CANCER TREATMENT REVIEWS 2001; 27: 261273

doi: 10.1053/ctrv.2001.0235, available online at http://www.idealibrary.com on

CONTROVERSY

Breast cancer prevention: present and future

A. K. Salih and I. S. Fentiman
Department of Surgical Oncology, Guy's Hospital, London, UK
Increased risk of breast cancer may result from modifiable factors such as endogenous hormone levels, obesity, HRT, and nonlactation, or non-modifiable factors such as genetic susceptibility or increasing age. Those factors that are easiest to modify may
have a limited impact on the totality of breast cancer. The Gail model, based on known factors may be useful for estimating lifetime risk in some individuals. Tamoxifen prevention still remains contentious. In the NSABP-P1 study, there was a 49%
reduction in risk of breast cancer in women given tamoxifen but in the Italian and Royal Marsden trials, no effect on breast
cancer incidence was detected, possibly because of the different case-mix in these studies. Raloxifene, tested in the MORE trial
reduced the incidence of breast cancer by 65%. The effect was restricted to ER positive tumours: no reduction in ER negative
cancers was seen. Life-style factors such as diet, obesity, exercise, and age of first full term pregnancy and number of pregnancies have a mild to moderate impact on risk and so may have little effect on the incidence of breast cancer. Reduction of
alcohol intake could lead to a modest reduction in the risk of breast cancer but possibly adversely affect other diseases. So far,
studies of retinoids have not shown a benefit in terms of breast cancer risk reduction. Fat reduction and GnRH analogues
reduce mammographic density but have not yet been shown to affect risk. & 2001 Harcourt Publishers Ltd
Key words: Breast cancer; prevention; risk factors; genetic susceptibility tamoxifen; raloxifene.

INTRODUCTION
Breast cancer remains one of the most common epithelial neoplasms with 170,000 new cases estimated
annually in the US. Approximately one in ten women
in the developed world will be affected by breast
cancer during their lifetime (1) but only 510% have a
mutation in a cancer susceptibility gene (1,2). Almost
half of the genetic cases are due to mutations in BRCA 1
or BRCA 2 (3). The majority of cases are of unknown
aetiology making targeted prevention unachievable.
Significant breast cancer risk factors include age,
early age at menarche, late age of menopause and late
age at first pregnancy. These are not practically modifiable. Those factors that can be potentially modified,
albeit with difficulty, are endogenous hormone levels,
obesity, exercise, HRT, alcohol indulgence, lactation,
oral contraception and diet. Unfortunately, those

Correspondence to: I. S. Fentiman, Department of Surgical

Oncology, Guy's Hospital, London, SE1 9RT, UK.
0305-7372/01/027261 13 $35.00/0

factors that are easiest to modify may have a limited

impact on the totality of breast cancer (4).
Increased risk of breast cancer has also been found
to be associated with several reversible detectable
biomarkers, including serum estrogen and testosterone (5), mammographic breast density (6), insulin
growth factor-1 (7) and intraepithelial neoplasia (8).
Based on known risk factors for the development
of breast cancer, Gail et al. developed a model to
estimate the 5-year or life-time probability of disease
developing in an individual woman (9). This used
multivariate logistic regression of risk factors including race, age, age at first pregnancy, age of menarche,
nulliparity, first-degree relatives, and prior history of
benign breast disease, in particular atypical ductal
and lobular hyperplasia. Women with a previous
history of ductal carcinoma in situ (DCIS) or invasive
breast cancer were not considered in this model and
so it cannot be used to measure their risk. The Gail
model categorizes women into low, moderate and
high-risk groups.
In the US the model has been used to identify highrisk women for chemoprevention (10) but has not
& 2001 HARCOURT PUBLISHERS LTD

262

been popular in the UK. As another approach,

Feigelson and Henderson suggested developing a
multigenic model of breast cancer susceptibility and
then to screen women to determine those who carry a
combination of alleles that put them at significantly
increased risk (4). This method is still experimental.
The current available options for prevention of
breast cancer include endocrine chemoprevention,
life style modification and prophylactic mastectomy
with and without oophorectomy. As yet, none of
these approaches has been shown to reduce mortality
from the disease.

CHEMOPREVENTION
Tamoxifen
In 1986 Cuzick, Wang, and Bulbrook outlined the
theoretical basis for using tamoxifen in a prevention
trial (11). They argued this was a logical extension of
breast screening and that because of the evidence of
the efficacy of tamoxifen in the established disease,
without undue side-effects, the agent could block the
effect of more biologically available estrogen in
women at risk. This was backed up by observations
showing a reduction in contralateral breast cancers in
women given adjuvant tamoxifen for breast cancer
(12,13).

NSABP-P1 breast cancer trial

This trial started in April 1992 and closed in
September 1997 recruiting 13,388 women aged 35
years, the largest prevention trial to date (14). Almost
96% of the participants were white and the median
follow-up was 54.6 months. They were randomized
either to tamoxifen 20 mg (6, 681 women) or to placebo
(6,707 women) for five years. The trial was terminated prematurely because of evidence of a statistically significant reduction in risk of breast cancer risk
in the tamoxifen group.
All participants had an estimated 5-year risk of
1.66 according to a modified Gail model including
race, age, age at first live birth, age at menarche, age
at menopause, nulliparity, number of benign biopsies
and atypical ductal hyperplasia (ADH) (9). Of the
entrants, 31% were aged 60 with no other risk
factor. The study also included women with a history
of lobular carcinoma in situ (LCIS) treated with
excision alone. Women with histories of deep vein
thrombosis, pulmonary embolism and DCIS were
excluded from the study.
The result was a 49% reduction in invasive breast
cancer (P < 0.0001, risk ratio 0.51, 95% confidence

A . K. SALIH AND I. S. FENTIMAN

TABLE 1 Results of the NSABP P-1 prevention trial
Feature

Breast cancer rate

per 1000 women
Placebo

Risk ratio
(95% CI)

Tamoxifen

Overall invasive
Overall DCIS

2.7
6.8

1.4
3.4

0.50 (0.330.77)
0.51 (0.390.66)

Age
49
5059
60

6.7
6.3
7.3

3.8
3.1
3.3

0.56 (0.370.85)
0.49 (0.290.81)
0.45 (0.270.74)

ADH
Yes
No

10.1
6.4

1.4
3.6

0.14 (0.030.47)
0.56 (0.420.73)

LCIS
Yes
No

13.0
6.4

5.7
3.3

0.44 (0.161.06)
0.51 (0.391.09)

First degree FH
0
1
2
3

6.4
6.0
8.7
13.7

3.0
3.0
4.8
7.0

0.46
0.52
0.55
0.51

(0.240.84)
(0.360.37)
(0.300.97)
(0.151.55)

TABLE 2 Annual morbidity rates in the NSABP-P1 trial

Morbidity

Rate per 1000

women

Risk ratio
(95% CI)

Placebo Tamoxifen
Thrombo-embolism
Deep vein thrombosis 0.8
Pulmonary embolism 0.2
Stroke
0.9

1.3
0.7
1.4

1.60 (0.912.86)
3.01 (1.159.27)
1.59 (0.932.77)

Endometrial cancer
49 years
50 years

1.1
0.8

1.3
3.0

1.21 (0.413.60)
4.01 (1.7010.9)

Fractures
Hip
Hip/Spine

0.8
5.3

0.5
4.3

0.55 (0.251.15)
0.81 (0.631.05)

interval 0.390.66). The risk reduction was greater in

women who had had a previous diagnosis of atypical
hyperplasia or LCIS. There was a reduction in the
annual incidence of invasive breast cancer from 6.8
per 1000 women in the placebo group to 3.4 per 1000
in the tamoxifen group. This result is similar to that
which was expected from the adjuvant studies with
regard to contralateral breast cancer (15). There were
175 cases of invasive breast cancer in the placebo
group compared with 89 cases in the tamoxifen
group. This reduction in the risk was seen within the
first year and continued throughout the period of
the study. Tamoxifen was effective in preventing
breast cancer in all age subgroups (49, 5059 and

BREAST CANCER PREVENTION

60 years) as well as in women with histories of

atypical hyperplasia and LCIS.
Tamoxifen however had an inhibitory effect on
oestrogen receptor positive (ER) tumours only and
showed no effect on ER-tumours. The incidence of
ER invasive breast cancer was reduced from 5 per
1000 in the placebo group to 1.6 per 1000 in the tamoxifen group. Estrogen receptor positive tumour was
reduced by 69% (risk ratio 0.31, 95% CI 0.220.45).
There was a slight increase in ER-negative tumours
(OR 1.22, 95% CI 0.742.03). The result also showed a
reduction of 50% in the incidence of non-invasive
breast cancer including DCIS and LCIS (P 0.002,
risk ratio 0.50, 95% confidence interval 0.330.77).
There was also a significant reduction in the development of small tumours (2 cm) compared with
large lesions. The reduction in the incidence of invasive breast cancer was equally marked in women both
with and without a family history of breast cancer.
In the tamoxifen group there was a 19% reduction
in osteoporotic fractures compared with the placebo
group. There was no significant difference in the
incidence of fatal and non-fatal cardiovascular events
despite the fact that tamoxifen by its estrogenic effect
on lipids reduces low density lipoproteins (LDL)
cholesterol by 1020%. In postmenopausal women,
two adjuvant trials have shown reductions in death
from myocardial infarction and admission for cardiac
disease (16,17).
There was a 2.5-fold increase in risk of endometrial
cancer in the tamoxifen group (OR 2.53 (95% CI
1.354.97), similar to that found in the tamoxifen
adjuvant trial overview of the adjuvant trials (15). This
effect was seen in women aged 50 and above, OR
4.01 (95% CI 1.7010.90). Additionally, there was
a significant increase in the incidence of vascular
events in the tamoxifen group, mainly in women aged
50 years. There was a three-fold increase in the
incidence of pulmonary embolism, a 60% increase in
the incidence of deep vein thrombosis and a 59%
increase in strokes.
Hot flushes were reported by 78% of the tamoxifen
group and 65% of the controls (P 0.001). Vaginal
discharge occurred in 55% and 34% respectively
(P 0.001).
Menstrual irregularity and vaginal bleeding were
slightly higher but not to a statistically significant
degree. There was no difference between the two
groups with regard to weight gain, and mood change.
Because so few deaths occurred in either group
(tamoxifen 3, placebo 6), there was no evidence that
tamoxifen reduces mortality from breast cancer. A
recent analysis of the risks and benefit concluded that
tamoxifen is more beneficial for younger women (18).
Health related quality of life (HRQL) for 11,064
women followed up for 36 months was evaluated (17).
There was no significance difference between two

263

groups with regard to the proportion of participants

scoring above a clinical significant level on the
Center for Epidemiological Studies-Depression scale
(CES-D). No significant difference was noted in the
Medical Outcome Study SF-36 of physical and mental
status. However, this study showed a higher incidence
of gynaecological symptoms and sexual dysfunction
for the tamoxifen treated women but no change in
overall sexual activities.
Because of concerns over the side effects of tamoxifen particularly in women over 50, it is not clear
which groups of women should receive it as a prevention therapy. It has been recommended that
women should receive tamoxifen only when their
risk approaches 1% per year for women with an intact
uterus and 0.5% for hysterectomized women (18).
There is some concern that HRT given simultaneously
might increase the thromboembolic effect of the
tamoxifen (19).
The effectiveness of tamoxifen for prevention of
primary breast cancer beyond 5 years is uncertain.
The NSABP-14 adjuvant trial found that 5-years of
tamoxifen treatment for estrogen receptor-positive
breast cancer reduced the risk of new primary cancer
in the contralateral breast and this was not further
reduced by continuation for an additional 5 years.

European tamoxifen prevention trials

Following the Internet announcement of the NSABP
P-1 results in April 1998, two smaller Europe studies
were published in the Lancet (20,21). Both studies
randomized women to tamoxifen 20 mg daily versus
placebo and preliminary results showed no reduction
in breast cancer incidence. The four published chemoprevention trials are outlined in Table 3.

Italian tamoxifen chemoprevention trial

To avoid endometrial stimulation, only hysterectomized women were recruited (20). The aim was to
recruit 20,000 women but because of low compliance
and participant dropout (>25%), only 5408 women
aged 3570 years with a normal or low risk of
developing breast cancer were eventually studied.
After a median follow-up of 46 months there was no
difference in the incidence of breast cancer (placebo
22, tamoxifen 19). Although the result of this study
contradicted the result of the NSABP P-1 study, there
was some evidence of a reduction in the incidence of
breast cancer (19 versus 11, OR 0.58) in the women
who took tamoxifen for more than one year. This
finding may not be significant because of the small
number of cancers detected in this study.
Interestingly, there was only one case of breast
cancer in the women who were on tamoxifen and

264

A . K. SALIH AND I. S. FENTIMAN

TABLE 3

Outline of chemoprevention trials

NSABP

ITALIAN

RMH

MORE

Total
Median age
Aged <50 y
Agent versus placebo

13,388
50-59
37
Tamoxifen 20 mg

5,408
51
38
Tamoxifen 20 mg

2,471
47
62
Tamoxifen 20 mg

Median follow-up months

HRT use
Breast cancer risk

46
12%
Normal/low

70
26%
Family history

First degree family history

54.6
< 10%
High 1.6%
within 5 years
76%

7,705
67
Few
Raloxifene 60
or 120 mg
40
10%
Osteoporosis

12%

96%

12%

Compliance
Agent
Placebo

76%
80%

80%
75%

74%
86%

78%
75%

Breast cancers
Agent
Placebo
OR

124
224
0.51

19
22
0.91

34
36
0.94

22/2
32
0.35

* Measured by Modified Gail model; OR, Odds ratio.

HRT compared with eight in the placebo and HRT

group (0.02). This suggests that tamoxifen is more
potent in preventing breast cancer when combined
with exogenous estrogens. Tamoxifen increased
thromboembolic disease. The majority of vascular
events in this study were superficial phlebitis
(33 cases in the tamoxifen treated group versus nine
in the control group), followed by deep vein thrombosis (six cases versus three in the control group).
There was no evidence for increased pulmonary
embolism in this trial (one case in each group). The
results should be interpreted with caution because
of the low power and compliance of the study (20%
of the required sample was achieved) and because
it included mainly low and normal risk women.

The Royal Marsden tamoxifen pilot study

In this study 2471 women with a family history
of breast cancer were randomized to tamoxifen
(20 mg/day) versus placebo (21). Median follow-up
was 70 months and family history of breast cancer
was the only risk factor requirement for entry. The
women in this study were younger than those in the
NSABP P-1 group (62% versus 40% aged <50 years)
and the majority had a strong family history of breast
cancer. It was estimated that approximately 36% of
the participants in this study had at least an 80%
chance of harbouring a genetic mutation gene for
breast cancer. There were 36 breast cancers in the
placebo group compared with 34 cases in the
tamoxifen group. The study failed to show any effect
for tamoxifen in reducing the risk of breast cancer in
this group of women. However the sample size of
the study was small and the women in this study

were allowed to continue with HRT and even to start

it if that was indicated (26% of the subjects took
estrogens during the trial).
One possible explanation of why this result conflicts with NSABP-P1 trial is that approximately 70%
of genetically transmitted cancers (BRCA1/2) are ER
negative and unlikely to be affected by tamoxifen.
Against this, oophorectomy early in life has been
shown to reduce the risk of breast cancer among
BRCA1 carriers significantly (see below). There was
evidence of increased endometrial cancer (four cases
in the tamoxifen group versus one in the control
group) and a higher incidence of deep vein thrombosis and pulmonary embolism (seven cases versus
four in the control group). Hot flushes and vaginal
discharge were significantly higher in the tamoxifen
group (P 0.001 for both). There was a higher
incidence of menstrual irregularity and bleeding
(P 0.002). Nausea was significantly higher (P 0.02)
but no difference was observed in the incidence of
weight gain, or mood change.

MORE (Multiple Outcomes of

Raloxifene Evaluation)
This study was designed primarily to evaluate the
effect of the selective estrogen receptor modulator
(SERM) raloxifene on osteoporosis (22). Only postmenopausal women under the age of 80 years were
recruited for this study. The median age for entry was
accordingly much higher than in the tamoxifen trials.
No risk factor for breast cancer was needed for entry
and indeed there are some data suggesting that

BREAST CANCER PREVENTION

265

the hypoestrogenization associated with low bone

density may be protective in terms of breast cancer
(23,24).
In this trial 2576 women were assigned to receive
placebo and 5129 to receive raloxifene (2557 took
60 mg/day and 2572 took 120 mg/day). Accordingly,
the number of women receiving raloxifene was twice
that in the placebo group (5129 versus 2576). Their
mean age was 66.5 years. Almost 96% of the women
were white, and 12.3% reported a family history of
breast cancer. The study showed the greatest reduction in breast cancer risk (relative risk 0.35, 95% CI
0.210.58). Twenty-two breast cancers were found in
the raloxifene group (5129 women) and 32 cancers in
the placebo group (2576 women). The reduction was
particularly marked in the case of invasive breast
cancer.
During the three years of this study 27 cases of
invasive breast cancer were detected among 2576
women in the placebo group compared with 13
among the 5129 women treated with raloxifene
(relative risk [RR], 0.24; 95% CI, 0.130.44; P < 0.001).
Raloxifene reduced the risk of newly diagnosed
breast cancer by 76% during a median of 40 months
of treating postmenopausal women for osteoporosis.
Raloxifene, like tamoxifen, reduced estrogen
receptor positive breast cancer by 90% but was not
effective in reducing the incidence of estrogen negative tumours, supporting the concept that raloxifene
acts by interacting with estrogen receptors in the
breast to competitively inhibit estrogen-induced
DNA transcription (26). In order to prevent one
breast cancer, 126 women need to be treated.
Side effects of raloxifene are shown in Table 4.
There was no increase in risk of endometrial cancer
but there was more thromboembolic disease in those
taking raloxifene. No significant difference in the rate
of thromboembolic disease was found in the 60 and
120 mg groups. The agent was well tolerated:
33 women (0.6%) assigned to the raloxifene group

and 2 (0.1%) assigned to the placebo group discontinued treatment because of hot flushes (P 0.001).
Influenza-like syndromes, endometrial cavity fluid,
peripheral oedema, and leg cramps were reported
more frequently in the raloxifene group. In the MORE
trial raloxifene reduced the risk of vertebral fractures
but not of other fractures (28).
It appears that raloxifene is more potent than
tamoxifen in reducing breast cancer but it is difficult
to compare the results of the studies. The women in
NSABP-P1 were, on average, younger and at lower
risk compared with those in the MORE study. Like
tamoxifen, it is not clear how long this estrogen
receptor modulator will be able to prevent the
development of breast cancer. That is why, it is
important to determine the long-term effects of
raloxifene and other selective estrogen receptor
modulators because metastatic breast cancer can
develop resistance to tamoxifen after long-term
exposure (29,30). Adjuvant tamoxifen treatment for
primary breast cancer reduces the chances of contralateral breast cancer when used for five years, but
this effect is not seen when it is used for more than
five years. The MORE trial is continuing to assess
the effectiveness and safety of the longer-term use
of raloxifene. If the result of this study is confirmed by further follow-up, raloxifene might be
preferred over tamoxifen for reduction in the risk of
breast cancer and fractures in women with an intact
uterus (24).

STAR trial
This trial, initiated by NSABP, is a secondgeneration breast cancer prevention trial. It is a randomized double-blind trial that evaluates 22,000
postmenopausal women with an increased risk of
breast cancer. Women will be randomized to receive

TABLE 4 Rate of side effects among women assigned to 60 or 120 mg of raloxifene hydrochloride or placebo
Side effect

Placebo

Raloxifene 60 mg

Raloxifene 120 mg

P value

Influenza syndrome
Hot flushes
Leg cramps
Peripheral oedema
Diabetes
Thromboembolism
Endometrial cancer
Vaginal bleeding
Endometrial cavity fluid
Hypercholesterolemia
Hypertension

293
165
96
114
14
8
4
62
43
121
231

346
249
178
134
31
25
4
67
60
55
177

345
299
178
168
28
24
2
56
66
50
194

0.01
<0.001
<0.001
0.01
0.01
0.002
0.67
0.99
0.02
<0.001
0.01

(11.4)
(6.4)
(3.7)
(4.4)
(0.5)
(0.3)
(0.2)
(3.1)
(5.7)
(4.7)
(9.0)

(13.5)
(9.7)
(7.0)
(5.2)
(1.2)
(1.0)
(0.2)
(3.4)
(8.1)
(2.2)
(6.9)

(13.4)
(11.6)
(6.9)
(6.5)
(1.1)
(0.90)
(<0.1)
(2.8)
(8.7)
(1.9)
(7.5)

P value for combined raloxifene hydrochloride treatment groups versus placebo. All data are presented as
numbers (percentages).

266

A . K. SALIH AND I. S. FENTIMAN

tamoxifen 20 mg daily or raloxifene 60 mg daily for

five years. It is based on the positive results of
tamoxifen in the prevention of breast cancer (NSABP
P-1) trial and the possibility that raloxifene is as
effective as tamoxifen with fewer side effects (MORE
trial).

IBIS (International Breast Cancer

Intervention Study)
This is an ongoing study of 6037 women randomized
to tamoxifen (20 mg) versus placebo (31). The intended duration of the trial is 5 years. Although pathological and endocrine factors like nulliparity and
benign breast disease have been considered, the main
criteria for entry were based on family history of
breast cancer (for detail see 31). The estimated risk of
breast cancer for entry was ten-fold for women aged
3539 years, four-fold for women aged 4044 years,
and two-fold for women aged 4570 years compared
to the normal population. In this study 91% of the
women had at least one first-degree relative with
breast cancer and 20% had two or more first-degree
relatives with breast cancer. Like the RMH study,
the women in this study were generally younger
than in other chemoprevention studies (NSABP-P1
and MORE). The median age for entry was 50 years.
No results are yet available from this study.
Several questions remain unanswered.






Which groups of women benet from tamoxifen

chemoprevention?
What is the optimal duration of the treatment?
How long the effect of tamoxifen will last in
preventing breast cancer?
Can tamoxifen be replaced an agent with fewer
side effects?
Is tamoxifen is actually preventing the cancer or
simply delaying it?

Some of these questions may be answered by the

ongoing IBIS trial in which the Steering Committee
has agreed that the study will not be terminated
prematurely so that the impact of stopping tamoxifen
on subsequent breast cancer risk can be determined.

CHANGE OF LIFE STYLE

There is some conflicting epidemiological evidence
about life style effects on the incidence of the breast
cancer. The marked increase in the incidence of breast
cancer among Asian-American women within a
decade of their immigration to the US, is an obvious
evidence of the influence of western life style, in
particular diet, on the incidence of breast cancer (32).

There are several factors that have been reported to

be associated with breast cancer. These factors for
example include diet, obesity, exercise, and age of
first full term pregnancy and number of pregnancies.
Although these factors are reported to have mild to
moderate risk relationships with breast cancer, it is
uncertain that modification of these factors will alter
the incidence of breast cancer.
It is difficult to test the hypothesis that the reduction in dietary fat will result in reduction in the
incidence of breast cancer in the view of the conflicting evidence. While there are arguments to support
the role of fat in the promotion of breast cancer (33),
there are other studies that failed to show that relation (34). Experimental studies suggested that highfat diet acts as promoter for carcinogenesis (35,36).
Significant reduction in the level of serum oestradiol
has been shown in a meta-analysis of dietary fat
intervention studies (37). Although increased serum
estrogen level is considered as a breast cancer risk
factor, it is uncertain whether a reduction in the level
of oestradiol will ultimately reduce breast cancer
significantly (38). The results of the ongoing randomized controlled study (the American Women Health
Initiative Study), that examines the effects of low-fat
diet on the reduction of breast cancer and other
chronic diseases among postmenopausal women are
awaited (39).
Meta-analysis of case control but not cohort studies
suggest a possible weak association of fat with breast
cancer. That association has been found particularly
for saturated fats in older women (40,42). Hunter et al.
(1996) presented a pooled analysis of seven cohort
studies of fat intake in relation to the risk of breast
cancer. The conclusion from this analysis, showed that
a reduction in fat consumption in midlife, in western
countries, is unlikely to produce significant reduction
in the incidence of breast cancer (40). Holmes et al.
reported no association between the amount or types
of fat with breast cancer risk after a long follow up of
88, 795 women in a cohort study (43).
In an overview of 12 case-control studies presented
by Howe et al., a significant association between fat
and breast cancer was reported among postmenopausal women (P 0.0002), but the effect among premenopausalwomenwasnotsignificant(41).However,
regression analysis from 21 countries, looking at
fat consumption per capita and its relation to the
incidence of breast cancer suggested that, among
postmenopausal women, a 50% reduction in dietary
fat results in a 2.5-fold reduction in breast cancer
risk.
This effect was less consistent in the premenopausal women. Non-fat calorie supply and gross
national product per capita added no further explanation of the variation in the incidence of cancer
among those countries (44).

BREAST CANCER PREVENTION

This inconsistency of the results might reflect

either lack of association between breast cancer and
dietary fat or difficulty in measuring actual fat intake
or both. With the current data, the role of fat reduction as a mean of achieving reduction in the risk of
breast cancer is undefined.
Obesity in postmenopausal women increases the
risk of breast cancer, but in premenopausal women is
associated with reduced risk. Regular exercise and
reduction of weight can reduce the risk of breast
cancer in postmenopausal women (45,46,47). In these
women, the possible mechanism of risk reduction
may be mediated through decreases in the serum
level of estrogen, insulin and insulin like growth
factor 1, IGF-1 (47). Lean premenopausal women have
higher serum levels of insulin and IGF (48). Possibly
exercise reduces the risk of breast cancer by preventing obesity especially among postmenopausal
women (49).
There is compelling evidence that alcohol increases the risk of breast cancer (50). For every 10 g/day
of alcohol there is a 9% increase in the risk of breast
cancer. It has been shown that alcohol raises the level
of estrogen in both urine and serum. It is possible that
the reduction of alcohol consumption could lead to
a modest reduction in the risk of breast cancer (54)
but might have an adverse effect in terms of heart
disease.
Smoking is not among the risk factors for breast
cancer. It causes reduction in urinary estrogen in
premenopausal women (55), elevation of androgen in
postmenopausal women (56), and early menopause
(57). All these changes are associated with reduced
risk of breast cancer but no reduction in incidence has
been found in smokers. The anti-oestrogenic effect of
smoking might lead to a reduction in hormonedependent breast cancers but obviously it increases
the risk of lung cancer and heart diseases (58). In one
study, smokers of more than 40 cigarettes per day had
a significantly higher chance of dying from breast
cancer compared with non-smokers (59).
It seems that consumption of vegetables rich
in anti-oxidant carotenoids is associated with
decreased incidence of breast cancer among premenopausal women (60). It has been shown that
Vitamin D derivative and retinoids enhance apoptosis and reduce the level of insulin growth factor
level (61,62). There is increasing evidence that raised
insulin growth factor (IGF-1) is associated with
increased risk of breast cancer (63).
In an Italian randomized trial of 3000 women with
small node negative breast cancer they were given
the synthetic retinoid (vitamin A analogue) fenretinide, or placebo for 5 years (64). There was a significant reduction in the risk of contralateral breast
cancer in premenopausal women but an increased
risk in postmenopausal women. Overall there was no

267

effect on the prevention of a second cancer. A phase II

trial examining the effect of fenretinide in postmenopausal women on HRT is ongoing (65). Retinoid, rexinoid and Vitamin D analogues currently are
under investigation as candidates for a prevention
trial.
Postmenopausal women on hormone replacement
therapy (HRT) for five years or more have their risk of
breast cancer increased by 35% (66). The risk reverts
to normal after 5 years of HRT cessation (66). HRT
that consists of estrogen and progesterone may carry
a higher risk of breast cancer than HRT containing
estrogen alone (67). As a result, it would be sensible to
avoid the progesterone in hysterectomized women.
There is some evidence of a better survival rate for
women diagnosed with breast cancer while taking
HRT compared with those of the same age not on
HRT (68).
There is a small but significant risk of breast cancer
among oral contraceptive pill (OCP) users but generally cancers diagnosed in women on OCP are less
advanced compared with women not taking OCP
(69). The increased risk is reverts to normal after ten
years of cessation. Taking into consideration the
advantages of both HRT and OCP, these usually
outweigh the potential breast cancer risks. Nulliparity or first full-term pregnancies after age 30 are
associated with a mildly increased risk of breast
cancer but current career demands mean that many
women are unable to modify this reproductive risk.
Ionizing radiation may be carcinogenic at relatively low dosage in the developing breast. Low-dose
scalp irradiation for treatment of ringworm in Israeli
children led to an excess of breast cancers (relative
risk: 2.9) after a follow-up of more than 30 years (70).
Among women who had radiation for acute postpartum mastitis there was a four-fold increase in
breast cancers after 25 years of follow-up (71). Other
than protecting the developing breast from ionizing
radiation and avoidance of excessive radiation from
mammography this is not applicable for prevention
but may provide clues about the likely time scale
from induction to presentation of breast cancer.

PREVENTION THERAPY FOR BRCA1/2

GENE MUTATION CARRIER
Highly penetrative germline mutations in cancer
predisposition genes are the cause of 510% of breast
cancers and ovarian cancers (72). Of these genetic
susceptibility cases, about half are due to BRCA1/2
mutation (3). Further mutations in other genes await
discovery. The cumulative life risk of invasive breast
cancer in the women with BRCA1 or BRCA2 mutation is about 7085% and for ovarian epithelial cancer

268

A . K. SALIH AND I. S. FENTIMAN

about 2565% (1,7375). Non-carriers of the mutated

genes, in families with a known mutation, have the
same risk as the general population.
It has been shown that up to 90% of healthy firstdegree female relatives of patients with breast
and ovarian cancers are potentially interested in
BRCA1/2 testing, (76,77). In terms of DNA testing for
BRCA1/2 mutation among the unaffected members
of the families with BRCA mutation, Lerman (76)
reported that 66% of the unaffected females and 48%
of males were ready to undergo testing, while Meijers-Heijboer et al. (78) reported that 57% of females
and 22% of males were eventually ready for testing.
This difference might be due to differences in the
counselling process, characteristics of the studied
groups and mode of enrolment of these families. The
important factors that influence the decision for
BRCA testing in both male and female are parenthood (having children), whether the subject specially
women have chosen surveillance or prophylactic
treatment and the age of the subject (78,79).
The current options that are available for the
women with BRCA1/2 mutation are regular surveillance, chemoprevention, prophylactic mastectomy and oophorectomy. There is little evidence to
suggest that changes of life styles have any effect on
reducing the risk of breast cancer in this group of
women. Brunet et al. reported that smoking reduces
the risk of breast cancer in BRCA1/2 mutation carriers (80). Interestingly, the age at first pregnancy
seems to have no protective effect on breast cancer in
mutation carrier (82). In counselling this group of
patients these facts need to be made clear.

relatives with breast cancer had a similar reduction in

the incidence of invasive and non-invasive breast
cancers compared to those without a family history of
breast cancer. No effect was seen however in the
RMH study (23), in which 96% of the women had at
least one first-degree relative with breast cancer. This
suggests that probably tamoxifen is not an ideal
chemoprevention agent in this group of patients. In
the MORE study, it is unlikely that there were any
BRCA1/2 mutation carriers in this group of women
so the preventive role of raloxifene in high-risk cases
is unknown. Only 30% of breast cancers among
BRCA1 carriers are ER positive (83). In the carriers of
the BRCA2 mutation there are higher percentages of
ER positive tumours (84). For this reason current
chemoprevention therapy is likely to be less effective
in mutation carriers. It is possible that chemoprevention and oophorectomy have more effect on
BRCA2 mutation carriers where a higher percentage
of tumours are ER. This may partly explain the
reduction in breast cancer risk among women with
family history of breast cancer, in the NSABP-P1.
Interestingly prophylactic oophorectomy has been
shown to reduce breast cancer risk among BRCA1
carriers significantly (RR 0.53, 95% CI 0.330.84).
The results of the NSABP-P1 and oophorectomy in
reducing the risk of breast cancer indicate that more
studies are needed to evaluate the effects of antiestrogen therapy in reducing the risk of breast cancer
among the carriers of gene mutations.

Surveillance

In carriers of BRCA1/2 mutations who have the

entire field of mammary epithelium at risk of neoplasia, bilateral prophylactic mastectomy would appear to be a drastic but effective treatment. Although it
is likely that this would be beneficial the efficacy and
risk of relapse in residual tissue remain unquantified.
There are no randomized trials, nor any comprehensive national registers from which the necessary
data can be collected which can be used to advise
patients at risk (83).
There are two types of prophylactic mastectomy
subcutaneous and total both of which can be performed with and without immediate reconstruction.
In subcutaneous mastectomy, the overlying skin is
spared together with the nipple-areolar complex.
With either type of mastectomy, it is not possible
to eradicate the chance of developing breast
cancer completely because cancer can develop
even in a microscopic amount of breast tissue. As it
might be expected the amount of retained breast
tissue will be higher in cases of subcutaneous
mastectomy (84).

Women with a family history of breast cancer are at

increased risk of breast cancer at a younger age but
their breast tissue is denser and mammographic
screening is less sensitive. There is uncertainty
regarding the efficacy of screening in women with a
family history of breast cancer. Because the risk is
present at an early age, it has become common
practice to initiate screening at an early age in the
absence of clear benefit. Despite early diagnosis of
breast cancer among high-risk young women under
regular surveillance, it is likely that at least a quarter
of those contracting breast cancers will ultimately die
of distant metastasis (82).

Chemoprevention
In the NSABP-P1 trial (13), women of all age groups,
on the tamoxifen arm, with one or more first-degree

Prophylactic mastectomy

BREAST CANCER PREVENTION

269

TABLE 5 Follow-up of patients treated by bilateral prophylactic

mastectomy
Author

Number Risk

Pennisi (85)
1500
Ziegler (87)
510
Hartmann (86) 425
214

Follow-up Cancers

Low/moderate 9 years
High
9 years
Moderate
14 years
High
14 years

0.6%
1.18%
4 (0.94%)
3 (1.4%)

The two major series are summarized in Table 5

(85,86). Pennisi reported the results of prophylactic
subcutaneous bilateral mastectomies in 1500 women
of whom 30% were lost to follow-up and only 20%
had a first-degree relative with breast cancer (85).
After nine years follow-up, nine breast cancers
developed (0.6%). Ziegler and Kroll re-analysed the
data for 510 high-risk women in whom 6 (1.18%)
developed subsequent breast cancer (87).
Hartmann et al. reported 14-year follow-up after
prophylactic mastectomies in 639 women with a
family history of breast cancer (86). Of these 90%
were subcutaneous and >90% had immediate reconstruction. The incidence of breast cancer for the highrisk group (214 women) was 1.4%. The estimated risk
reduction in this review was at least 90%. All 7 cancers occurred among women who had subcutaneous
mastectomy.
The majority of cancers developed in the axilla and
upper outer quadrant after both total and subcutaneous prophylactic mastectomies (88,89,90,91). This
reflects the fact that excision of the axillary tail of the
breast is technically difficult in subcutaneous mastectomy. Additionally, when performing total mastectomy it may be difficult to know exactly where to
stop dissecting in the axilla.
These series of mastectomies were performed
before the diagnosis of genetic mutation become
available. Schrag et al. constructed a model to evaluate the impact of bilateral prophylactic mastectomy
(BPM) on the carriers of BRCA mutations (92). In this
model BPM was found to reduce the risk of breast
cancer by 85% resulting in a gain of 2.95.3 years of
life span if the procedure was performed at the age of
30 years, but no significant gain if performed at the
age of 60 years. The combination of BPM and
oophorectomy was predicted to gain 3.27.6 years.
In a separate analysis, Grann et al. predicted that
BPM would reduce the risk of breast cancer by up to
90% (93). The gain in life span was 2.83.4 years for
BPM, and 3.36.0 years for the combination of BMD
with prophylactic oophorectomy. However there is
only preliminary evidence to suggest that BPM is
effective in reducing the risk of breast cancer. After
16 years follow-up Hartmann et al. reported no breast
cancer among 18 women with BRCA1/2 mutations

who underwent BPM (94). In another retrospective

study, Meijers-Heijboer et al. reported no breast cancer
in 76 carriers of BRCA1/2 when they were followedup for a median of 27 months following their
mastectomies (95).
There are large variations in the acceptability of
the BPM option among unaffected women with
BRCA mutation. Lynch et al. reported in two separate
studies an uptake of 11/31 (35%) and 2/12 (17%)
(96,97). Meijers-Heijboer reported that among Dutch
women 35/68 (51%) opted for BPM (78). The predictive factors for prophylactic mastectomy were parenthood and age of the women. No woman older than
55 years opted for prophylactic mastectomy (78).
Although prophylactic mastectomy is a mutilating
and irreversible procedure, affecting body image and
inhibiting sexual relations, women who have had
adequate counselling rarely express regret. Instead
they are relieved from the fear of cancer (78,98,99).
The group that accepted PBM had reduction of
their psychological morbidity (P < 0.001) and anxiety
(P 0.001). There was higher anxiety among those
declining the procedure (99). In this study, where the
majority of the women had reconstructive surgery
following their mastectomies there was no difference
in the sexual activity or body image compared with
women who declined the procedure (98).
It is important that the women being considered
for BPM should be managed by a multidisciplinary
team including a clinical geneticist, a clinical specialist breast care nurse, a breast surgeon and sometimes
a plastic surgeon. They should also be offered a protocol of cancer genetic risk assessment and a clinical
psychological assessment. As reconstruction has to
be offered to every woman considered for BPM, the
breast surgeon needs to have good experience in
breast reconstruction, or work closely with a plastic
surgeon will be required. Patients should be shown
photographs of good, satisfactory and poor cosmetic
results.
When BRCA mutation carriers develop breast
cancer their annual risk of contralateral breast cancer
is 5.6% (100) and this has led some to consider prophylactic contralateral mastectomy in this group of
patients. This may not affect survival: the first primary clinically detected breast cancer determines the
survival of breast cancer patient (101,102). Because of
the increased risk of ovarian cancers in women with
the BRCA1 mutation women bilateral oophorectomymay also be of benefit (103). There is evidence
that oophorectomy early in life leads to reduced
breast cancer risk (104). In a case-control study
Rebbeck et al. compared 43 BRCA1 mutation carriers
who had prophylactic oophorectomies with 79 carriers that had no surgery with an average follow-up
of 8 years (53). Bilateral oophorectomy resulted in a
50% reduction in the incidence of breast cancer. This

270

result was not affected by the use of hormone replacement therapy.

FUTURE PREVENTION TRIALS

Further chemoprevention trials with aromatase
inhibitors, for example, anastrazole, letrazole and
others, in combination with bone preserving agents
such as oral biphosphonates are in an active stage of
planning (105). These agents do not increase the
chance of uterine cancer and cause less thromboembolic disease (106). It is possible that the new
generation of estrogen receptor modulators (107), for
example, LY 353381 (Arzoxifene), are an attractive
subjects for future trials, as preliminary data indicate
that they lack uterine agonistic effect and probably
have fewer adverse effects than the traditional
SERMs.
Aiming at the reduction of the exposure to the
ovarian hormones which has been shown to be a risk
factor for breast cancer, Spicer et al. in a pilot study,
have shown the feasibility of suppressing the ovarian
functions with gonadotrophin releasing hormone
agonist (LHRH) regimens combined with low-dose
hormone replacement (to avoid the side effect of
hypoestrogenization) (108). This approach resulted
in a reduction of mammographic density which may
be a surrogate measure of breast cancer risk.
Targeting nulliparity as a risk factor for breast
cancers: short-course hormonal combinations that
mimic pregnancy for nulliparous women in their
early twenties might reduce the risk of breast cancer
(109). Reduction in the level of estrogen or estrogen
metabolites can be achieved by soy/isoflavones.
In vitro, Genistein (a phyto-estrogen) decreased cell
growth and enhanced differentiation of human breast
cancer cells (110). However, when Key et al. reported
an interventional prospective study, there was no
reduction in breast cancer risk in women taking
phyto-estrogen (111).
There are several potentially reversible risk markers that are associated with breast cancer. These
include aberrant methylation and histone deacetylation of the promoter region of many tumour suppressor genes (112115). The combination of histone
deacetylase inhibitors combined and demethylating
agents provides a new approach to prevention that
might work for both ERve and ERve tumours
(116,117). Other observed changes are increased expression of cyclo-oxygenase-2 (COX-2), tissue polyamines, angiogenesis and protease activity (118121).
Harris et al. have reported that the women regularly
taking non-selective COX inhibitors (non-steroidal
anti-inflammatory drugs, NSAIDS), have a 50%
reduction in breast cancer risk (P<0.01) (122). These

A . K. SALIH AND I. S. FENTIMAN

inexpensive relatively non-toxic agents are suitable

for chemoprevention trials and a COX-2 (celecoxib),
Tyrosine kinase inhibitor (ZD 1839) and polyamine
synthesis inhibitor (difluoromethylornithine), are in
an active planning stage for prevention testing. These
agents might be used lor both pre- and postmenopausal women without altering the menstrual
cycle or inducing hot flushes.
It is possible that pairing tyrosine kinase inhibitors
to SERMs like tamoxifen can decrease the chance of
tamoxifen resistance in ER precancerous lesion
(122). Another group of agents that act by increasing
apoptosis is currently under investigation for prevention trials and they include perillyl alcohol
(a monoterpene) (123) and sulfone metabolite of
sulindac (124).
Prevention of breast cancer has come a long way
since the idea of using tamoxifen was first proposed
(125). Knowledge of what can and cannot be achieved
with endocrine intervention is now leading to a new
generation of trials examining modulation of other
non-endocrine biochemical pathways. ldentification
of new risk factors and novel biochemical agents
should lead in time to a significant chance of population prevention of breast cancer.

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