Download Weight gain in relation to cancer risk

Weight gain in relation to cancer risk
Thesis Sandra van den Broek, Augustus – November 2008
Supervised by A. May, Julius Centre
INTRODUCTION: Obesity has been recognized as an increasing problem in the western
countries. Obesity, determined as a single measurement of weight (and height) at a certain
moment, has already been associated with an increased risk for several cancers. Nevertheless,
weight change seems to be a more appropriate measure for adiposity in humans.
AIM: Systematically review the effect of weight gain (throughout life) on the risk of several
types of cancers.
MATERIAL AND METHODS: We selected 58 studies, which investigated the relation of
weight gain with breast cancer or/and ovarian cancer or/and endometrial cancer or/and
prostate cancer or/and colorectal cancer. Furthermore, of all the studies we evaluated the
study design, the characteristics of the study populations, the method of exposure assessment,
specific cancer outcomes, confounding factors and effect modifiers.
RESULTS: The studies discussed differed with respect to study design, sample size and
confounding factors (within a certain cancer outcome). The majority of studies assessed
weight gain information retrospectively (by recall), and were entailed by numerous biases.
Only a few studies assessed weight gain prospectively. However, this studies only
investigated the effect of short-term weight gain.
Increases of risk for post-menopausal cancers in relation to weight gain were reported in
many studies, however only in non-HRT users. Studies which also stratified on menopausal
status, did not find this effect in pre-menopausal women. For the other cancers discussed, no
consistent increases or decreases in risk were found.
CONCLUSION: Weight gain seems to increase the risk for post-menopausal breast cancer.
In contrast, weight gain does not seem to change the risk for pre-menopausal breast cancer.
Ovarian cancer, endometrial cancer, prostate cancer and colon-rectal cancer were not studied
as extensively as breast cancer in relation to weight gain. Before drawing any conclusions
about these type of cancer, more large, prospective studies are needed.
Introduction
In the last years obesity has been recognized as an increasing problem. In the world
there are more than 1 billion people overweight, of which 300 million are severely obese1.
When people have a Body Mass Index (BMI) over 30, it is called obesity. Obesity is known
as a major contributor to the burden of chronic diseases in the world, such as cardiovascular
diseases and diabetes2. Obesity as a risk factor for cardiovascular diseases is known for many
years, however, more recently many studies have been performed investigating the relation
between cancer and obesity3. Obesity, determined by a single measurement of weight (and
height) at a certain moment, has been shown to be associated with an increased risk of
postmenopausal breast cancer, oesophagus cancer, pancreas cancer, colorectal cancer,
endometrial cancer and kidney cancer 3. Some biological mechanisms have been suggested
underlying the associations of different cancers and obesity. Although the most mechanisms
are not fully understood, it seems to be there is evidence for the relation between cancer risk
and obesity 4;5.
Obesity as a risk factor for cancer is studied extensively, because of the possibility of
modifying this risk factor. However, the question arises whether obesity, determined by a
single measurement of weight (and height) at a certain moment (weight and BMI), is really a
good measure of adiposity. Firstly, adiposity is the presence of adipose tissue, and weight and
BMI might not reflect this correctly. People can have the same weight or BMI, but have
differences in amount of adipose tissue. Weight gain during adulthood reflects an increase in
adipose tissue, and is probably a much better measure adiposity. Secondly, when measuring
obesity at one point of time, the influence of long-term weight patterns during life cannot be
taken into account. When measuring weight gain during life, periods of sensitivity to
adiposity can be studied. Weight change patterns and time periods of different biological
relevance can then be identified6;7.
Taken together, weight gain is an interesting and appropriate measure to study
adiposity in relation to cancer risk. The World Cancer Research Fund project (2007) already
suggested a probable association with post menopausal breast cancer8. In this review we will
give an overview of studies determining the association of cancer risk and weight gain. We
will determine the cancers where a possible association with weight change is suggested by
the biological mechanism, and where at least two studies are addressed to the subject. The
cancers we will discuss are the hormone-related cancers (breast cancer, ovarian cancer,
endometrial cancer and prostate cancer) and colorectal cancer. Furthermore, we will include
(new) studies, not taken into account in the World Cancer Research Fund project (2007)3.
With this review, we aim to further elucidate the relation of cancer risk and weight change.
When knowing more about weight change as a risk factor, advice can be given with regard to
weight change during life. This knowledge can be incorporated in public health guidelines for
cancer prevention.
Materials and Methods
For our study selection we selected all publications of original studies concerning the
relation between weight change and cancer risk. Up to Augustus 2008 we searched the
electronic database of PUBMED (MEDLINE) for potential relevant studies. The following
free text keywords were used: ‘cancer risk’, ‘weight change’, ‘cancer’, ‘weight gain’ in
combinations. We selected studies that were published after 1990, and could be purchased
through PUBMED. Only the cancers types were more than two publications have been
addressed to the relation with weight gain were included in the current review leading to the
exclusion of lung cancer, thyroid cancer, renal cell carcinoma and oesophagus cancer. The
cancers discussed are the hormone-related cancers (breast cancer, ovarian cancer, endometrial
cancer and prostate cancer) and colorectal cancer. Criteria for inclusion of the studies were
that they were written in English, to contain information about how the exposure variable
(weight gain) was assessed and that they considered cancer morbidity or mortality as an
outcome. With this criteria, we included 57 studies for our review (breast cancer, 28; ovarian
cancer, 6; endometrial cancer; 5, prostate cancer; 7, colorectal cancer; 4, all cancer/several
separate cancers; 6) . Note that weight loss in relation to cancer risk is not taken into account
in this present review.
Results
Weight gain and cancer risk
Many studies have been performed determining the association between weight gain
and cancer risk. The majority of the studies focus on the relation of breast cancer and weight
gain. Only few studies determined the relation between ovarian cancer, endometrial cancer,
prostate cancer and colorectal cancer, and weight change.
In this review, the studies differ extensively between each other, so we will list some
of the major differences between studies. Firstly, we will discuss the different cancer sites and
their relation to weight gain separately. This is because associations between weight gain and
different cancer types might differ. Secondly, differences in time in which the weight gain has
occurred will be taken into account. Weight gain during different time periods might have
different effects on the association with cancer risk. Most studies performed so far, only
investigated weight gain during adult life; i.e. from around age 20 to the age at study entry.
Some other studies also determine short-term weight gain or weight gain during a specific
period of life. Lastly, the way the weight change information is assessed, also differs between
the studies. Most studies gathered the information retrospectively, which might be a source of
extensive recall bias. Only a few studies assessed the weight gain prospectively.
Total cancers
Most studies addressing weight change in relation to cancer risk, only use one type of
cancer as an outcome. Six studies also addressed “all cancer” morbidity or mortality. This
were all cohort studies, of which four studies assessed weight gain prospectively. The two
studies9;10 which assessed weight change retrospectively, both report only cancer mortality
and found an increased risk in cancer mortality in relation to adult weight gain (resp. RR
2.44; CI 95% 1.71–3.46, p-trend <0.001 and RR 1.5; CI 95% 1.1–1.9, p-trend 0.009). The
other four studies11-14 assessed the weight gain prospectively, and focussed on short term
weight gain (1-16 years). In contrast, these studies did not find any increased risk for cancer
mortality11;12 or morbidity13;14 (see Table 1).
Breast Cancer
Breast cancer and long-term adult weight gain
Breast cancer is the most prevalent hormonal cancer in women15. Far out the most
studied cancer in relation to weight change, is breast cancer 13;16-43. All these studies assessed
weight change retrospectively, except one13. This study determined the relation of breast
cancer with short-term weight change and considered other cancers as an outcome.
Furthermore, most studies only considered post-menopausal breast cancer as an
outcome16;18;20;23;27-30;35;40-43, probably because previous evidence showed no association
between pre-menopausal breast cancer and obesity3.
Far out the most used measure of weight change is long-term adult weight gain. The
majority of the cohort studies addressing the subject of post-menopausal breast cancer and
adult weight gain, found an increased risk for post-menopausal breast cancer16;18;20;26;27;29;42;43.
The increased relative risks for post-menopausal breast cancer in relation to adult weight gain
vary extensively between the studies (see Table 2). In addition, Morimoto et al. 29 also
stratified by age of diagnosis in their analysis. Also for post-menopausal breast cancer
diagnosed in younger women (between the ages 50 and 69), an increased risk in relation to
adult weight gain was reported (age 50-59: RR 2.50; CI 95% 0.71–8.74, p-trend 0.007 and
age 60-69: RR 4.42; CI 95% 1.35–14.44, p-trend 0.001). However, when the age of diagnosis
of post-menopausal breast cancer was between 70 and 79, no increased risk was reported
anymore (RR 0.81; CI 95% 0.33–1.96, p-trend 0.99). Several cohort studies which found a
positive association of adult weight gain and post-menopausal breast cancer, also stratified on
HRT use. These studies only found the increased risk in non-HRT users16;18;20;27;29. Feigelson
et al.43 investigated the effect of adult weight gain in women who never used HRT. In this
study, they investigated on the risk of different types, histology’s (receptor status),
localizations and grades of post-menopausal breast cancer. The authors reported an increased
post-menopausal breast cancer risk in relation to adult weight gain, for all different histology
types of breast cancer, except for estrogen or progesterone receptor negative breast cancers
and breast cancers which were negative for both receptors (see Table 2). Only one cohort
study addressing the relation between post-menopausal breast cancer and adult weight gain,
did not find an significant increased risk for post-menopausal breast cancer in relation to adult
weight gain. Van den Brandt et al.44 found inconsistent increases in risk, with no significant
trends (see Table 2).
Pre-menopausal breast cancer risk in relation to adult weight was investigated only
sporadically and just one cohort study was addressed to this subject. Lahman et al.27 did not
find any risk for pre-menopausal breast cancer in relation to adult weight gain (see Table 2).
Besides cohort studies, also many case-control studies have been performed
determining the relation between breast cancer risk and adult weight change17;19;21;22;24;25;28;3034;36-38;45
. Results of the case-control studies are less consistent, however, most case-control
studies again showed an increased risk for post-menopausal breast cancer in relation to adult
weight gain21;22;24;28;31-33;37;38. Hirose et al.24 stratified on age of diagnosis and did not see any
increased risk for the ages of diagnosis 30-39, 40-49 and 50-59. However, when the diagnosis
was over age 60 (post-menopausal breast cancer), an increased risk was seen for breast cancer
in relation to adult weight gain (RR 2.11; CI 95% >1, p-trend < 0.001). Rosenberg et al.30
showed an increased risk for both estrogen and progesterone receptor positive postmenopausal breast cancers but not for receptor negative post-menopausal breast cancers.
Likewise, Han et al. 22reported an increased risk for the estrogen or progesterone positive
breast cancer only.
Several of the case-control studies also stratified on menopausal status in their
analysis21;22;24;31-33;37;38. The majority of these studies found an increased risk for postmenopausal breast cancer in relation to adult weight gain, whereas no relation was seen for
pre-menopausal21;22;24;28;31-33;37;38. Ziegler et al. 41 included women of age 20 to 55 in their
study. They stratified on age of diagnosis in their analysis. Only for breast cancers diagnosed
over age 50, an increased risk was shown in relation to adult weight gain (RR 1.63; CI
95%0.72-3.71, p-trend 0.04). Again they did not report an increased risk for breast cancer
diagnosed between the ages 30 and 50 (presumably pre-menopausal breast cancer) (age 3040: RR 0.77; CI 95% 0.32-1.89, p-trend 0.43 and age 40-50: RR 1.35; CI 95% 0.65-2.82, ptrend 0.43). In addition, Verla-Tebit et al.36 also did not found an changed risk of premenopausal breast cancer in relation to weight gain. Even more, Coates et al. 17 showed a
decreased risk for breast cancer in relation to adult weight gain in young women (less than 44
years of age at diagnosis of breast cancer). When stratifying on tumor grade, the decrease in
risk was restricted to early stage, lower grade breast cancer types (see Table 2).
One of the case-control studies addressing the subject of breast cancer and adult
weight change did not distinguish between pre- and post-menopausal breast cancer19. This
study reported an increased risk for breast cancer in relation to adult weight gain.
Kotsopolous et al.25 included only women with a BRCA1 or BRCA2 mutation and reported
no increased risk for breast cancer in relation to adult weight gain overall and also when
stratifying on age of diagnosis (age of diagnosis between 30 and 39 or age of diagnosis over
40)).
Almost all the studies investigating both pre-menopausal breast cancer risk and postmenopausal breast cancer risk, found an difference in risk for both types. So did Wenten et
al.37 and Slattery et al. 32, however they reported that an increased risk for breast cancer in
relation to weight gain was independent of menopausal status for Hispanics.
Breast cancer and periods of weight gain
Next to determining adult weight change, it is interesting to determine time periods or
patterns of weight gain which might have different biological relevance. Several cohort and
case-control studies addressing weight change in relation to breast cancer risk, also took into
account different weight change periods throughout life 16;18;19;22;23;29. Ahn et al.16 divided the
weight gain during adult hood in different periods of time. Weight gain in the early
reproductive years (18-35 years of age), weight gain in the late reproductive years (35-50
years of age) and weight gain during the peri- and post menopausal time (50 years to current
age) all resulted in an increased risk for post-menopausal status in non-HRT users only
(relative risk of resp. 1.89 (1.11-3.22), 2.29 (1.51-3.46), 1.89, (1.20 – 2.79) for 30 to 39.9 kg
of weight gain, versus stable weight (-1.9 – 1.9 kg)). Likewise, Han et al.22 divided weight
gain throughout life in ten-year intervals. An increased risk of postmenopausal breast cancer
was associated with weight gain in the age intervals 30–39 (OR 1.72, 95% CI 1.14– 2.59),
40–49 (OR 1.92, 95% CI 1.17–3.15) and 60–69 (OR 1.94, 95% CI 1.21–3.10). After
adjustment for total adult weight gain (20 years of age to current age), odds ratio’s were
attenuated. On the other hand, Eng et al.19 did not found an increased risk for postmenopausal
breast cancer in relation to weight gain during the age period 20 to 30 years of age.
Nevertheless, they reported that women who gained more than 11 kg during the peri- and
post-menopausal years experienced a 1.62 times higher risk than women whose weight
remained unchanged. Similarly, Eliassen et al.18 showed that women who gained more than
10 kg of weight after menopause compared with weight maintenance, were at increased risk
for post-menopausal breast cancer (RR. 1.18; 95% CI, 1.03-1.35). In addition, Morimoto et al.
29
showed a non-significant increased risk for women with postmenopausal weight gain (see
Table 2).
Harvie et al. 23 investigated different weight change patterns and their influence on
post-menopausal breast cancer risk. The most frequent observed pattern of weight change
over time was a consistent increase, and these women were observed to have the highest rates
of post-menopausal breast cancer compared to other patterns of weight change. Weight gain
from age 30 to age 50 followed by weight loss, was related to a lower risk. Also women who
gained weight from age 18 to 30, but lost weight from age 30 to the menopause, experienced
risk reductions. The lowest risk groups were women who maintained or lost weight during
these three age intervals (see Table 2).
Breast cancer and short-term weight gain
Furthermore, only one study assessed the effect of short-term weight change on the
risk of breast cancer. Rapp et al. 13 determined weight gain during an average period of 6.9
years prospectively. No changed risk was seen for breast cancer in relation to short –term
weight gain (RR 0.87; CI 95% 0.61–1.24, p-trend 0.63). Rapp et al. 13 did not stratify on
menopausal status and did not adjust for specific confounders of breast cancer such as parity
and family history of breast cancer (see Table 2).
Ovarian cancer
Ovarian cancer and long-term adult weight gain
Only a few studies have been addressed to the relation of ovarian cancer and adult
weight gain46-51 . Four of these studies, one case-cohort study51, and three case control
studies48-50, did not find any significant change in risk in relation to adult weight gain. The
only cohort study 46 addressed to this subject found a decreased risk of ovarian cancer in
relation to adult weight gain (RR 0.61; 95% CI 0.40-0.95, p-trend 0.006). However, after
using a two-year time lag the risk attenuated (RR 0.63; 95% CI, 0.40-1.01, p-trend 0.02). On
the other hand, Greer et al.47 conducted a case-control study, and found an increased risk for
ovarian cancer in relation to adult weight gain (OR 1.38; 95% CI, 1.04-1.85, p-trend 0.11).
When stratifying for parity, they only found an increased risk for the nulliparous women (OR
3.73; CI 95%,1.88-7.42, p-trend 0.001), but not for the parous women (OR 1.09; CI 95%,
0.78-1.51, p-trend 0.99) (see Table 3).
Ovarian cancer and short-term weight gain
One study prospectively assessed the effect of short-term weight change on the risk of
ovarian cancer. Rapp et al. 13 reported an increased risk for ovarian cancer in relation to 7 year
period of weight gain (RR 2.48; CI 95% 1.05-5.85, p-trend 0.03). This study did not adjust for
specific confounders of ovarian cancer such as oral contraceptive use and parity (see Table 3).
Endometrial cancer
Endometrial cancer and long-term adult weight gain
Five studies investigated the relation of endometrial cancer and adult weight gain 52-56. Four of
these studies, one cohort53, one case-cohort46 and two case-control studies54;56, found an
increased risk for endometrial cancer in relation to adult weight change. Though, Terry et
al.53, who conducted the cohort study, found an increase in risk when they adjusted for weight
at age 25 (RR 2.1; CI 95%, 1.3–4.71). However, when they corrected in their analysis for
weight at the moment of enrolment in the study, this effect disappeared (RR 1.0; CI 95%, 0.5–
2.0). Of the other studies which found an increased risk, two studies corrected for weight or
BMI at age 2052;56 and one study corrected for recent BMI54. Xu at al.56 stratified on
menopausal status in their analysis. For both groups they found an increased risk (premenopausal women (OR 2.8; CI 95 %,1.4–5.7), post-menopausal women (OR 3.1; CI 95%,
1.8–5.5)). On the other hand, Weiderpass et al.55 conducted a case-control study and did not
find a significant increased risk (OR 1.4; CI 95%, 0.8-2.3) (see Table 4).
Endometrial cancer and periods of weight gain
Xu at al.56 also investigated weight gain during several different periods of time
throughout life. For pre-menopausal women they determined weight gain during the periods
between age 20 to 30 and 30 to 40. For both periods they found increased risks for premenopausal breast cancer (resp. RR 1.7; CI 95% 1.1–2.6, p-trend < 0.01 and RR 1.9; CI 95 %
1.2–3.1, p-trend < 0.01). For postmenopausal women they assessed weight gain during the
periods between age 20 to 30, 30 to 40, 40 to 50 and 50 to 60. Again they found increased
risks for also post-menopausal endometrial cancer (resp. RR 1.4; CI 95% 1.0–2.0, p-trend <
0.06 and RR 1.6; CI 95 % 1.1–2.3, p-trend < 0.01 and RR 2.0; CI 95% 1.3–2.9, p-trend < 0.01
and RR 1.6; CI 95 % 1.0–2.6, p-trend < 0.01). Thus, no different effects for different weight
gain periods throughout life in relation to endometrial cancer risk were reported (see Table 4).
Endometrial cancer and short-term weight gain
One study assessed the effect of short-term weight change on the risk of endometrial
cancer. Rapp et al.13 reported no risk change for endometrial cancer in relation to 7 years
weight gain (RR 0.72; CI 95% 0.33-1.57, p-trend 0.23). This study did not adjust for specific
confounders for endometrial cancer in their analysis, such oral contraceptive use and parity
(see Table 4).
Prostate cancer
Prostate cancer and long-term adult weight change
In older men, prostate cancer is one of the most prevalent cancers57. A total of seven
large studies have been conducted in the relationship between adult weight change and
prostate cancer risk58-64. All studies did not find significant changes in risk of prostate cancer
in relation to adult weight gain58-64. Although, a decreased risk of prostate cancer was found in
two sub-analysis of two studies61,64. Littman et al.61 divided the outcome in aggressive and
non-aggressive prostate cancers and showed a decreased risk for the non-aggressive prostate
cancers only (non-aggressive prostate cancers (RR 0.67; CI 95 %, 0.47- 0.95, p-trend 0.04),
aggressive prostate cancers. (RR 0.94; CI95 %, 0.61-1.5, p-trend 0.92). On the other hand,
Wright et al.64 found an increased risk of prostate cancer mortality (OR 2.98, CI 95%, 0.99–
9.04, p-trend 0.009), but did not find any effect prostate cancer morbidity (see Table 5).
Prostate cancer and periods of weight change
One of the studies 58 addressed to the subject of weight change and prostate cancer
risk, investigated next to long-term adult weight gain, weight gain between age 50 and the
current age in men of 65 and older. Cerhan et al.58 did not find any change in risk for prostate
cancer in relation to the adult weight gain (RR 0.7; CI 95% 0.4-1.4, p-trend 0.3), however,
they found an increase in risk for prostate cancer in relation to the weight gain from age 50 to
current age (RR 1.3; CI 95% 0.7-2.2, p-trend 0.04) (see Table 5).
Prostate cancer and short-term weight change
Three prospective cohort studies investigated the relation of short-term weight gain
and prostate cancer risk. Rodriguez et al.62 determined weight gain during the last ten years
and reported no risk for overall prostate cancer (RR 0.89, CI 95%, 0.79-1.00), as well for nonaggressive, aggressive, Stage D or fatal cases of prostate cancer (resp. RR 0.89; CI 95%,
0.78-1.02, RR 0.88; CI 95%, 0.71-1.08 and RR 0.97 ; CI 95%, 0.71-1.33). Likewise, Samanic
et al.14 observed no risk for prostate cancer in relation to 6 year weight gain (RR 0.75; CI 95%
0.49-1.15, p-trend >0.5). Oppositely, Rapp et al.13 also determined weight gain over an
average period of 6.9 years, and reported a decreased risk for prostate cancer in relation to
short-term weight gain (RR 0.43; CI95% 0.24-0.76, p-trend 0.05)13. Samanic et al.14 and
Rapp et al. 13 both did not adjust for specific confounders for prostate cancer in their analysis,
such as family history of prostate cancer (see Table 5).
Colorectal cancer
Colorectal cancer and long-term adult weight change
Colorectal cancer was only investigated four times in relation to adult weight gain65-68.
In addition, two studies have been performed investigating the relation of adult weight gain
and adenomas69;70. Adenomas are precursor lesions for the majority of invasive colon cancers.
Tamakoshi et al.66 conducted a cohort study among men and women, and considered colon
cancer mortality as outcome. For women, they only included females who where lean at begin
adulthood (BMI < 22) and found an increased risk for colorectal cancer in relation to adult
weight gain (RR 3.41; CI 95%, 1.29–9.02), however, for men a decrease of risk was reported
(RR 0.62, CI 95%, 0.08–4.61). Russo et al.65 also included men and women in their casecontrol study and found a for both sexes a decrease in risk for colorectal cancer in relation to
long-term weight gain (men (OR 0.75, CI 95%, 0.63–0.88, p-trend <0.001), women , (OR
0.66 CI 95%, 0.54–0.80, p-trend <0.001)). However, they only took into account weight gain
from age 30 years or 50 years to current age, and not total adult weight gain from age 20 to
baseline. Furthermore, Trentham-Dietz et al68 performed a case-control study with only
female participants, and found an increased risk for all large bowel cancers in relation to adult
weight gain. When stratifying on different locations of the bowel, the increased risk was only
still present for colon- and left colon cancers, but not for rectal cancer and right colon cancer.
Also Thygesen et al.67 determined adult weight gain in relation to colorectal cancer in a cohort
study, but did not find any changed risk (resp. RR 1.41; CI 95%, 0.83–2.41) (see Table 6).
Colorectal cancer and short-term weight change
Three prospective cohort studies were conducted addressing short-term weight change
in relation to colorectal cancer risk. Thygesen et al. 67 used combined data on weight change
between two consecutive questionnaires (weight change 1986–1988) in relation to the risk
over the next 2 years (colon cancer risk 1988–1990). They did a risk for colon cancer in
relation to short-time weight gain (RR 1.46, CI 95%, 0.86–2.50). Rapp et al.13 and Samanic et
al.14 investigated weight gain over an average period of respectively 6.9 and 6 years and did
not find a risk for colon cancer in relation to weight change. Rapp et al.13 stratified on sex,
but found no increased risk for both men and women. Samanic et al.14 only used male
participants in their study (see Table 6).
Discussion
In our review we discussed studies addressing the relation of weight gain and cancer
risk. Weight gain reflects an increase in adipose tissue, and is probably a much better
measure for adiposity than weight and BMI measured at a single moment in time. For most
cancer types, studies give inconsistent results about their relation with weight gain and often
only a small number of good studies have been performed. Whereas, for breast cancer it is
clear weight gain increases the risk of post-menopausal breast cancer, but not pre-menopausal
breast cancer. This increase in risk of post-menopausal breast cancer in relation to weight gain
is only present in non-HRT users.
Many hypothesis have been made understanding the relation between weight gain
(adiposity) and cancer. The link is thought to be mediated by the metabolic and endocrine
effects of adipose tissue. It is suggested that chronic hyper insulinemia plays an important
role. Chronic hyper insulemenia and insulin resistance (consequence of chronic hyper
insulemenia) are probably caused by increased release of free fatty acids, resistin, tumour
necrosis factor-a and on the other hand decreased release of adiponectin, caused by excess
body weight. This chronic hyper insulemenia is thought to contribute to tumour development
via several pathways. These pathways are shown in figure 1. It should be mentioned that
because of the differences in etiology of the different types of cancer, for each type different
underlying mechanisms/pathways might be important in relation to weight gain. In addition,
not much is still known about these pathways, but they are thought to be highly mediated by
enhanced levels of cytokines and adipokines through the excess adipose tissue, which can
lead to subclinical inflammatory states and via this increase tumour development4-6.
Discussing all the pathways goes beyond the scope of this review. Here we will discuss only
the hormonal pathway since the majority of cancers discussed in relation to weight gain in this
review were hormonal cancers. Enhanced hormone secretion caused by excess body weight
seems to be one of the major factors which might influence increased hormonal cancer risk in
relation to adiposity. Excess adipose tissue enhances the synthesis and bioavailability of many
hormones (such as estrogens and androgens) via several different ways. Adipose tissue
produces enzymes, which stimulate the formation of estrogens from androgenic precursors.
Also insulin lowers concentrations of certain hormone-binding globulin, which have a high
binding affinity for hormones. This results in an increase in the bio availability of estrogens.
Also high insulin concentrations increase the synthesis of androgens by the ovaries and also
the adrenal gland. Moreover, hormones are known to play a role in regulating cell
differentiation, proliferation and apoptosis. This might increase the risk of cancer in tissues
that are sensitive to hormones 4-6;71.
Figure 1. Proposed biological mechanisms linking adiposity with cancer. Abbreviation used
in the figure; GH = growth hormone, IGF = insulin-like growth factor, IGFBP = insulinlike growth factor binding protein, GHBP = growth hormone binding protein, NF-kB =
nuclear factor kB, IKKb = IkB kinase ß, PPARs = peroxisome proliferator-activated
receptors, FFA = free fatty acids, TNFa = tumor necrosis factor. Figure from article of
Renehan et al. 5 , adjusted by A.J. van den Broek.
Many epidemiological studies have been conducted providing more evidence for the
presence of an association between cancer and adiposity. In this review we discussed
epidemiological studies addressing the subject of cancer risk and weight gain.
The studies investigating the relation of weight gain and cancer risk differ extensively
between each other. The study design is an important difference. Both cohort studies and
case-control studies have been discussed in this review. In a cohort study a sufficient followup time is needed to gather enough cases for your analysis, certainly when the cancer is rare.
Moreover, the completeness of the follow-up should also be taken into account. The size of
the study is of course important. Larger studies can more easily detect little effects, with
smaller confidence intervals. The quintiles of weight gain used differ between the studies.
Some studies only use small changes of weight gain, while others compare large differences.
This can affect the comparing of different studies. Also the time period over which the weight
gain occured differ between the studies. Most studies look at long-term adult weight gain
(over 30 years), however, some studies look at short-term weight gain of maximum 20 years.
If both time periods of weight gain have the same effect on cancer risk can be discussed. It
should be taken into account that weight change patterns throughout whole life might have an
effect on the relation of the short-term weight gain and cancer formation, however, short-term
weight gain might be more interesting regarding advice for public health. The way the weight
gain is assessed differ extensively between all the studies. Most of the studies discussed in
this review asses the weight gain retrospectively (i.e. recalled weight at age 20). The majority
of this retrospective studies investigate only long-term adult weight gain in relation to cancer.
Although validation studies72;73 have been conducted showing that recalling weight in earlier
life is a appropriate way to assess the weight gain, it still might be a source of recall bias.
Only a few studies assessed the weight gain prospectively11-14;62;67, but these studies only
look at short term weight gain. Furthermore, it should be noted that confounding is an
important subject for these studies. Which confounders should be adjusted for is dependent on
the investigated cancer. Due to lack of information, some studies might not adjust for all the
potential confounders. Also an important confounder in weight gain and cancer research,
independent of the type of cancer, is the potential of a different effect of weight gain in lean
women and in more heavy women. Adjusting for weight at the start of the weight gain period
should be considered because this reflects differences in start weight of participants, however,
some studies might adjust for weight at the end of follow-up. We will not discuss all these
aspects for every study, but we will look at the overall reliability of the epidemiological
evidence. In this review we discussed the results for each cancer type separately, because of
different relations between specific type of cancers and adiposity. However, some studies
looked at several cancer types together.
Total cancers
All cancer mortality in relation to adult weight gain was only investigated in two
studies9;10 which assessed the adult weight gain retrospectively. These studies showed a clear
significant increased risk, however, both studies are potential sources of bias because of
recalling of the weight gain. The studies were of large size, had sufficient cases in their
analysis and a long follow-up (median follow-up of 24 years and 17 years). However , they
only included young women in their study. In addition, four other studies11-14 addressing the
subject of weight gain and cancer morbidity or mortality, did not find any increased risk.
These studies had less potential for recall bias because of prospective weight gain assessment.
It should be mentioned these studies only investigated short term weight gain, which might
have other effects than adult weight gain. Jeffreys et al.11 looked at weight change over a
period of 16 years and had a follow-up of 35 years, but included only a small number of
subjects. Maru et al.12 only investigated weight gain over one year, which might be too short
to eliminate influences of weight change patterns during life. Rapp et al.13 and Samanic et
al.14, both large studies with long follow-up periods (resp. median follow-up of 8 years and 28
years), looked at weight gain over about six years. Because of the selected study populations
and differences in weight change periods it is hard making any conclusions about weight gain
in relation to cancer risk. Furthermore, these studies take all cancer types together, though, all
cancers might have different biological mechanisms underlying their associations with risk
factors4;5. Some cancers can be affected by weight gain, however, others might not. In
addition, adjustment for specific confounders for separate cancers in these analysis is often
not done. In conclusion, it might be more appropriate to separate the different cancers for the
investigation of the effect of weight gain on cancer risk.
Pre- and post-menopausal breast cancer
Breast cancer is the most studied cancer in relation to weight gain. All the studies
investigating adult weight gain as the exposure in relation to breast cancer, assessed the
weight gain retrospectively. so were sensitive for recall bias. Post-menopausal was studied the
most in relation to adult weight gain. An increased risk was found for post-menopausal breast
cancer in relation to adult weight gain in almost all cohort studies16;18;20;26;27;29;42;43. These
were all large studies, with a long follow-up period. Only one cohort study did not find an
increased risk. Van den Brandt et al.35 analyzed their data with a case-cohort approach, so
was much smaller than the other cohort studies. In addition, also most case-control studies
showed an increased risk for post-menopausal breast cancer in relation to adult weight
gain21;22;24;28;31-33;37;38. Almost all these studies included a of large number cases and controls.
Unfortunately, no studies have been conducted in the relationship between weight gain and
post-menopausal breast cancer risk which asses the weight gain prospectively. These studies
will give more reliable results, because of the exclusion of the recall bias present in the studies
discussed here. Although, still there seems to be enough evidence supporting a relation
between weight gain and post-menopausal breast cancer risk. This has been shown in a large
number of studies with consistent results. This relationship of post-menopausal breast cancer
and weight gain might also be explained by an underlying biological mechanism. After
menopause, adipose tissue is the major source for the synthesis of estrogens (from androgenic
precursors); hormone levels are enhanced by excess adipose tissue74;75. Keys et al.76
performed a pooled analysis of nine studies. They showed that the risk of breast cancer
increases in post-menopausal women in with higher concentrations of circulating hormones.
Another study also investigating this, reported the same observations77. Also other
mechanisms are suggested (see figure 1), however, the hormonal mechanism is most
supported.
Previous evidence showed no association between pre-menopausal breast cancer and
obesity3. This might be explained by different effects of hormones pre- and post-menopausal.
However, the relation of adiposity and pre-menopausal breast cancer is not fully understood.
There is some evidence that pre-menopausal women with excess body weight have more
irregular and an-ovulatory menstrual cycles and because of that they a have decreased
exposure to estrogens and progesterone78. It should be taken into account that exclusion of
women with reported irregular menses and/or infertility did change the lack of association
between adult BMI and premenopausal breast cancer risk79.
Similar to the studies addressing obesity and pre-menopausal breast cancer3, all casecontrol studies we discussed in this review that were addressed to the relation of weight gain
and pre-menopausal breast cancer risk did not find any increased risk21;22;24;28;31-33;37;38. Most
case-control studies again had a sufficient number of cases and controls included. Only one
cohort study27 was addressed to this subject. This study was large, and had a sufficient (5.8
years) time of follow-up to included enough cases. Even more, Coates et al. 17conducted a
large case-control study which included over 1500 cases and found an decreased risk for premenopausal breast cancer in relation to adult weight gain. Again no study has been conducted
on the relationship between weight gain and pre-menopausal breast cancer risk which
assessed the weight gain prospectively. The only study which assessed the weight gain
prospectively in relation to breast cancer, was a cohort study13 which did not distinguish
between pre- and post-menopausal breast cancer. Rapp et al. 13 did not find any change in
risk. It should be noted that it was a large study with 8 years of follow-up. They determined
weight gain over an period of 7 years, which might have another effect than long-term adult
weight gain on the breast cancer risk. Also, they did not adjust for specific confounders such
as parity and age at menarche probably because of lack of information, however adjustment
for this confounders is important when investigating breast cancer as the outcome. Because of
the many studies which investigated the relation of breast cancer and weight gain, it seems
that different conclusions can be made about post- and pre- menopausal breast cancer in
relation to weight gain. Post-menopausal breast cancer risk is increased, however there is no
change in pre-menopausal breast cancer risk in relation to weight gain. Although many
studies which investigated these relations were well performed, only one study assessed the
weight gain prospectively but did not distinguish between pre- and post-menopausal breast
cancer. To even more support the evidence of the relations between breast cancer and weight
gain, more prospective studies should be done.
Only a small number of studies determined specific periods of weight gain throughout
life16;18;19;22;23;29, like peri-menopausal weight gain. No differences were seen in the studies
between specific periods. This might be due to the fact that stratification on weight gain
periods leads to smaller subgroups for the analyses. As a results, no conclusion can be drawn
about periods with more sensitivity for weight gain. Larger studies with better specified
periods of weight gain should be done to elucidate the different effects of specific periods of
weight gain.
Hormone replacement therapy (HRT) has already been linked to post-menopausal
breast through its influence on hormone levels. The underlying mechanism of the relation of
adiposity and breast cancer is thought to be mediated by hormones76;77. Different effects of
post-menonopausal breast cancer risk in relation to weight gain in HRT users and HRT nonusers, may be due to the higher estrogen levels from hormone replacement therapy than those
derived from adipose tissue in overweight women. This is the reason why many studies
addressing post-menopausal breast cancer and adult weight gain stratified on HRT (possible
effect modifier). Most of the studies taking HRT into account, were large cohort studies with
a long follow-up. All these studies found and increased risk of post-menopausal breast cancer
in relation to adult weight gain only in women who never used HRT16;18;20;27;29.This difference
in risk for post-menopausal breast cancer between HRT users and nonusers, can be explained
by the fact that current HRT use increases estrogen levels circulating in the blood. The use of
HRT may obscure the effect of adiposity (weight gain) on post-menopausal breast cancer80.
Three studies22;30;43 , one cohort and two case-control studies, also investigated postmenopausal breast cancer with respect to receptor status. All three studies showed an
increased risk for post- menopausal breast cancer with both the estrogen and progesterone
receptor positive, in relation to adult weight gain, but not for the estrogen or progesterone
receptor negative breast cancers and breast cancers which were negative for both receptors.
Furthermore, Han et al. 22 reported an increased risk for estrogen or progesterone positive
post-menopausal breast cancer. Although the stronger associations for receptor positive post-
menopausal with weight gain can be supported by the suggested hormonal mechanism of the
relation of post-menopausal breast cancer and adiposity 74;75, it is hard to draw any
conclusions out of only three studies. Certainly when taking into account the small numbers in
the subgroups of different types of tumors. In the future studies should pay attention to the
size of the subgroups of the studies when looking at specific sub types of cancers, because
often these groups are too small to detect any changes.
Ovarian cancer
Ovarian cancer in relation to weight gain was investigated in seven studies13;46-51. Six
of these studies assessed weight gain retrospectively, and investigated long-term adult weight
gain46-51. Four of these studies, of which three case-control studies, found no risk for ovarian
cancer in relation to adult weight gain 48-51. The other three studies found controversial
results13;46;47. The only cohort study46, consisted out of 249 cases with 20 years of follow-up,
reported a decreased risk. Greer et al.47 conducted a case-control study with over 700 cases,
and found an increased risk for ovarian cancer in relation to adult weight gain . The only
study which did assesed the weight gain prospectively found a significant increased risk for
ovarian cancer in relation to weight gain over a period of 7 years. However, in this study only
53 ovarian cancer cases occurred over a follow-up of 8 years, and they did not adjust for
specific confounders for ovarian cancer, probable because of lack of information, which
makes the results less reliable. Because differences in study design and the controversial
results, it is hard to make any conclusions about the risk of ovarian cancer risk in relation to
weight gain. However, an underlying biological mechanism between ovarian cancer and
adiposity suggest an association. Also for ovarian cancer the hormonal mechanism is believed
to be involved in the etiology of ovarian cancer in relation to adiposity81. To further elucidate
the relation between ovarian cancer and weight gain, more studies should be done, preferable
with prospectively assessed weight gain.
Endometrial cancer
Endometrial cancer in relation to adult weight change was also investigated only in a
few studies 13;52-56, of which only one was conducted prospectively 13. Most of these studies,
found an increased risk for endometrial cancer in relation to adult weight gain. This studies
consisted of one cohort53 study which included only twins, had a follow-up period of more
than 20 years and was very large. In this study the increase in risk was only present when
adjusting for weight at current age in the analysis, not when adjusting for weight at age 25.
Moreover, there was no consistency in adjustment for confounders in the studies. Some
studies corrected for weight at the start of the weight gain period, but some studies adjusted
for weight at baseline (current weight). Which is the appropriate adjustment is hard, however
it seems to be important to adjust for weight at the start of the weight gain period because of
elimination of the effect of the differences of weight at the start. However, it is surprising
such big difference is shown by Terry et al. 53 between both adjustments. In addition, this
study only adjusted for the confounder age next to the weight adjustment, however, more
confounders are considered to be important in the relation between weight gain and
endometrial cancer risk. The only study55 which did not reported any increased risk for
endometrial cancer in relation to adult weight gain was a case-control study which only
included post-menopausal women. Although, another other study56 which stratified on
menopausal status, found for both pre- and post-menopausal endometrial cancer and increased
risk. Furthermore, oone study 13 assessed weight gain prospectively. They found no risk for
ovarian cancer in relation to short-term weight gain over 7 years. Although the study included
100 cases over a follow-up period of 8 years, they did not adjust for specific confounders of
endometrial cancer such as oral contraceptive use and parity. The differences in results of the
short-term weight gain and adult weight gain studies might be explained by a different effect
of a short or long weight gain period on the endometrial cancer risk. Another study82 was
conducted determining weight gain in relation with uterine leiyomatoma (diagnosed by
hysterectomy), which is a non-malignant cancer precursor lesion of the endometrial. This
study included pre-menopausal black women and found an increased risk for uterine
leiyomatoma in relation to adult weight gain (retrospectively assessed) (RR 1.88; CI 1.113.05), and supports an association of endometrial cancer in relation to weight gain. In
summary, most of the studies report an increased risk of endometrial cancer in relation to
weight gain. Also, the underlying biological mechanisms suggest an association. Similar to
ovarian cancer, a hormonal biological mechanism is suggested to cause an association
between this cancer and adiposity83;84. However, the differences in study designs of the
studies determining weight gain in relation to endometrial cancer make it hard to draw any
conclusion. So, to support the evidence for an increased risk of endometrial cancer in relation
to weight gain, more large prospective studies should be done.
Prostate cancer
Prostate cancer is one of the most prevalent cancer in men, certainly in older men57.
Because prostate tissue is sensitive to hormones, it is often associated and studied in relation
with obesity15. Circulating testosterone levels decrease as a result of excess body weight85.
Testosterone is thought to contribute to the growth and progression of prostate cancer86.
Other hypotheses that support relation of adiposity and prostate cancer include alterations in
insulin and bio available circulating insulin-like growth factor I levels (see above). High
circulating concentrations of IGF-I have been associated with higher risk of prostate
cancer71;87;88. However, the exact mechanism of is still not understood.
Also epidemiological studies investigated the relation of prostate cancer with weight
gain to support an association. Most of the studies did not find any risk for prostate cancer in
relation to weight gain58-64. These studies all assessed the adult weight gain retrospectively,
however, most were of large size. Wright et al.64 included more than 5500 cases in their
cohort study during a follow-up of 5 year. Both other cohort studies were smaller, although
Littman et al.61 included more than 800 cases, but Cerhan et al.58 included only 45 cases. The
study of Cerhan et al.58 was also one of the studies which found an trend of an increased risk
for prostate cancer in relation to weight gain from age 50 to current age, but had only 69 cases
in this sub-analysis, and included only men over 65 of age. Wright et al.64 found an increased
risk for the mortality of prostate cancer, not for prostate cancer morbidity, but again included
for the mortality analysis only 76 cases, though for the morbidity analysis 5594. Interesingly,
studies investigating short-term weight gain reported an decreased risk for prostate cancer.
Both cohort studies13;62 included a sufficient number of cases, and assessed the weight gain
prospectively, which make it reliable. However, they did not adjust for specific prostate
cancer confounders in their analysis, probably because of lack of information. In addition,
Litmann et al. 61 reported also a decreased risk for non-aggressive prostate cancers, including
more than 400 cases, and Schuurman et al.63 used the case-cohort approach, and found an
decreased risk for both the subgroups well differentiated and poorly-differentiated prostate
cancer, but not for moderately differentiated tumours. It should be noted that this analysis
included around 200 cases, a much smaller groups than the other studies. Though, one large
prospective cohort study14, with 28 years of follow-up and more than 1800 included cases,
again found no change of risk but looked at a weight gain over six years. In summary, the
results of the studies addressing weight gain in relation to prostate cancer are not consistent.
Although some large prospective studies which studied short-term weight gain suggested a
decreased risk, many other studies which look at long-term weight gain did not support this
finding. The diversity in design of the studies make it hard to draw any conclusion, although a
relation of prostate cancer and weight gain might be explained by an underlying mechanism.
More large prospective studies looking at both long-term and short-term weight gain should
be done to investigate the possible relation between prostate cancer and weight gain.
Colorectal cancer
The only non-hormonal cancer discussed in this review is colorectal cancer. The
mechanism underlying the association of adiposity and colorectal cancer is mostly unclear. It
is suggested it might involves direct effects of insulin (as a result of the chronic hyper
insulenemia due to excess body weight) and increases of free/bio available IGF-15;71;89.
Another mechanism might be increases in bile acids which might be toxic to the colon
mucosa90;91. The epidemiological studies addressed to this subject, give controversial results.
Most studies studied only men or women, or stratified for sexe in their analysis. Thygesen et
al. 67 conducted a very large cohort study, and also assessed weight gain over 10 years
prospectively, but did not stratify on sexe. This study67 did not report any change. In
addition, three other studies did not find any change in risk. These were again two studies13;14
which assessed the weight gain prospectively. One of these studies included only a small
number of cases13, however the other study14 included more than 900 cases and had a followup of over 28 years. A disadvantage of these two studies is that they did not adjust for this
specific confounders of colorectal cancer in their analysis, probably due to lack of
information. All the three studies13;14;67 which assessed the weight gain prospectively looked
at short term weight gain over maximal 10 years, which might have a different effect on
colorectal cancer risk compared to long-term adult weight gain. Four retrospective studies65-68
investigated the relation of adult weight gain and colorectal cancer. Tamakoshi et al.66
reported an increased risk for colorectal cancer in relation to adult weight gain only in
women, but they had only included 34 cases in his cohort study. Trentham-Dietz et al.68
included only females in their large case-control study, and again found an increased risk for
colorectal cancer. The other case-control study 65 reported for both women and men a
decreased risk for colorectal cancer in relation to adult weight gain, and had about 2000
controls and 600 cases in their analysis, but looked at weight gain through a shorter period,
between the ages of 30 and 50, which might have other effects than the long-term period of 18
years of age to age at enrolment of the study. Two other studies69;70, which were not discussed
in the results, might be important answering questions about colorectal cancer and weight
gain. These studies did not use colorectal cancer as the outcome, but precursor lesions of
colorectal cancer; colon adenomas and colorectal polyps. Sedjo et al. 70 investigated the
relation of 10-year weight gain on the risk of colon adenomas in a small prospective cohort
study with 137 cases and a follow-up of two years. They found an increased risk for both
males and females together. In contrast, the case-control study of Bird et al. 69 did not find
any risk for colorectal polyps in relation to adult weight gain, but, on the other hand found
again an increased risk for colorectal polyps in relation to short-term (ten year) weight gain. It
was interesting Bird et al. 69 investigated both long-term and short-term weight gain,
unfortunately, they did not asses the weight gain prospectively. In summary, the studies in
colorectal cancer and weight gain did not report consistent results. Given the diversity in
study design of the studies, it is hard to draw any conclusion about the relation of colorectal
cancer and weight gain. Although some of the studies in the relation between colorectal
cancer and weight gain were already done prospectively, the previous results indicate more
evidence for a relation between weight gain and colorectal cancer should be generated by
doing more large prospective studies investigating both short-term and long-term weight gain.
Weight loss and cancer risk
Weight loss, also important in this topic of research, but of course less important for
public health given the recent problems with obesity, was not discussed in this review. This
was because we decided to focus on weight gain, because most articles were addressed to this
subject particular. However, some articles also took into account weight loss, but did not
mention the intention of the loss. The intention of the loss is important, because unintentional
weight loss can bias the results. One study of Parker et al.92, determined weight loss
throughout life (age 18 to current age) in post-menopausal women in relation to many
cancers. For intentional weight loss they found a decreased risk for all cancer incidence (RR
0.89; CI 95% 0.79–1.00), but not in relation to unintentional weight loss (RR 1.09; CI 95%
0.97–1.21). The same results were shown for post-menopausal breast cancer (intentional
weight loss: RR 0.81 (0.66–1.00), unintentional weight loss: RR 1.16; CI 95% 0.97–1.39) but
not for other cancers (colon and endometrial cancer). This again supports a relation for breast
cancer and adiposity. For the other cancers no effect was shown, however, these groups of
cases were much smaller than breast cancer cases. Although we did not discuss weight loss
studies in this review, they can be taken into account when determining the relation between
cancer and adiposity. Also weight loss reflects adiposity, and good studies can give valuable
information.
In conclusion, although many studies investigated the relation of breast cancer and
weight gain, studies determining the risk of other cancers were only done sporadically. For
these cancers, the results were often not consistent, and because of the diversity of the design
of these studies it is hard to draw any conclusions. Larger and prospective cohort studies
should be conducted, investigating both the effects of short-term and long-term weight gain
on cancer risk. When looking at both short-term and long-term weight gain in one study, more
can be said about the probable different relations with cancer. In addition, recalling
information on body weight retrospectively will always give a lot of bias, so prospective
studies will be more reliable. However, still only a few studies used a prospective method to
assess the weight gain and only one study investigated both short-term and long-term weight
gain together. Whereas, still there seems to be much evidence for a relationship between adult
weight gain and an increased post-menopausal breast cancer risk (with the exception of
current HRT users), and on the other hand no increased risk for pre-menopausal breast cancer.
These relations can also be explained by the underlying hormonal mechanism of adiposity and
breast cancer risk. Although, still only one prospective study have been conducted in the
relation between breast cancer and weight gain, which did not distinguish between pre- and
post-menopausal breast cancer. Unfortunate, because this studies will even more support the
suggested relation.
It is very important to elucidate the relation between cancer and weight gain because
obesity is a growing problem. Knowledge of the relation between weight gain and cancer
risk, with already the support of this review, will have implications for public health guides
and should be taken into account with regard to given advice on weight gain throughout life.
Reference List
(1) WHO - Obesity and oveerweight. 2008.
Ref Type: Generic
(2) DeClercq V, Taylor C, Zahradka P. Adipose tissue: the link between obesity and
cardiovascular disease. Cardiovasc Hematol Disord Drug Targets 2008;8:228-237.
(3) World Cancer Research Fund (WCRF) report: Food, Nutrition, Physical Activity and
the Prevention of Cancsr: a Global Perspective. 211-227. 2007.
Ref Type: Generic
(4) Calle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence and
proposed mechanisms. Nat Rev Cancer 2004;4:579-591.
(5) Renehan AG, Roberts DL, Dive C. Obesity and cancer: pathophysiological and
biological mechanisms. Arch Physiol Biochem 2008;114:71-83.
(6) Ballard-Barbash R. Anthropometry and breast cancer. Body size--a moving target.
Cancer 1994;74:1090-1100.
(7) Ballard-Barbash R, Schatzkin A, Taylor PR, Kahle LL. Association of change in body
mass with breast cancer. Cancer Res 1990;50:2152-2155.
(8) World Cancer Research Fund (WCRF) report: Food, Nutrition, Physical Activity and
the Prevention of Cancsr: a Global Perspective. 227-228. 2007.
Ref Type: Generic
(9) Hu FB, Willett WC, Li T, Stampfer MJ, Colditz GA, Manson JE. Adiposity as
compared with physical activity in predicting mortality among women. N Engl J Med
2004;351:2694-2703.
(10) Manson JE, Willett WC, Stampfer MJ et al. Body weight and mortality among
women. N Engl J Med 1995;333:677-685.
(11) Jeffreys M, McCarron P, Gunnell D, McEwen J, Smith GD. Body mass index in early
and mid-adulthood, and subsequent mortality: a historical cohort study. Int J Obes
Relat Metab Disord 2003;27:1391-1397.
(12) Maru S, van der Schouw YT, Gimbrere CH, Grobbee DE, Peeters PH. Body mass
index and short-term weight change in relation to mortality in Dutch women after age
50 y. Am J Clin Nutr 2004;80:231-236.
(13) Rapp K, Klenk J, Ulmer H et al. Weight change and cancer risk in a cohort of more
than 65,000 adults in Austria. Ann Oncol 2008;19:641-648.
(14) Samanic C, Chow WH, Gridley G, Jarvholm B, Fraumeni JF, Jr. Relation of body
mass index to cancer risk in 362,552 Swedish men. Cancer Causes Control
2006;17:901-909.
(15) World Cancer Research Fund (WCRF) report: Food, Nutrition, Physical Activity and
the Prevention of Cancsr: a Global Perspective. 2007.
Ref Type: Generic
(16) Ahn J, Schatzkin A, Lacey JV, Jr. et al. Adiposity, adult weight change, and
postmenopausal breast cancer risk. Arch Intern Med 2007;167:2091-2102.
(17) Coates RJ, Uhler RJ, Hall HI et al. Risk of breast cancer in young women in relation
to body size and weight gain in adolescence and early adulthood. Br J Cancer
1999;81:167-174.
(18) Eliassen AH, Colditz GA, Rosner B, Willett WC, Hankinson SE. Adult weight change
and risk of postmenopausal breast cancer. JAMA 2006;296:193-201.
(19) Eng SM, Gammon MD, Terry MB et al. Body size changes in relation to
postmenopausal breast cancer among women on Long Island, New York. Am J
Epidemiol 2005;162:229-237.
(20) Feigelson HS, Jonas CR, Teras LR, Thun MJ, Calle EE. Weight gain, body mass
index, hormone replacement therapy, and postmenopausal breast cancer in a large
prospective study. Cancer Epidemiol Biomarkers Prev 2004;13:220-224.
(21) Friedenreich CM, Courneya KS, Bryant HE. Case-control study of anthropometric
measures and breast cancer risk. Int J Cancer 2002;99:445-452.
(22) Han D, Nie J, Bonner MR et al. Lifetime adult weight gain, central adiposity, and the
risk of pre- and postmenopausal breast cancer in the Western New York exposures and
breast cancer study. Int J Cancer 2006;119:2931-2937.
(23) Harvie M, Howell A, Vierkant RA et al. Association of gain and loss of weight before
and after menopause with risk of postmenopausal breast cancer in the Iowa women's
health study. Cancer Epidemiol Biomarkers Prev 2005;14:656-661.
(24) Hirose K, Tajima K, Hamajima N et al. Effect of body size on breast-cancer risk
among Japanese women. Int J Cancer 1999;80:349-355.
(25) Kotsopoulos J, Olopado OI, Ghadirian P et al. Changes in body weight and the risk of
breast cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res
2005;7:R833-R843.
(26) Lahmann PH, Lissner L, Gullberg B, Olsson H, Berglund G. A prospective study of
adiposity and postmenopausal breast cancer risk: the Malmo Diet and Cancer Study.
Int J Cancer 2003;103:246-252.
(27) Lahmann PH, Schulz M, Hoffmann K et al. Long-term weight change and breast
cancer risk: the European prospective investigation into cancer and nutrition (EPIC).
Br J Cancer 2005;93:582-589.
(28) Magnusson C, Baron J, Persson I et al. Body size in different periods of life and breast
cancer risk in post-menopausal women. Int J Cancer 1998;76:29-34.
(29) Morimoto LM, White E, Chen Z et al. Obesity, body size, and risk of postmenopausal
breast cancer: the Women's Health Initiative (United States). Cancer Causes Control
2002;13:741-751.
(30) Rosenberg LU, Einarsdottir K, Friman EI et al. Risk factors for hormone receptordefined breast cancer in postmenopausal women. Cancer Epidemiol Biomarkers Prev
2006;15:2482-2488.
(31) Shu XO, Jin F, Dai Q et al. Association of body size and fat distribution with risk of
breast cancer among Chinese women. Int J Cancer 2001;94:449-455.
(32) Slattery ML, Sweeney C, Edwards S et al. Body size, weight change, fat distribution
and breast cancer risk in Hispanic and non-Hispanic white women. Breast Cancer Res
Treat 2007;102:85-101.
(33) Trentham-Dietz A, Newcomb PA, Storer BE et al. Body size and risk of breast cancer.
Am J Epidemiol 1997;145:1011-1019.
(34) Trentham-Dietz A, Newcomb PA, Egan KM et al. Weight change and risk of
postmenopausal breast cancer (United States). Cancer Causes Control 2000;11:533542.
(35) van den Brandt PA, Dirx MJ, Ronckers CM, van den HP, Goldbohm RA. Height,
weight weight change, and postmenopausal breast cancer risk: The Netherlands
Cohort Study. Cancer Causes Control 1997;8:39-47.
(36) Verla-Tebit E, Chang-Claude J. Anthropometric factors and the risk of premenopausal
breast cancer in Germany. Eur J Cancer Prev 2005;14:419-426.
(37) Wenten M, Gilliland FD, Baumgartner K, Samet JM. Associations of weight, weight
change, and body mass with breast cancer risk in Hispanic and non-Hispanic white
women. Ann Epidemiol 2002;12:435-4.
(38) Wu AH, Yu MC, Tseng CC, Pike MC. Body size, hormone therapy and risk of breast
cancer in Asian-American women. Int J Cancer 2007;120:844-852.
(39) Lund E, Adami HO, Bergstrom R, Meirik O. Anthropometric measures and breast
cancer in young women. Cancer Causes Control 1990;1:169-172.
(40) Mannisto S, Pietinen P, Pyy M, Palmgren J, Eskelinen M, Uusitupa M. Body-size
indicators and risk of breast cancer according to menopause and estrogen-receptor
status. Int J Cancer 1996;68:8-13.
(41) Ziegler RG, Hoover RN, Nomura AM et al. Relative weight, weight change, height,
and breast cancer risk in Asian-American women. J Natl Cancer Inst 1996;88:650660.
(42) Barnes-Josiah D, Potter JD, Sellers TA, Himes JH. Early body size and subsequent
weight gain as predictors of breast cancer incidence (Iowa, United States). Cancer
Causes Control 1995;6:112-118.
(43) Feigelson HS, Patel AV, Teras LR, Gansler T, Thun MJ, Calle EE. Adult weight gain
and histopathologic characteristics of breast cancer among postmenopausal women.
Cancer 2006;107:12-21.
(44) van den Brandt PA, Dirx MJ, Ronckers CM, van den HP, Goldbohm RA. Height,
weight weight change, and postmenopausal breast cancer risk: The Netherlands
Cohort Study. Cancer Causes Control 1997;8:39-47.
(45) Shoff SM, Newcomb PA, Trentham-Dietz A et al. Early-life physical activity and
postmenopausal breast cancer: effect of body size and weight change. Cancer
Epidemiol Biomarkers Prev 2000;9:591-595.
(46) Fairfield KM, Willett WC, Rosner BA, Manson JE, Speizer FE, Hankinson SE.
Obesity, weight gain, and ovarian cancer. Obstet Gynecol 2002;100:288-296.
(47) Greer JB, Modugno F, Ness RB, Allen GO. Anthropometry and the risk of epithelial
ovarian cancer. Cancer 2006;106:2247-2257.
(48) Lubin F, Chetrit A, Freedman LS et al. Body mass index at age 18 years and during
adult life and ovarian cancer risk. Am J Epidemiol 2003;157:113-120.
(49) Olsen CM, Nagle CM, Whiteman DC, Purdie DM, Green AC, Webb PM. Body size
and risk of epithelial ovarian and related cancers: a population-based case-control
study. Int J Cancer 2008;123:450-456.
(50) Rossing MA, Tang MT, Flagg EW, Weiss LK, Wicklund KG, Weiss NS. Body size
and risk of epithelial ovarian cancer (United States). Cancer Causes Control
2006;17:713-720.
(51) Schouten LJ, Goldbohm RA, van den Brandt PA. Height, weight, weight change, and
ovarian cancer risk in the Netherlands cohort study on diet and cancer. Am J
Epidemiol 2003;157:424-433.
(52) Schouten LJ, Goldbohm RA, van den Brandt PA. Anthropometry, physical activity,
and endometrial cancer risk: results from the Netherlands cohort study. Int J Gynecol
Cancer 2006;16 Suppl 2:492.
(53) Terry P, Baron JA, Weiderpass E, Yuen J, Lichtenstein P, Nyren O. Lifestyle and
endometrial cancer risk: a cohort study from the Swedish Twin Registry. Int J Cancer
1999;82:38-42.
(54) Trentham-Dietz A, Nichols HB, Hampton JM, Newcomb PA. Weight change and risk
of endometrial cancer. Int J Epidemiol 2006;35:151-158.
(55) Weiderpass E, Persson I, Adami HO, Magnusson C, Lindgren A, Baron JA. Body size
in different periods of life, diabetes mellitus, hypertension, and risk of postmenopausal
endometrial cancer (Sweden). Cancer Causes Control 2000;11:185-192.
(56) Xu WH, Xiang YB, Zheng W et al. Weight history and risk of endometrial cancer
among Chinese women. Int J Epidemiol 2006;35:159-166.
(57) Website RIVM; Prostaatkanker
Omvang van het probleem
Hoe vaak komt prostaatkanker voor en hoeveel mensen sterven eraan? 2009.
Ref Type: Generic
(58) Cerhan JR, Torner JC, Lynch CF et al. Association of smoking, body mass, and
physical activity with risk of prostate cancer in the Iowa 65+ Rural Health Study
(United States). Cancer Causes Control 1997;8:229-238.
(59) Friedenreich CM, McGregor SE, Courneya KS, Angyalfi SJ, Elliott FG. Case-control
study of anthropometric measures and prostate cancer risk. Int J Cancer
2004;110:278-283.
(60) Giles GG, Severi G, English DR et al. Early growth, adult body size and prostate
cancer risk. Int J Cancer 2003;103:241-245.
(61) Littman AJ, White E, Kristal AR. Anthropometrics and prostate cancer risk. Am J
Epidemiol 2007;165:1271-1279.
(62) Rodriguez C, Freedland SJ, Deka A et al. Body mass index, weight change, and risk of
prostate cancer in the Cancer Prevention Study II Nutrition Cohort. Cancer Epidemiol
Biomarkers Prev 2007;16:63-69.
(63) Schuurman AG, Goldbohm RA, Dorant E, van den Brandt PA. Anthropometry in
relation to prostate cancer risk in the Netherlands Cohort Study. Am J Epidemiol
2000;151:541-549.
(64) Wright ME, Chang SC, Schatzkin A et al. Prospective study of adiposity and weight
change in relation to prostate cancer incidence and mortality. Cancer 2007;109:675684.
(65) Russo A, Franceschi S, La VC et al. Body size and colorectal-cancer risk. Int J Cancer
1998;78:161-165.
(66) Tamakoshi K, Wakai K, Kojima M et al. A prospective study of body size and colon
cancer mortality in Japan: The JACC Study. Int J Obes Relat Metab Disord
2004;28:551-558.
(67) Thygesen LC, Gronbaek M, Johansen C, Fuchs CS, Willett WC, Giovannucci E.
Prospective weight change and colon cancer risk in male US health professionals. Int J
Cancer 2008;123:1160-1165.
(68) Amy Trentham Dietz, Polly A.Newcomb, Pamela M.Marcus, Barry E.Storer. The
association of body size and large bowel cancer risk in Wisconsin (United States)
women. Cancer Causes and Control 1995, 6, 30-36 , 30-36. 1995.
Ref Type: Generic
(69) Bird CL, Frankl HD, Lee ER, Haile RW. Obesity, weight gain, large weight changes,
and adenomatous polyps of the left colon and rectum. Am J Epidemiol 1998;147:670680.
(70) Sedjo RL, Byers T, Levin TR et al. Change in body size and the risk of colorectal
adenomas. Cancer Epidemiol Biomarkers Prev 2007;16:526-531.
(71) Renehan AG, Zwahlen M, Minder C, O'Dwyer ST, Shalet SM, Eger M. Insulin-like
growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and
meta-regression analysis. Lancet 363, 1346-1353. 2004.
Ref Type: Magazine Article
(72) Spencer EA, Roddam AW, Key TJ. Accuracy of self-reported waist and hip
measurements in 4492 EPIC-Oxford participants. Public Health Nutr 2004;7:723-727.
(73) Troy LM, Hunter DJ, Manson JE, Colditz GA, Stampfer MJ, Willett WC. The validity
of recalled weight among younger women. Int J Obes Relat Metab Disord
1995;19:570-572.
(74) Key TJ, llen NE, erkasalo PK, anks E. Energy balance and cancer: the role of sex
hormones. Proc.Nutr.Soc. 60, 81-89. 2001.
Ref Type: Magazine Article
(75) Siiteri PK. Adipose tissue as a source of hormones. Am.J.Clin.Nutr. 45, 277-282.
2009.
Ref Type: Magazine Article
(76) Key Teal. Endogenous sex hormones and breast cancer in postmenopausal women:
reanalysis of nine prospective studies. J.Natl.Cancer Inst. 94, 606-616. 2002.
Ref Type: Magazine Article
(77) Rinaldi Seal. Anthropometric measures, endogenous sex steroids and breast cancer
risk in postmenopausal women: A study within the EPIC cohort. Int.J.Cancer 118,
2832-2839. 2006.
Ref Type: Magazine Article
(78) Stoll B. Impaired ovulation and breast cancer risk. Eur.J.Cancer. 33, 1532-1535. 1997.
Ref Type: Magazine Article
(79) Weiderpass E, Braaten T, Magnusson C, Kumle M, Vainio H, Lund E et al. A
prospective study of body size in different periods of life and risk of premenopausal
breast cancer. Cancer.Epidemiol.Biomarkers.Prev. 13, 1121-1127. 2004.
Ref Type: Magazine Article
(80) Hankinson SE, Willett WC, Manson JE, Colditz GA, Hunter DJ, SpiegelmanD et al.
Plasma sex steroid hormone levels and risk of breast cancer in postmenopausal
women. J.Natl.Cancer Inst. 90, 1292-1299. 1998.
Ref Type: Magazine Article
(81) Risch HA. Hormonal etiology of epithelial ovarian cancer, with a hypothesis
concerning the role of androgens and progesterone. J.Natl.Cancer Inst. 90, 17741786. 1998.
Ref Type: Magazine Article
(82) Wise LA, Palmer JR, Spiegelman D et al. Influence of body size and body fat
distribution on risk of uterine leiomyomata in U.S. black women. Epidemiology
2005;16:346-354.
(83) Key TJ, Pike MC. The dose-effect relationship between 'unopposed' oestrogens and
endometrial mitotic rate: its central role in explaining and predicting endometrial
cancer risk. Br.J.Cancer 57, 205-212. 1988.
Ref Type: Magazine Article
(84) Key TJ. Hormones and cancer in humans. Mutat.Res. 333, 59-67. 1995.
Ref Type: Magazine Article
(85) Gapstur SM, Gann PH, Koop P, Colangelo L, Longcope C, Liu K. Serum androgens
concentrations in young men: a longitudinal analysis of associations with age, obesity,
and race. The CARDIA Male Hormone Study. Cancer Epidemiol.Biomarkers Prev.
11, 1041-1047. 2002.
Ref Type: Magazine Article
(86) Cunha GR, Hayward SW, Wang YZ, Ricke WA. Role of the stromal
microenvironment in carcinogenesis of the prostate. Int.J.Cancer 107, 1-10. 2003.
Ref Type: Magazine Article
(87) Chan JM, Stampfer MJ, Ma J ea. Insulin-like growth factor-I (IGF-I) and IGF binding
protein-3 as predictors of advanced-stage prostate cancer. J.Natl.Cancer Inst. 94, 10991106. 2002.
Ref Type: Magazine Article
(88) Mantzoros CS, Tzonou A, Signorello LB, Stampfer MJ, Trichopoulos D, Adami HO.
Insulin-like growth factor 1 in relation to prostate cancer and benign prostatic
hyperplasia. Br.J.Cancer 76, 1115-1118. 1997.
Ref Type: Magazine Article
(89) Giovannucci E. Insulin, insulin-like growth factors and colon cancer: a review of
the evidence. J.Nutr. 131, 3109-3120. 2001.
Ref Type: Magazine Article
(90) Giovannucci E, Colditz GA, Stampfer MJ. A meta-analysis of cholecystectomy
and risk of colorectal cancer. Gastroenterology 105, 130-141. 1993.
Ref Type: Magazine Article
(91) Hagiwara T, Kono S, Yin G, Toyomura K, Nagano J, Mizoue T et al. Genetic
polymorphism in cytochrome P450 7A1 and risk of colorectal cancer: the
Fukuoka Colorectal Cancer Study. Cancer Res. 65, 2979-2982. 2005.
Ref Type: Magazine Article
(92) Parker ED, Folsom AR. Intentional weight loss and incidence of obesity-related
cancers: the Iowa Women's Health Study. Int J Obes Relat Metab Disord
2003;27:1447-1452.