This document discusses the relationship between diet and cancer incidence based on various studies. It notes that early estimates suggested 35% of cancer deaths in the US could be prevented by dietary changes. Dietary factors like fat intake and consumption of fruits and vegetables have been examined in many epidemiological studies but results have been mixed, with some associations found but none described as conclusively proven. The complexity of diet makes definitively linking individual foods to cancer risk difficult.

1. BY
DR. NARESH JANGIR

2.  Over two decades ago, Doll and Peto speculated that 35%
(range: 10% to 70%) of all cancer deaths in the United
States may be preventable by alterations in diet.
 The magnitude of the estimate for diet exceeded that for
tobacco (30%) and infections (10%).
 Environmental factors such as diet may influence the
incidence of cancer through many different mechanisms
and at different stages in the cancer process.
 Simple mutagens in foods, such as those produced by the
heating of proteins, can cause damage to DNA, but dietary
factors can also influence this process by inducing
enzymes that activate or inactivate these mutagens, or by
blocking the action of the mutagen.

3.  Epidemiological studies try to identify relationships between the diet
of population groups and incidence of specific cancers
 Diet complexity makes identifying relationships difficult
◦ Thousands of chemicals in a diet
◦ Diets contain initiators, promoters and protective factors
◦ Changing one factor in the diet may change others, making
identifying individual factors difficult
◦ Many cancers have a long latency period, thus diet at initiation or
promotion may not be the same as at diagnosis

4.  The most widely used diet assessment instruments are the food frequency
questionnaire, the 7-day diet record, and the 24-hour recall.
 Although the 7-day diet record may provide the most accurate documentation of
intake during the week the participant keeps a diet diary, the burden of computerizing
the information and extracting foods and nutrients has prohibited the use of the 7-day
diet record in most large-scale studies.
 The 24-hour recall provides only a snapshot of diet on one day, which may or may
not be representative of the participant’s usual diet and is thus affected by both
within-person variation and seasonal variation.
 The food frequency questionnaire, the most widely used instrument in large
population-based studies, asks participants to report their average intake of a large
number of foods during the previous year.

5. Alcohol
 Besides body weight, alcohol consumption is the best established
dietary risk factor for cancer.
 Alcohol is classified as a carcinogen by the International Agency for
Research on Cancer.
 Consumption of alcohol increases the risk of numerous cancers,
including those of the liver, esophagus, pharynx, oral cavity, larynx,
breast, and colorectum in a dose-dependent fashion.
 Evidence is convincing that excessive alcohol consumption
increases the risk of primary liver cancer, probably through cirrhosis
and alcoholic hepatitis.

6.  At least in the developed world about 75% of cancers of the
esophagus, pharynx, oral cavity, and larynx are attributable to
alcohol and tobacco, with a marked increase in risk among drinkers
who also smoke, suggesting a multiplicative effect
 Mechanisms may include
1.Direct damage to the cells in the upper gastrointestinal tract,
2.Modulation of DNA methylation,
3.An increase in acetaldehyde, the main metabolite of alcohol,
which enhances proliferation of epithelial cells and is a recognized
carcinogen.

7.  The association between alcohol consumption and breast cancer is
notable because a small but significant risk has been found even
with one drink per day.
 Mechanisms may include an interaction with folate, an increase in
endogenous estrogen levels, and elevation of acetaldehyde.
 Some evidence suggests that the excess risk is reduced by
adequate folate intake possibly through an effect on DNA
methylation.

8.  High fat diets
◦ High dietary total fat and saturated fat may be related to
increased risk of breast, colon, endometrial and prostate cancer
 Omega-3 fatty acids however, may be protective
◦ Thus same dietary fat advice applies to cancer protection as to
heart disease
 Reduce total fat and saturated fat
 Increase omega-3 fatty acids

9.  High fat diets
◦ May increase cancer risk by increasing:
 Obesity
 Bile acid production
 Estrogen levels
◦ Because fat is calorie dense it is difficult to distinguish between
the effects of high dietary fat, and total calories

10.  The Women’s Health Initiative Randomized Controlled Dietary
Modification Trial suggested no association between fat intake and
breast cancer incidence
 In a report of findings from the Nurses’ Health Study II cohort of
premenopausal women, higher intake of animal fat was associated
with an approximately 50% greater risk of breast cancer, but no
association was seen with intake of vegetable fat
 In the same cohort, intake of red meat and total fat during
adolescence was also associated with risk of premenopausal breast
cancer.

11.  In comparisons among countries, rates of colon cancer are strongly
correlated with national per capita consumption of animal fat and
meat, with correlation coefficients ranging between 0.8 and 0.9.
 Rates of colon cancer rose sharply in Japan after World War II,
paralleling a 2.5-fold increase in fat intake.
 Based on these epidemiologic investigations and on animal studies,
a hypothesis has developed that higher dietary fat increases
excretion of bile acids, which can be converted to carcinogens or act
as promoters.

12.  The Nurses’ Health Study suggested an approximately twofold
higher risk of colon cancer among women in the highest quintile of
animal fat intake than in those in the lowest quintile
 In a multivariate analysis of these data, which included red meat
intake and animal fat intake in the same model, red meat intake
remained significantly predictive of risk of colon cancer, whereas the
association with animal fat was eliminated.
 The apparently stronger association with red meat consumption
than with fat intake in most large cohort studies needs further
confirmation, but such an association could result if the fatty acids or
nonfat components of meat (e.g., the heme iron or carcinogens
created by cooking) were the primary etiologic factors.

13.  Although further data are desirable, the evidence from
international correlations, case-control and cohort
studies provides some support for an association between
consumption of fat-containing animal products and prostate
cancer incidence.
 Some evidence also indicates that animal fat consumption
may be most strongly associated with the incidence of
aggressive prostate cancer.
 Data are limited on the relation of fat intake to the
probability of survival after the diagnosis of prostate
cancer.

14.  High calorie intake
◦ In most epidemiologic studies, a positive association has been
seen with high calorie intake and promotion of breast, colon and
endometrial cancer
◦ Increased risk may be due to:
 Excess calories themselves
 Weight gain due to excess calories
 High fat intake that often supplies excess calories

15.  Fruits and vegetables contain antioxidants and minerals and are
good sources of fiber, potassium, carotenoids, vitamin C, folate, and
other vitamins.
 Although fruits and vegetables supply less than 5% of total energy
intake in most countries worldwide on a population basis, the
concentration of micronutrients in these foods is greater than in
most others.
 The comprehensive report of the World Cancer Research Fund and
the American Institute for Cancer Research published in 2007 and
titled Food, Nutrition, Physical Activity, and the Prevention of
Cancer: A Global Perspective reached the consensus based on the
available evidence: “findings from cohort studies conducted since
the mid-1990s have made the overall evidence, that vegetables or
fruits protect against cancers, somewhat less impressive. In no case
now is the evidence of protection judged to be convincing.

16.  The association between fruit and vegetable consumption and the
incidence of colon or rectal cancer has been examined
prospectively in at least six studies.
 In some of these prospective cohorts, inverse associations were
observed for individual foods or particular subgroups of fruits or
vegetables, but no consistent pattern emerged and many
comparisons revealed no such links.
 The results from the largest studies, the Nurses’ Health Study and
the Health Professionals’ Follow-Up Study, suggested no important
association between consumption of fruits and vegetables and
incidence of cancers of the colon or rectum during 1,743,645
person-years of follow-up.

17.  At least 12 prospective cohort studies have examined consumption
of some fruits and vegetables and incidence of stomach cancer.
 Seven of these studies considered total vegetable intake. Three
found significant protection from stomach cancer, whereas three did
not.
 Nine prospective cohort studies investigated the association
between fruit consumption and stomach cancer risk. Four studies
found an inverse association of borderline statistical significance.

18.  The most comprehensive evaluation of fruit and vegetable
consumption and the incidence of breast cancer was provided by a
pooled analysis of all cohort studies
 In a recent analysis within the Nurses’ Health Study, an inverse
association was seen between intake of vegetables and risk of
estrogen receptor–negative breast cancer.

19.  The relation between fruit and vegetable
consumption and the incidence of lung cancer was
examined in the pooled analysis of cohort studies.
 Overall, no association was observed, although a
modest increase in lung cancer incidence was
evident among participants with the lowest fruit
and vegetable consumption.

20.  Consumption of fruits and vegetables and some of their main
micronutrients appears to be less important in cancer prevention
than previously assumed.
 With accumulation of data from prospective cohort studies and
randomized trials, a lack of association of these foods and nutrients
with cancer outcomes has become apparent.
 Conversely, it is possible that, with the fortification of breakfast
cereal, flour, and other staple foods, the frequent consumption of
fruits and vegetables has become less essential for cancer
prevention.
 Nevertheless, an abundance of fruits and vegetables as part of a
healthy diet is recommended, because evidence consistently
suggests that it lowers the incidence of hypertension, heart disease,
and stroke.

21.  Dietary fiber was defined in 1976 as “all plant polysaccharides and
lignin which are resistant to hydrolysis by the digestive enzymes of
men.”52a Fiber, both soluble and insoluble, is fermented by the
luminal bacteria of the colon.
 Among the properties of fiber that make it a candidate for cancer
prevention are its “bulking” effect, which reduces colonic transit
time, and the binding of potentially carcinogenic luminal chemicals.
 Fiber may also aid in producing short-chain fatty acids that may be
directly anticarcinogenic, and fiber may induce apoptosis.

22.  In 1969, Dennis Burkitt hypothesized that dietary fiber is involved in
colon carcinogenesis.
 Initial analyses from the Nurses’ Health Study and the Health
Professionals’ Follow-Up Study found no important association
between dietary fiber and colorectal cancer.
 A significant inverse association between fiber intake and incidence
of colorectal cancer was reported from the EPIC study.
 The NIH-AARP study, including 2,974 cases of colorectal cancer,
confirmed the lack of association between total dietary fiber and
colorectal cancer risk

23.  Investigators have speculated that dietary fiber may reduce the risk
of breast cancer through reduction in intestinal absorption of
estrogens excreted via the biliary system.
 Relatively few epidemiologic studies have examined the association
between fiber intake and breast cancer.
 In a meta-analysis of ten case-control studies, a significant inverse
association was observed.
 Results from at least six prospective cohort studies consistently
suggested no association between fiber intake and breast cancer
incidence.

24.  The results from retrospective case-control studies of fiber intake
and gastric cancer risk are inconsistent.
 In the Netherlands Cohort Study, dietary fiber was not associated
with incidence of gastric carcinoma.
 Further investigation through prospective cohort studies must be
completed before conclusions about the relation between fiber
intake and stomach cancer incidence can be drawn.

25.  Regular consumption of red meat has been associated with an
increased risk of colorectal cancer.
 In a recent meta-analysis the increase in risk associated with an
increase in intake of 120 g/d was 24%.
 The association was strongest for processed meat; the relative risk
of colorectal cancer was 1.36 for a consumption of 30 g/d.
 No overall association has been observed between red meat
consumption and breast cancer in a pooled analysis of prospective
cohorts.
 However, among premenopausal women in the Nurses’ Health
Study II the risk for estrogen-receptor– and progesterone-receptor–
positive breast cancer doubled with 1.5 servings of red meat per day
compared to three or fewer servings per week.

26.  Mechanisms through which red meat may increase cancer risk
include anabolic hormones routinely used in meat production in the
United States, heterocyclic amines, and polycyclic aromatic
hydrocarbons formed during cooking at high temperatures, the high
amounts of heme iron, and nitrates and related compounds in
smoked, salted, and some processed meats that can convert to
carcinogenic nitrosamines in the colon.

27.  The role of calcium in the prevention of colorectal cancer is not
entirely clear, but in the pooling project of prospective studies of diet
and cancer, a modest inverse association was seen.
 Conversely, high intake of lactose from dairy products has been
associated with a modestly higher risk of ovarian cancer.
 In multiple studies high intake of calcium or dairy products has been
associated with an increased risk of prostate cancer.
 A meta-analysis of prospective studies generated an overall relative
risk of advanced prostate cancer of 1.33 (95% CI, 1.00 to 1.78) for
the highest versus the lowest intake categories of dairy products.
 Thus, although the findings are not entirely consistent and are
complicated by the widespread use of prostate-specific antigen
(PSA) screening in the United States, the global evidence suggests
an association between regular consumption of dairy products and
the risk of prostate cancer.

28.  Vitamin D is currently one of the most promising agents in cancer prevention research.
 In 1980, Garland and Garland hypothesized that sunlight and vitamin D may reduce the risk of
colon cancer.
 A meta-analysis, including five nested case-control studies with prediagnostic serum, suggested a
reduction of colorectal cancer risk by about half among individuals with serum 25(OH)D levels of
more than 82 nmol/L compared to individuals with less than 30 nmol/L.
 Vitamin D levels may particularly affect colorectal cancer prognosis; colorectal cancer mortality
was 72% lower among individuals with 25(OH)D concentrations of 80 nmol/L or higher.
 Although the data are not entirely consistent, high intake and high plasma levels of vitamin D
have been associated with a decreased risk of several other cancers, including cancer of the
breast, prostate,and pancreas.
 Activation of vitamin D receptors by 1,25(OH)2D induces cell differentiation and inhibits
proliferation and angiogenesis.
 Solar ultraviolet-B radiation is the major source of plasma vitamin D, and dietary vitamin D without
supplementation has a minor effect on plasma vitamin D.
 To achieve sufficient plasma levels through sun exposure, at least 15 minutes of full-body
exposure to bright sunlight is necessary. Sunscreen effectively blocks vitamin D production.
Populations who live in geographic areas with limited or seasonal sun exposure may benefit from
vitamin D supplementation of 1,000 IU/d.

29.  Folate is a micronutrient commonly found in fruits and vegetables, particularly
oranges, orange juice, asparagus, beets, and peas.
 Folate may affect carcinogenesis through various mechanisms: DNA methylation,
DNA synthesis, and DNA repair.
 Folate deficiency is related to incorporation of uracil into human DNA and to an
increased frequency of chromosomal breaks.
 A number of epidemiologic studies suggest that a diet rich in folate lowers the risk of
colorectal adenomas and colorectal cancer.
 Because folate content in foods is generally relatively low, is susceptible to oxidative
destruction by cooking and food processing, and is not well absorbed, folic acid from
supplements and fortification plays an important role.
 Pooled results from nine prospective studies suggests that intake of 400 to 500
mcg/d is required to minimize risk.

30.  The role of soy products has been considered for breast
carcinogenesis.
 In Asian countries, which traditionally have a high consumption of
soy foods, breast cancer rates have been low until recently.
 Soybeans contain isoflavones, phytoestrogens that compete with
estrogen for the estrogen receptor. Hence, soy consumption may
affect estrogen concentrations differently depending on the
endogenous baseline level.
 childhood intake of soy was more relevant to breast cancer
prevention than adult consumption.

31.  Carotenoids, antioxidants prevalent in fruits and vegetables,
enhance cell-to-cell communication, promote cell differentiation, and
modulate immune response.
 In 1981, Doll and Peto speculated that beta carotene may be a
major player in cancer prevention and encouraged testing of its
anticarcinogenic properties-- a reduced cancer risk—especially of
lung cancer—with high intake of carotenoids.
 The particularly pronounced antioxidant properties of lycopene, a
carotenoid mainly found in tomatoes, may explain the inverse
associations with some cancers.
 Frequent consumption of tomato-based products has been
associated with a decreased risk of prostate, lung, and stomach
cancers.
 Bioavailability of lycopene from cooked tomatoes is higher than from
fresh tomatoes, making tomato soup and sauce excellent sources of
the carotenoid.

32.  Foods and nutrients are not consumed in isolation, and, when evaluating the role of
diet in disease prevention and causation, it is sensible to consider the entire dietary
pattern of individuals.
 The search for associations between distinct patterns such as the “Western
pattern”—characterized by high consumption of red and processed meats, high fat
dairy products, including butter and eggs, and refined carbohydrates, such as
sweets, desserts, and refined grains—and the “prudent pattern”—defined by frequent
consumption of a variety of fruits and vegetables, whole grains, legumes, fish, and
poultry—and the risk of cancer has been largely disappointing.
 Notable exceptions were the link between a Western dietary pattern and colon
cancer incidence and an inverse relation between a prudent diet and estrogen
receptor–negative breast cancer, but these findings have to be confirmed in
additional studies.

33.  Some cancers may originate early in the course of life.
 A high birth weight is associated with an increase in the risk of
childhood leukemia,premenopausal breast cancer, and testicular
cancer.
 Tall height is an indicator of the risk of many cancers and is in part
determined by nutrition during childhood.
 Until recently, most studies focused on the role of diet during adult
life. However, the critical exposure period for nutrition to affect
cancer risk may be earlier, and since the latent period for cancer
may span several decades, diet during childhood and adolescence
may be important
 In a study nested in the Nurses’ Health Study cohorts that used data
recalled by mothers, frequent consumption of french fries was
associated with an increased risk of breast cancer, while whole milk
consumption was inversely related to risk.

34.  Some of the most promising research at present is in the areas of
vitamin D, milk consumption, and the effect of diet early in life on
cancer incidence.
 Recent nutrition changes in countries previously maintaining a more
traditional diet such as Japan and some developing countries have
already been followed by increased cancer rates, providing a setting
to study the effect of change over time.
 Additional insight may come from studies on gene–nutrient
interaction and epigenetic changes induced by diet.
 To improve observational research methods, refined dietary
assessment methods including identification of new biomarkers will
be advantageous.

35.  A wealth of data are available from observational studies on diet and
cancer, and the current evidence supports suggestions made by Doll and
Peto that approximately 30% to 40% of cancer may be avoidable with
changes in nutrition.
 Excessive energy intake and lack of physical activity, marked by rapid
growth in childhood and being overweight, have become growing threats to
population health and are a major contributor to rising cancer rates.
1. Engage in regular physical activity.
2. Avoid overweight and weight gain in adulthood.
3. Limit alcohol consumption..

36. 1. Replace red meat and dairy products with fish, nuts, and legumes..
2. Consider taking a vitamin D supplement.
3. Consume lots of fruits and vegetables.
4. Consume whole grains and avoid refined carbohydrates and sugars

37.  Physical activity is defined as any movement of the body that results
in energy expenditure.
 Here we focus on recreational physical activity, also called leisure-
time physical activity or exercise, and occupational physical activity,
including household activity.
 Occupational physical activity typically occurs over a longer period
of time and generally requires less energy expenditure per hour
than bouts of strenuous or moderate recreational physical activity.
 The distinction between recreational and occupational activity is
important because increasing mechanization and technological
advances have led to decreased occupational physical activity in
developed areas of the world, perhaps contributing to a decrease in
overall physical activity.

38.  Obesity is defined as the condition of being extremely overweight.
 In epidemiological studies, the usual, but not necessarily the best
measure of body mass in adults is Quetelet’s Index, or body mass
index (BMI), which is measured as weight in kilograms (kg) divided
by the square of height in meters (m2).
 The estimated proportion of the U.S. population that is obese,
defined by having a BMI of 30 kg/m2 or greater, is 32.2% and 35.5%
for adult men and women, respectively.
 Physical inactivity has likely contributed to the high prevalence of
obesity in the United States--less than 5% of U.S. adults achieve 30
minutes per day of physical activity.

39.  Epidemiological evidence for a role of physical activity or obesity in
relation to cancer risk exists for cancers of the breast, colon,
endometrium, esophagus, and kidney.
 Evidence is accumulating to link at least one of these “exposures” to
incidence of pancreatic cancer, gallbladder cancer, non-Hodgkin
lymphoma (NHL), and advanced prostate cancer.
 The evidence for an association between either physical activity or
obesity and lung and ovarian cancer is inconclusive.

40.  Low level of physical activity is an established breast cancer risk
factor among postmenopausal women and, to a lesser extent,
premenopausal women.
 Obesity appears to have a paradoxical relationship with breast
cancer risk in that it is an established breast cancer risk factor
among postmenopausal women, but may offer some protection for
breast cancer among premenopausal women.
 The epidemiological literature has shown with relative consistency
that breast cancer risk is reduced by increasing level of physical
activity.
 One of the earliest studies, a case-control study of women 40 years
or younger, showed a dramatic reduction in risk of approximately
50% among women who averaged about 4 hours of activity per
week during their reproductive years.

41.  In the California Teachers Study (CTS), a prospective cohort study
of over 133,000 female public school professionals, increasing
levels of long-term strenuous recreational physical activity were
associated with decreasing risk of in situ and invasive breast cancer.
 In the CTS data, a variable combining strenuous and moderate
long-term recreational physical activity was associated with reduced
risk of estrogen receptor-negative but not estrogen receptor-positive
invasive breast cancer.
 A recent report from the Nurses’ Health Study II has shown that
recreational physical activity during youth, defined as between ages
12 and 22 years, may have a larger impact on premenopausal
breast cancer risk than activity at older ages; these results did not
differ by estrogen-receptor status.

42.  Results from the National Institutes of Health-American Association of
Retired Persons Diet and Health Study cohort showed that recent
moderate-to-vigorous intensity recreational physical activity, and not activity
at earlier age periods, was associated with decreased postmenopausal
breast cancer risk, again with no apparent difference by tumor subtype.
 EPIC reported that increased physical activity in the form of household
activity (highest vs. lowest quartile) was associated with a reduction in
breast cancer risk of approximately 30% among premenopausal and 20%
among postmenopausal women, but neither recreational activity nor
occupational activity was significantly associated with risk.

43.  In summary, epidemiological studies investigating the association
between physical activity and breast cancer risk have produced
relatively consistent results showing a reduction in breast cancer
risk with increasing level of physical activity.
 The effect, most well established for recreational activity, has been
observed in both premenopausal and postmenopausal women, and
in women of different populations.
 Adult obesity and adult weight gain have both been associated with
increased breast cancer risk among postmenopausal women.
 A pooled analysis of data from eight prospective studies indicated
that breast cancer risk increased approximately 18% per 5
kg/m2 increase in BMI.
 Paradoxically, overweight or obese premenopausal women have an
estimated 10% to 30% decreased risk of breast cancer compared
with normal-weight or thinner women.

44.  Hormones are central in the discussion of biological mechanisms
linking both physical activity and obesity with breast cancer risk.
 Physical activity can alter menstrual cycle patterns in
premenopausal women, and hormone profiles in both
premenopausal and postmenopausal women.
 Physical activity may lower body fat among children, which in turn
may delay age at menarche.Later age at menarche has been
associated with reduced breast cancer risk.
 Physical activity may reduce the frequency of ovulatory
cycles.Having less frequent and therefore fewer cumulative
ovulatory cycles is likely to reduce the lifetime exposure of the
breast to endogenous ovarian hormones,proven proliferative
agents.

45.  The breast tissue of overweight or obese perimenopausal and
postmenopausal women with relatively high risk of breast cancer has been
shown to have cytologic abnormalities and higher epithelial cell counts than
that of normal-weight women.
 In contrast, obese premenopausal women experience menstrual cycle
disturbances, including anovulatory cycles and secondary amenorrhea,
thereby lowering their cumulative exposure to estradiol and progesterone.
 Other likely mechanisms that may link physical activity and obesity,with
breast cancer risk include aspects of immune function, inflammatory
mechanisms, oxidative stress and DNA repair capability, metabolic
hormones, and growth factors.

46.  The epidemiological literature suggests that increased physical activity is
protective for colon cancer.
 The CTS. Mai et al. reported that combined lifetime moderate and
strenuous leisure-time physical activity was modestly associated with colon
cancer risk in the CTS. The CTS participants who exercised at least 4 hours
per week during their reproductive years had 25% lower risk of colon
cancer relative to those who exercised no more than 30 minutes per week.
 Importantly, among postmenopausal CTS participants, those who had
never used menopausal hormone therapy experienced a 46% decrease in
colon cancer risk if they averaged at least 4 hours of exercise per week,
whereas those who had used menopausal hormone therapy experienced
no benefit from exercise.

47.  It has been argued that distal and proximal colon cancers have distinct etiologies.
 In contrast to colon cancer, nearly all epidemiological studies have failed to show a
relationship between physical activity and rectal cancer risk. However, the National
Institutes of Health-American Association of Retired Persons Diet and Health Study
shows a modest reduction in rectal cancer risk for men but not for women after 6.9
years of follow-up.
 Obesity is an established risk factor for colon cancer in both men and women,
although the relative risks for men have been marginally higher than those for
women.
 The adverse impact of overweight and obesity on colon cancer risk is stronger for
cancers of the distal than for the proximal colon.
 In the EPIC study, both high body weight and high BMI were statistically significantly
associated with increased colon cancer risk in men, but not in women; however,
other measures of adiposity including waist circumference and waist-to-hip ratio were
associated with colon cancer risk in both men and women.
 Again, no association between these adiposity measures and colon cancer risk was
evident among postmenopausal women who had used menopausal hormone
therapy, and no association was observed between any measure of adiposity and
rectal cancer risk.

48.  The mechanisms explaining the relationship between physical
activity and colon cancer are not clearly established, but include the
impact on insulin sensitivity and IGF profiles, and inflammation, as
well as some colon-specific mechanisms.
 Physical activity may stimulate stool transit in the colon, thereby
decreasing the exposure of colonic mucosa to carcinogens in the
stool.
 Alternatively, physical activity-induced decreases in prostaglandin
E2 may decrease colonic cell proliferation rates and increase colonic
motility.
 In addition to steroid hormones, which have been clearly implicated
as biological modifiers of the effect of physical activity and obesity
on colon cancer risk, as previously discussed, the insulin and IGF
pathways have been proposed as mediators of the associations
between these exposures and colon cancer risk.

49.  In particular for obesity, the link can be inferred because obesity can lead to insulin
resistance, a syndrome characterized by high circulating insulin levels.
 High insulin levels appear to promote cell proliferation and tumor growth in the
colon and may also suppress expression of IGF binding proteins 1 and 2, leading to
increased bioavailable IGF-1 levels.
 In a recent nested colon cancer case-control study, Ma et al reported that men in the
highest quintile of circulating IGF-1 concentration were at significantly higher risk for
colon cancer.
 Another possible mechanistic pathway involves inflammation. Individuals with chronic
colon conditions, such as inflammatory bowel disease, have higher colon cancer
incidence than those without these conditions.
 Thus, obesity-induced inflammation may mediate the association between obesity
and colon cancer by causing DNA damage in the colon and promoting the
development of colon cancer, or more directly, by inducing insulin resistance

50.  The evidence for an association between physical activity and endometrial
cancer risk is accumulating but is not as definitive as that for the association
between obesity and endometrial cancer or physical activity and
postmenopausal breast cancer.
 The epidemiological literature to date has suggested that risk of endometrial
cancer is decreased 20% to 40% in women who are in the highest versus
lowest category of physical.
 Although physical activity is associated with decreased risk of endometrial
cancer in both normal-weight and obese women, two recent studies have
suggested that this association is more pronounced for obese.

51.  In contrast, epidemiological studies have established the existence
of a strong association between obesity and endometrial cancer
risk.
 Some studies have suggested a linear trend between increasing
body weight and increasing endometrial cancer risk among
postmenopausal women, whereas the association between body
weight and endometrial cancer among premenopausal women may
be present only among obese women.
 Moreover, BMI appears to exert an effect on risk of endometrial that
is independent of physical activity.
 Like breast and colon cancer, endometrial cancer is another
hormone-dependent cancer; in fact, one of the best-established risk
factors for endometrial cancer is menopausal hormone therapy in
the form of unopposed estrogen.Thus, physical activity and obesity
are likely to influence endometrial cancer risk by altering
endogenous hormone profiles.

52.  As described earlier, heavier postmenopausal women have higher
circulating levels of estrogen than do lighter postmenopausal
women because of the aromatization of androstenedione in adipose
tissue. This is pertinent to endometrial cancer risk because this
aromatization occurs in the absence of progesterone, which
counteracts the proliferative effects of estrogen on endometrial
tissue.
 Physical activity may counter the proliferative effects of estrogen
either directly or by restricting weight gain. Some evidence also links
elevated insulin levels and diabetes to endometrial cancer risk.
 Clearly, physical inactivity and obesity play a role in the
development of insulin insensitivity and diabetes, providing another
mechanism by which they may influence endometrial cancer risk.

53.  Several case-control studies and one cohort study have examined the
association between physical activity and risk of adenocarcinoma of the
esophagus.
 Zhang et al. reported that participation in recreational physical activity more
than once per week was associated with decreased risk of esophageal
cancer in a non–statistically significant manner.
 Lagergren et al.reported no association between total, usual physical
activity (recreational and occupational) and esophageal adenocarcinoma.

54.  Results from the cohort study also support the hypothesis that
physical activity lowers risk of esophageal adenocarcinoma but not
squamous cell esophageal cancer.
 High BMI has been implicated as a risk factor for adenocarcinoma
of the esophagus in three population-based case-control studies
conducted in the United States and Sweden; esophageal
adenocarcinoma risk appears to increase directly with increasing
level of usual or recent BMI.
 Lagergren et al.reported a 16-fold increased risk of esophageal
adenocarcinoma when participants with a BMI in the obese range
(>30 kg/m2) were compared with the leanest participants (BMI <22
kg/m2). With disease usually developing after age 60 years, the
largest risks are observed among individuals who have been
consistently heavy for an extended period of time.

55.  The possible biologic mechanisms linking increased physical activity to
decreased esophageal adenocarcinoma risk include site-specific and
general cancer mechanisms.
 It is possible that physical activity decreases digestive track transit time in a
manner relevant to the stomach and esophagus.
 General cancer mechanisms include physical activity’s impact on the
immune system or steroid hormone pathways.
 It is likely that obesity impacts esophageal adenocarcinoma risk by
influencing gastroesophageal reflux disease.
 Gastroesophageal reflux symptoms, which are more common among obese
than normal-weight individuals and increase in prevalence as BMI
increases, have been associated with risk of esophageal adenocarcinoma.
 Gastroesophageal reflux may cause changes in the esophageal epithelium,
leading to Barrett’s esophagus, a precursor condition for esophageal
adenocarcinoma.

56.  At least six cohort studies and one case-control study have
investigated the association between kidney cancer and
physical activity, with mixed results.
 In the Hawaii and Los Angeles Multiethnic Cohort Study,
increased recreational physical activity was associated with
increased kidney cancer risk among women but not among
men.
 Results from a large Canadian case-control study showed no
effect of physical activity on kidney cancer risk among either
sex.
 Obesity, in addition to high blood pressure and diabetes, is an
established risk factor for kidney cancer.
 Early studies showed that the association between obesity and
renal cell cancer was stronger among women than men.
 Recent reports, however, have shown a more equal impact of
BMI on kidney cancer risk among women and men, with an
approximate 7% increase in risk per unit increase in BMI.

57.  Gallbladder cancer occurs more frequently in women than in men,
and the major risk factor is a history of gallstones, which have been
associated with use of exogenous estrogens.
 To date, we have found no epidemiological literature investigating
the possible association of physical activity and gallbladder cancer,
although several studies have assessed the possible association
between obesity and cancer of the gallbladder.
 Evidence from cohort and case-control studies has provided strong
evidence that increased BMI is an independent risk factor for cancer
of the gallbladder.
 In a recent population-based case-control study conducted in
Shanghai, higher BMI at all ages and a greater waist-to-hip ratio
were associated with an increased risk of gallbladder cancer among
subjects with and without a history of gallstones, suggesting that
both overall and perhaps abdominal obesity may be important in the
etiology of this disease.

58.  Studies addressing physical inactivity and obesity as potential risk
factors for NHL have been mixed, in part because they have not had
a sufficient number of cases to assess risk by NHL subtype.
 A large population-based case-control study in the United States
reported that high BMI does not increase risk of NHL overall, but
that extreme obesity (BMI ≥35 kg/m2) was associated with 70%
greater risk of diffuse NHL compared with individuals with normal
BMI.
 Further, nonoccupational physical activity was associated with lower
risk of NHL overall, but was strongest for diffuse NHL.
 The prospective CTS cohort has shown that, among women,
adiposity at age 18 was more important to overall B-cell NHL risk
than adiposity later in life; no association was reported between
long-term or recent recreational physical activity in this study.

59.  More than 20 studies have assessed the potential association
between physical activity and prostate cancer.
 In a review of the literature, Friedenreich and Orenstein concluded
that prostate cancer risk is reduced 10% to 30% when comparing
the most active with the least active men and suggested that it may
be high levels of physical activity earlier in life that are most relevant
to this disease.
 In a Canadian population-based case-control study of advanced
prostate cancer, defined as stage T2 or higher, in which lifetime
histories of activity were assessed, physical activity during
adolescence and overall lifetime strenuous activity were modestly
related to lower prostate cancer risk.
 The early epidemiological literature on the potential association
between obesity and prostate cancer provided no consistent
evidence of a relationship association.

60.  In studies that excluded localized or low-grade prostate cancer,
results have supported an association between obesity and
advanced prostate cancer.
 Freedland et al have proposed that obesity may be protective for
early-stage disease, but it may be a risk factor for aggressive
prostate cancer.
 A cohort study conducted by the American Cancer Society in which
obesity was associated with a 14% to 16% reduced risk for low-
grade prostate cancer, but a 22% increased risk for nonmetastatic
high-grade prostate cancer, and a 54% increased risk for metastatic
or fatal prostate cancer supports the explanation provided by
Freedland et al.
 Proposed mechanisms include paradoxical effects of testosterone
on low-grade versus more advanced prostate cancer and alterations
in insulin and circulating IGF-1 profiles.

61.  The existence of relationships between physical activity or obesity and lung cancer
risk is controversial. Physical activity may be protective for lung cancer, yet this effect
is not considered well established.
 A meta-analysis of nine studies published between 1966 and 2003 reported a 13%
decreased risk for lung cancer associated with moderate recreational physical activity
and a 30% decreased risk associated with strenuous activity. The impact appeared to
be slightly stronger among women than among men.
 Several studies have suggested the existence of an inverse association between
increasing BMI and lung cancer risk.
 However, this inverse effect may have been due to weight loss caused by preclinical
disease; this hypothesis is supported by the fact that the association disappears as
length of follow-up increases. The inverse effect may also have arisen due to residual
confounding by smoking; in fact, no association between BMI and lung cancer is
seen in nonsmokers

62.  The literature on risk of ovarian cancer in relation to physical activity and obesity has been
inconclusive.
 More than 18 studies have assessed the impact of physical activity on ovarian cancer risk. Risks
of ovarian cancer with increasing physical activity range from no change to 67%.
 Results from a recent analysis of data from the American Cancer Society Cancer Prevention
Study II cohort showed no evidence for an association between physical activity and ovarian
cancer risk; however, an association between history of sedentary behavior (sitting ≥6 hours per
day vs. <3 hours per day) was associated with more than a 50% increase in ovarian cancer risk.
 The evidence for an association between obesity and increased ovarian cancer risk is weak, with
few studies showing a statistically significant result.
 A meta-analysis of 16 studies investigating the possible association between adult obesity and
ovarian cancer risk indicated that adult obesity increases risk for ovarian cancer; the overall
pooled effect estimate indicated that adult obesity was associated with a 30% increase in ovarian
cancer risk

63. Physical Activity Overweight/Obesity
Breast,
postmenopausal
+++ +++
Breast, premenopausal ++ ++ (protection)
Colon +++ +++
Endometrium + +++
Esophagus,
adenocarcinoma
? +++
Kidney/renal cell ? +++
Gallbladder ? ++
Pancreas ? ++
Non-Hodgkin
lymphoma
? +
Prostate, aggressive + +
Lung + ?
Ovary ? ?
.