`
`Tamoxifen and Toremifene in Breast Cancer:
`
`Comparison of Safety and Efficacy
`
`By Aman U. Buzdar and Gabriel N. Horiobagyi
`
`Pur ose: Tamoxifen is currently the standard hor-
`monal treatment of breast cancer, both for metastatic
`disease and in the adiuvant setting. A new antiestro-
`gen, toremifene, was approved recently for use in
`managing metastatic breast cancer in postmenopausal
`women.
`
`Methods: Toremifene is structurally similar to tamoxi-
`fen, diffEring only by a single chlorine atom, and has a
`similar pharmacologic profile. The maior difference be-
`tween the two compounds is in the preclinical activity;
`chronic, high-dose tamoxifen is hepatocarcinogenic in
`the rat, whereas toremifene is not. Neither agent is
`hepatocarcinogenic in mice, hamsters, or humans; there-
`fore, clinical relevance of the rat data may not be
`significant.
`
`In a worldwide phase Ill trial, the two agents
`Results:
`demonstrated comparable efficacy and safety against
`
`VER THE NEARLY 20 YEARS since its introduction
`
`in the United States, tamoxifen has become firmly
`established as the standard in the hormonal treatment of both
`
`early and advanced breast cancer. First approved for the
`treatment of advanced breast cancer in postmenopausal
`women, tamoxifen’s indications have expanded to include
`advanced breast cancer in premenopausal women, in men,
`and as adjuvant therapy for both node-positive and node-
`negative disease. The uses of tamoxifen have broadened due
`to its efficacy in prolonging disease—free survival and
`reducing mortality rates, as well as a 39% reduction in the
`risk for contralateral breast cancer.1 Patients with estrogen
`receptor (ER)-positive breast cancer seem to derive the
`greatest benefit from tamoxifen therapy.
`Recently, a variety of new antiestrogen compounds have
`begun to receive attention as potential successors to tamoxi-
`fen. One of these,
`toremifene,
`is a tamoxifen analog,
`differing chemically by only a single chlorine atom (Fig 1).
`Toremifene has received Food and Drug Administration
`approval for use in treating metastatic breast cancer in
`
`From Department ofBreast and Gynecology Medical Oncology, The
`University of Texas, MD Anderson Cancer Center, Houston, TX
`Submitted February 18, 1997; accepted July 21, 1997.
`Address reprint requests to Aman U. Buzdar, MD, MD Anderson
`Cancer Center, 1515 Holcombe Blvd, Box 56, Houston, TX 77030.
`Email abuzdar@notes.mdacc.tmc.edu.
`© 1998 by American Society of Clinical Oncology.
`0732-183X/98/1601-0012$3.00/0
`
`metastatic breast cancer. Both agents have shown a
`significant hypocholesterolemic effect after long-term
`administration.
`
`Conclusion: Due to the paucity of long-term clinical
`data on toremifene, important unresolved questions
`remain, which include its effects on bone mineral den-
`sity, the frequency of cardiac events, and the risk for
`endometrial cancer. Tamoxifen has been associated
`with maintenance of bone mineral density, a reduction
`in cardiac events, and a slightly increased risk of endo-
`metrial cancer. Toremifene is not likely to be used as
`second-line therapy after tamoxifen failure due to cross-
`resistance, and its ultimate place in therapy of ad-
`vanced breast cancer remains to be determined.
`
`J Clin Oncol 16:348-353. © 1998 by American Society
`of Clinical Oncology.
`
`postmenopausal women. Because long-term data on toremi-
`fene are lacking, the drug is not yet indicated for adjuvant
`use. The purpose of this review is to address the similarities
`and differences of toremifene and tamoxifen, both in the
`laboratory and in the clinic.
`
`PRECLINICAL PHARMACOLOGIC ACTIVlTY
`
`The pharmacologic profile of toremifene appears to be
`similar to that of tamoxifen in terms of ER binding,
`antitumor activity, and estrogenic activity.2 Both agents bind
`ER with an affinity 5% of that of estradiol. In uterotrophic
`assays, toremifene exhibits lower estrogenic activity than
`tamoxifen at low and moderate doses; however, the maxi—
`
`mum estrogenic and antiestrogenic activity of the two agents
`is similar.3
`
`In a human ER-positive breast cancer cell line (MCF—7
`cells),
`the effects of toremifene are similar to those of
`tamoxifen—~growth inhibition at
`low concentrations and
`oncolytic activity at high concentrations.4 Tamoxifen inhib-
`ited growth of MCF-7 cells more than toremifene in a
`comparative study of 10‘6~m01/L concentrations of various
`antiestrogens.5
`The in vivo effects of the two agents were similar against
`dimethyl benzanthacene-induced rat mammary cancer, with
`the difference that 45 mg/kg toremifene showed an antitu-
`mor effect, while the same dose of tamoxifen was lethal to
`the rats.4
`
`348
`
`Journal of Clinical Oncology, Vol 16, No 1 (January), 1998: pp 348-353
`
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`TAMOXIFEN AND TOREMIFENE COMPARISON
`
`349
`
`A
`
`CI
`
`O
`
`—\— NMe2
`
`0
`
`_\— NM92
`
`Fig 1. Structure of (A) toremifene and (B) tamoxifen.
`
`RISK FOR SECONDARY CANCERS
`
`Hepatocellular Cancer
`
`One major difference between toremifene and tamoxifen
`is the hepatocarcinogenicity reported in animal studies.
`Chronic (3 to 12 months), high-dose tamoxifen (11.3 to 22.6
`mg/kg, two doses per day) is hepatocarcinogenic in the rat
`(but not in other species), whereas toremifene at doses up to
`48 mg/kg is not.6 (Note that the recommended dose of
`tamoxifen for humans is 20 mg/d, which is roughly 0.3
`mg/kg.) This effect of tamoxifen is both species- and
`strain-specific; tamoxifen is not hepatocarcinogenic in the
`mouse and may even exert a protective effect
`in the
`hamster.7 In addition, Fischer rats seem to be markedly less
`sensitive to tamoxifen than Wistar or Lewis rats.
`
`Toremifene is not devoid of genotoxicity. Both agents
`have shown genotoxic potential
`in MCL-S cells,3 and
`long-term toremifene has been linked to osteosarcoma in the
`mouse. Moreover, Dragan et al9 demonstrated that both
`tamoxifen and toremifene can function as promoters of rat
`liver and kidney tumors initiated by the carcinogen diethyl—
`nitrosamine (DEN).
`The genotoxicity of tamoxifen in the rat has been ascribed
`
`to the presence of DNA adducts in rat liver tissue. The
`frequency of DNA adducts may account for the species and
`strain differences in carcinogenicity, as DNA adduct levels
`are substantially higher in susceptible rat strains than in
`other rat strains, mice, hamsters, and humans.7 For example,
`the level of DNA adducts in mice treated with tamoxifen is
`
`a111
`30% to 40% of that seen in the rat.10 Phillips et
`conducted a cross—species experiment and measured the
`levels of DNA adducts in rat, mouse, and human hepatocytes
`incubated with tamoxifen. In rat and mouse hepatocytes, the
`levels of DNA adducts were greater than 10*7 adducts per
`nucleotide following incubation with 1 to 10 umol/L tamoxi-
`fen; however, in the human hepatocyte, no adducts were
`seen at a detection limit of 4 X 10'10 adducts per nucleotide
`(in the range of one adduct per cell).
`Four studies have evaluated the presence of DNA adducts
`in human tissue after administration of tamoxifen in breast
`
`cancer patients. Martin et al12 compared liver tissue DNA
`adduct levels in seven women treated with tamoxifen 20 mg
`for 6 to 44 months and seven control patients. DNA adduct
`levels ranged from 18 to 80 adducts per 108 nucleotides in
`tamoxifen-treated women, a level that was not significantly
`different from the control group.
`In a different study,13 DNA adducts were measured in the
`WBCs of seven women treated with tamoxifen (20 to 40 mg)
`for 3 months to 6 years for early breast cancer and compared
`with levels in three healthy control subjects. Similar levels
`of DNA adducts were seen in treated patients and controls,
`with a maximum reported level of 1.5 adducts per 108
`nucleotides, and the adducts observed differed from those in
`treated rats.
`
`Two studies have investigated DNA adduct levels in the
`human endometrium after tamoxifen treatment. These stud-
`
`ies used different methods to measure DNA adduct levels,
`
`which produced contrasting results. Carmichael et al14
`determined endometrial DNA adduct levels in 18 patients
`who received tamoxifen (10 to 40 mg) for 3 months to 9
`years and compared the levels with those in 16 control
`patients. Although both groups displayed a low level of
`DNA adducts as detected by phosphorus 32—postlabeling,
`the results of the two groups were indistinguishable. In the
`other study,” a low level of DNA adducts (2.7 adducts per
`109 nucleotides) was observed in the endometria of five of
`seven tamoxifen-treated patients (20 to 40 mg/d for 3
`months to 5 years), but none of five control patients. This
`study used high-performance liquid chromatography (HPLC)
`to analyze DNA adducts and used liver DNA from tamoxifen-
`treated rats as a positive standard. The differing methodolo—
`gies used in these studies require further analysis. It should
`be noted that the level of DNA adducts seen in the study
`reported by Hemminki et 3115 was far below that seen in the
`
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`350
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`BUZDAR AND HORTOBAGYI
`
`trial.22 The study
`compared in a worldwide phase III
`population included postmenopausal women with measur-
`able or assessable metastatic breast cancer with either
`
`hormone receptor—positive or unknown receptor status. Ex—
`clusion criteria included prior hormonal treatment or chemo-
`therapy for recurrent or metastatic disease, but adjuvant
`therapy was acceptable. Six hundred forty-eight patients
`were enrolled at 129 sites in six countries. Primary efficacy
`end points included response rate and progression-free
`interval, and secondary end points consisted of survival,
`response duration, and quality of life.
`There were no significant differences among the three
`treatment groups in response rate, median response duration,
`median time to progression, or overall survival (Fig 2 and
`Table l).
`
`Thirty—six patients died; the frequency of study deaths
`was 4% (tamoxifen), 9% (toremifene 60 mg), and 5%
`(toremifene 200 mg). The three groups also showed similar
`rates for tumor flare, elevated calcium levels, and cardiac
`events. Although rare, ocular abnormalities and thromboem-
`bolic events are known to be associated with tamoxifen and
`
`phase II studies have found similar effects with toremifene.23
`The phase III trial22 reported that tamoxifen and toremifene
`had similar effects on rates of cataracts (new or worsened)
`and thromboembolic events. However, corneal keratopa-
`thies were more common with 200 mg toremifene (n = 8)
`
`
`
`-Tamoxifen (20 mg)
`Toremifene (60 mg)
`Toremifene (200 mg)
`
`
`
`Progressivedisease_
`
`
` Stable disease—
`
`Complete+partialresponse_
`
`Partialresponse
`
`Completeresponse
`
`
`
`livers of chronically treated rats (3,000 adducts per 108
`nucleotides).16
`The contrasting results regarding DNA adducts in differ-
`ent species have been attributed to the profound differences
`in rodent and human metabolism of tamoxifen.17 It is also
`
`thought that human cells may have a greater ability to
`remove DNA adducts via detoxifying enzymes. Animal
`studies may not be a fair representation of the clinical use of
`tamoxifen; besides the substantial metabolic differences
`between rodents and humans, the threshold dose for carcino—
`
`genicity in the rat is an order of magnitude larger than the
`clinical therapeutic dose, and the drug is given for a greater
`proportion of the animal’s life span.7
`Although toremifene has not produced DNA adducts in
`rat liver, high doses of both compounds induced low levels
`of DNA adducts in rat and human microsomal systems and
`in cultured lymphocytes in vitro.18
`As no increase in hepatocellular cancer risk has been
`observed in more than 7.5 million woman~years of clinical
`experience with tamoxifen, the clinical relevance of its rodent
`carcinogenicity does not appear to be significant. Moreover, it is
`possible that the rare instances of liver cancer reported thus
`far could actually be cases of metastatic breast cancer.
`
`Endometrial Cancer
`
`Tamoxifen has been associated with an increased risk of
`
`endometrial cancer in breast cancer patients, on the order of
`two cases per 1,000 patients annually.19 There is currently
`not enough evidence to prove causality definitely; however,
`this effect has been attributed to the estrogenic activity of
`tamoxifen on the uterus.20 As toremifene is solely indicated
`for the treatment of metastatic breast cancer and few patients
`have received adjuvant therapy, there are clearly not enough
`data to assess the endometrial cancer risk of toremifene at
`
`this time. It will probably take many years and thousands of
`treated patients before the answer is known. However, it is
`important to note that tamoxifen and toremifene produce
`similar increases in the endometrial thickness of postmeno—
`pausal breast cancer patients, thereby demonstrating compa-
`rable estrogenic activity.21
`
`CLINICAL EFFICACY AND SAFETY
`
`The clinical
`
`trials’ data base on tamoxifen for both
`
`therapy of early breast cancer and palliative
`adjuvant
`therapy of late—stage breast cancer is enormous. Clinical
`experience with toremifene is limited at this time and only
`one large—scale study has compared the two agents.22
`
`First—Line Therapy of Metastatic Breast Cancer
`
`50
`
`40
`
`30
`
`20
`
`10
`
`Percentofpatients
`
`The efficacy and safety of two doses of toremifene (60 and
`200 mg/d) and a standard dose of tamoxifen (20 mg/d) were
`
`Fig 2. Clinical response rates for tamoxifen and toremifene (intent-to-
`lreal analysis). Dalu from Hayes et al.“
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`TAMOXIFEN AND TOREMIFENE COMPARISON
`
`351
`
`Table 1. Clinical Trial Data Comparing Toremifene and Tamoxifen
`(intent-to-treat analysis)
`
`
`
`Variable
`
`Tamoxifen
`20 mg
`
`Tommuene
`60 mg
`200 mg
`
`212
`221
`215
`No. of randomized patients
`18.4
`16.9
`19.1
`Median response duration (months)‘
`5.6
`5.6
`5.8
`Median time to progression (months)
`
`Overall survival (months) 30.1 3) .7 38.3
`
`
`
`NOTE. complete response + partial response + stable disease.
`Data from Hayes etal.22
`
`than with 60 mg toremifene (n = 4) or tamoxifen (n = 2).
`This condition resolved in all patients after cessation of
`treatment.
`
`Three percent of patients discontinued treatment due to
`toxicity,
`including three patients on tamoxifen, six on
`toremifene 60 mg, and 12 on toremifene 200 mg.
`The most common subjective complaints were pain,
`asthem‘a, anorexia, headache, diarrhea, vaginitis, rash, pruri-
`tis, depression, and insomnia;
`the distribution for these
`symptoms in the three groups was similar. The frequencies
`of prospectively assessed side effects are shown in Fig 3.
`There was an excess of AST abnormalities (2100 IU/L)
`not attributable to progressive disease in the high-dose
`toremifene arm compared with tamoxifen (10% v 2%;
`P < .05). In the low-dose toremifene group, more patients
`developed alkaline phosphatase abnormalities (2200 IU/L)
`than in the tamoxifen group (19% v 11%; P < .05).
`Quality-of—life analyses showed no differences among the
`three treatments with respect to enjoyment of life, pain,
`mood, or analgesic requirements.
`This study showed no advantage in using toremifene over
`
`tamoxifen for the management of metastatic breast cancer.
`Like tamoxifen, toremifene does not exhibit a dose-response
`relationship, and thus there appears to be no benefit of
`increasing the dose from 60 mg to 200 mg.
`
`Efizcacy of Toremifene in Tamoxifen-Resistant Metastatic
`Breast Cancer
`
`Two studies have evaluated the potential use of toremi-
`fene as second-line therapy after tamoxifen for the treatment
`of advanced breast cancer. Vogel et a123 conducted a phase II
`trial of toremifene (200 mg/d) in perimenopausal or post-
`menopausal women with advanced breast cancer who had
`either failed to respond to tamoxifen (n = 28), who had
`relapsed after a tamoxifen response (11 = 43), or who had
`relapsed on adjuvant
`tamoxifen (n = 31). Patients had
`hormone receptor-positive disease or had achieved a prior
`response on hormonal therapy. The objective response rate
`of toremifene was only 5% (median duration, 10.9 months),
`with an additional 23% of patients achieving stable disease
`(median duration, 7.8 months). The investigators were
`uncertain as to whether patients with stable disease derived a
`benefit from toremifene or just had an indolent disease
`course. Although patients were substantially pretreated, the
`investigators attributed the low objective response rate to
`major cross-resistance between toremifene and tamoxifen.
`Stenbygaard et al24 conducted a double-blind crossover
`trial of toremifene (240 mg/d) and tamoxifen (40 mg/d) in 66
`postmenopausal women with advanced breast cancer (ER-
`positive or receptor status unknown). After disease progres-
`sion on either
`toremifene or tamoxifen, patients were
`crossed over to the opposite treatment. Objective response
`rates for first-line therapy were 29% with toremifene and
`42% with tamoxifen (P not significant between treatments).
`Forty-four patients who progressed on first-line toremifene
`or tamoxifen were assessable for second-line response. No
`objective responses were observed, which indicates cross-
`resistance of the two agents.
`
`EFFECTS ON LIPIDS
`
`TWO clinical studies have demonstrated a hypocholesterol-
`emic effect of both tamoxifen and toremifene after 1 year of
`treatment.25=26 In the first study,25 24 postmenopausal women
`with advanced breast cancer were randomized to tamoxifen
`
`(40 mg/d) or toremifene (60 mg/d). After 12 months, serum
`cholesterol
`levels decreased by 8% (from a baseline of
`5.2 i 0.4 mmol/L) with tamoxifen and 12% (from a base-
`line of 5.8 i 0.3 mmol/L) with toremifene (P < .05 for both
`treatments). Low-density lipoprotein (LDL)-cholesterol lev-
`els decreased by 16% (from a baseline of 3.3 i 0.3 mmol/L)
`with tamoxifen and 15% (from a baseline of 3.5 i 0.3
`mmol/L) with toremifene (P < .05 for both treatments),
`
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`
`
`- Tamoxifen (20 mg)
`
`Toremifene (60 mg)
`r73 Toremifene (200 mg)
`
`40
`
`30
`
`20
`
`10
`
`0
`
`2c
`.9..
`
`3u—
`O..
`
`5e
`
`0)
`O.
`
`
`
`Nausea
`
`
`
`Hotflashes
`
`
`
`Vaginaldischarge
`
`Dizziness
`
`Edema
`
`
`
`Vomiting
`
`
`
`Vaginalbleeding
`
`Fig 3. Prospectiver assessed side effects of tamoxifen and toremifene
`(drug-related or indeterminate cause). “P < .05 v tamoxifen. Data from
`Hayes et al.22
`
`
`
`352
`
`BUZDAR AND HORTOBAGYI
`
`with no changes in high-density lipoprotein (HDL)-
`cholesterol or serum triglycerides. The investigators attrib—
`uted these effects to an interference in cholesterol synthesis
`via inhibition of the conversion of D8-cholestenol to lathos-
`
`terol; each agent produced substantial accumulation of
`Dg-cholestenol (40- to 55 -fold of baseline levels).
`In the second study,26 49 postmenopausal breast cancer
`patients were randomized to 20 mg/d tamoxifen or 60 mg/d
`toremifene.
`In both groups,
`total cholesterol and LDL-
`cholesterol were reduced by 11% and 20%, respectively
`(P s .01). Baseline total cholesterol levels were 6.16 i 1.03
`mmol/L and 5.88 :1: 1.16 mmol/L with tamoxifen and
`
`toremifene, respectively; baseline LDL-cholesterol levels
`were 4.01 3: 0.91 mmol/L (tamoxifen) and 3.74 i 1.03
`mmol/L (toremifene). HDL—cholesterol levels, which were
`lower in the toremifene group at baseline (1.36 i 0.33
`mmol/L v 1.63 i 0.40 mmol/L), decreased by 5% with
`tamoxifen and increased by 14% with toremifene, a differ-
`ence that was statistically significant (P = .001 between
`treatments). Triglycerides increased by 28% with tamoxifen
`(P = .013) and were unchanged in the toremifene group;
`however, weight gain was higher with tamoxifen (mean, 1.8
`kg v 1 kg). Apolipoprotein (Apo) B levels decreased by 7%
`with tamoxifen (P = .013) and by 10% with toremifene
`(P = .025). Apo A-1 and A—II levels were unchanged with
`tamoxifen, but increased with toremifene. Lipoprotein Lp,
`an independent risk factor for coronary heart disease,
`decreased by 34% with tamoxifen (P = .00002) and by 41%
`with toremifene (P = .00004). The clinical trials of adjuvant
`tamoxifen suggest that the favorable effects of tamoxifen on
`blood lipids may reduce the risk of cardiac events.1 Addi-
`tional studies are necessary to establish these findings and to
`determine if toremifene has a similar effect.
`
`EFFECTS ON BONE
`
`Several studies have documented preservation of lumbar
`spine bone mineral density in postmenopausal women who
`
`receive long-term tamoxifen therapy”,28 No studies have
`been published on toremifene and bone mineral density; how-
`ever, the drug is not yet approved for adjuvant use, and clinical
`experience with long-term toremifene (>1 year) is limited.
`
`CONCLUSION
`
`Toremifene is a new antiestrogen for the management of
`metastatic breast cancer.
`It appears to have a similar
`pharmacologic profile as tamoxifen, with the exception that
`it is not hepatocarcinogenic in laboratory rats. The clinical
`relevance of this difference does not appear to be significant,
`as tamoxifen has not been linked to an increased risk of liver
`
`cancer in patients. A more important, unresolved question is
`how toremifene will affect the risk for endometrial cancer in
`
`breast cancer patients, as this new agent shows similar
`estrogenic activity to tamoxifen in the human uterus. As
`toremifene has not yet been adequately studied in the
`adjuvant setting, long-term data are not available to address
`endometrial cancer risk, as well as its effect on bone mineral
`density and the frequency of cardiac events. Therefore, a
`true comparison is not possible at this time.
`The results of the toremifene phase III trial demonstrated
`comparable efficacy to tamoxifen against metastatic breast
`cancer. The rate of adverse events was similar with the
`
`exception of an excess of liver abnormalities in the high-
`dose toremifene group. Like tamoxifen, toremifene shows a
`lack of dose—response relationship, and this, in addition to
`increased toxicity, obviates use of the ZOO—mg dose.
`The ultimate place of toremifene in therapy will probably
`be determined only after the clinical database expands
`substantially. This agent is unlikely to be used as second—line
`therapy after tamoxifen failure due to the likelihood of
`cross—resistance.
`
`Although toremifene was being marketed as a safer
`antiestrogen in Great Britain,29 the available data are not suffi-
`cient to make such a claim; it would require careful controlled
`studies to demonstrate any safety benefit, if one actually exists.
`
`REFERENCES
`
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`2. Howell A, Downey S, Anderson E: New endocrine therapies for
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`4. Kangas L: Review of the pharmacological properties of toremi.
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`TAMOXIFEN AND TOREMIFENE COMPARISON
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`12. Martin EA, Rich KJ, White INH, et a1: 32P-Postlabelled DNA
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`15. Hemminki K, Rajaniemi H, Lindahl B, et a1: Tamoxifen-induced
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`16. Carthew P, Rich KJ, Martin EA, et 211: DNA damage as assessed
`by 32P-postlabelling in three rat strains exposed to dietary tamoxifen:
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`Carcinogenesis 16:1299-1304, 1995
`17, Tannenbaum SR: Comparative metabolism of tamoxifen and
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`18. Henmiinki K, Widlak P, Hou SM: DNA adducts caused by
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