Breast cancer is the leading cause of cancer death, and the most frequently diagnosed
cancer in women worldwide (Lacey et al, 2002). Large differences in rates of the disease
exist between countries, with higher rates in North America and Western Europe, and
lower rates in Asia and South America (Lacey et al, 2002). These differences are likely
to be due to environmental rather than genetic factors. The rates of breast cancer
change in migrants from low- to high-risk countries, who eventually acquire the rates
of their adopted country (Ziegler et al, 1993; Pike et al, 2002). Menstrual and reproductive
risk factors for breast cancer do not appear to account for these differences in rates
(Wu et al, 1996).
The differences in dietary practices between countries are well established, and could
contribute to the differences in breast cancer risk. Support for an influence of dietary
fat on breast cancer rates comes from its effect on mammary carcinogenesis in animals,
and human ecological data.
Two major meta-analyses, combining results from over 140 studies examining the relationship
between dietary fat and breast cancer risk in rats and mice, show dietary fat to be
a promoter of mammary carcinogenesis (Fay et al, 1997). This effect is independent
of the effects of caloric intake (Freedman et al, 1990). Human ecological studies
show a strong correlation (0.7 or more) between dietary fat intake, estimated from
national food balance data, and incidence and mortality of breast cancer worldwide.
(Prentice and Sheppard, 1990).
However, case–control and cohort studies that have examined the relationship between
dietary fat and breast cancer risk in humans have given inconclusive results. In 1993,
we conducted a meta-analysis of the 23 studies then published that gave risk estimates
for the total dietary fat, type of fat or for fat-containing foods (Boyd et al, 1993).
The number of published primary research papers on this issue has since then more
than doubled. The present analysis updates and expands our earlier meta-analysis to
include all studies on this relationship published since 1993.
METHODS
Assembly of literature
Case–control and cohort studies for inclusion in the analysis were identified by searching
the MEDLINE and PUBMED databases for literature on the intake of fat, fat subtypes
and fat-containing foods, and breast cancer risk over the period from January 1966
to July 2003. Reference lists of review articles and primary studies were also searched
for additional relevant literature.
A total of 46 risk estimates for total fat intake were obtained from the 45 independent
studies included in the meta-analysis (see Table 1
Table 1
Selected characteristics of (A) case–control studies: total fat and (B) cohort studies:
total fat
Author
Country
No. of cases
No. of controls
Type of controls
Dietary assessment
Partition
RR total fat
Quality score
(A)
Challier (1998)
France
345
345
Centre
Diet historya
,
b
Quintile
1.71 (0.77,3.76)
6/7
De stefani et al (1998)
Uruguay
365
397
Hospital
Food freqb
,
c
Quartile
1.53 (0.89,2.62)
6/7
Ewertz and Gill (1990)
Denmark
1474
1322
Population
Food freqb
,
c
Quartile
1.45 (1.17,1.80)
3/7
Franceschi et al (1996)
Italy
2569
2588
Hospital
Food freqb
,
c
Quintile
0.81 (0.63,0.99)
6/7
Graham et al (1982)
USA
1803
917
Hospital
Food freqb
,
c
Quartile
0.9 (0.5,1.5)
5/7
Graham et al (1991)
USA
439
494
Population
Food freqb
,
c
Quartile
0.93 (0.63,1.38)
5/7
Hirohata et al (1985)
Japan
212
424
Hospital and neighbourhood
Diet historyb
Quartile
1.01 (0.60,1.71)
3/7
Hirohata et al (1987)
Hawaii
Japanese
J 183
183
Neighbourhood
Diet historyb
Quartile
1.5 (0.8,2.9)
5/7
Caucasian
C 161
161
Neighbourhood
Diet historyb
Quartile
1.3 (0.6,2.6)
Holmberg et al (1994)
Sweden
265
432
Population
Food freqb
,
c
Quartile
1.3 (not given)
6/7
Ingram et al (1991)
Australia
99
209
Population
Food freqb
,
c
Median of fat intake
1.4 (0.8,2.5)
5/7
Katsouyanni et al (1988)
Greece
120
120
Hospital
Food freqc
90th vs 10th percentiles
1.36 (0.69,2.67)
4/7
Katsouyanni et al (1994)
Greece
820
1546
Hospital
Food freqc
Quintile
0.94 (0.85,1.05)
5/7
Landa et al (1994)
Spain
100
100
Hospital
Food freqc
Tertile
0.29 (0.1,0.7)
4/7
Lee et al (1991)
Singapore
200
420
Hospital
Food freqc
Tertile
0.75 (0.41,1.36)
4/7
Levi et al (1993)
Switzerland
107
318
Hospital
Food freqc
Tertile
1.53 (0.86,2.71)
5/7
Mannisto et al (1999)
Finland
310
454
Population
Food freqa
–
c
Quintile
0.7 (0.3,1.6)
7/7
Martin-Moreno et al (1994)
Spain
762
988
Population
Food freqa
–
c
Quartile
0.98 (0.74,1.29)
7/7
Miller et al (1978)
Canada
400
400
Population
Diet historyb
Tertile
1.6 (0.9,3.0)
5/7
Nunez et al (1996)d
Spain
139
136
Hospital
Diet history
Tertile
2.04 (0.84,4.99)
4/7
Potischman et al (1998)
USA
1647
1501
Population
Food freqc
Quartile
1.00 (0.8,1.2)
4/7
Pryor et al (1989)
USA
172
190
Population
Food freqb
,
c
Quartile
0.7 (0.3,1.5)
5/7
Richardson et al (1991)
France
409
515
Hospital
Diet history
Tertile
1.6 (1.1,2.2)
6/7
Rohan et al (1988)
Australia
451
451
Population
Food freqa
–
c
Quintile
0.9 (0.59,1.38)
6/7
Shun-Zhang et al (1990)
China
186
372
Population & hospital
Diet historyb
Quintile
1.67 (1.01,2.05)
6/7
Toniolo et al (1989)
Italy
250
499
Population
Diet historyb
Quartile
1.8 (0.98,3.29)
6/7
Trichopoulou et al (1995)
Greece
820
1548
Hospital
Food freqb
,
c
Quintile
1.01 (0.94,1.08)
6/7
Van't Veer et al (1990, 1991)
Netherlands
133
289
Population
Diet historyb
Per 24 g fat
1.54 (1.06,2.22)
6/7
Wakai et al (2000)
Indonesia
226
452
Hospital
Food freqb
,
c
Quartile
5.43 (2.14,13.77)
6/7
Witte et al (1997)
USA/Canada
140
222
Sisters
Food freqa
–
c
Quartile
0.4 (0.2,0.8)
6/7
Yuan et al (1995)
China
834
834
Population
Food freqc
Per 90 g fat
1.2 (0.7,2.0)
5/7
Zaridze et al (1991)
Moscow
139
139
Clinic
Food freqc
Quartile
0.52 (0.04, 6.99)
5/7
Total cases
16 280
Total controls
18 966
(B)
Bingham et al (2003)
UK
168
672
Population
Diet historyb
Quintile
1.31 (0.65,2.64)
6/6
Cho (2003)
USA
714
90 655
Population
Food freqa
–
c
Quintile
1.25 (0.98, 1.59)
6/6
Gaard et al (1995)
Norway
248
24 897
Population
Food freqa
–
c
Quartile
1.25 (0.86,1.81)
6/6
Graham et al (1992)
USA
359
18 586
Population
Food freqa
–
c
Quintile
0.99 (0.69,1.41)
6/6
Holmes et al (1999)
USA
2956
88 795
Population
Food freqa
–
c
Quartile
0.97 (0.94,1.00)
5/6
Howe et al (1991a, b)
Canada
519
56 837e
Population
Diet historya
,
b
Quartile
1.35 (1.00,1.82)
6/6
Jones et al (1987)
USA
99
5495
Population
24 h recall
Quartile
0.34 (0.16,0.73)
3/6
Knekt et al (1990)
Finland
54
3988
Population
Diet historyb
Tertile
1.72 (0.61,4.82)
6/6
Kushi et al (1992)
USA
459
34 388
Population
Food freqa
–
c
Quartile
1.16 (0.87,1.55)
6/6
Thiebaut and Clavel-Chapelon (2001)f
France
838
65 879g
Population
Food freqa
–
c
Quartile
1.37 (0.99,1.89)
6/6
Toniolo et al (1994)
USA
180
14 291h
Population
Food freqa
–
c
Quintile
1.49 (0.89,2.48)
6/6
van den Brandt et al (1993)
Netherlands
471
62 573i
Population
Food freqa
–
c
Quintile
1.08 (0.73,1.59)
6/6
Velie et al (2000)
USA
996
40 022
Population
Food freqa
–
c
Quintile
1.07 (0.86.1.32)
6/6
Wolk et al (1998)
Sweden
674
61 471
Population
Food freqa
–
c
Quartile
1.0 (0.76,1.32)
6/6
Total cases
8735
Total population
568 549
a
Self-administered.
b
Diet assessment method validated.
c
Food Frequency Questionnaire.
d
Article translated from Spanish.
e
No. of controls in calculation of RR=1182.
f
Article translated from French.
g
No. of controls in calculation of RR=62 211.
h
No. of controls in calculation of RR=829.
i
No. of controls in calculation of RR=1598.
for references). Risk estimates for types of fat were also extracted from the 33 studies
that provided them.
Studies were also identified that contained information regarding food groups and
breast cancer risk. The three most common foods for which risk estimates were given
in these studies were determined (meat, milk and cheese) and used in the present meta-analysis.
Two studies, which defined food groups in a manner that could not be adapted to this
analysis, were excluded (Katsouyanni et al, 1986; Lubin et al, 1986). Risk estimates
pertaining to the intake of these foods were obtained from a total of 36 papers (see
Table 2
Table 2
Selected characteristics of (A) case–control studies: food and (B) cohort studies:
food
Author
Country
No. of cases
No. of controls
Type of controls
Dietary assessment
Food
No of categoriesa
RRi
CI
Quality score
(A)
Ambrosone et al (1998)
USA
740
810
Population
Food freqb
Meatc
4
0.92
(0.25, 3.32)
5/7
De stefani et al (1997)
Uruguay
352
382
Hospital
Food freqb
,
d
Meat
4
2.26
(1.24, 4.12)
5/7
Ewertz and Gill (1990)
Denmark
1474
1322
Population
Food freqb
,
d
Meat
6
0.94
(0.63, 1.40)
3/7
Milk
5
1.45
(1.02, 2.07)
5/7
Franceschi et al (1995)
Italy
2569
2588
Hospital
Food freqb
,
d
Meat
4
0.99
(0.69, 1.41)
6/7
Milk
5
0.81
(0.67, 0.98)
Cheese
5
0.98
(0.81, 1.18)
Hirohata et al (1987)
USA
183
183
Population
Diet historyd
Meat
4
1.5
(0.7,3.1)
5/7
Hislop et al (1986)
Canada
846
862
Population
Food freqb
,
e
Meat
3
1.16
(0.90, 1.48)
3/7
Milk
3
1.55
(1.18, 2.05)
Holmberg et al (1994)
Sweden
265
432
Population
Food freqb
,
d
Meat
8
0.8
(0.5, 1.2)
6/7
Ingram et al (1991)
Australia
99
209
Population
Food freqb
Meat
2
1.6
(0.9, 2.8)
3/7
Milk
2
0.9
(0.5, 1.6)
Kato et al (1992)
Japan
908
908
Hospital
Unspecified
Meat
3
0.75
(0.60, 0.94)
2/7
Landa et al (1994)
Spain
100
100
Hospital
Food freqb
Meat
3
1.21
(0.31, 4.66)
4/7
La Vecchia et al (1987)
Italy
1108
1281
Hospital
Food freqb
Meat
3
1.39
(1.12, 1.71)
4/7
Le et al (1986)
France
1010
1950
Hospital
Food freqb
Milk
3
1.8
(1.3, 2.4)
5/7
Cheese
3
1.5
(1.0, 2.3)
Lee et al (1991)
Singapore
200
420
Hospital
Food freqb
Meat
3
1.4
(0.77, 2.53)
4/7
Levi et al (1993)
Switzerland
107
318
Hospital
Food freqb
Meatc
3
1.45
(0.56, 3.72)
5/7
Milk
3
1.15
(0.68, 1.96)
Cheese
3
2.99
(1.7, 5.25)
Lubin et al (1981)
Canada
577
826
Population
Food freqb
Meat
3
1.42
(1.0, 2.0)
4/7
Milk
4
0.77
(0.5, 1.3)
Cheese
3
1.11
(0.9, 1.4)
Mannisto et al (1999)
Finland
310
454
Population
Food freqb
,
d
,
e
Meat
5
0.66
(0.12, 3.72)
7/7
Milk
4
1.7
(0.8, 3.66)
Cheese
4
0.75
(0.3, 1.7)
Matos et al (1991)
Argentina
196
205
Neighbourhood
Food freqb
Meat
3
1.4
(0.7, 2.9)
4/7
Potischman et al (1998)
USA
1647
1501
Population
Food freqb
Meat
4
1.18
(1.0, 1.5)
4/7
Richardson et al (1991)
France
409
515
Hospital
Diet historyb
Meat
3
1
(0.7, 1.4)
6/7
Cheese
3
1.4
(1.0, 1.9)
Talamini et al (1984)
Italy
368
373
Hospital
Food freq
Meat
3
1.3
(0.7, 2.2)
4/7
Milk
3
3.2
(1.85, 5.8)
Toniolo et al (1989)
Italy
250
499
Population
Diet historyd
Meatc
4
1.15
(0.82, 1.62)
6/7
Milk
4
1.73
(1.16, 2.6)
Cheese
4
2.6
(1.7, 4.0)
Trichopoulou et al (1995)
Greece
820
1548
Hospital visitors
Food freqb
,
d
Meat
5
1.07
(0.99, 1.15)
6/7
Milk
5
1.0
(0.93, 1.08)
Van't Veer et al (1989)
Netherlands
133
289
Population
Diet history
Milk
Per 225 g
0.81
(0.59, 1.12)
4/7
Cheese
Per 60 g
0.56
(0.33, 0.95)
Witte et al (1997)
USA/Canada
140
222
Population
Food freqb
,
d
,
e
Meat
4
0.6
(0.3, 1.3)
6/7
Wang et al (2000)f
China
2063
2063
Neighbourhood
Food freqb
Milk
Per 500 g
1.49
Not given
Total cases
16 734
Total controls
20 038
(B)
Cho (2003)
USA
714
90 655
Population
Food freqb
,
e
,
d
Meatc
5
1.11
(0.92, 1.35)
6/6
Gaard et al (1995)
Norway
248
25 897
Population
Food freqb
,
e
,
d
Meat
4
2.28
(1.29, 4.03)
6/6
Milk
4
1.71
(0.86, 3.38)
Gertig et al (1999)
USA
466
466
Population
Food freqb
,
d
,
e
Meatc
3
1.06
(0.48, 2.33)
6/7
Hirayama (1978)
Japan
139
142 857
Population
National nutrition survey
Meat
2
1.7
(0.8, 3.8)
3/6
Hjartaker et al (2001)
Norway
317
48 844
Population
Food freqb
,
d
,
e
Milk
3
0.51
(0.27, 0.96)
5/6
Kinlen (1982)
Britain
62
2813
Population
Unspecified
Meat
2
1.2
(0.8, 1.6)
2/6
Knekt et al (1996)
Finland
88
4697
Population
Food freqb
,
d
Milk
3
0.42
(0.24, 0.74)
4/6
Cheese
3
1.25
(0.75, 2.08)
Mills et al (1989)
USA
215
20 341
Population
Food freq
Meatc
3
1.11
(0.47, 2.66)
4/6
Milk
3
0.94
(0.66, 1.33)
Cheese
3
1.43
(0.99, 2.06)
Thiebaut and Clavel-Chapelon (2001)g
France
838
65 879
Population
Food freqb
,
d
,
e
Cheese
4
0.92
(0.74, 1.13)
6/6
Toniolo et al (1994)
USA
180
829
Population
Food freqb
,
d
,
e
Meat
5
1.44
(0.68, 3.04)
6/6
van den Brandt et al (1993)
Netherlands
437
62 573h
Population
Food freqb
,
d
,
e
Meat
Not given
1.23
(0.63, 2.37)
6/6
Vatten et al (1990)
Norway
152
14 500
Population
Food freqb
,
d
Meat
3
1.8
(1.1, 3.1)
4/6
Total cases
3783
Total controls
476 200
a
Food Frequency Questionnaire.
b
Self-administered.
c
Diet assessment method validated.
d
No. of categories refers to the number of categories of frequency of consumption into
which the food intakes were partitioned. The RR is the highest vs lowest level of
consumption.
e
Article translated from Chinese.
f
Article translated from French.
g
No. of controls in calculation of RR=1598.
h
Measurement of food intake assessed for validity.
i
RR presented for various types of meat combined to reflect total meat consumption.
for references), 16 of which also contained relative risk estimates associated with
total fat intake. Nested case–control studies were treated as cohort studies for these
analyses. If study results were presented in more than one article, the most recent
analysis was used.
Extraction and classification of data
Descriptive data regarding the number and type of subjects, estimates of mean daily
dietary fat intake, method of dietary assessment and the partitioning of intakes for
the calculation of relative risks were extracted from each article along with an estimate
of relative risk and its associated 95% confidence (CI) interval. In these studies,
the intake of fat or fat-containing foods was usually partitioned into tertiles, quartiles
or quintiles. The relative risk of breast cancer comparing the highest with the lowest
category of intake was extracted from each study. Relative risks and CIs were calculated
for three studies (Graham et al, 1982, 1991; Yuan et al, 1995) and confidence intervals
were calculated for five studies (Hirayama, 1978; Kinlen, 1982; Levi et al, 1993;
Landa et al, 1994; Toniolo et al, 1994) by cell frequencies shown in the data or standard
error values (Fleiss, 1981), and are thus unadjusted for other variables.
If the risk of breast cancer associated with the dietary variables was expressed in
more than one way, the estimate extracted from the study was the one that reflected
the greatest degree of controlling for confounders (i.e. risk factors and/or energy).
When both hospital and population controls were used for comparison separately, the
results for population controls were chosen for analysis. As few studies provided
complete data for pre- and postmenopausal women separately, we chose the relative
risk for the whole group if available. In some reports unadjusted relative risks were
given, accompanied by an explicit statement that the estimate was unchanged by adjustment
for energy or other risk factors. In these cases, the relative risk given was regarded
as having been adjusted.
In some instances, more than one estimate of risk were combined in order to increase
the comparability of the studies. For example, in a number of studies of fat-containing
foods, separate estimates of risk for red meat, poultry or pork consumption were reported.
These separate risk estimates were combined into a total meat group by averaging the
log of the risk estimates. CIs were calculated for the average relative risk using
the variances of each separate risk estimate. In two studies, relative risk estimates
were given for pre- and postmenopausal women separately (Pryor et al, 1989; Ambrosone
et al, 1998) and in one study, risk estimates were given for pre- and postmarriage
separately (Wakai et al, 2000). In each of these cases, the estimates were combined
into one to represent all women in the manner described above. Similarly, in the cohort
study reported by Hirayama (1978), relative risks given for meat intake divided by
age category were combined to produce one risk estimate for the population.
Methodological standards
A quality score was calculated for each study included in the meta-analysis. Four
investigators (NFB, LJM, KNV and BSC) independently scored the studies based on predetermined
methodological standards and any differences were resolved by discussion. The criteria
included the provision of details on how the population had been assembled, whether
histological confirmation of breast cancer had been obtained, the methods used to
control for observer bias, a description of the method of measurement of nutrient
and/or food intake, including data on validation and reproducibility and whether or
not adjustment of risk estimates for potential confounding factors such as energy
intake and traditional risk factors for breast cancer had been performed. Quality
scores were not used to weigh the individual estimates of risk, but were used to divide
the studies into groups for a stratified analysis based on quality score.
Statistical methods and analysis
Studies were classified as case–control or cohort and statistical analyses were performed
for each study design separately as well as for all studies combined. Analyses were
also performed on subgroups of studies based on quality score, geographical area,
type of control population and other study characteristics.
Statistical analyses were performed using SAS (SAS Institute, Inc., Cary, NC, USA)
software and graphical displays of the results produced using S-PLUS (Insightful,
Inc., Seattle, WA, USA) software. The data required by SAS for each study included
the natural log of the adjusted odds ratios, and its 95% CI. From these, the program
calculated the summary risk estimate and the associated standard error, which was
used to determine the 95% CI.
Owing to diversity in the location, design and analysis of the various studies, we
were aware that the true effects being estimated were likely to vary among studies.
There were two sources of variability that had to be addressed: the usual sampling
variation in the estimates and variation in the underlying parameter. To account for
both sources of variation in this meta-analysis, we used the method of DerSimonian
and Laird (1986), employing the SAS MIXED procedure in which the magnitude of the
heterogeneity is estimated, and accounted for by assigning a greater variability to
the estimate of the overall effect. Thus, we did not assume that the studies represented
the same effect. Rather, the effects came from some statistical distribution of effects.
The random effects model does not rely on homogeneity; on the contrary, it assumes
heterogeneity. We also employed additional subgroup and regression analyses to try
to account for the observed differences between studies, and to examine the potential
influence of study design and execution, study population, geographical location,
adjustment variables, partitioning cut points and methods of analysis.
RESULTS
Characteristics of studies reported
A total of 45 published studies, containing 46 estimates of risk, examined the role
of dietary fat in relation to breast cancer risk by an analysis of nutrient intake.
Of these, 31 were case control and 14 were cohort in design, and they contained a
total of 25 015 cases of breast cancer and over 580 000 control or comparison subjects.
Table 1 summarises selected characteristics of the published studies that examined
the role of dietary fat in relation to breast cancer risk through an analysis of nutrient
intake. In all, 22 studies were carried out in European countries (including Russia),
five in Asian countries, and 15 in North America. In addition, two studies were conducted
in Australia and one in Uruguay.
The studies included in Table 1 had varied methods of execution and analysis. A total
of 27 studies used population-based comparison or controls, 12 selected comparison
subjects from hospital or clinics, two studies selected comparison subjects from both
these sources and four selected controls from other defined populations (i.e. sisters,
neighbourhood, or centre). In total, 32 studies obtained dietary data using food frequency
questionnaires, 12 with diet histories, one with a 24-h diet recall and one with food
records and food frequency questionnaire. Food frequency questionnaires were sometimes
administered by interview, and sometimes self-administered, and differed substantially
in the number of food items included (data not shown in the table).
All the studies included in Table 1 analysed the relationship between breast cancer
risk and nutrient intake by partitioning intake, 13 by quintiles, 21 by quartiles,
seven by tertiles and one at the median. One study used deciles of intake and two
used specific increments in fat intake. A total of 26 studies met at least six of
the methodological standards that were applied, 16 met four or five standards and
three met fewer than four standards.
Estimates of risk for nutrient consumption
Figure 1
Figure 1
Relative risks for (A) total fat (B) saturated fat (C) monounsaturated fat and (D)
polyunsaturated fat intake and breast cancer risk. CIs are 95%. Closed diamond=relative
risk adjusted for energy intake. Open diamond=relative risk unadjusted for energy
intake. Grey diamond=summary relative risk results of the meta-analysis.
shows the estimates of the risk of breast cancer generated by these studies for total
fat, as well as saturated, monounsaturated and polyunsaturated fat, and indicates
where risk estimates have been adjusted for energy intake and for established breast
cancer risk factors. For total fat, the summary relative risk for all 46 estimates
was 1.13 (95% CI: 1.03–1.25). Cohort studies had a summary relative risk of 1.11 (95%
CI: 0.99–1.25) and case–control studies had a relative risk of 1.14 (95% CI: 0.99–1.32).
Summary relative risks for both cohort and case–control studies that adjusted for
energy intake and traditional risk factors for breast cancer were 1.13 (95% CI: 1.04–1.23)
and 1.22 (95% CI: 0.91–1.63), respectively. The summary relative risks for saturated
fat were greater than unity for all studies combined (RR, 1.19; 95% CI: 1.06–1.35),
case–control studies alone (RR, 1.23; 95% CI: 1.03–1.46) and cohort studies alone
(RR, 1.15; 95% CI: 1.02–1.30). The summary relative risk for monounsaturated fat was
1.11 (95% CI: 0.96–1.28) for all studies, 1.12 for case–control studies alone (95%
CI: 0.94–1.32) and 1.10 for cohort studies alone (95% CI: 0.83–1.44). The summary
relative risks for polyunsaturated fats were below unity for all studies and case–control
studies alone (all studies, 0.94; 95% CI: 0.80–1.10, case control, 0.50; 95% CI: 0.39–0.63),
but above unity for cohort studies alone (1.11; 95% CI: 1.00–1.22).
Replication of published results of a combined analysis of cohort studies
To determine whether the methods used in the present paper could replicate those based
upon an analysis using the data from individual studies, we applied our methods to
a group of studies that were the subject of a previously published pooled analysis
of seven cohort studies by Hunter et al (1996). For our analysis, we extracted risk
estimates and 95% CIs from the original papers and calculated the summary risk estimates
as described above. Estimates for total fat were available for five of the seven studies
analysed by Hunter et al (Howe et al, 1991a; Graham et al, 1992; Kushi et al, 1992;
Willett et al, 1992; van den Brandt et al, 1993). Comparing our results with those
of Hunter's analysis, the summary relative risks for total fat were, respectively,
1.06 (95% CI: 0.92–1.23) and 1.05 (95% CI: 0.94–1.16), for saturated fat 1.05 (95%
CI: 0.90–1.23) and 1.07 (95% CI: 0.95–1.20), for monounsaturated fat 0.96 (95% CI:
0.83–1.10) and 1.01 (95% CI: 0.88–1.16) and for polyunsaturated fat 1.14 (95% CI:
0.98–1.34) and 1.07 (95% CI: 0.97–1.17), respectively. Our calculations thus produced
risk estimates and CIs very similar to those reported from the pooled analysis.
Characteristics of studies reporting analysis according to foods
The 37 studies that examined food consumption in relation to breast cancer risk, 25
case–control and 12 cohort in design, included a total of 20 571 cases and over 490 000
control or comparison subjects. The 37 studies contained 31 estimates of risk for
meat, 16 for milk and 11 for cheese. There is some overlap, as 16 studies reported
risk in relation to consumption of both nutrients and foods, and are therefore included
in both Figures 1 and 2
Figure 2
Relative risks for (A) meat (B) milk and (C) cheese intake and breast cancer risk.
CIs are 95%. Closed diamond=relative risk adjusted for energy intake. Open diamond=relative
risk unadjusted for energy intake. Grey diamond=summary relative risk results of the
meta-analysis.
.
Table 2 summarises selected characteristics of the published studies that examined
the role of diet in relation to breast cancer risk by an analysis of food intake.
A total of 20 studies were carried out in European countries, 10 in North America,
four in Asian countries and one in each of Argentina, Australia and Uruguay. A total
of 24 studies used population-based comparison or controls, 10 selected comparisons
from hospitals and three selected comparisons from other populations (i.e. neighbourhood
and hospital visitors). All but seven studies obtained dietary data using a food frequency
questionnaire, of which two used unspecified methods.
All the studies included in Table 2 analysed the relationship between breast cancer
risk and food intake by partitioning intake. Differences in the methods of partitioning
existed not only between studies but also within studies analysing intake of different
foods. In all, 13 studies met at least six of the methodological standards that were
applied, 18 met four or five, and six met fewer than four standards.
Estimates of risk for food consumption
Figure 2 shows the distribution of the estimates of risk of breast cancer and the
95% CIs generated by the studies for intake of meat, milk and cheese. The summary
relative risks for meat intake were 1.17 (95% CI: 1.06–1.29) for all studies, 1.13
(95% CI: 1.01–1.25) for case–control studies alone and 1.32 (95% CI: 1.12–1.56) for
cohort studies alone. The summary relative risks for milk were 1.12 (95% CI: 0.88–1.43)
for all studies, 1.25 (0.99–1.58) for case–control studies alone and 0.76 (95% CI:
0.42–1.40) for cohort studies alone, and the summary relative risks for cheese were
1.26 (95% CI: 0.96–1.66) for all studies and 1.30 (95% CI: 0.89–1.92) for case–control
studies alone.
Analysis of sources of variation for studies of total fat and breast cancer risk
As has already been noted, the studies included in the analysis differed in a number
of aspects of their design and execution, and were reported from countries that are
known to have wide differences in breast cancer risk. We examine below the influence
of some of these sources of heterogeneity on the results presented in the previous
sections. Owing to the small number of studies available after division into subgroups,
we have confined our attention to those studies that reported the results of nutrient
analysis for total fat intake and breast cancer risk.
The principal sources of variation in the study methodology examined were the extent
to which studies met the methodological standards described above, the sources from
which control or comparison groups were selected, the partitioning of nutrient intake
and the geographic region where the studies were carried out.
Methodological standards
The summary relative risks were calculated for studies classified according to the
proportion of methodological standards met (see Methods section). The summary relative
risk for the relationship of total fat intake to breast cancer risk, for all 26 studies
that met 80% or more of the standards, was 1.17 (95% CI: 1.03–1.32). For the 11 studies
that met between 70 and 80% of standards, the summary relative risk was 1.08 (95%
CI: 0.93–1.24), and for the nine studies that met 70% or less of the standards the
relative risk was 0.91 (95% CI: 0.59–1.40).
Source of controls
The summary relative risk for total fat and breast cancer risk was 1.14 (95% CI: 1.04–1.25)
for the 25 studies in Figure 1 that selected control or comparison groups from defined
nonhospital populations. The 11 case–control studies in this group had a summary relative
risk of 1.12 (95% CI: 0.96–1.31). The 14 case–control studies that selected controls
from hospital populations had a summary relative risk of 1.11 (95% CI: 0.84–1.47).
Partitioning of nutrient intake
The summary relative risk for studies that partitioned nutrient intake into quintiles
was 1.07 (95% CI: 0.94–1.21) for all studies and 1.01 (95% CI: 0.83–1.24) for case–control
studies; for studies that used quartiles, 1.12 (95% CI: 0.95–1.32) for all studies
and 1.16 (95% CI: 0.91–1.48) for case–control studies; and for studies that used tertiles,
1.15 (95% CI: 0.66–1.99) for all studies and 1.07 (95% CI: 0.56–2.05) for case–control
studies.
Geographic variation
To examine the possible influence of the country in which they were carried out, studies
were divided into four geographical categories. The summary relative risk for European
studies (n=22) was 1.17 (95% CI: 1.02–1.34); for North American studies (n=15) 1.04
(95% CI: 0.91–1.18) and for Asia (n=6) 1.42 (95% CI: 0.87–2.30).
Regression analysis
To examine the independent contribution of the factors considered above, regression
analysis was carried out, in which the log of the relative risk for total fat intake
in each study, weighted by the reciprocal of its variance, was the dependent variable
and study quality score, geographical area, study design and type of controls were
the independent variables. However, univariate analysis showed none of these variables
to be significantly associated with the response; but, the type of controls and geographic
location were significantly associated with the log-relative risk when they were both
in the model. Studies using population-based controls had higher relative risks than
those using hospital-based controls (P=0.002), and both European and Asian studies
had higher relative risks than North American studies (P=0.006 and 0.05, respectively).
Interactions between all four variables were examined and no significant interactions
were found.
DISCUSSION
This quantitative summary of the published literature on the risk of breast cancer
associated with dietary fat intake suggests that a higher intake of fat is associated
with an increased risk of breast cancer. The summary relative risk for all studies
that examined nutrient intake is calculated from the results of cohort and case–control
studies, and in contrast to our previous publication, the results from these different
designs for epidemiological investigation gave very similar results. This conclusion
is based on 45 studies that contain a total of 25 015 cases of breast cancer and 580 000
control or comparison subjects. The summary risk estimates from all case–control and
cohort studies were very similar, although neither was statistically significant.
The combined estimate, however, was statistically significant as was the summary risk
estimate for cohort studies that met 80% or more of the quality standards.
Other differences between our earlier analysis and the present findings are summarised
in Table 3
Table 3
Summary risks for 1993 and present meta-analyses
Fat/food type
Variable
1993 revised analysis
Present analysis
Total fat
Number of studies
Case–control
16
31
Cohort
7
14
Combined
23
45
All studies
Case–control
1.26 (1.10–1.45)
1.14 (0.99–1.32)
Cohort
1.02 (0.80–1.31)
1.11 (0.99–1.25)
Combined
1.17 (1.03–1.32)
1.13 (1.03–1.25)
High quality
Case–control
1.45 (1.15–1.84), N=5
1.22 (0.91–1.63), N=13
Cohort
1.07 (0.93–1.24), N=6
1.13 (1.04–1.23), N=13
Combined
1.23 (1.06–1.43), N=11
1.17 (1.03–1.32), N=26
Country
North America
1.03 (0.85–1.24), N=10
1.04 (0.91–1.18), N=14
Europe
1.44 (1.30–1.60), N=8
1.17 (1.02–1.34), N=21
Asia
—
1.42 (0.87–2.30), N=6
Other
1.13 (0.84–1.51), N=5
1.20 (0.93–1.56), N=4
Types of fat
Saturated
Number of studies
11
22
Summary risk, all studies
1.21 (0.98–1.49)
1.18 (1.04–1.34)
Monounsaturated
Number of studies
15
24
Summary risk, all studies
1.19 (1.01–1.40)
1.10 (0.95–1.28)
Polyunsaturated
Number of studies
15
24
Summary risk, all studies
0.97 (0.83–1.13)
0.92 (0.78–1.09)
Food types
Meat
Number of studies
17
31
Summary risk, all studies
1.20 (1.07–1.34)
1.17 (1.06–1.29)
Milk
Number of studies
10
16
Summary risk, all studies
1.22 (0.91–1.64)
1.12 (0.88–1.43)
Cheese
Number of studies
6
11
Summary risk, all studies
1.32 (0.90–1.93)
1.26 (0.96–1.66)
. (The software used for our earlier analysis contained a programming error, which
had a small influence on the results, but did not affect the conclusions of the paper.
The table shows the corrected values of the published results.) Compared to the 1993
analysis, which was based on 23 studies, the present analysis based on 45 studies,
gave smaller odds ratios for case–control studies, and slightly larger relatives risks
for cohort studies. Neither study design gave significant estimates of risk in the
previous or present analysis, but the combined estimates were significant in both.
Among studies of higher quality, the estimate from cohort studies was significant
in the present results, while the estimate from case–control studies was no longer
significant. Strong evidence of substantial variation in results according to the
geographical location of the study was present in both analyses. Point estimates of
risk associated with fat intake were highest in Asia, lowest in North America and
intermediate in Europe, findings that may be related to differences in the underlying
variation in dietary fat intake in the populations in these regions.
Different studies partitioned fat intake in different ways, but an examination of
the results obtained suggested that partitioning by tertiles, quartiles or quintiles
gave very similar estimates. Among the major subtypes of fat, we found that saturated
fat was significantly associated with breast cancer risk in both case–control and
cohort studies, and that results were significant in the present but not the previous
analysis. Mono- and polyunsaturated fat were not significantly associated with breast
cancer in either case–control or cohort studies, or in summaries of all studies in
the present analysis.
Our conclusion about the relationship of dietary fat to risk of breast cancer is supported
to some degree by studies of specific foods. Of the studies that examined intake of
foods in relation to risk of breast cancer, the largest number had examined meat consumption,
which was significantly associated with breast cancer risk in this meta-analysis,
in the overall estimate of risk and in both case–control and cohort studies considered
separately. Fewer studies examined milk and cheese intake in relation to breast cancer
risk, and although point estimates for the summary relative risks of all studies were
greater than unity for both foods, neither was statistically significant.
Although this meta-analysis was based on published results, we were able to generate
results similar to those of a previously published combined analysis of a subset of
the cohort studies examined here. The differences between the results obtained in
case–control and cohort studies might be attributable to recall bias, but as similar
results were found here in the two research designs it is not likely that this potential
source of bias has a major influence.
The biological plausibility of an association between dietary fat and breast cancer
risk is shown by the effect that dietary fat intake has on mammary carcinogenesis
in animals (see, for reviews, Freedman et al, 1990; Welsch, 1994),which appears to
be distinct from the effect of calories, as well as by the known biological effects
of fat. Potential mechanisms include the generation from fatty acids of eicosanoids,
the generation of free radicals and mutagenic compounds such as malondialdehyde by
lipid peroxidation and the modulation of genes that are involved in mammary carcinogenesis
(Cohen et al, 1986).
Despite the strong evidence that breast cancer is influenced by environmental factors,
and the consistency of the ecological analyses suggesting that dietary fat is one
of these factors, epidemiological investigations of the relationship of dietary fat
to breast cancer incidence based upon the measurement of dietary intakes in individuals
with case–control and cohort studies, have given much less consistent results. However,
in considering these results, and those given above in our quantitative summary of
the published literature, we need to consider the effects of the relative homogeneity
of fat intake within populations and error in the measurement of fat intake, both
factors that are expected to attenuate any true association between dietary fat and
breast cancer.
For example, homogeneity is shown by the range across quintiles of total fat intake
in the Nurses Health Study (Willett et al, 1987), a large cohort study in North America,
which was only 32–44% of calories, compared to the international range of 15% or less
to more than 40% of calories. This narrow range of fat intake is expected, from international
data, to be associated with a relative risk of only 1.4 in the highest quintile of
fat intake relative to the lowest. When the measurement error known to be associated
with the food frequency questionnaire used is taken into account, this estimate of
the relative risk is reduced to 1.16, a figure that is close to the summary relative
risk of our meta-analysis (Prentice et al, 1988).
Measurement error in the food frequency questionnaires used in most studies may lead
to overestimation of the range of intakes and may also lead to attenuation of risk
(Prentice, 2003). The cohort study of Bingham et al (2003) showed a small and nonsignificant
increase in the risk of breast cancer when fat intake was estimated from a food frequency
questionnaire, but a larger and significant increase when estimated from food records
obtained from the same subjects.
Experimental trials, in which the range of fat intake is increased beyond that seen
in most Western populations, are a means of overcoming the limitations of observational
epidemiology that arise from homogeneity of intake and measurement error, and provide
the strongest evidence available concerning a causal relationship of dietary fat intake
to breast cancer risk. Further, such trials are the only means available to determine
whether breast cancer risk in high-risk subjects can be reduced by changing dietary
fat intake.