevant
`information. Randomized clinical trial data were preferred over preclinical or Phase I and II trial data.
`DATA SYNTHESIS: A total of 52 clinical papers (including 10 reviews) and 17 clinical abstracts were evaluated reporting results from
`controlled Phase |—||l studies and pilot studies. Eleven preclinical papers (including 2 reviews) and 6 preclinical abstracts were also
`included. Fulvestrant has little effect on sex hormone endocrinology, bone metabolism, and lipid biochemistry and appears unlikely
`to be the subject or cause of CYP3A4-mediated drug interactions. Tamoxifen has a protective effect on bone (due to its partial
`estrogen agonist activity) and reduces plasma low-density lipoprotein cholesterol but increases triglyceride levels. The aromatase
`inhibitors have variable effects on lipid profiles and sex hormone endocrinology but have detrimental effects on bone due to
`inhibition of estrogen synthesis. Drug interactions have been noted between tamoxifen and anticoagulants and tamoxifen and
`aromatase inhibitors, which may be due to CYP-mediated mechanisms.
`CONCLUSIONS: Fulvestrant appears to have little effect on sex hormone endocrinology, bone metabolism, and lipid biochemistry and
`is unlikely to be subject to or the cause of CYP3A4rmediated drug—drug interactions. As such, fulvestrant represents a valuable new
`endocrine therapy for the treatment of ABC and broadens the options available to clinicians in the treatment of this disease.
`KEY WORDS: advanced breast cancer, aromatase inhibitors, estrogen, fulvestrant, tamoxifen.
`,4/7/7 P/rarmacol/7er 2008:40:1572—83.
`
`Published Online, 15 Aug 2006, WM/mt/7eanna/5.30/77, DOI 10.1345/aph.1G401
`
`he treatment of advanced breast cancer (ABC) is es-
`sentially palliative, in that its goal is to halt or slow dis-
`ease progression for as long as possible and manage symp-
`toms, rather than achieve a cure. In postmenopausal wom-
`en, approximately 75% of breast cancers are estrogen
`receptor (ER)— and/or progesterone receptor (PgR)—posi—
`tive,‘ and their growth is stimulated by both systemic es-
`trogen and estrogen produced within the tumor by the en-
`zyme aromatase. Endocrine therapy targets ER-mediated
`tumor growth and is as effective as cytotoxic chemothera-
`py, but is better tolerated by patients.’
`
`Author information provided at the end of the text.
`
`Currently available endocrine treatments for hormone
`receptor—positive ABC include the third—generation, non-
`steroidal aromatase inhibitors anastrozole and letrozole,
`the steroidal aromatase inhibitor exemestane, the selective
`ER modulator tamoxifen, and the ER antagonist fulves-
`trant. Aromatase inhibitors reduce circulating estrogen lev-
`els by blocking the production of estrogen by the aro-
`matase enzyme (the primary source of estrogen in post-
`menopausal women), while fulvestrant and tamoxifen are
`active at the ER itself, inhibiting ER—related tumor growth
`and signaling by blocking the action of estrogens at the
`ER. Tumors eventually develop resistance to individual
`endocrine therapies, leading to disease progression. Pa-
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`tients must then be switched to another endocrine treat-
`ment with a different mode of action to circumvent such
`
`resistance. Increasing the range of available endocrine
`agents, therefore, invites the possibility of extending the
`period of endocrine treatment before cytotoxic chemother-
`apy is the only option.
`The current National Comprehensive Cancer Network
`guidelines recommend that tamoxifen or an aromatase in-
`hibitor be used as first—line endocrine therapy for ABC and
`that cytotoxic chemotherapy be employed only when the
`patient has derived no clinical benefit from 3 consecutive en-
`docrine treatments? Clinical trial data show that aromatase
`inhibitors are at least as effective as tamoxifen as first—line
`
`therapy for hormone receptor—positive ABC, but offer sever-
`al tolerability advantages, including reduced incidence of
`vaginal bleeding and thromboembolic events.” As such,
`aromatase inhibitors should be considered as first—lirre en-
`
`docrine therapy for hormone receptor—positive ABC .7
`Fulvestrant is an endocrine agent, an ER antagonist with
`no estrogen—agonist effects," and it is the latest addition to
`the endocrine therapy armamentariurn. Fulvestrant binds
`the ER and prevents it from dimerizing, a necessary step
`preceding the binding of the ER dimer to, and the subse-
`quent transcription of, estrogen—sensitive genes in the cell
`nucleus. Transcription of estrogen—sensitive genes is abro-
`gated because fulvestrant blocks both activation functions
`on the ER. In addition, binding of fulvestrant to the ER
`subsequently increases the rate of ER degradation and re-
`duces the amount of ER protein in the cell.94° In compari-
`son, tamoxifen blocks only one activation function and
`some ER— dependent gene transcription is possible, which
`accounts for tamoxifen’s estrogen—agonist effects in some
`tissues.“
`
`In Phase IH trials, fulvestrant has proven to be at least as
`effective as anastrozole in postmenopausal women whose
`ABC had progressed during prior endocrine therapy (usu-
`ally tamoxifen). Fulvestrant was also well tolerated and
`was associated with a significantly lower incidence of joint
`disorders compared with anastrozole.”
`Because many patients with ABC are postmenopausal
`women, consideration of the wider effects of endocrine
`therapies will be influenced by the particular characteris-
`tics of this population. The effects of cancer therapies on
`bone and blood lipid profiles must be considered due to the
`possibility of patients experiencing concurrent osteoporo-
`sis or cardiovascular disorders. In addition, as patients age,
`it is likely that they will be receiving treatment for concur-
`rent medical conditions, and it is desirable that their cancer
`treatment does not affect such drug therapy.
`We review aspects of the pharmacologic profiles of the
`4 most frequently prescribed endocrine treatments for
`ABC, focusing on fulvestrant as the newest addition to this
`field. Fulvestrant 250 mg once monthly is the only treat-
`ment to be administered by intramuscular injection; ta-
`
`moxifen 20 mg, anastrozole 1 mg, letrozole 2.5 mg, and
`exemestane 25 mg are all once— daily oral medications. We
`focus particularly on the clinical pharmacology relating to
`estrogen levels, effects on bone homeostasis and lipid pro-
`files, and potential for drug— drug interactions of these
`agents. For completeness, we have included safety data re-
`lating to the adjuvant treatment of early breast cancer
`(EBC) where applicable, as such data describe the safety
`aspects of these therapies over a potentially longer time
`course compared with ABC treatment.
`
`Data Sources
`
`Principal literature and review articles were obtained via a
`MEDLINE search (1991—March 2006). Key search terms
`included fulvestrant, tamoxifen, aromatase inhibitors, phar-
`macology, and breast cancer. Further data sources were
`identified from the bibliographies of selected articles.
`
`Clinical Pharmacology
`
`The effect of endocrine therapies on circulating estrogen
`levels, or modification of the action of the ER, has the po-
`tential to influence other body processes, such as endome—
`trial maintenance, bone homeostasis, and blood lipid com-
`position; when making treatment decisions, the possibility
`of an effect on such systems must be balanced with the
`probability of disease progression.
`In premenopausal women, estrogen secretion by the
`ovaries is regulated by the sex steroids follicle-stimulating
`hormone (FSH) and luteirrizing hormone (LH; Figure l).
`A small contribution to total body estrogen is made by the
`aromatization of systemic androgens in peripheral tissue
`by the aromatase enzyme. FSH and LH are in turn regulat-
`ed by LH—releasirrg hormone (LHRH), which is released
`by the hypothalamus and stimulates LHRH receptors in
`the pituitary gland. The menstrual cycle of premenopausal
`women results from the pulsatile secretion of LHRH, FSH,
`and LH, and the action of both positive and negative feed-
`back control. After menopause, ovarian estrogen produc-
`tion ceases and peripheral aromatase becomes the primary
`estrogen source. The systemic level of estrogen falls
`markedly, while FSH and LH levels rise to a plateau. In
`postmenopausal women, increased levels of estrogen or
`drugs with estrogen—agonist effects, such as tamoxifen,
`may still stimulate uterine proliferation and cause gyneco-
`logic adverse events such as vaginal bleeding and endome—
`trial cancer?
`
`Sex hormones are carried in the blood by sex hormone
`binding globulin (SHBG), a protein produced by the liver
`and regulated by systemic estrogens and androgens. In-
`creased SHBG levels increase the capacity of the systemic
`blood supply for estrogens. Consequently, the effects of ABC
`therapies on both the levels of sex hormones and of SHBG
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`are pertinent when considering their impact on systemic es-
`trogen levels. These effects are summarized in Table 1.
`
`FU LVESTRANT
`
`Both preclinical and clinical data support the lack of es-
`trogen—agonist effects with fulvestrant treatment. Preclinical
`studies in immature female rats showed that fulvestrant, un-
`like tamoxifen, was completely devoid of uterotrophic activ-
`ity. Moreover, coadministration of fulvestrant with either
`estradiol or tamoxifen completely blocked the maximal and
`
`partial uterotrophic activity of estradiol or tamoxifen, respec-
`tively, in a dose—dependent manner."
`Fulvestrant’s lack of estrogen—agonist activity has also
`been demonstrated in a clinical study involving healthy
`volunteers.“ This single—center, double—blind, randomized,
`parallel—group trial evaluated the effects on the endometrium
`of fulvestrant 125 and 250 mg with or without ethinylestra—
`diol in 30 postmenopausal women. In addition to blocking
`the proliferative effects of ethinylestradiol on the en-
`dometrium, fulvestrant had no proliferative effects on
`healthy uterine tissue over the 14 day assessment period.
`
`Premenopause
`
`Pulsatile release,
`with peak preceding
`ovulation
`Negative feedback
`
`control by estradiol
`
`Postmenopause
`Unrestrained
`release leads to
`elevated FSH
`and LH
`
`Adrenal
`glands
`
`ACTH
`
`Androgens
`
`Systemic
`
`androgens
`
`Conversion in peripheral
`tissue via aromatase
`
`
`
`LHRH
`
`__‘
`
`_.
`
`Hypothalamus
`6)
`
`
`
`Pituitary gland
`
`FSH and LH
`
`Postmenopause
`
`High plateau level
`
`Cyclic release with
`peak around ovulation
`release stimulated by
`LHRH
`Negative and positive
`
`Premenopause
`
`Small contribution
`to total systemic
`estrogen
`
`Postmenopause
`
`Primary estrogen
`source
`
`
` Premenopause
`feedback by estradiol
`
`Follicle’,gyr
`ovary
`._ 3”
`
`
`Total systemic estrogen
`
`"°5""°"°P‘*"s°
`Low plateau level
`
`Estrogen levels
`fluctuate cyclically
`Release stimulated
`by FSH and LH
`
`Figure 1. Control of sex steroid levels in pre- and postmenopausal women. ACTH = adrenocorticotropic hormone; FSH = follicle-stimulating hormone; LH = luteiniz-
`ing hormone; LHRH = LH—releasing hormone.
`
`Table 1. Influence of Endocrine Breast Cancer Therapies on Clinical Phannacology in Postmenopausal Women
`Parameter
`
`Drug
`Fulvestrant
`
`FSHILH
`small increase
`
`Tamoxifen
`
`decrease
`
`Aromatase
`inhibitors
`
`SHBG
`
`Estrogen
`
`Clinical Effect
`
`no significant changes
`significant increase
`
`significant suppression
`with exemestane
`
`no significant effect; no agonist activity
`significant increase; also, estrogen
`agonist activity
`significant decrease
`
`no specific concerns
`increased incidence of gynecologic events and
`endometrial proliferation
`small differences in estrogen suppression
`among drugs; unlikely to be important
`
`FSH = follicle—stimulating hormone; LH = luteinizing hormone; SHBG = sex hormone—binding globulin.
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`In a 12 week clinical trial comparing fulvestrant with
`goserelin in premenopausal patients with uterine fibroids
`(n = 307), fulvestrant did not significantly alter endometri-
`al thickness or change endometrial histology.“ It can there-
`fore be assumed that fulvestrant has no proliferative effect
`on the healthy human endometrium.
`The effect of fulvestrant on endocrine parameters was
`measured as part of the laboratory chemistry investigations
`of 2 Phase III comparative studies versus anastrozole in
`851 postmenopausal women with ABC that had pro-
`gressed after adjuvant endocrine therapy or after first—line
`endocrine therapy for ABC (primarily with tamoxifen).15’1“
`Small increases in mean FSH and LH levels were ob-
`
`served in both treatment groups, consistent with a feed-
`back mechanism in the pituitary gland triggered either by
`cessation of tamoxifen, which has been shown to reduce
`serum levels of FSH and LH,” or by the initiation of anties—
`trogen therapy without agonist properties. Median estradiol
`levels remained unchanged in both treatment groups
`throughout the studies.15’1“ The majority of patients (96-
`97%) in each of these trials had received tamoxifen at
`some point as either adjuvant or first—line therapy for ABC,
`and baseline SHBG levels were elevated in this population
`as a result of tamoxifen ’s partial estrogen—agonist activity.
`Consequently, the concentration of SHBG decreased over
`time with subsequent fulvestrant or anastrozole treatment.
`Previously, a small study of 19 patients with ABC resistant
`to tamoxifen reported similar findings.” LH and FSH lev-
`els increased in the patients after withdrawal of tamoxifen
`and initiation of fulvestrant and then plateaued, suggesting
`no effect of fulvestrant on the pituitary—hypothalamic axis.
`In this study, no significant changes were observed in
`serum SHBG levels.
`
`The lack of impact on endometrial proliferation or sys-
`temic estrogen levels with fulvestrant treatment is an im-
`portant factor compared with the consequences of in-
`creased estrogen activity in the uterine tissue of post-
`menopausal women treated with tamoxifen (as discussed
`below). The gynecologic adverse events experienced by
`patients receiving tamoxifen are not only distressing for
`patients, but also lead to unnecessary investigation to
`check for the presence of endometrial malignancy in pa-
`tients who already have a significant illness.”
`
`TAMOXI FEN
`
`The estrogenic activity of tamoxifen is associated with
`significantly increased plasma levels of SHBG.2°>“ De-
`creased plasma levels of FSH and LH have also been ob-
`served.17’2°'“ Tamoxifen treatment has also been associated
`
`with a change m the balance of plasma estrogens, with in-
`creased plasma estrone sulfate levels, increased estrone
`sulfatezestradiol ratio, and decreased estradiol levels, but
`no effect on plasma estrone levels.” Furthermore, tamox-
`
`Pharmacologic Profile of Fulvestrant
`
`ifen’s weak estrogen—agonist effects may contribute to the
`phenomenon of tumor flare (temporary worsening of tu-
`mor lesions accompanied by diffuse musculoskeletal pain,
`erythema, and hypercalcemia associated with the initiation
`of antiestrogen treatment).’3v“
`Tamoxifen has long been associated with an increased
`risk of endometrial cancer and gynecologic abnormalities
`as a result of its estrogen—agonist properties in uterine tis-
`sue.“ The effect of tamoxifen on estrogen levels, and its
`estrogen—agonist properties in certain tissues, have an im-
`pact on its use. While the significance of an increased risk
`of endometrial cancer with long—term tamoxifen therapy
`depends on the individual patient’s prognosis, short-term
`gynecologic problems associated with tamoxifen therapy
`(eg, increased incidence of endometrial proliferation and
`vaginal bleeding and discharge) have resulted in aromatase
`inhibitors being recommended as first—line endocrine ther-
`apy for ABC.’
`
`AROMATASE INHIBITORS
`
`All 3 aromatase inhibitors (the nonsteroidal anastrozole
`and letrozole and the steroidal exemestane) effectively re-
`duce estrogen levels in postmenopausal women through
`the inhibition of aromatase—mediated conversion of andro-
`
`gens (androstenedione and testosterone) to estrogens (es-
`trone and estradiol). One study compared the extent of
`suppression of plasma estrone, estrone sulfate, and estradi-
`ol after 6 weeks of treatment with letrozole or anastrozole
`
`in postmenopausal women with metastatic breast cancer.“
`Although letrozole significantly reduced plasma estrone
`(84.3% vs 81.0%; p = 0.019) and estrone sulfate (98% vs
`93.5%; p = 0.019) levels compared with anastrozole, there
`were no significant differences in the reduction in estradiol
`levels (84.9% vs 87.8%, respectively). It is likely that once
`a certain threshold of aromatase inhibition has been
`
`achieved, these small differences in estrogen suppression
`between the aromatase inhibitors will not lead to clinically
`significant differences in overall efficacy.” However, it is
`not yet known whether the greater reduction in estrone and
`estrone sulfate with letrozole will result in a greater inci-
`dence of the long—term adverse effects of estrogen depriva-
`tion such as bone loss, particularly in the adjuvant setting.
`With exemestane treatment, estradiol levels were sup-
`pressed by 92.2%, estrone levels by 94.5%, and estrone
`sulfate by 93.2% after 6-8 weeks.“
`In contrast to exemestane, which has weak androgenic
`properties,” anastrozole and letrozole have no androgenic,
`progestogenic, or estrogenic activity that may result in ef-
`fects such as weight gain, acne, or hypertrichosis.” Indirect
`comparisons show that anastrozole has the highest degree of
`selectivity for aromatase compared with letrozole and ex-
`emestane and. consequently, has the least effect on adreno—
`steroidogenesis.”
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`AU Buzdar and JFR Robertson
`
`Therefore, aromatase inhibitors provide effective reduc-
`tion of estradiol levels in postmenopausal women for the
`treatment of ABC. However, aromatase inhibitors are not
`suitable for ABC monotherapy in premenopausal wom-
`en,” as their effect on estradiol levels is negligible com-
`pared with the background level of circulating ovarian es-
`trogens. Furthermore, administration of aromatase in-
`hibitors to premenopausal women has been shown to
`increase systemic estrogen by activation of the negative
`feedback control of estradiol by FSH.”
`
`Effects on Bone
`
`Estrogens inhibit bone resorption and maintain bone
`homeostasis.“ In postmenopausal women, the main source
`of endogenous estrogen is the aromatization of androge-
`nous precursors in peripheral tissue (including bone os-
`teoblasts and chondrocytes). Consequently, estrogen levels
`within bone tissue may be independent of systemic estro-
`gen levels.35 The effects of cancer therapies on bone home-
`ostasis are important when considering the increasing inci-
`dence of osteoporosis with age following menopause com-
`bined with the common presence of bone metastases in
`ABC patients. The effects of endocrine treatments for
`ABC on bone metabolism are summarized in Table 2.
`
`menopausal women, coupled with the similar affinities of
`fulvestrant and estradiol for the ER, may have negated any
`biological effect of fulvestrant on bone turnover. Further
`research is necessary to assess the effect of fulvestrant on
`bone turnover in postmenopausal women with ABC. This
`consideration will become especially pertinent if fulves-
`trant is considered for the adjuvant treatment of EBC in the
`future.
`
`TAMOXIFEN
`
`In postmenopausal women, the weak estrogen agonist
`activity of tamoxifen can lead to significant increases in
`bone mineral density, particularly in the lumbar spine."°>“
`Significant decreases in markers of bone resorption (eg,
`urinary cross-linked aminoterminal telopeptide of type I
`collagen) and markers of bone formation (eg, osteocalcin)
`have also been observed with tamoxifen treatment, further
`
`confirming the protective effect of this agent in post-
`menopausal women.“ However, as bisphosphonates con-
`fer additional benefit over tamoxifen with respect to main-
`tenance of bone mineral density, tamoxifen should not be
`considered a substitute for bisphosphonate therapy for
`women with breast cancer and concurrent osteoporosis or
`osteopenia.“
`
`FU LVESTRANT
`
`AROMATASE INHIBITORS
`
`The effect of fulvestrant on bone was initially investi-
`gated in rats. The available data suggest that fulvestrant ap-
`pears to reduce cancellous bone volume, which comprises
`only a small proportion of total bone,“ and its effects are
`consistent with blockade of ER—mediated bone resorption
`and formation.”
`
`In a clinical study involving premenopausal women un-
`dergoing hysterectomy, fulvestrant did not produce changes
`in markers of bone resorption (cross—linked N—telopeptides
`and unbound deoxypyridinoline), suggesting that it did not
`affect bone turnover in this patient group.”33 However, the
`administration of a single 250 mg dose of fulvestrant to a
`group of premenopausal women with breast cancer 2-3
`weeks prior to primary surgery was found to have no effect
`on ER, PgR, and Ki67 protein levels.” It is therefore possi-
`ble that the logarithmically higher endogenous estradiol
`levels in premenopausal women compared with post-
`
`In a study of healthy volunteers, both steroidal and non-
`steroidal aromatase inhibitors were shown to increase
`markers of bone tumover.“ Anastrozole increased markers
`
`of bone resorption and formation in clinical studies,
`whereas letrozole increased bone resorption markers, but
`without a compensatory increase ir1 bone formation mark-
`ers."""" However, any differences between the non-
`steroidal aromatase inhibitors regarding their clinical ef-
`fects on bone are not yet known. The steroidal aromatase
`inhibitor exemestane appears to increase both markers of
`formation and resorption to a greater extent than does ei-
`ther of the nonsteroidal agents.“
`Clinical trials including postmenopausal women with
`BBC have confirmed that aromatase inhibitors have detri-
`
`mental effects on bone, which may give rise to an in-
`creased risk of osteopenia, osteoporosis, and an increased
`susceptibility to fractures. In the ATAC (Anastrozole, Ta-
`
`Table 2. Influence of Endocrine Breast Cancer Therapies on Bone Metabolism in Postmenopausal Women
`Clinical Effect
`
`Effect on Bone Metabolism Markers
`
`no changes in bone resorption in postmenopausal women;
`further data required
`significant decreases in bone resorption and formation
`increased bone resorption and formation markers
`
`no specific concerns; further data required
`
`protective effect leading to reduced fractures
`increased risk of fracture from reduced serum estrogen levels
`
`Drug
`Fulvestrant
`
`Tamoxifen
`
`Aromatase inhibitors
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`moxifen, Alone or in Combination) trial, postmenopausal
`women with EBC were randomized to receive anastrozole,
`tamoxifen, or both therapies for 5 years as adjuvant treat-
`ment following primary surgery. In the initial report of re-
`sults at a median treatment duration of 33.3 months, 5.9%
`of patients in the anastrozole—only arm reported fractures,
`as opposed to 3.6% in the tamoxifen-only arm, a statisti-
`cally significant difference (p < 0.0001) but not necessarily
`a surprising observation, given the known protective effect
`of tamoxifen on bone.“ Fracture rate in the combination
`
`therapy arm was 4.9%. At a follow—up of 37 months, inci-
`dence of fracture was 7.1%, 4.4%, and 5.7% for the anas-
`
`trozole, tamoxifen, and combination arms, respectively, in-
`dicating a stabilization of the difference in fracture rates
`between the monotherapy groups.“ The combination arm
`was subsequently discontinued due to similar efficacy
`compared with the tamoxifen— only group, and at the com-
`pleted treatment analysis of ATAC (median follow—up 68
`mo), the incidence of fracture was 11.0% and 7.7% for the
`anastrozole and tamoxifen arms, respectively.“
`Letrozole has been shown to increase bone loss at the
`
`clavicle and rib in postmenopausal patients with ABC.“ In
`addition, the National Cancer Institute of Canada MA.17
`study compared 5 years’ letrozole treatment with placebo
`following completion of 5 years’ adjuvant tamoxifen in
`postmenopausal women with EBC.“ This study found
`that, at 1.9 years’ follow—up, letrozole showed a trend to-
`ward increased osteoporosis (5.8% and 4.5%, respectively)
`and fractures (3.6% and 2.9%, respectively) compared
`with placebo.
`Although early preclinical studies suggested that ex-
`emestane might have a protective effect on bone,” this
`finding is not supported by clinical trial data. In post-
`menopausal patients with advanced breast cancer, exemes—
`tane increased markers of bone formation and resorption.5"'5“
`In a 5 year trial assessing the effect of switching from ta-
`moxifen to exemestane after 2-3 years versus continued ta-
`moxifen therapy (median follow—up 2.5 y), more exemes—
`tane—treated patients developed osteoporosis (7.4% vs 5 .7%;
`p = 0.05), and there was also a trend toward more fractures
`
`Pharmacologic Profile of Fulvestrant
`
`in this group (3.1% vs 2.3%; p = 0.08).” Exemestane has
`also been found to decrease bone mineral density at the lum-
`bar spine and femoral neck relative to placebo to approxi-
`mately the same extent as anastrozole (~2% per year) in
`postmenopausal women being treated for EBC.“
`
`Effects on Lipids
`
`low—density lipoprotein
`Elevated total cholesterol,
`cholesterol (LDL—C), and ratio of total cholesterol to high-
`density lipoprotein cholesterol (HDL—C) are important risk
`factors for the development and progression of cardiovas-
`cular disease.” High levels of HDL—C are associated with
`a reduced risk of coronary heart disease (CHD). Healthy
`postmenopausal women experience a decrease in the HDL
`C:LDL—C ratio, possibly as a result of reduced estrogen
`production (irrespective of hormone replacement therapy
`usage) and therefore are already at elevated risk of cardio-
`vascular disease. Thus, drugs that alter lipid profiles may
`have an impact on the risk of cardiovascular morbidity,
`such as CHD and thromboembolic conditions, and mortal-
`ity. The effects of these endocrine therapies on lipid profile
`are summarized in Table 3.
`
`FU LVESTRANT
`
`The effect of fulvestrant on lipid variables was monitored
`as part of laboratory investigations in 2 Phase III compara-
`tive studies of fulvestrant versus anastrozole as second-line
`
`endocrine therapy for breast cancer.15J“ The most robust as-
`sessments of plasma lipids are performed on blood samples
`from fasting patients. However, only samples from non-
`fasting patients were available for lipid assessments in
`these trials. No major changes in lipid variables occurred
`with either treatment. Mean triglyceride and HDL—C levels
`did not change, whereas total cholesterol and LDL—C lev-
`els were mildly increased with fulvestrant treatment.
`In both treatment groups, unusually high levels of
`cholesterol were reported in samples from approximately
`10% of non—fasting patients who were considered to have
`normal levels at baseline.“ In the combined analysis of
`
`Table 3. Influence of Endocrine Breast Cancer Therapies on Lipid Profile in Postmenopausal Women
`
`Lipid Profile Component
`
`TC
`
`LDL—C
`
`HDL-C
`
`Triglycerides
`
`Clinical Effect
`
`small increase
`decrease
`
`small increase
`decrease
`
`no effect
`increase
`insignificant fluctuations
`increased incidence of hypercholesterolemia
`conflicting data; decrease/no effect
`no effect/decrease
`
`no effect
`increase
`
`no data
`no effect/decrease
`
`no significant changes
`no cardioprotection
`no significant profile changes
`no |ong—term data
`no |ong—term data
`
`Drug
`
`Fulvestrant
`Tamoxifen
`Anastrozole
`Letrozole
`Exemestane
`
`HDL—C = high—density lipoprotein cholesterol; LDL—C = low—density lipoprotein cholesterol; TC = total cholesterol.
`
`www.theannals.c0m
`
`2006 September, Volume 40 I
`The Annals ofPharmacotherapy I
`Downloaded from at‘:p.§agepub.oom at JOHNS HOPKINS UNIVERSITY on January 25; 2015
`
`1577
`
`AstraZeneca Ex. 2078 p. 6
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`
`
`AU Buzdar and JFR Robertson
`
`these trials,” there were no significant differences in rates
`of thromboembolic disease between patients receiving ful-
`vestrant and those receiving anastrozole. There were also
`no significant differences in terms of thromboembolic dis-
`ease between patients receiving fulvestrant and tamoxifen
`as first—line endocrine therapy for ABC.“
`
`TAMOXI FEN
`
`Long—term tamoxifen treatment has differential effects
`on lipid profiles with respect to cardiovascular risk factors.
`For example, it lowers total serum cholesterol and LDL—C
`levels‘“3 and has also been shown to increase HDL—C lev-
`
`els ir1 some studies.‘‘‘'‘5 However, the estrogenic effect of
`tamoxifen on the liver also significantly increases serum
`triglyceride levels.‘5>“‘ Tamoxifen therapy has been shown
`to increase the risk of thromboembolic events (stroke, pul-
`monary embolism, deep—vein thrombosis)” and to exert no
`cardioprotective effect in the adjuvant setting when 5 years
`of endocrine therapy is given following primary surgery to
`reduce the risk of cancer recurrence .4 Although it was antic-
`ipated that tamoxifen may have a favorable influence on
`lipid profiles, these effects have not been translated into a
`protective effect with respect to cardiovascular and tl1rom—
`boembolic morbidity and mortality.“
`
`AROMATASE INHIBITORS
`
`The 3 third—generation aromatase inhibitors have some-
`what different effects on lipid profiles. Data from compara-
`tive studies of anastrozole and tamoxifen suggest that
`anastrozole does not markedly affect lipid profiles com-
`pared with baseline values. Small increases in total choles-
`terol and LDL—C and a decrease in HDL—C were observed
`after 84 weeks of anastrozole treatment for ABC.“ A 12
`
`week study of anastrozole versus tamoxifen in Japanese
`women with EBC reported unchanged total cholesterol
`and LDL—C levels, increased HDL—C, and decreased tri-
`glycerides in the anastrozole arm, albeit in a population
`with traditionally low rates of CHD.” Similar theoretically
`beneficial but nonsignificant changes in lipid profile were
`reported with anastrozole in a 12 week trial comparing ad-
`juvant treatments for breast cancer.”
`These data are supported by those from a smaller study
`(N = 44) in postmenopausal women with ABC in which
`32 weeks of anastrozole treatment did not significantly al-
`ter any lipid parameters.“ In the completed treatment anal-
`ysis of the ATAC trial, there were significantly fewer is-
`chemic cerebrovascular events and venous thromboembol-
`
`ic events in the anastrozole group compared with the
`tamoxifen group, although no effect on the incidence of is-
`chemic cerebrovascular disease was observed.”
`
`Letrozole significantly increased total cholesterol and
`LDL—C from baseline after 8 and 16 weeks of treatment in
`
`a study of 20 women with ABC.” Another study reported
`no significant effect of letrozole on lipid profiles.“ Recent-
`ly, there has been a presentation of initial efficacy and tol-
`erability data from the primary core analysis of the Breast
`International Group (BIG) 1-98 trial, a study including
`8010 women randomized to receive either letrozole or ta-
`
`moxifen as adjuvant therapy.” At a median follow—up of
`25.8 months, 43.5% of patients receiving letrozole had ex-
`perienced hypercholesterolernia, compared with 19. 1% of
`those receiving tamoxifen. Of these instances, 80% (letro-
`zole)