What are the real risks for breast cancer?

Abstract

There is a steady drumbeat of peer-reviewed medical articles relating risks of breast cancer from a variety of factors. Whether or not the reported factors are under the control of any given individual, they have been trumpeted by the lay media and are responsible for the understandable finding among women that breast cancer generates more anxiety than heart disease, even though the number of US women who died of heart disease in 2010 is over seven and a half times the number who fell victim to breast cancer. This article attempts to reduce the anxiety-inducing barrage of these reports by orienting physicians to better understand the validity of reported breast cancer risk factors. We hope to provide this understanding by: explaining the difference between relative and absolute risk, encouraging application of the 95% confidence interval to better evaluate the statistical validity of any given risk factor; placing the reported risk factors in the context of an accepted risk factor like cigarette smoking and lung cancer; and communicating the limits of statistical validity in the absence of reproducibility. This review will, to a small degree, provide a balance to the reports currently dominating the literature.

Full text

CLIMACTERIC 2011; Early Online, 1–6
OPINION Received 31-07-2011
© 2011 International Menopause Society Revised 03-09-2011
DOI: 10.3109/13697137.2011.624215 Accepted 13-09-2011
Correspondence: Dr A . Z. Bluming, Hematology Oncology Medical G roup of the San Fer nando Valley, 16133 Ventura Boulevard, Encino, 91436 USA
Association. Only 8% of women recognized that heart
disease and stroke were the leading cause of death, and
killed more women each year than the next 16 causes of death
combined – including diabetes, all forms of cancer, AIDS,
and accidents ’
3 . Even among a population of 63 566 women
with diagnosed breast cancer who were 66 years of age or
older at diagnosis, heart disease was responsible for more
deaths than breast cancer
4 .
To date, the strongest known factors that signifi cantly
increase the risk of breast cancer are, unfortunately, out of an
individual woman ’ s control: being female, increasing age
5,6 ,
having a strong family history of breast cancer, and carrying
one of the genes associated with an increased tendency to
develop breast cancer, of which the most important are cur-
rently acknowledged to be BRCA1 and BRCA2. This latter
congenital risk factor has been estimated to increase the life-
time risk of breast cancer by almost seven-fold
7,8 .
With this state of affairs, it is not surprising that identifying
controllable risk factors that may contribute to future breast
cancer development has become a minor industry. And so,
with dizzying frequency, yet another epidemiological study
makes headlines, yet another food or behavior is announced
that increases a woman ’ s risk of breast cancer. These studies,
which are almost always further sensationalized and exagger-
ated by the media, both refl ect women ’ s anxiety about breast
cancer – and amplify it.
American women are understandably frightened of developing
breast cancer, the most common cancer affecting women in
this country. The American Cancer Society estimates that, in
2010, about 207 000 women developed invasive breast can-
cer; 54 010 developed non-invasive breast cancer; and 39 840
died of breast cancer
1 . And yet 90% of the women who are
diagnosed with breast cancer this year will probably be cured
following initial treatment
2 .
In spite of that heartening statistic, breast cancer generates
more anxiety than heart disease even though the number of
US women who died of heart disease in 2010 (306 246) is
over seven and a half times the number who fell victim to
breast cancer
1 . Some have suggested that the reason women
fear breast cancer more than heart disease is that breast cancer
affects women at a younger age than does heart disease.
However, in every decade over age 40, more women die of
heart disease than die of breast cancer
1 . This disproportionate
fear is not a new fi nding. Over 13 years ago, an editorial in
The Lancet noted: ‘ … in a survey commissioned by the
National Council on the Aging (NCOA) of 1000 women
between the ages of 45 and 64, 61% said that the disease they
most feared was cancer – predominantly breast cancer. By
contrast, only 9% said that the condition they most feared
was the disease most likely to kill them – heart disease. ’ The
editorial added: ‘ These fi ndings are almost identical to a sur-
vey released earlier this year (1997) by the American Heart
What are the real risks for breast cancer?
A. Z. Bluming and C. Tavris *
Hematology Oncology Medical Group of the San Fernando Valley, Encino; * Social Psychologist, Los Angeles, USA
Key words: BREAST CANCER , RISK FACTORS , RISK COMMUNICATION
ABSTRACT
There is a steady drumbeat of peer-reviewed medical articles relating risks of breast cancer from a variety of
factors. Whether or not the reported factors are under the control of any given individual, they have been
trumpeted by the lay media and are responsible for the understandable fi nding among women that breast
cancer generates more anxiety than heart disease, even though the number of US women who died of heart
disease in 2010 is over seven and a half times the number who fell victim to breast cancer. This article attempts
to reduce the anxiety-inducing barrage of these reports by orienting physicians to better understand the valid-
ity of reported breast cancer risk factors. We hope to provide this understanding by: explaining the difference
between relative and absolute risk, encouraging application of the 95% confi dence interval to better evaluate
the statistical validity of any given risk factor; placing the reported risk factors in the context of an accepted
risk factor like cigarette smoking and lung cancer; and communicating the limits of statistical validity in the
absence of reproducibility. This review will, to a small degree, provide a balance to the reports currently
dominating the literature.
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What are the real risks for breast cancer? Bluming and Tavris
2 Climacteric
Although there is no shortage of published risk factors,
there is a shortage of critical assessments of what they mean.
Table 1 lists many of the published risk factors linked to breast
cancer incidence. A risk factor of less than 1 suggests a reduced
risk; a risk of 1 suggests the factor confers neither an increased
nor a decreased risk of breast cancer. A risk factor of greater
than 1 suggests an increased risk. A risk of 1.14 means a 14%
increased risk.
The risks listed in this table are expressed as relative risks,
the way they are typically reported by researchers and then
by the media. The problem is that relative risks often appear
to be more important than they are
9 . Two major consensus
projects on the reporting of clinical trials have concluded
that stating relative risks alone is often deceptive; results
should be provided in absolute numbers, not only as percent-
age changes
10–13 . For example, if we read that the relative
Table 1 Risk factors reported to be associated with the development of breast cancer
Relative risk 95% confi dence interval Reference
Dietary fi ber intake 0.31 0.20  0.47 27
Signifi cant weight gain from age 21 to present 0.52 0.32  0.83 28, 29
Garlic and onions 7 – 10 ti mes/week 0.52 0.340.78 30
High level of stress 0.60 0.37 0.97 31
Grapefruit 0.60 0.37 0.98 32
Fish oil 0.68 0.50  0.92 33
Large body build at menarche 0.69 0.49 0.96 28, 29
Conjugated equine estrogen 0.77 0.59 1.01 34
Aspirin 0.80 0.71 0.90 35
Coffee consumption  5 cups/day 0.80 0.64  0.99 36
Above average weight at 12 years 0.85 0.74  0.98 37
Low income 0.85 0.84  0.87 38
Cigarette smoking 1.06 1.01  1.10 39
Birth weight 1.09 2.00  17.0 0 40
Fish intake 1.14 1.03 1.26 41
Birth length  51 c m 1.17 1.02  1. 35 42
Use of antihypertensive medicine  5 years 1.18 1.02 1. 36 43
Exposure to light at night 1.22 1.121.31 44
Cigarette smoking 1.24 1.06 1.44 45
Premarin/progestin 1.24 1.01 1.54 46
Premarin/progestin 1.26 1.00 1.59 47
Alcohol 1.26 1.06 1.44 45
French fries (1 additional serving /week) 1.27 1.12  1.4 4 48
Physical abuse in adulthood 1.28 1.07 1.52 49
Grapefruit 1.3 1.06  1.58 50
Digoxin (current users) 1.39 1.32 1.46 51
Night shift work 1.51 1.36  1.68 52, 53
 15 kg weight gain during pregnancy 1.61 1.03 2.52 54
Cigarettes at least 10/day 1.7 1.20 2.43 55
Flight attendant (Finnish) 1.87 1.15 2.23 56, 57
Father

 40 years old (premenopausal breast cancer) 1.9 1.12  3.26 58
Dutch famine 2.01 0.92  4.41 59
Placental weight 2.05 1.15  3.64 60
Antibiotic use 2.07 1.48 2.89 61
Increased carbohydrate intake 2.22 1.63  3.04 62
Left-handedness (premenopausal) 2.41 1.35  4.30 63
Intercristal width * of  30 cm in a mother who was born  40 weeks ’ gestation 3.7 2.1  6.8 64
Flight attendant (Icelandic) 4.1 1.70  8.50 65
Betel quid chewing 4.78 2.87 8.00 66
Electric blanket use 4.9 1.5015.6 67
Vitamin D defi ciency 5.83 2.31  14 .7 68, 69
Intercristal width * of  30 cm in a mother who had given bir th previously 7.2 3.4 15.4 64
Tobacco smoking and lung cancer 26.07 6.58  103.3 70
* , The intercristal width is the maximal width bet ween the iliac crests
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Climacteric 3
risk of breast cancer is increased by 300% in women who
eat a bagel every morning, that sounds serious, but it is not
informative. We would need to know the baseline absolute
number of new breast cancer patients before introduction of
the risk factor. If the number shifted from one in 10 000
women to three in 10 000 women, that is a 300% relative
increase, but, as an absolute increase of only 2 per 10 000,
it is very likely a random artifact. If the risk had jumped
from 100 to 300 per 10 000, also a 300% relative increase,
we might reasonably be concerned. In large epidemiological
studies that generally include tens of thousands of people, it
is very easy to fi nd a small relationship that may be considered
‘ signifi cant ’ by statistical convention but which, in practical
terms, means little or nothing because of the low absolute
numbers.
A reliance on relative risks alone can mistakenly infl ate the
results of medical studies. In 1998, tamoxifen was reported
to show a 48% decrease in breast cancer development com-
pared to placebo when administered to healthy women
believed to be ‘ at increased risk of the disease ’ (i.e. they were
female, and they were over 60)
14 . Yet the absolute difference
between the treatment group and the control group was only
1.3% (2.7% vs. 1.4%)
15 . Should healthy women really be
given tamoxifen on the basis of such a trivial difference? The
study, however, was widely publicized as having found a
‘ nearly 50% decrease in risk ’ .
This is why scientists who are working to promote statisti-
cal literacy, especially in helping the public and physicians
understand actual versus infl ated risks of diseases and treat-
ments, emphasize that knowing the baseline of absolute num-
bers when comparing two groups is essential
9 . It is also why
they are encouraging scientists to move away from the tradi-
tional reliance on statistical signifi cance and replace it with
measures of a relationship’ s strength
16–22 . One such measure
is the confi dence interval (CI)
23,24 . A 95% CI provides a range
(an interval) with a specifi ed probability that a given result,
with continued replications, will be due to chance only 5%
of the time. In the case of large-scale epidemiological studies,
if the spread of the confi dence interval includes the
number 1.0, the result is usually considered not statistically
signifi cant. Generally speaking, the lower limit of the 95% CI
should be at least 3.0 before the fi nding is considered a strong,
reliable one
25 .
Now take another look at Table 1. To put matters in
perspective, we included one factor that has reliably, with
extensive replications, been linked to cancer: cigarette smok-
ing and lung cancer. None of the other factors listed here have
been consistently shown to be important as a risk factor for
breast cancer development. On the contrary, most are the
result of post-hoc statistical manipulation, such as data
mining or retrospective substratifi cation, in an effort to fi nd
a publishable, ‘ signifi cant ’ result
26 .
For example, the association with exposure to the Dutch
famine
59 was found only among women who were exposed
to severe famine when they were between the ages of 2 and
9. The association with antibiotics
61 depended upon the
indication for antibiotic administration. The association with
electric blanket use
67 was most pronounced for those using
the device for more than 10 years, but only after the women
who used it for more than 6 months per year were omitted.
A decreased risk reported in association with grapefruit
intake
32 related only to estrogen receptor-negative (ER-) pro-
gestogen receptor-negative (PR-) tumors and was found only
among women eating one or more grapefruit per day, while
eating only a quarter of a grapefruit per day was associated
with an increased breast cancer risk
50 . The increased risk
among women on antihypertensive medication
43 was confi ned
to those with ER  tumors and held only for pre- or perimeno-
pausal women. The increased risk associated with digoxin
51
was noted only among current users. Some of the associations
appear absurd, such as that linking an increased risk of breast
cancer to one additional serving of French fries per week dur-
ing childhood
48 . And how can eating a quarter of a grapefruit
every day increase a woman ’ s risk
50 while eating one or more
grapefruit reduces it
32 ?
Of the 40 separate risk factors listed in Table 1, two –
alcohol use and hormone replacement therapy – have gar-
nered the most attention, reporting an increased relative risk
of 24 – 26%. So let us consider these factors more closely. The
fi ndings on alcohol are a mess of inconsistencies and data
mining: alcohol has most recently been reported to increase
breast cancer risk only in women who imbibed at least 15 g
per day or approximately seven drinks per week, but this
association was noted only among those women with ER 
breast cancer
45 . The increased risk was reported in three
case – control studies
71–73 and two cohort studies
74,75 , but four
other case – control studies
76–79 and another cohort study
80
failed to confi rm this result. Other research suggests that there
are good health-related reasons to limit alcohol ingestion, but
fear of breast cancer should not be one of them.
The most widely publicized risk factor in Table 1 is that
reportedly associated with postmenopausal HRT
46,47 , inges-
tion of conjugated equine estrogen alone or in conjunction
with progestin. Notice, however, that the increased relative
risk was minor (24% and 26%) and weak (the confi dence
interval contains a 1 for the 26% increased risk). The clini-
cal signifi cance of this association and the benefi t/risk ratio
of HRT remain subjects of active debate, given that the
fi ndings have been contradicted by many other studies
81 .
Indeed, although estrogen was the original candidate for the
suggested association between HRT and breast cancer, and
hence the marketing of the original selective serotonin
receptor modu lators (SERMs) as estrogen blocking agents,
recently estrogen alone has been reported to decrease breast
cancer risk
34,82 .
In order to make intelligent health decisions for ourselves
and those under our care, we must be able to balance the
potential benefi ts of a medication, a food, a vitamin, or an
activity against potential risks. We can do this only when the
data are presented to us clearly and accurately
83,84 , without
an attempt to dazzle us with alleged ‘ alarms ’ and ‘ break-
throughs ’ that use statistics to disguise actual results.
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What are the real risks for breast cancer? Bluming and Tavris
4 Climacteric
One may legitimately wonder about the motivations
behind the publication of so much misleading information
85 .
Although he used the word passions, not statistics, Roger
L ’ Estrange ’ s warning, written over three centuries ago, reso-
nates today. He said: ‘ It is with our passions as it is with
fi re and water, they are good servants but bad masters ’
86 .
Confl ict of interest A.Z.B. has, in the past, been
compensated on an hourly basis for testimony as an expert
witness on behalf of defendant, Wyeth Pharmaceuticals.
Source of funding Nil.
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