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Update on Breast Cancer Prevention

Update on Breast Cancer Prevention

ABSTRACT: Four randomized prospective trials have evaluated tamoxifen for chemoprevention of breast cancer. The National Surgical Adjuvant Breast and Bowel Project P-1 trial reported that tamoxifen reduced the risk of invasive breast cancer by 49%. Two smaller European trials, the Royal Marsden Hospital Chemoprevention Trial and the Italian Tamoxifen Prevention Study, demonstrated no decrease in the incidence of breast cancer among women using tamoxifen. The International Breast Cancer Intervention Study confirmed that tamoxifen can reduce the risk of breast cancer in healthy women. The Multiple Outcomes of Raloxifene Evaluation trial, which evaluated the use of raloxifene (Evista) to prevent osteoporosis, found that the risk of invasive breast cancer decreased by 76%. A uniform theme in these trials is that tamoxifen reduces the risk of breast cancer among women at high risk for the disease. Tamoxifen is currently approved for breast cancer risk reduction. However, because of the side effects associated with its use (ie, endometrial cancer and thromboembolism), other agents are being investigated. The Study of Tamoxifen and Raloxifene is designed to compare the efficacy of tamoxifen and raloxifene in reducing breast cancer risk. Aromatase inhibitors will also be studied in the setting of chemoprevention for breast cancer.

Chemoprevention can be defined
as the use of specific natural
or synthetic chemical agents
to reverse, suppress, or prevent the
progression of premalignant lesions
to invasive carcinoma.[1,2] Tamoxifen
is classified as a first-generation
selective estrogen-receptor modulator
(SERM). It is a proven treatment for
breast cancer, which has encouraged
its testing as a chemopreventive agent
in healthy women.[3]

Four randomized prospective clinical
trials have used tamoxifen as a
chemopreventive agent for breast cancer.
Two of the trials-the National
Surgical Adjuvant Breast and Bowel
Project (NSABP) P-1 study and the
International Breast Cancer Intervention
Study (IBIS-I)-did demonstrate
a reduction in breast cancer risk with
tamoxifen. The Royal Marsden Hospital
Chemoprevention Trial, a pilot
study for the IBIS-I trial, and the initial
analysis of the Italian Tamoxifen
Prevention Study revealed no decrease
in the incidence of breast cancer
among women using tamoxifen.

Raloxifene (Evista) is a secondgeneration
SERM that prevents loss
of bone mineral density. The Multiple
Outcomes of Raloxifene Evaluation
(MORE) trial was originally
designed to determine whether raloxifene
reduced the risk of fracture in
postmenopausal women with osteoporosis,
with the incidence of breast
cancer as a secondary end point.

In this article, we review data from
each of these five studies and discuss the
differences among the trials (Table 1).

Breast Cancer Prevention Trial

In 1992, the National Cancer Institute
in collaboration with the NSABP
launched the Breast Cancer Prevention
Trial (BCPT, P-1).[4] The primary aim
of this double-blind, placebo-controlled,
randomized clinical trial was to determine
whether tamoxifen administered
for 5 years prevented invasive breast
cancer in women at increased risk. Eligible
women were age 60 or older,
were age 35 to 59 with a 5-year predicted
risk of breast cancer of at least
1.66%, or had a history of lobular carcinoma
in situ (LCIS). Risk was estimated
using the Gail model,[5] which
considers current age, age at menarche,
age at first live birth, number of firstdegree
relatives with breast cancer, and
the number of breast biopsies ever
performed. A previous diagnosis of
atypical hyperplasia doubles the estimated
risk.

Between June 1, 1992, and September
30, 1997, 13,388 women entered
the trial and were randomly
assigned to receive tamoxifen at
20 mg/d or placebo. Almost all the
participants were white (96.4%), more
than one-third (37.1%) had had a hysterectomy,
and more than one-half
(56.8%) had one first-degree relative
with breast cancer. The trial was
stopped in March 1998, and results
were reported, because statistical significance
had been achieved in a number
of study end points.

Trial Results
The median follow-up time was
54.6 months. Through July 1998, a
total of 368 invasive and noninvasive
breast cancers developed among the
13,175 women with evaluable end
points. The overall risk of invasive
breast cancer was reduced by 49%.
There were 175 cases of invasive
breast cancer in the placebo group
compared with 89 in the tamoxifen
group (risk ratio = 0.51; 95% confidence
interval [CI] = 0.39-0.66;
P < .00001). The annual rate of invasive
breast among women taking
tamoxifen was 3.4 per 1,000 women,
compared with 6.8 per 1,000 women
taking placebo. The risk of invasive
breast cancer was reduced in all groups
in the trial.

For noninvasive breast cancer, risk
was reduced by 50%, with 69 cases in
women receiving placebo and 35 in
those receiving tamoxifen (P < .002).
The average annual rate of noninvasive
breast cancer per 1,000 women
was 2.68 in the placebo group compared
with 1.35 in the tamoxifen
group. The BCPT showed that tamoxifen
confers a substantial net benefit
in women with a diagnosis of either
LCIS or atypical hyperplasia. For
women with a history of LCIS, the
reduction in risk was 56% (risk ratio
= 0.44; 95% CI = 0.16-1.06), and
for women with a history of atypical
hyperplasia, risk was reduced by 86%
(risk ratio = 0.14; 95% CI = 0.03-
0.47). Tamoxifen reduced the incidence
of estrogen-receptor-positive
tumors by 69%, but there was no difference
in the incidence of estrogenreceptor-
negative tumors.

The incidence of osteoporotic fractures
involving the hip, spine, and radius
was reduced by 19% among
women taking tamoxifen (111 events
vs 137 events in the placebo group),
and the 45% reduction in fractures of
the hip missed reaching statistical significance
because of the small number
of events reported.

Adverse Effects
Women who received tamoxifen
had a 2.53 times greater risk of developing
invasive endometrial cancer
than did women who received placebo
(95% CI = 1.35-4.97). The average
annual rate per 1,000 women was
2.30 in the tamoxifen group and 0.91
in the placebo group. The increased
risk was seen predominantly among
women aged 50 and over (in women
49 or younger, the risk ratio was 1.21
with a 95% CI = 0.41-3.60; in women
older than 50, the risk ratio was
4.01 with a 95% CI = 1.70-10.90).
All cases of invasive endometrial cancer
that occurred among women receiving
tamoxifen were classified as
stage 0 or I according to the International
Federation of Gynecology and
Obstetrics (FIGO).

The number of thromboembolic
events increased among women taking
tamoxifen, particularly those aged
50 years and older. The event rate for
pulmonary embolism reached statistical
significance.

The rate of cataract development
increased marginally (by 14%) in
women taking tamoxifen who were
free of cataracts at the time of study
entry. The only symptomatic differences
between the placebo and tamoxifen
group were bothersome hot
flashes and vaginal discharge. Bothersome
hot flashes were reported by
46% of women in the tamoxifen group
compared with 29% in the placebo
group. Moderately bothersome or
worse vaginal discharge was reported
in 29% of women in the tamoxifen
group compared with 13% of those in
the placebo group. This randomized
clinical trial provided the first information
to support the hypothesis that
breast cancer can be prevented in
women at increased risk for the
disease.

Italian Tamoxifen
Prevention Study

The Italian Tamoxifen Prevention
Study was initiated in October
1992.[6] This double-blind placebocontrolled,
randomized trial evaluated
tamoxifen in healthy women aged
35 to 70 years. In view of the potential
side effect of endometrial cancer,
the study was restricted to women
who had undergone a hysterectomy.
Recruitment for the study started in
October 1992 and ended in July 1997.
The trialist and data-monitoring committee
decided to end recruitment primarily
because 26% of women
dropped out of this study; 5,408 women
were randomized to receive tamoxifen
at 20 mg/d or placebo for 5 years.
Among the 5,378 women with complete
data, 48.3% had a bilateral
oophorectomy, and 18.2% had at least
one first-degree relative or an aunt
with breast cancer. Women were allowed
to take hormone replacement
therapy (HRT) while participating in
the study. The primary end points were
reduction in the frequency and mortality
of breast cancer.

At a median follow-up of 46
months, 41 cases of breast cancer
were reported-19 among women in
the tamoxifen arm and 22 among
women in the placebo arm (P = .6).
The number of deaths from vascular
disease were lower than expected
from the Italian national rates. A subgroup
analysis that was not part of
the original protocol revealed a protective
effect for tamoxifen among
women who took HRT during the
study period. At the time that the initial
results were reported, the conclusion
was that tamoxifen did not confer
a significant protective effect against
breast cancer in women at normal or
slightly reduced risk of the disease.
Also, women who were using HRT
benefited from the administration of
tamoxifen.

Study Update
An update of the Italian Tamoxifen
Prevention Study was reported
in 2002.[7] At an extended median
follow-up of 81.2 months, 79 cases
of breast cancer had been identified.
Breast cancer was diagnosed in 45 of
2,708 women receiving placebo and
34 of 2,700 women receiving tamoxifen
(odds ratio = 0.76; 95% CI =
0.47-1.60). The difference was not
statistically significant (P = .215).
Among women who took HRT during
the trial, the cumulative frequency
of breast cancer was 0.92%
(0.17-1.66) in the tamoxifen group
and 2.58% (1.30-3.85) in the
placebo group. Among women who
used HRT either at baseline or during
the study, breast cancer was diagnosed
in 17 of 791 receiving placebo
and 6 of 793 receiving tamoxifen
(P = .022).

The update supported the trial's
original conclusion that tamoxifen
provides some benefit in the prevention
of breast cancer, but the difference
was nonsignificant in women
with a normal or slightly reduced risk
of the disease. The results also suggest
that tamoxifen seems to reduce
the risk of breast cancer in women
who use HRT compared with nonusers
of HRT.

Subgroup Analysis
In a subgroup analysis, Veronesi
et al[8] were able to identify a group
of women at increased risk for estrogen-
receptor-positive breast cancer.
This group consisted of women taller
than 160 cm (the median height of the
overall study cohort), with at least
one functioning ovary, who had
reached menarche no later than age
13, and who had no full-term pregnancy
before age 24. This group of
702 (13%) women was classified as
high risk. The remaining group of
4,693 (87%) women was classified as
low risk. Information on required
baseline characteristics was missing
for 13 women.

In the high-risk group, the risk of
breast cancer was increased threefold
over that in the low-risk group (hazard
ratio = 3.32; 95% CI = 1.78-6.17).
Tamoxifen reduced the incidence of
breast cancer in the high-risk group
(n = 3 vs n = 15 in the placebo group,
P = .003); however, it had no effect in
the low-risk group (tamoxifen = 31,
placebo = 30; P = .89). It is important
to emphasize that this subgroup analysis
was not used as a stratification
factor at the time of randomization.
Thus, these findings need to be
confirmed in randomized prospective
trials.[9]

Royal Marsden Hospital
Chemoprevention Trial

The Royal Marsden Hospital
Chemoprevention Trial was initiated
in 1986 as a preliminary pilot study
for IBIS-I.[10,11] The aim of this randomized,
placebo-controlled chemoprevention
trial was to assess whether
tamoxifen would prevent breast cancer
in healthy women at increased
risk for the disease based on family
history. Each participant had at least
one first-degree relative under age 50
with breast cancer, one first-degree
relative with bilateral breast cancer,
or one affected first-degree relative
of any age and another affected firstdegree
or second-degree relative.
Women were allowed to take HRT
during this study.

Between October 1986 and April
1996, 2,494 women between the ages
of 30 and 70 were randomized to receive
tamoxifen at 20 mg/d or placebo
for up to 8 years. The primary end
point was the occurrence of breast
cancer. The median follow-up was 70
months, and 2,471 of the women were
analyzed.

A total of 70 invasive and noninvasive
breast cancers occurred among the
women in this trial. The frequency of
breast cancer was the same for women
receiving tamoxifen or placebo
(tamoxifen = 34, placebo = 36; relative
risk = 1.06; 95% CI = 0.7-1.7),
and there appeared to be no interaction
between the use of HRT and the
effect of tamoxifen on breast cancer
occurrence. A total of 12 cases developed
among 523 women who received
HRT while on tamoxifen, compared
with 13 of 507 women receiving placebo
(P = .6). An update of this
trial[12,13] reported 75 cases of breast
cancer in the placebo group compared
with 62 in the tamoxifen group (odds
ratio = 0.83; 95% CI = 0.58-1.16).

International Breast Cancer
Intervention Study

Between April 1992 and March
2001, 7,152 women aged 35 to 70
years and at high risk for breast cancer
were enrolled in the IBIS-1 trial
and randomized to receive tamoxifen
at 20 mg/d for 5 years or placebo.[14]
Eligible women had risk factors for
breast cancer indicating at least a twofold
relative risk among those aged
45 to 70 years, a fourfold relative risk
among those aged 40 to 44 years, and
a 10-fold relative risk among those
aged 35 to 39 years. Approximately
60% had two or more first-degree
relatives with breast cancer; one-third
of women had previously undergone
hysterectomies. Use of HRT was permitted,
and approximately 40% of
women used such therapy at some
point during the trial. The primary
end point was the incidence of breast
cancer, including ductal carcinoma
in situ (DCIS).

Trial Results
A total of 7,139 women were included
in the analysis. At a median
follow-up of 50 months, 170 breast
cancers had been diagnosed (including
DCIS). The rate was 32% (95%
CI = 8%-50%) lower in the tamoxifen
group than in the placebo group
(tamoxifen = 69, placebo = 101;
P = .01). The risk of developing
estrogen-receptor-positive invasive
tumors was reduced by 31%, but
there was no reduction in the risk of
estrogen-receptor-negative tumors.

Among women taking HRT during
the trial, 38 cases of breast cancer
occurred in the placebo group and 29
in the tamoxifen group (odds ratio =
0.76; 95% CI = 0.47-1.23). Among
women who received HRT before the
trial only, 21 cases of breast cancer
developed in the placebo group and 9
in the tamoxifen group (odds ratio =
0.43; 95% CI = 0.20-0.91). A nonsignificant
twofold increase in the incidence
of endometrial cancer was
found in the tamoxifen group (tamoxifen
= 11, placebo = 5; odds ratio =
2.20; 95% CI = 0.80-6.06).

The women enrolled in this trial
were at moderately increased risk of
developing breast cancer, with 60%
of the study cohort having a 10-year
risk ranging from 5% to 10%. Participation
in the trial required at least a
twofold relative risk for breast cancer
for women aged 45 to 70 years, a
fourfold relative risk for women aged
40 to 44 years, and a 10-fold relative
risk for women aged 35 to 39 years.
Risk factors used included a combination
of family history, lobular carcinoma
in situ, atypical hyperplasia,
nulliparity, and benign breast biopsies.
The IBIS-I investigators used a
model to predict the absolute 10-year
risk of developing breast cancer, but
the details of their model have not
been published. In contrast, 44% of
the women in the NSABP BCPT had
greater than a 3% 5-year risk of developing
breast cancer, as determined
using the validated Gail model.[5]
Among women enrolled in the BCPT,
tamoxifen reduced the risk of breast
cancer by 34% in high-risk women
without either atypia or LCIS, which
is nearly identical to the 32% reduction
in risk seen in the IBIS-I study.

Although there was no overall difference
in the effect of tamoxifen
among women who used HRT compared
with those who had never used
HRT, tamoxifen did reduce the incidence
of breast cancer in women who
had used HRT before enrollment in
IBIS-I. This reduction is remarkably
similar to the findings in the Italian
tamoxifen study. In IBIS-I as in the
Italian trial, tamoxifen produced a differential
effect based on the status of
participants' use of HRT. Women who
used HRT during the trial achieved a
24% reduction in the risk of invasive
breast cancer with tamoxifen use, similar
to the 27% reduction observed
among women who had never used
HRT; women who had used HRT only
before initiating tamoxifen therapy
(and not during the trial) had a statistically
significant 57% reduction in
the risk of breast cancer.

Adverse Events
All the women in the IBIS-I trial
who developed endometrial cancer
were postmenopausal at diagnosis.
Most of the endometrial cancers occurred
in women older than age 50 at
the time of randomization. All were
FIGO stage I except for one case in
the placebo group that was stage II.
The rate of thromboembolic events
was 2.5 times greater in the tamoxifen
group than in the placebo group
(95% CI = 1.5-4.4; P = .001), and
42% of these events occurred within
3 months of surgery or after periods
of immobility. There were no differences
in the number of cerebrovascular
accidents, myocardial infarctions,
or other vascular events between treatment
groups. A significant excess of
deaths from all causes occurred in the
tamoxifen group (25 vs 11, P = .028).
This increase in mortality is of concern,
but is not statistically rigorous
due to the multiple, unplanned comparisons
in the analysis.

In summary, IBIS-I confirmed that
tamoxifen can reduce the risk of breast
cancer in healthy women. Temporary
cessation of tamoxifen should be considered
during and after major surgeries
or periods of immobilization to
reduce the risk of thrombosis, according
to the investigators.

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