Articles
Breast cancer and breastfeeding: collaborative reanalysis ofindividual data from 47 epidemiological studies in 30 countries,including 50 302 women with breast cancer and 96 973 womenwithout the disease
Collaborative Group on Hormonal Factors in Breast Cancer*
IntroductionAlthough childbearing is known to protect against breast
Background Although childbearing is known to protect against
cancer, what contribution breastfeeding has on this
breast cancer, whether or not breastfeeding contributes to
protective effect, if any, has been difficult to determine.
Breastfeeding is closely related to many other aspects ofchildbearing—for example, women breastfeed only after
Methods Individual data from 47 epidemiological studies in
they have had a child, and the earlier they commence
30 countries that included information on breastfeeding
childbearing, the more children they have and the longer
patterns and other aspects of childbearing were collected,
their lifetime duration of breastfeeding. No single study
checked, and analysed centrally, for 50 302 women with
has been large enough to reliably characterise the relative
invasive breast cancer and 96 973 controls. Estimates of the
contributions of such closely related factors in breast
relative risk for breast cancer associated with breastfeeding in
cancer. This study combines data from 47 epidemiological
parous women were obtained after stratification by fine
studies conducted in 30 countries, to examine the relation
divisions of age, parity, and women’s ages when their first
between breastfeeding and breast cancer, taking careful
child was born, as well as by study and menopausal status.
account of the effects of other related aspects ofchildbearing.
Findings Women with breast cancer had, on average, fewerbirths than did controls (2·2 vs 2·6). Furthermore, fewer
parous women with cancer than parous controls had ever
Contributing studies and collection of data
breastfed (71% vs 79%), and their average lifetime duration of
The Collaborative Group on Hormonal Factors in Breast
breastfeeding was shorter (9·8 vs 15·6 months). The relative
Cancer has brought together worldwide data from
risk of breast cancer decreased by 4·3% (95% CI 2·9–5·8;
epidemiological studies of women with breast cancer to
p<0·0001) for every 12 months of breastfeeding in addition to
describe the relation between breast cancer and various
a decrease of 7·0% (5·0–9·0; p<0·0001) for each birth. The
reproductive, hormonal, and other factors.1–4 Case control
size of the decline in the relative risk of breast cancer
and cohort studies were eligible for the collaboration if they
associated with breastfeeding did not differ significantly for
had data for at least 100 women with incident invasive
women in developed and developing countries, and did not
breast cancer and had recorded information on each woman
vary significantly by age, menopausal status, ethnic origin, the
with respect to reproductive factors and use of hormonal
number of births a woman had, her age when her first child
preparations. For data from cohort studies, a nested case
was born, or any of nine other personal characteristics
control design was used, in which four randomly selected
examined. It is estimated that the cumulative incidence of
controls per case were matched for age at diagnosis and,
breast cancer in developed countries would be reduced by
where appropriate, broad geographical region. The methods
more than half, from 6·3 to 2·7 per 100 women by age 70, if
of identifying studies and of data collection, checking, and
women had the average number of births and lifetime duration
correction, have been described elsewhere.1–4
of breastfeeding that had been prevalent in developing
Data were collated and analysed on individual women
countries until recently. Breastfeeding could account for
centrally so that analyses could be done with as similar
almost two-thirds of this estimated reduction in breast cancer
definitions across studies as possible. Details sought from
principal investigators of each participating study includeddata collected regarding each woman’s total number of
Interpretation The longer women breast feed the more they
pregnancies, her age at each pregnancy, and the outcome
are protected against breast cancer. The lack of or short
of each pregnancy. A woman’s parity was defined as the
lifetime duration of breastfeeding typical of women in
total number of births, be they livebirths or stillbirths. In
developed countries makes a major contribution to the high
some studies, details of past births did not include
incidence of breast cancer in these countries.
stillbirths, and for those studies a woman’s parity wastaken to be the total number of livebirths. Information was
sought on the total number of children each woman hadbreastfed, her total (lifetime) duration of breastfeeding,and whether or not each individual live-born child hadbeen breastfed, and, if so, for how long. Included in theseanalyses are data from 45 published5–49 and two
unpublished studies (Cancer Research UK, unpublished
Correspondence to: Prof Valerie Beral, Cancer Research UK,
data) that contributed data on lifetime duration of
Epidemiology Unit, Gibson Building, Radcliffe Infirmary, Oxford
breastfeeding, all but eight6–8,20,23,33,44,47 of which also
provided information on the number of children breastfed.
THE LANCET • Vol 360 • July 20, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing
Figure 1: Details and results from studies that contributed data on breastfeeding and breast cancer*Results of two unpublished studies are also cited here. †Ten developing countries. ‡Three developed countries. Statistical analysis and presentation of results
mathematical models sacrifices some statistical power but
The statistical methods used are similar to those used in
has the advantage of avoiding assumptions about the
previous reports.1–3 In this study, data from different
precise forms of any relations in the data. The stratified
studies are combined by means of the Mantel-Haenszel
O–E values, together with their variances and covariances,
stratification technique, the stratum-specific quantities
yield both statistical descriptions (odds ratios,
calculated being the standard observed minus expected
subsequently referred to as relative risks) and statistical
(O–E) numbers of women with breast cancer, together
tests (p values). When only two groups are compared,
with their variances and covariances.50 Use of these simple
relative risk estimates are obtained from O–E values by the
stratified O–E values in preference to more complex
one-step method,50 as are their standard errors (SE) and
THE LANCET • Vol 360 • July 20, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing
Lifetime duration of breastfeeding (months)
Data are means unless otherwise indicated. *Excludes 7992 nulliparous cases, 13 379 nulliparous controls, and 3816 women with missing values.
Table 1: Relation between lifetime duration of breastfeeding and various other aspects of childbearing in parous cases and controls*
CIs. When more than two groups are compared, variances
with women whose total duration was 6 months or less
are estimated by treating the relative risks as floating
for some analyses. Where appropriate, a trend in the
absolute risks (FARs).51 This approach yields floated
relative risk of breast cancer with increasing duration
standard errors (FSE) and floated CIs (FCI). The use of
of breastfeeding is calculated. In such instances, the
FARs rather than conventional methods does not alter the
duration of breastfeeding associated with a particular
relative risks but slightly reduces the variances attributed to
category is taken to be the median duration within
the relative risks that are not defined as 1·0, and also
reduces unwanted covariances between them. Presentation
In general, results in the text are presented as relative
of the results in this way enables valid comparisons
risks and their appropriate standard errors (SE or FSE).
between any two exposure groups, even if neither is the
Where results are presented in the form of plots, relative
baseline group. Any comparison between groups must take
risks and their corresponding CIs or FCIs are represented
the variation in each estimate into account by summing the
by squares and lines, respectively. The position of the
variances of the logarithms of the two FARs.
square indicates the value of the relative risk and its area is
To ensure that women in one study are compared
inversely proportional to the variance of the logarithm of
directly only with similar women in the same study, all
the relative risk, thereby providing an indication of the
analyses are routinely stratified by study,by centre within study, by fine divisions
of age (16–19, 20–24, 25–29, by singleyears from 30 to 79, 80–84, and 85–89years), by age at first birth (Ͻ20, 20–24,
25–29, у30), and by menopausal status(premenopausal, Ͻ5 or у5 years sincemenopause, hysterectomy before
appropriate, parous women are furtherstratified by fine divisions of parity
lifetime duration of breastfeeding was 6months or less, and the tendency forthe duration to be reported as multiples
of 6 or 12 months (see the webfigure athttp://image.thelancet.com/extras/01art9187webfigure.pdf), this variable
7–18, 19–30, 31–54, Ͼ54 months) for
certain analyses. Most studies thatrecorded information on breastfeeding
period, such as a week, a month, oreven longer, before she was classified as
Figure 2: Relative risk of breast cancer in parous women according to breastfeeding
*Calculated as floating absolute risk (FAR), and stratified by study, age, age at first birth, and
THE LANCET • Vol 360 • July 20, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing
amount of statistical information available for that
increasing duration of breastfeeding, but this aspect of
particular estimate. Owing to the large number of relative
childbearing is less strongly related to lifetime duration of
risk estimates calculated, results are generally given with
breastfeeding than is parity or the number of children
their appropriate 99% CIs or 99% FCIs, with 95% CIs or
breastfed. Thus, there is considerable potential for any
effect of breastfeeding on the risk of breast cancer to be
To investigate the contribution of childbearing and
confounded by the effects of each birth and, to a lesser
breastfeeding patterns prevalent in developed countries to
extent, by the ages women were when their children were
the incidence of breast cancer in these countries, the
incidence that would have occurred if the women had had
To separate out the effects of breastfeeding from those
the patterns of childbearing and breastfeeding that had
of other aspects of childbearing, the first step was to
been typical for Asian and African countries until
describe the relation between breast cancer and certain
recently,53,54 is estimated by applying the relative risks
reproductive factors, in the absence of breastfeeding. Then
obtained in this report to age-specific incidence rates for
any additional contribution from breastfeeding is
breast cancer in developed countries around 1990.1–4,52 The
examined, taking account of the role of reproductive
cumulative incidence of breast cancer up to age 70 years is
patterns and of other potential confounding factors.
then calculated from the estimated age-specific results.
Having established, in the study population as a whole,what the independent effect of breastfeeding is, the
consistency of the main results is examined across various
The sponsors of the study had no role in study design, data
subgroups of women and across studies and study designs.
collection, data analysis, data interpretation, or writing ofthe report. Breast cancer in relation to childbearing in women whonever breastfed
12 214 (29%) parous cases and 16 900 (21%) parous
Altogether 50 302 women with invasive breast cancer
controls had never breastfed (table 1). Analyses restricted
(cases) and 96 973 women without breast cancer
to these 29 114 women provide a description of the
(controls) from 47 studies in 30 countries are included in
relation between breast cancer and childbearing patterns,
these analyses (figure 1). Among the cases, the median
that is not affected by breastfeeding. The younger such
year of diagnosis was 1988 and the average age at
women were when they commenced childbearing, the
diagnosis was 50·1 years. Cases had, on average, fewer
lower was their relative risk of breast cancer; the relative
births than did controls (2·2 vs 2·6) and a greater
risk declining by 3·0% (SE 0·3%; p<0·0001) for each year
proportion were nulliparous (16% vs 14%). The
younger that women were when their first child was born.
proportion of parous women who had ever breastfed was
After stratifying by women’s ages when their first child was
also lower in cases than in controls (71% vs 79%). The
born, as well as by study, age, and menopausal status, the
average parity and average total duration of breastfeeding
relative risk of breast cancer also decreased with the
in parous women varied across countries, largely
number of births a woman had (figure 2). In the absence of
reflecting the small family size and short lifetime duration
breastfeeding, each birth reduces the relative risk of breast
of breastfeeding that have characterised women in many
developed countries during the past century. Theproportion of parous women who had ever breastfed was
Breast cancer in relation to breastfeeding
lowest in the USA, at around 50%, whereas in Japan,
Figure 2 shows the relative risk of breast cancer by parity,
Scandinavia, and developing countries more than 90% of
for women who had breastfed, as well as for women who
parous women had ever breastfed. Overall, the average
had never done so. Women with one child who had never
lifetime duration of breastfeeding was 9·8 and 15·6
breastfed are taken to have a relative risk of 1·0. The
months, respectively, for parous cases and controls. As
relative risk of breast cancer declines with increasing parity
expected, the lifetime duration of breastfeeding was
much shorter for women in developed than developingcountries (average 8·7 and 29·2 months, respectively, incontrols).
Table 1 shows, for parous cases and controls, the
distribution of lifetime duration of breastfeeding and therelation of that factor to various other indices of
childbearing. The mean parity and mean number ofchildren breastfed were greater for women with longerlifetime durations of breastfeeding. The age women were
when their first child was born decreased slightly with
Lifetime duration of breastfeeding (years)
*Calculated as floating absolute risk (FAR), with corresponding floated standarderror (FSE), and stratified by study, age, parity, age at first birth, and
Figure 3: Relative risk of breast cancer in parous women in
relation to lifetime duration of breastfeeding
Table 2: Relative risk of breast cancer in parous women, in
*Calculated as floating absolute risk (FAR), and stratified by study, age,
relation to lifetime duration of breastfeeding
parity, age at first birth, and menopausal status.
THE LANCET • Vol 360 • July 20, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing
in women who had ever and who had never breastfed.
However, at each parity the relative risk is slightly lower for
women who had breastfed than for women who had not(relative risk for ever versus never having breastfed,
adjusted for parity and other factors shown in figure 2 is
Separating out the unique contribution of breastfeeding
to the risk of breast cancer is not straightforward; women
breastfeed only after they have had a birth, the lifetime
duration of breastfeeding increases with increasing parity
(table 1); and the independent effect of each birth on the
risk of breast cancer is substantial in the absence ofbreastfeeding (figure 2). Hence, the effect of each birth
needs to be considered carefully when looking at the
relation between breastfeeding and breast cancer.
Moreover, the reported lifetime duration of breastfeeding
is not very accurate, with values often rounded to multiples of 6 or 12 months, especially for women who
breastfed for long periods (see the webfigure at
http://image.thelancet.com/extras/01art9187webfigure.
pdf). Additionally, comparatively few women in the studiesincluded here had breastfed for long periods—only 7% of
the cases and 15% of the controls reported lifetime
durations of breastfeeding of longer than 30 months(table 1). So, even in this large dataset, examination of the
relation between breastfeeding and breast cancer is
hampered by the potential for confounding, as well as by
measurement errors and the limited numbers withsubstantial exposures.
The potential confounding by parity can be virtually
eliminated by stratification of all analyses by fine divisions
of parity. The estimated relative risks of breast cancer,
according to lifetime duration of breastfeeding shown in
table 2, are stratified by parity from 1 up to 8+, as well as
by study, age, age at first birth, and menopausal status.
The relative risk of breast cancer declines with increasingduration of breastfeeding, the estimated reduction in the
relative risk per 12 months of breastfeeding being 4·5%
(0·7%; p<0·0001; figure 3). Because there is some
variation between studies in the classification of womenwhose lifetime duration of breastfeeding was short,
sensitivity analyses were done, grouping together women
with lifetime durations of 0 and 6 months or less. Whenthis was done, the estimated decline in the relative risk of
breast cancer was virtually unchanged, at 4·3% (0·8%;
p<0·0001) per 12 months of breastfeeding. Because this
latter approach provides a more consistent classificationacross studies than the former, women with reported
lifetime durations of breastfeeding of 0 and 6 months or
less are grouped together subsequently when trends are
Analyses similar to those in table 2 have been done
separately for women of parity 1, 2, 3, 4, 5, and 6 or more
(figure 4, and webtable 1 at http://image.thelancet.com/
extras/01art9187webtable1.pdf). The relative risk of breastcancer declined with increasing duration of breastfeeding
at each parity, and the magnitude of the decline did not
vary significantly across women of different parity (2 for
heterogeneity 1·3; p=0·9). However, the standard errorsand hence the confidence intervals for each parity-specific
Figure 4: Reduction in the relative risk of breast cancerassociated with breastfeeding in various subgroups of parous
*Stratified by study, age, parity, age at first birth, and menopausal
status, where appropriate. The dotted vertical line represents the overallresult for all parous women; information on each characteristic listed wasnot necessarily available for all women and averages of the subgroup-specific relative risks might therefore differ slightly from the result for all
THE LANCET • Vol 360 • July 20, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing
but none of the estimates variedsignificantly according to the factors
developing countries (2 0·2; p=0·7) by age
at diagnosis (2 0·5; p=0·5), menopausal
status (2 0·2; p=0·7), or family history of
breast cancer (2 0·3; p=0·6). Although the
magnitude of the decline of the relative risk
designs (figure 1: 2 for heterogeneity
breastfeeding for tumours localised to the
beyond the breast (decline in relative risk of
Cumulative incidence of breast cancer per 100 women
[1·7%], respectively, for each year ofbreastfeeding). There was no significant
difference in the extent of tumour spread
among women with breast cancer (2 2·7;
Figure 5: Estimated cumulative incidence of breast cancer in developed countries
if women had family sizes and breastfeeding patterns typical for developingcountries
Cumulative incidence of breast cancer
*Cumulative incidence of breast cancer typical for women in developed countries around
1990;1–4,52 †estimated incidence of breast cancer in developed countries if women had, on
breast cancer up to age 70 years was 5–7
average, 6·5 births instead of 2·5, and if women breastfed each child, on average, for 24
months instead of a lifetime mean of 8·7 months; such values have been typical of developingand developed countries until recently.53,54
1–2 per 100 in Asian and Africancountries.52 Women who would have beenof childbearing age during the 1950s make
estimate are wide. Likewise, the decline in the relative risk
substantial contributions to these estimates of cumulative
of breast cancer associated with breastfeeding does not
risk. In 1955–60 women in developed countries had, on
vary significantly according to the age women were when
average, between two and three births, whereas women in
they began childbearing (webtable 1 on The Lancet
Asian and African countries had, on average, between six
website, figure 4; 2 for heterogeneity 1·5; p=0·7).
and seven births.53 Among parous women from developed
The relative risk of breast cancer declined by 3·4%
countries in this study, the average duration of
(0·9%; p<0·0001) for each child breastfed. However, this
breastfeeding was about 3 months per child (the lifetime
association seems to be secondary to breastfeeding
average duration of breastfeeding was 8·7 months for
duration, since additional stratification by lifetime duration
parous controls from developed countries), which
of breastfeeding substantially reduced the 2 test for trend
contrasts with a median duration of breastfeeding of
with number of children breastfed, from 15·9, down to a
around 24 months per child in rural areas of Asia and
non-significant value of 0·9. Conversely, the association of
breast cancer with increasing duration of breastfeeding
To assess the contribution of the small family sizes and
persisted after adjustment for the number of children
short lifetime duration of breastfeeding to breast cancer
breastfed (3·8% [1·0%] decline in the relative risk for each
incidence in developed countries around 1990, the
12 months breastfeeding; p<0·0001).
relative risks obtained here were applied to the age-
The effect of ten other potential confounding factors
specific incidence rates typical for developed countries at
(ethnic origin, education, family history of breast cancer,
that time.1,2 Figure 5 shows the cumulative incidence of
age at menarche, height, weight, body-mass index, and
breast cancer in developed countries and estimated
use of hormonal contraceptives, alcohol, and tobacco)
cumulative incidence under the assumption that each
on the trends shown in figure 3 was examined.
woman had, on average, 6·5 births instead of 2·5, and that
Additional adjustment for each of these factors in turn did
women breastfed each child for 24 months instead of
not materially alter the magnitude of the effect of
3 months. The contribution to the estimated reduction in
breastfeeding on the relative risk of breast cancer (see
the incidence of breast cancer from the additional births—
webtable 2 at http://image.thelancet.com/extras/01art9187
ie, without breastfeeding—is distinguished from the
contribution from breastfeeding itself in figure 5. Overall,the larger family sizes and longer lifetime duration of
breastfeeding typical in developing countries until recently
The magnitude of the decline in the relative risk of breast
are estimated to more than halve the cumulative incidence
cancer associated with each year of breastfeeding was
of breast cancer in developed countries, from 6·3 to 2·7
calculated separately for various subgroups of women,
per 100 women by age 70 years. Part of this estimated
including women from developed and developing
reduction in incidence is due to the additional births, but
countries, women of different ages, ethnic origins, familial
almost two-thirds is due to the longer lifetime duration of
patterns of disease, and 11 other possibly relevant factors,
THE LANCET • Vol 360 • July 20, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing
Lifetime duration of breastfeeding is closely related to
Our analyses here show that the relative risk of breast
the number of children breastfed, and when the data are
cancer is reduced by 4·3% (95% CI 2·9–5·8) for each year
additionally stratified by the number of children breastfed
that a woman breastfeeds, in addition to a reduction of
the trend for the risk of breast cancer associated with
7·0% (5·0–9·0) for each birth. These relations are
increasing duration of breastfeeding remained significant.
significant and are seen consistently for women from
By contrast, the apparent association between breast
developed and developing countries, of different ages and
cancer and the number of children breastfed was no longer
ethnic origins, and with various childbearing patterns and
significant after the data were additionally stratified by
The 47 studies that contributed data were of different
Potential confounding by other factors such as age,
designs and included women with a wide range of
study (and centre within study), and menopausal status are
reproductive and breastfeeding patterns. Since the
minimised by stratification. The fine stratification used in
decrease in the relative risk of breast cancer is
these analyses means that no direct comparisons are made
comparatively small for each year of breastfeeding, some
between women in one study and women in another, and
studies would, by chance alone, find significant
that breastfeeding patterns in women with breast cancer
associations and others would not; this possibility is
are compared only with the pattern in women of exactly
particularly true for studies done in North America and
the same age and parity, with a similar age at first birth and
many European countries, where women tend to
age at menopause. Although the stratification was fine
breastfeed for a short time, if at all. When all studies are
enough to avoid substantial confounding, it was not
considered together, there was no significant variation in
excessively fine, since much of the statistical information
the results across study design; there was, however, some
content remained (an example of how to calculate the
variation between studies, which could be due to
amount of statistical information lost by stratification is
differences between studies in the way that breastfeeding
given elsewhere4). Potential confounding by ten additional
was defined. The overall results were not affected unduly
factors was examined, but separate adjustment for each in
by a single study or group of studies.
turn did not materially alter the relative risk estimates
As far as can be ascertained, more than 80% of the
(see webtable 2 at http://image.thelancet.com/extras/
worldwide epidemiological data on breast cancer and
01art9187webtable2.pdf). Furthermore, the results did
breastfeeding are included in this collaboration, and the
not suggest that any of the factors examined, including
findings from the ten studies that are not included55–64 are
age, weight, family history of breast cancer, and
generally consistent with these results. In the 1920s, Lane-
menopausal status, significantly modified the magnitude of
Claypon in the UK55 reported that the children of women
the relative risks, although there is limited power to detect
with breast cancer were less likely to have been breastfed
for 1 year or longer than the children of controls (19%,
Most women reliably report the number of children they
172 of 921, vs 33%, 457 of 1392). The findings of a
have had, and hence differential reporting of births by cases
parallel study by Wainwright in the USA56 showed a
and controls, or misclassification of parity is unlikely to be a
smaller difference in the same direction (28%, 472 of
serious problem. Even though stillbirths are not counted
1714, vs 29%, 718 of 2451). Six of the eight other studies
among the births for some studies, they represent about 1%
not included here57–62 published results on ever versus never
of all births, and so the omission of stillbirths would have
breastfeeding adjusted by age, parity, and age at first birth,
little effect on the findings with respect to parity. By
and the combined relative risk for ever having breastfed
contrast, women’s reporting of the length of time that they
from these studies is 0·93 (95% CI 0·87–1·00; p=0·05).
breastfed is not so accurate, and there is a strong tendency
The other two studies63,64 presented results according to
for women to round to the nearest 6 months. Studies done
duration of breastfeeding only, and the relative risk of
in developing countries have shown that, even when
breast cancer was seen to decline with increasing duration
women gave birth in the previous 3–5 years, they still tend
to report their duration of breastfeeding as multiples of 6 or12 months,54 and that women who are educated tend to
overestimate the length of time that they breastfed.65 Most
When studying the effect of each birth on the risk of breast
women included in this collaborative reanalysis would have
cancer, potential confounding by breastfeeding can be
given birth decades before they were asked about their
eliminated by looking at the relation between parity and
breastfeeding practices, and no published data could be
the relative risk of breast cancer in women who never
found investigating reporting errors in lifetime duration of
breastfed. When this is done, it is clear that, in the absence
breastfeeding in such circumstances. The inevitable
of breastfeeding, each birth has an independent effect,
misclassification of women would, if anything, be expected
reducing the relative risk of breast cancer by 7·0% per
to lead to an underestimation of the true effect of
birth. When studying the effect of breastfeeding, however,
there is potentially extensive confounding by parity and, to
There is no strong evidence in these data to suggest
a lesser extent, by age at first birth. All analyses that
there might be differential recall or reporting of
examine the risk of breast cancer in relation to lifetime
breastfeeding by cases and controls, since the results from
duration of breastfeeding have therefore stratified women
cohort studies, in which breastfeeding details were
into eight groups according to the number of births they
collected prospectively, are in line with results from case-
had (1, 2 . . . 7, 8+), thereby effectively eliminating
control studies, in which information was collected
confounding by parity, and stratified further according to
retrospectively (relative declines of 4·6% [1·8%] and 4·1%
their age at first birth (<20, 20–24, 25–29, and у30),
[0·7%], respectively, figure 1). The results for tumour
thereby minimising counfounding due to that factor.
stage show little difference in the extent of tumour spread
Stratification of the data by finer divisions of age at first
according to duration of breastfeeding, which also suggests
birth did not substantially alter the results. The trends
that there is little or no differential detection of breast
according to duration of breastfeeding do not vary
cancer according to breastfeeding practices.
significantly by parity or age at first birth, indicating no
About half the women included in these analyses had
strong interaction with these factors (figure 4).
breastfed for a total of 6 months or less, with only 7% of
THE LANCET • Vol 360 • July 20, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing
the cases and 15% of the controls breastfeeding for longer
by mimicking the effect of breastfeeding therapeutically or
than 30 months. No distinction was made between
in some other way. In the meantime, important reductions
exclusive breastfeeding and breastfeeding with
in breast-cancer incidence could be achieved if women
supplementary feeds; this, taken together with likely
considered breastfeeding each child for longer than they do
measurement errors in the reported lifetime duration of
now. About 470 000 women in developed countries and
breastfeeding, and the limited statistical power, means that
320 000 women in developing countries were diagnosed
there remains some uncertainty about the magnitude of
with breast cancer in 1990.67 Based on the estimates
the protective effect of breastfeeding on the risk of breast
obtained here, if women in developed countries had 2·5
cancer. Measurement errors would, if anything, be
children, on average, but breastfed each child for 6 months
expected to result in an underestimation of the true effect
longer than they currently do, about 25 000 (5%) breast
of breastfeeding on breast cancer. Because breastfeeding
cancers would be prevented each year, and if each child
patterns could well account for a large part of the variation
were breastfed for an additional 12 months about 50 000
in breast-cancer incidence between developed and
(11%) breast cancers might be prevented annually. There
developing countries, there is a need for further research
are obvious economic and social consequences to
on this topic. Future epidemiological studies need to focus
prolonging breastfeeding, and these results indicate that
on populations in which breastfeeding was common for
there are benefits to the mother, as well as the known
relatively long durations, and should attempt to collect
information on the use of supplementary feeds and onerrors in the reporting of lifetime duration of breastfeeding. Members of the collaborative group on hormonal factors in breastcancer
Although this collaboration was not set up to consider
Analysis and writing committee—V Beral, D Bull, R Doll, R Peto,
mechanisms, laboratory research to elucidate how
breastfeeding protects against breast cancer is of direct
Steering Committee—D Skegg (chairman), G Colditz, B Hulka,
public-health relevance, since it might be possible to
C La Vecchia, C Magnusson, T Miller, B Peterson, M Pike, D Thomas, F van Leeuwen.
prevent a substantial proportion of breast cancers in
Collaborators are listed in the webappendix at
developed countries if it were possible to mimic the effects
http://image.thelancet.com/extras/01art9187webappendix.pdf
Conflict of interest statementNone declared. Public-health implicationsApplication of our results to incidence rates typical of
developed countries around 1990 suggests that major
We thank the women with and without breast cancer who took part in this
reasons for the high incidence rates of breast cancer in
research. Central pooling, checking, and analysis of data was supported by
such countries are the small family size and the short
Cancer Research UK, and the UNDP/UNFPA/WHO/World Bank specialprogramme of research, development and research training in human
duration of breastfeeding that were characteristic of
women in these countries during the past century. Indeed,if women had larger family sizes and longer lifetimedurations of breastfeeding that were typical of developing
countries until recently, the cumulative incidence of breastcancer in developed countries is estimated to be reduced
Collaborative Group on Hormonal Factors in Breast Cancer. Breastcancer and hormonal contraceptives: collaborative reanalysis of
by more than half (from 6·3 to 2·7 per 100 women) by age
individual data on 53 297 women with breast cancer and 100 239
70 years. Part of this estimated reduction in incidence is
women without breast cancer from 54 epidemiological studies. Lancet
due to the large family size, but almost two-thirds is due to
1996; 347: 1713–27.
breastfeeding. Thus, much of the difference in breast-
Collaborative Group on Hormonal Factors in Breast Cancer. Breastcancer and hormonal contraceptives: further results. Contraception 1996;
cancer incidence between developed and developing
54 (suppl 3): 1S–106S.
countries seems to be accounted for by these reproductive
Collaborative Group on Hormonal Factors in Breast Cancer. Breast
factors, since the cumulative risk of breast cancer by age 70
cancer and hormone replacement therapy: collaborative reanalysis of
in most Asian and African countries around 1990 was
data from 51 epidemiological studies of 52 705 women with breast
between 1 and 2 per 100 women.52 Nevertheless, the
cancer and 108 411 women without breast cancer. Lancet 1997; 350: 1047–59.
average family size and duration of breastfeeding are
Collaborative Group on Hormonal Factors in Breast Cancer.
declining rapidly in such countries,54,66 and breast-cancer
Familial breast cancer: collaborative reanalysis of individual data
incidence has subsequently begun to rise, especially in
from 52 epidemiological studies including 58 209 women with
breast cancer and 101 986 women without the disease. Lancet 2001; 358: 1389–99.
For women to have a lifetime duration of breastfeeding
Vessey M, Baron J, Doll R, McPherson K, Yeates D. Oral
that was typical of women in developing countries and yet
contraceptives and breast cancer: final report of an epidemiologic study.
have the small family sizes typical for women in developed
Br J Cancer 1983; 47: 455–62.
countries would be virtually impossible. However, in that
6 Lê MG, Bachelot A, Doyon F, Kramar A, Hill C. Oral
hypothetical situation, these findings suggest that the
contraceptive use and breast cancer or cervical cancer: preliminaryresults of a French case-control study. In: Hormones and sexual factors
incidence of breast cancer in developed countries would be
in human cancer aetiology. Amsterdam: Elsevier Science, 1984.
reduced by 42%, solely by the longer duration of
Lubin F, Wax Y, Modan B. Role of fat, animal protein and dietary fibre
breastfeeding. Thus, the short duration of breastfeeding
in breast cancer aetiology: a case-control study. J Natl Cancer Inst 1986;
typical of women in developed countries makes a major
77: 605–12.
contribution to the high incidence of breast cancer in these
Meirik O, Lund E, Adami HO, Bergstrom R, Christoffersen T, BergsjoP. Oral contraceptive use and breast cancer in young women: a joint
national case-control study in Sweden and Norway. Lancet 1986; 2:
To expect that substantial reductions in breast-cancer
incidence could be brought about today by women
McPherson K, Vessey MP, Neil A, Doll R, Jones L, Roberts M. Early
returning to the pattern of childbearing and breastfeeding
oral contraceptive use and breast cancer: results of another case-control
that typified most societies until a century or so ago is
study. Br J Cancer 1987; 56: 653–60.
10 Ewertz M, Duffy SW. Risk of breast cancer in relation to reproductive
unrealistic. However, if in the future the mechanism of the
factors in Denmark. Br J Cancer 1988; 58: 99–104.
protective effect of breastfeeding on breast cancer were
11 Rohan TE, McMichael AJ. Oral contraceptive agents and breast cancer:
understood, it might be possible to prevent breast cancer
a population-based case-control study. Med J Aust 1988; 149: 520–26.
THE LANCET • Vol 360 • July 20, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing
12 Yuan J-M, Yu MC, Ross RK, Gao Y-T, Henderson BE. Risk factors for
experience and breast cancer risk among postmenopausal women.
breast cancer in Chinese women in Shanghai. Cancer Res 1988; 48: Cancer Epidemiol Biomarkers Prev 1998; 7: 365–69.
41 McCredie MRE, Dite GS, Giles GG, Hopper JL. Breast cancer in
13 Layde PM, Websterm LA, Baughman AL, Wingo PA, Rubin GL,
Australian women under the age 40. Cancer Causes Control 1998; 9:
Ory HW, and The Cancer and Steroid Hormone Study Group. The
independent associations of parity, age at first full term pregnancy, and
42 Hirose K, Tajima K, Hamajima N, et al. Comparative case-referent
duration of breastfeeding with the risk of breast cancer. J Clin Epidemiol
study of risk factors among hormone-related female cancers in Japan.
1989; 42: 963–73. Jpn J Cancer Res 1999; 90: 255–61.
14 Rosero-Bixby L, Oberle MW. Fertility change in Costa Rica 1960–84:
43 Hopper JL, Chenevix-Trench G, Jolley D, et al. Design and analysis
analysis of retrospective lifetime reproductive histories. J Biosoc Sci
issues in a population-based case-control-family study of the genetic
1989; 21: 419–32.
epidemiology of breast cancer, and the Co-operative Family Registry for
15 Siskind V, Schofield F, Rice D, Bain C. Breast cancer and breast
Breast Cancer Families (CFRBCS). Monogr Nat Cancer Inst 1999; 26:
feeding: results from an Australian case-control study. Am J Epidemiol
1989; 130: 229–36.
44 Magnusson C, Baron JA, Correia N, Bergstrom R, Adami H-O, Persson
16 UK National Case-Control Study Group. Oral contraceptive use and
I. Breast cancer risk following long-term oestrogen- and oestrogen-
breast cancer risk in young women. Lancet 1989; 1: 973–82.
progestin-replacement therapy. Int J Cancer 1999; 81: 339–44.
17 Paul C, Skegg DCG, Spears GFS. Oral contraceptives and risk of breast
45 Million Women Study Collaborative Group. The Million Women
cancer. Int J Cancer 1990; 46: 366–73.
Study: design and characteristics of the study population. Breast Cancer
18 Clavel F, Andrieu N, Gairard B, et al. Oral contraceptives and breast
Research 1999; 1: 73–80.
cancer: a French case-control study. Int J Epidemiol 1991; 20: 32–38.
46 Chang-Claude J, Eby N, Kiechle M, Bastert G, Becher H.
19 Weinstein AL, Mahoney MC, Nasca PC, Leske MC, Varma AO. Breast
Breastfeeding and breast cancer risk by age 50 among women in
cancer risk and oral contraceptive use: results from a large case-control
Germany. Cancer Causes Control 2000; 1: 687–95.
study. Epidemiology 1991; 2: 353–58.
47 Gajalakshmi V. Diet and cancers of the stomach, breast and lung. Asian
20 Lee HP, Gourley L, Duffy SW, Esteve J, Lee J, Day NE. Risk factors for
Pacific J Cancer Prev 2000; 1 (suppl): 39–43.
breast cancer by age and menopausal status: a case-control study in
48 Gao YT, Shu XO, Dai Q, et al. Menstrual, reproductive factors and
Singapore. Cancer Causes Control 1992; 3: 313–22.
breast cancer risk in urban Shanghai, People’s Republic of China. Int J
21 Wang Q-S, Ross RK, Yu MC, Ning J-P, Henderson BE, Kimm HT. A
Cancer 2000; 87: 295–300.
case-control study of breast cancer in Tianjin, China. Cancer Epidemiol
49 Tryggvadóttir L, Tulinius H, Eyfjord JE, Sigurvinsson T. Breastfeeding
Biomarkers Prev 1992; 1: 435–39.
and reduced risk of breast cancer in an Icelandic cohort study on breast
22 Yang CP, Daling JR, Band PR, Gallagher RP, White E, Weiss NS. Non
cancer. Am J Epidemiol 2001; 154: 37–42.
contraceptive hormone use and risk of breast cancer.
50 Peto R, Pike M, Armitage P, et al. Design and analysis of randomized
Cancer Causes Control 1992; 3: 475–79.
clinical trials requiring prolonged observation of each patient. Br J
23 Ferraroni M, Gerber M, Decarli A, et al. HDL-cholesterol and breast
Cancer 1976; 34: 585–612.
cancer: a joint study in Northern Italy and Southern France.
51 Easton DF, Peto J, Babiker AGAG. Floating absolute risk: an
Int J Epidemiol 1993; 22: 772–80.
alternative to relative risk in survival and case-control analysis avoiding
24 Kalache A, Maguire A, Thompson SG. Age at last full-term pregnancy
an arbitrary reference group. Stat Med 1991; 10: 1025–35.
and risk of breast cancer. Lancet 1993; 341: 33–36.
52 Parkin DM, Whelan SL, Ferlay J, et al. Cancer incidence in five
25 Morabia A, Szklo M, Stewart W, Schuman L, Thomas DB. Consistent
continents. Lyon: IARC Scientific Publication, 1997.
lack of association between breast cancer and oral contraceptives using
53 Cho LJ. Estimated refined measures of fertility for all major countries of
either hospital or neighborhood controls. Prev Med 1993; 22: 178–86.
the world. Demography 1964; 1: 359–74.
26 Thomas DB, Noonan EA, and the WHO Collaborative Study of
54 Anon. Breastfeeding and complementary infant feeding, and the
Neoplasia and Steroid Contraceptives. Breast cancer and prolonged
postpartum effects of breastfeeding. Demographic and Health Surveys
lactation. Int J Epidemiol 1993; 22: 619–26.
Comprehensive Studies (1999) Number 30, Macro International Inc,
27 Land CE, Hayakawa N, Machado SG, et al. A case-control interview
study of breast cancer among Japanese A-bomb survivors, II:
55 Lane-Claypon JE. A further report on cancer of the breast, with special
interactions with radiation dose. Cancer Causes Control 1994; 5: 167–76.
reference to its associated antecedent conditions. In: Reports on public
28 Newcomb PA, Storer BE, Longnecker MP, et al. Lactation and a
health and medical subjects. Number 32. London: Ministry of Health,
reduced risk of premenopausal breast cancer. N Engl J Med 1994; 330:
56 Wainwright JM. A comparison of conditions associated with breast
29 Rookus MA, van Leeuwen FE, for the Netherlands Oral Contraceptives
cancer in Great Britain and America. Am J Cancer 1931; 15: 2610–45.
and Breast Cancer Study Group. Oral contraceptives and risk of breast
57 Michels KB, Willett WC, Rosner BA, et al. Prospective assessment of
cancer in women aged 20–54 years. Lancet 1994; 344: 844–51.
breastfeeding and breast cancer incidence among 89 887 women. Lancet
30 White E, Malone KE, Weiss NS, Daling JR. Breast cancer among young
1996; 347: 431–36.
US women in relation to oral contraceptive use. J Natl Cancer Inst 1994;
58 Romieu I, Hernández-Avila M, Lazcano E, Lopez L,
86: 505–14.
Romero-Jaime R. Breast cancer and lactation history in Mexican
31 Brinton LA, Daling JR, Liff JM, et al. Oral contraceptives and breast
women. Am J Epidemiol 1996; 143: 543–52.
cancer risk among younger women. J Natl Cancer Inst 1995; 87:
59 Freudenheim JL, Marshall JR, Vena JE, et al. Lactation history and
breast cancer risk. Am J Epidemiol 1997; 146: 932–38.
32 La Vecchia C, Negri E, Franceschi S, et al. Oral contraceptives and
60 Stuver SO, Hsieh C-C, Bertone E, Trichopoulos D. The association
breast cancer: a cooperative Italian study. Int J Cancer 1995; 60:
between lactation and breast cancer in an international case-control
study: a re-analysis by menopausal status. Int J Cancer 1997; 71:
33 Lipworth L, Katsouyanni K, Stuver S, Samoli E, Hankinson SE,
Trichopoulos D. Oral contraceptives, menopausal estrogens, and the
61 Gilliland FD, Hunt WC, Baumgartner KB, et al. Reproductive risk
risk of breast cancer: a case-control study in Greece. Int J Cancer 1995;
factors of breast cancer in Hispanic and non-Hispanic white women. 62: 548–51. Am J Epidemiol 1998; 148: 683–92.
34 Levi F, Pasche C, Lucchini F, La Vecchia C. Alcohol and breast cancer
62 Coogan PF, Rosenberg L, Shapiro S, Hoffman M. Lactation and breast
in the Swiss Canton of Vaud. Eur J Cancer 1996; 32A: 2108–13.
carcinoma risk in a South African population. Cancer 1999; 86: 982–89.
35 Rossing MA, Stanford JL, Weiss NS, Habel LA. Oral contraceptive use
63 Furberg H, Newman B, Moorman P, Millikan R. Lactation and breast
and risk of breast cancer in middle-aged women. Am J Epidemiol 1996;
cancer risk. Int J Epidemiol 1999; 28: 396–402. 144: 161–64.
64 Zheng T, Duan L, Zhang B, et al. Lactation reduces breast cancer risk
36 Viladiu P, Izquierdo A, de Sanjose S, Bosch FX. A breast case-control
in Shandong Province, China. Am J Epidemiol 2000; 152: 1129–35.
study in Girona, Spain: endocrine, familial and lifestyle factors.
65 Huttly SRA, Barros FC, Victora CG, Beria JU, Vaughan JP. Do
Eur J Cancer 1996; 5: 329–35.
mothers overestimate breastfeeding duration? An example of recall bias
37 Enger SM, Ross RK, Bernstein L. Breastfeeding history, pregnancy
from a study in Southern Brazil. Am J Epidemiol 1990; 132: 572–75.
experience and risk of breast cancer. Br J Cancer 1997; 76: 118–23.
66 Anon. Demographic and Health Surveys, 28: fertility levels, trends and
38 Thomas DB, Gao DL, Self SG, et al. Randomized trial of breast self-
differentials. Calverton: Macro International, 1998.
examination in Shanghai: methodology and preliminary results. J Natl
67 Parkin DM, Pisani P, Ferlay J. Estimates of the worldwide incidence of
Cancer Inst 1997; 89: 355–65.
25 major cancers in 1990. Int J Cancer 1999; 80: 827–41.
39 Thomas HV, Key TJ, Allen DS, et al. Reversal of relation between body
68 WHO Collaborative Study Team on the Role of Breastfeeding on the
mass and endogenous estrogen concentrations with menopausal status.
Prevention of Infant Mortality. Effect of breastfeeding on infant and
J Natl Cancer Inst 1997; 89: 396–97.
child mortality due to infectious diseases in less developed countries: a
40 Enger SM, Ross RK, Paganini-Hill AL, Bernstein L. Breastfeeding
pooled analysis. Lancet 2000; 355: 451–55.
THE LANCET • Vol 360 • July 20, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing
IS 8 July 2001 sleeping tablets, tranquillisers and anti-depressants Introduction With the advent of the ‘anti-dementia’ compliance with medication a problem tranquillisers and anti-depressants, used she is behaving in a disturbed fashion, or behaviour problems that arise during the her wishes. Doctors are expected to take information sheet briefly describes these for giving
CORE CURRICULUM IN NEPHROLOGY Disorders of Sodium and Water ● Na intake controlled by Na appetite, dietary COMPOSITION OF BODY FLUIDS ● Typical Western diets contain 2 to 6 g of Na Total Body Water (TBW) ● Na elimination regulated by factors that● Two thirds of TBW is inside cells (intracel-● One third of TBW is outside cells (extracel- Mechanisms of Renal Na Excretion