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Mama Prevencion
Mama Prevencion
CONTROVERSY
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
262
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).
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)
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)
263
264
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
46
12%
Normal/low
70
26%
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
265
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
267
268
Surveillance
Chemoprevention
In the NSABP-P1 trial (13), women of all age groups,
on the tamoxifen arm, with one or more first-degree
Prophylactic mastectomy
269
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%)
270
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