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Clinical Trials |
Department of Academic Biochemistry, Royal Marsden Hospital, London SW3 6JJ [M. D., J. S., M. H.]; Edinburgh Breast Unit, Edinburgh EH4 2XU [J. M. D.]; Breast Unit, Leeds General Infirmary, Leeds LS1 3EX [K. H.]; SmithKline Beecham Pharmaceuticals, Harlow CM19 5AW [E. H.], United Kingdom
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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At present there are limited data on idoxifene’s anti-breast cancer activity. In phase I studies, metastatic breast cancer patients have received idoxifene at doses of 10–60 mg/day for 1 week followed by treatment at a dose of 20 mg/day until disease progression. Evidence of response was seen in 2 of 14 patients in one study and 3 of 10 patients in a second (2) . In a phase II study comparing 40 mg/day idoxifene and 40 mg/day tamoxifen, idoxifene was associated with evidence of clinical activity in patients with tamoxifen-resistant advanced breast cancer. Similar safety profiles were seen with both compounds (1) .
At doses of 5 and 10 mg/day, idoxifene produced a significant reduction in biochemical markers of bone turnover in postmenopausal women (4) . Significant reductions were also observed in total cholesterol, low-density lipoprotein, and total cholesterol/high-density lipoprotein ratio (5) . Thus, idoxifene has the properties of a SERM: it expresses antagonist activity in breast cancer cells and a low level of agonist activity on the uterus (in model systems) coupled with agonist activity on bone and lipid metabolism.
It would be valuable to establish during early clinical development of SERMs (and other agents) the growth-suppressant effects of specific drug dosages and the subpopulations of tumors in which these effects occur. We report a study that explored the efficacy of idoxifene in breast cancer by means of the evaluation of biological markers of tumor proliferation (Ki67 labeling index) and apoptotic index in patients scheduled for surgery with primary breast cancer. ER and PR expression were also evaluated both as predictors of response and markers of antiestrogenic effects.
Earlier studies have shown that a short course of treatment with tamoxifen or the pure antiestrogen ICI 182780 prior to surgery caused a significant reduction in the Ki67 labeling index of primary breast tumors (6 , 7) . Recent work has demonstrated that responders but not nonresponders to tamoxifen therapy show a significant decrease in Ki67 after 14 days (8) . Thus, changes in proliferation in response to short-term challenge with an antiestrogen may be predictive of clinical effectiveness.
Significantly higher levels of apoptosis have also been found in human
tumors during their treatment with tamoxifen or ICI 182780
(9)
. This confirms the observations of estrogen
deprivation-induced apoptosis found in xenograft studies (10
, 11)
, and these findings recently have been extended by
demonstrating that idoxifene itself induces apoptosis in xenograft
systems (12)
. Thus, induction of apoptosis may also be a
marker of pharmacological effectiveness of endocrine therapy. It is
well established that breast tumor ER and PR expression is predictive
of clinical response to endocrine therapy. Response to
antiestrogen therapy in human breast cancer has been observed in
50% of patients with ER-positive tumors and 75% that are positive
for both ER and PR (13)
.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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14 days prior to
surgery, to a maximum of 21 days. Tumor biopsy samples were taken
before the start of treatment and at surgery for the measurement of
Ki67 labeling index, apoptotic index, and ER and PR expression.
Clinical assessments and laboratory tests were performed to evaluate
the tolerability of study treatment. The protocol was approved by each
local Ethical Committee.
Inclusion and Exclusion Criteria.
Postmenopausal female patients were enrolled. Postmenopausal status was
defined as >12 months since last menses; in patients whose last menses
was 
12 months before the start of treatment and in patients who were
amenorrheic as a result of surgery, follicle-stimulating hormone and
luteinizing hormone levels were to lie in the postmenopausal
range (follicle-stimulating hormone 
35 IU/L; luteinizing hormone 40
IU/L). Patients had to have a histological or cytological diagnosis of
primary breast cancer and an operable lesion 2 cm in size. Lesion
sizes of <2 cm could, however, be considered if, in the
investigator’s opinion, a good quality core-needle biopsy could be
obtained using a 14-gauge needle. Grading was performed by central
review by a single pathologist (Dr. N. Nasiri, Royal Marsden Hospital,
London, United Kingdom) on the excision biopsy specimen.
Patients were enrolled only if they had a performance status 2
(Eastern Cooperative Oncology Group-WHO scale), a life
expectancy of 4 months, and no known renal or hepatic impairment.
Patients with metastatic breast cancer (stage IV) or who had received
prior therapy for breast cancer or with previous malignancies within
the last 5 years at other sites were excluded. Other exclusion criteria
were concurrent medical or psychiatric problems unrelated to breast
cancer; treatment with another investigational drug; concomitant
treatment with hormone replacement therapy, coumarin-type anticoagulant
therapy, or oral or i.v. corticosteroids; and a known hypersensitivity
to tamoxifen or tamoxifen analogues.
Study Procedures.
Patients were screened within 2 weeks prior to receiving study
medication to determine eligibility for entry into the study. Eligible
patients were randomized to receive a blinded treatment regimen of
either idoxifene or placebo and were then evaluated clinically prior to
surgery and 1 week after surgery/withdrawal. The following procedures
were carried out: complete medical history and physical examination,
hematology and blood chemistry evaluations; 12-lead electrocardiogram,
chest X-ray, computed tomography or magnetic resonance imaging
scan, or ultrasound if clinically indicated. Documentation of
lesion size, and histopathological type and grade were performed on the
tumor excision biopsy obtained at surgery. Clinical assessments and
laboratory tests were performed to evaluate the tolerability of study
treatment. In the safety evaluation, clinical interpretation was based
on review of displays of adverse experiences. Principal considerations
in this evaluation were time to onset, severity, study medication, and
investigator-reported relationship of an adverse experience with
the study medication.
Primary and Secondary Efficacy Variables.
The primary study end point was the change in Ki67 tumor proliferation
score from pretreatment to posttreatment biopsy. Secondary efficacy
variables were the changes in apoptotic index, and ER and PR expression
from pretreatment to posttreatment.
Study Medication.
Idoxifene was supplied as white, circular, biconvex tablets containing
40 mg of idoxifene. Placebo tablets were of identical appearance. Study
medication was provided in plastic bottles containing 21 tablets of
either idoxifene or placebo. The bottles were labeled with information
including protocol number, job number, patient number, directions for
use, the quantity of tablets supplied, warning statements, and storage
conditions. Patients took one tablet (either 40 mg of idoxifene or
placebo) p.o. once a day for 14–21 days. No instructions were given
with respect to the timing of study medication in relation to meals.
Treatment duration was dependent on the date of surgery. Patients
continued on the study drug for a minimum of 14 days to a maximum of 21
days. Surgery was to take place within 21 days of commencing study
medication. At each study site, patient numbers were randomly linked to
packaged medication supplies. The medication code was to be broken only
in the event of a serious adverse experience that the investigator
could not adequately treat without knowledge of the identity of study
medication. The numbers of bottles and tablets dispensed for each
patient were maintained and reconciled with the study medication
record.
Tumor Samples.
Before the start of study medication, a core-cut biopsy of the
primary breast tumor was obtained using a 14-gauge needle, and at
surgery a representative sample of the excision tumor was obtained from
the operative specimen. Both specimens were fixed in 10% neutral
buffered formalin and embedded in paraffin wax. The embedded blocks
were sent to the Royal Marsden Hospital, London, United Kingdom for
processing and analysis. Sections (3 µm thick) of the paraffin wax
blocks were cut onto positively charged slides and dried overnight at
37°C before being used to determine Ki67, apoptosis, ER, and PR by
previously published immunohistochemical methods.
Analytical Methods.
Measurement of cell proliferation was by immunocytochemical assay using
the MIB1 mouse monoclonal antibody to Ki67 (14)
. Ten
high-powered fields were scored. Measurement of apoptosis was by
TdT-mediated dUTP-biotin nick end labeling; the apoptotic index
was expressed as a percentage: (no. of cells displaying apoptotic
bodies x 100) ÷ (total no. of cells) (14)
. Three
thousand tumor cells/section were counted for apoptotic index.
Demonstration of ER expression was by the Novocastra 6F11 mouse
monoclonal antibody (15)
and of PR was by the Novocastra
1A6 antibody (11)
. ER and PR expression was assessed
semiquantitatively by determining the percentage of tumor cells stained
by the primary antibody and assessing the intensity of staining, using
a score of 0 to 3, which corresponded to negative, weak, intermediate,
and strong staining intensities in 10 high-powered fields. The
percentage of tumor cells in each of these categories was used to
calculate the overall H-score, ranging from 0 to 300. Tumors with a
score >20 were considered positive for either ER or PR. In all cases,
pairs of samples from the same patient were stained and scored in the
same assay batch. Scoring was conducted by one analyst (M. H.) and
was subject to quality control checks by a second (J. S.).
Statistical Analysis.
Study participants were randomly assigned to receive either 40 mg of
idoxifene or placebo using the technique of randomly permuted blocks.
A total of 50 patients (25 per arm) with positive ER status were to be
recruited for this study. It was expected that 70 patients would
need to be enrolled to achieve this number because in most cases ER
status would be unknown at the time of study entry. The sample size was
based on those of previous studies reporting decreased Ki67 levels
after presurgical treatment with antiestrogens (6
, 7)
.
Patients were considered to have completed the study as planned and to
be evaluable if they met all eligibility criteria, were found to be ER
positive, and had both pre- and posttreatment biopsies taken that
contained sufficient tumor cells for analysis (efficacy evaluable
population).
The primary efficacy evaluation was based on the Ki67 tumor proliferation score. The arithmetic difference between scores obtained from the pretreatment needle biopsy and excised tumor biopsy were determined for each patient (described as absolute change). These differences were compared by a Mann-Whitney nonparametric analysis. Similar analyses were performed for the apoptotic index, ER, and PR.
Evaluation of safety data included all randomized patients (ITT population) and were summarized as descriptive statistics.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Baseline characteristics for breast cancer data and for
histopathological grade of the tumors from these 57 evaluable patients
are shown in Table 1
. Twenty-one and 18
of the patients, respectively, were positive for PR.
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The numbers and percentages of patients who had concomitant conditions other than their breast cancer on entry to the study and who received prior and concomitant medications were similar in both treatment groups. The mean duration of study medication was 16.5 days for patients randomized to idoxifene and 18.0 days for patients randomized to placebo.
Biomarker Data.
Except where stated, all data below relate only to the efficacy
evaluable population, i.e., ER positive and eligible for all
criteria. The changes in biomarkers are summarized in Table 2
.
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, and the
mean changes are shown in Table 2
. The change in Ki67 labeling index
was significantly greater for idoxifene than placebo (P = 0.0043). The change was from a mean pretreatment level of 19.7 ± 2.7% (mean ± SE) to 13.4 ± 3.4% giving a mean change
of -6.3 ± 1.9%. In the idoxifene-treated group, one patient
(patient A) had much higher pretreatment and on-treatment Ki67 than all
others (82.3 and 91.7%, respectively). There was no evidence of
technical failure being responsible for these extreme results.
Exclusion of this patient from the data analysis resulted in a mean
pretreatment Ki67 labeling index of 17.6 ± 1.7% and
posttreatment index of 10.7 ± 2.2%, with a mean change of
-6.8 ± 1.9%. There was no significant effect in the
placebo-treated ER-positive tumors: the mean change was +1.0 ±
1.4%.
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Patients positive for both ER and PR in the idoxifene-treated group
showed a mean fall from 18.6 ± 3.5% to 11.5 ± 4.2%,
giving a mean change of -7.1 ± 1.6% (P =
0.0034; Fig. 2
). Excluding patient A from
this analysis led to a change from 15.5 ± 1.5% to 7.5 ±
1.4%, a mean change of -7.9 ± 1.4%. Thus, the decrease as a
proportion of the baseline was greater in the ER-positive/PR-positive
group than in the ER-positive group as a whole.
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, and the mean changes are shown in
Table 2
. The mean difference between pretreatment and on-treatment
samples was very small for both the idoxifene group (+0.02 ±
0.05%) and the placebo group (+0.04 ± 0.05%). The difference
between the two treatment groups was not statistically significant
index (P = 0.7200), showing that idoxifene had no
significant effect on the apoptotic index. The mean pretreatment level
in the ER-negative group was higher than in the ER-positive group
(1.6% and 0.9%, respectively). The ER-negative patients showed
no effect of either therapy on the apoptotic index. There was no
significant increase in apoptosis after idoxifene treatment in tumors
positive for both ER and PR (P = 0.99).
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and 5
,
and the mean changes are shown in Table 2
.
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Considering all patients, PR expression showed a minor mean increase in the immunohistochemical score in the idoxifene-treated group with very little change in the placebo group. The difference in the change between the two groups did not reach statistical significance (P = 0.078). However, in those patients who were PR positive prior to treatment, there was an increase in the H-score of 26 ± 10 in the idoxifene group and a decrease in the placebo group of 2 ± 8, showing a significant interaction with treatment (P = 0.0002).
Safety.
Idoxifene was well tolerated. Seven patients in the idoxifene group and
six in the placebo group had adverse experiences considered by the
investigator as suspected as being or probably related to study
treatment. The most frequently reported adverse event was hot flushes
of mild intensity in three patients in the idoxifene group and
dyspepsia in two patients in the placebo group. There were very few
laboratory abnormalities in patients randomized to study medication,
and all were considered as clinically nonsignificant.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In this study, idoxifene led to a pronounced change in mean Ki67 in
ER-positive but not ER-negative patients. Overall in the
idoxifene-treated ER-positive patients, the fall was to 65% of
baseline levels. Comparison of these changes with those reported in the
earlier studies with other antiestrogens is not valid because, as well
as being in different populations, those studies used a different
antibody to Ki67 in frozen rather than formalin-fixed biopsies.
Nonetheless, the data indicate that idoxifene, like these other two
drugs, should be an effective anti-breast cancer drug in ER-positive
patients.
The lower Ki67 in the ER-positive group and the greater proportional
change in Ki67 in the group that was also positive for PR (to 50%
of baseline levels) are consistent with expectations: it is known that
proliferation is generally higher in ER-negative tumors (6
, 16)
and that tumors positive for PR as well as ER have a greater
likelihood of responding to endocrine therapy (13)
.
It is possible that the results underestimate the effects that
idoxifene would have at steady state. The terminal half-life of the
drug is 5
weeks3
such that after a median 16.5 days of treatment only approximately half
of one half-life would have elapsed. The plasma levels at the time of
excision would approximate to only one-fourth those of steady-state
levels, and the drug exposure over the preceding 16.5 days would be
represented by an exponential function toward these levels. Thus, the
impact on proliferation is likely to be equivalent to that which an
idoxifene dose of 10 mg/day or less would achieve at steady state [the
pharmacokinetics of idoxifene being linear (2)
]. To have
achieved steady-state levels by 16.5 days in this study would have
required a loading dose of idoxifene substantially above that
administered previously to humans.
A number of studies have shown that apoptosis can be induced by estrogen withdrawal or by an antiestrogen, both in vitro and in animal model systems (10 , 11 , 17 , 18) . In an earlier small study by our group, apoptosis was also found to be significantly higher in patients treated with ICI 182780 compared with controls; in patients treated with tamoxifen apoptosis showed a small change with borderline statistical significance in patients with ER-positive tumors (9) . Recently, we also have shown that idoxifene treatment of estrogen-supported MCF7 xenografts leads to increased apoptosis (12) . Thus, the absence in this study of a significant increase in apoptotic index after treatment with idoxifene was surprising. There may be a number of reasons why this change was not observed. It is possible that the exposure of the tumor to relatively low doses of idoxifene over the treatment period may be insufficient for any impact on apoptosis. The use of pretreatment biopsies containing relatively small amounts of tissue may lead to tumor heterogeneity, influencing the accuracy of the data, particularly for a rare event such as apoptosis. However, the studies referenced above in which increases in apoptosis were seen had no greater statistical power than this study and used relatively similar clinical samples. In addition, our previously published data on the reproducibility of measurements using core-cuts showed only a marginally poorer precision for apoptosis than for Ki67 (14) . The data may reflect the true effect of idoxifene on breast tumors in vivo, i.e., that despite effects seen in model systems there is no effect on apoptosis in patients.
As noted above, the measurement of ER and PR content is of importance when evaluating the likely response to endocrine therapy. The greater decrease in ER levels in the idoxifene-treated patients than in the placebo group is consistent with some, but not all, earlier data with tamoxifen (6 , 19) , but it is not as great an effect as that seen with ICI 182780 (7) , which decreases stability of the ER protein (20) . In vitro estrogen deprivation leads to increases in ER in breast cancer cells because estrogen enhances ubiquitinproteasomal degradation of ER (21) . This is consistent with our observations of increased ER levels in MCF7 human breast cancer xenografts on estrogen withdrawal (11) . The mechanism for the decreased ER levels with idoxifene and tamoxifen is not known but may also relate to ligand-dependent proteasomal degradation.
The decrease in ER shown in the placebo group emphasizes the importance of placebo controls in this sort of study. This decrease may have occurred as a result of histological fixation differences between core-cuts and excision biopsies. Other possible explanations are that the taking of a core-cut may itself induce a change in ER in the tumor or that systematic differences in scoring between core-cuts and excisions might occur despite efforts to avoid this. A further consideration is that the change in the ER H-score may result from a conformational change in ER induced by the binding of idoxifene, which could influence the binding to antibody.
PR is an estrogen-induced gene, and its expression is considered as denoting an intact estrogen response mechanism (21) . By extension, decreases in PR expression may be considered indicative of an antiestrogenic effect as seen with ICI 182780 (7) . In contrast, the early increases seen in PR after initiating tamoxifen treatment are considered indicative of an early predominance of an agonist effect of tamoxifen [at least on the PR gene (22, 23, 24) ], although this does not indicate lack of efficacy: those patients showing an increase in PR (after a median 13 days of tamoxifen) have a greater likelihood of response (23) . The trend toward an increase in PR with idoxifene but lack of a statistically significant effect may indicate that idoxifene has some agonist activity on this parameter in the breast, but less than tamoxifen, which is consistent with its lower uterotropic effect than tamoxifen in rodents (1) .
Idoxifene was well tolerated, and no major side-effects or changes in laboratory values were observed, consistent with other reports on its clinical usage.
This is only the second report of a randomized biomarker study [the first was the study of ICI 182780 (7) ] during a prescribed period of time between diagnosis and the time at which a patient is scheduled for surgery. Medical treatment is not conventionally offered during this time, and it offers the opportunity to assess and compare new drugs once their safety has been established. Importantly, changes in Ki67 over this period by tamoxifen relate to subsequent response to therapy (8) . The consistency of the data derived here with those that would be expected of an effective SERM not only supports idoxifene being an effective anti-breast cancer agent, it also supports the further exploitation of this clinical scenario with novel therapies.
In conclusion, idoxifene showed a significant antiproliferative effect in ER-positive breast cancer as shown by the decrease in the Ki67 labeling index with no effect in ER-negative cancers. This is consistent with idoxifene being an effective anti-breast cancer agent in ER-positive tumors.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 To whom requests for reprints should be
addressed, at Department of Academic Biochemistry, Royal Marsden
Hospital, London SW3 6JJ, United Kingdom. Phone: 44 171 808 2887; Fax:
44 171 376 3918; E-mail: mitch{at}icr.ac.uk 
2 The abbreviations used are: SERM, selective
estrogen receptor modulator; ER and PR, estrogen and progesterone
receptor; ITT, intention to treat.
3 Data on file at SmithKline Beecham.
Received 1/ 4/00; revised 3/13/00; accepted 3/16/00.
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