Diets and breast or colon cancers

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Hi All,

Below are a series of reports regarding new studies

of how our diets with respect to eating red meat and

fruits and vegetables may be related to our

incidence of cancer, and the results suggest that

there is no benefit and harm, respectively, for their

consumption, it seems.

Diet and cancer for the causation of breast cancer

has been previously been shown to be of variable

risk for incidence of breast cancer. So eating our

fruits and vegetables may not help. For red meats,

colon cancer does appear to be a risk for their

consumption. Both studies and summaries of

them are in the latest issue of Lancet.

Please see the below.

Study bolsters cancer-red meat link

Another casts doubt on fruits' and vegetables' benefits

CHICAGO, Illinois (AP) -- Two studies shed new light on the link

between diet and cancer, bolstering evidence that red meat may raise

colorectal cancer risks but casting doubt on whether fruits and

vegetables can help prevent breast cancer.

The new research doesn't settle the questions, partly because both

studies asked about eating habits only in adulthood. Some researchers

think that may have less impact on cancer risk than lifelong eating

habits.

Breast cancer risk, especially, may be more dependent on a woman's

diet during adolescence, when breast cells are rapidly dividing and

are more vulnerable.

Still, both studies are consistent with evolving thinking about

specific foods and their influence on cancer risks. The studies are

published in Wednesday's Journal of the American Medical Association.

In numerous previous studies examining diet and cancer, the

relationship between meat consumption and colorectal cancer is the

among the strongest, with most finding that eating lots of red meat

and processed meats increases the risk.

The new study, led by American Cancer Society researchers and

involving 148,610 men and women aged 63 on average, is among the

biggest. Participants recorded their meat intake in 1982 and again in

1992-93. Those with a high meat intake were about 30 to 40 percent

more likely to develop lower colon or rectal cancer than those with a

low intake.

High meat intake for men was at least 3 ounces daily -- about the

size of a large fast-food hamburger -- and 2 ounces daily for women.

Low intake was about 2 ounces or less of red meat no more than twice

weekly for men and less than an ounce that often for women.

Slightly higher risks were found for a high consumption of

processed meats including bacon and bologna.

Study co-author Dr. Thun, the cancer society's

epidemiology chief, said the results should be put into perspective:

Smoking, obesity and inactivity are still thought to be more strongly

linked with colon cancer than eating lots of red meat.

Still, Thun said, the results support cancer society dietary

guidelines recommending against heavy meat consumption and favoring a

variety of healthful foods.

The breast cancer study, involving 285,526 European women, found

no protective effect from fruits and vegetables in women questioned

about diet and followed for an average of about five years.

Studies on whether diets rich in fruits and vegetables might

protect against various cancers including breast, colon and stomach

cancer have had mixed results, though no effect was seen in some of

the more recent research on breast cancer.

The results don't rule out that a diet rich in fruits and

vegetables might reduce breast cancer risks for certain subgroups of

women, including those with a family history of breast cancer, said

lead author Dr. Petra Peeters of University Medical Center Utrecht in

The Netherlands.

But even if they don't help prevent breast cancer, fruits and

vegetables, as well as limiting red meat intake, are good for the

heart, said Dr. Walter Willett, a Harvard University nutrition expert

and author of a book promoting those habits.

" Fortunately, substituting pistachio-encrusted salmon and

gingered brown basmati pilaf for roast beef with mashed potatoes and

gravy is not a culinary sacrifice, " Willett said in a JAMA editorial

accompanying the studies.

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The Associated Press.

No. 2, January 12, 2005

This Week in JAMA

JAMA. 2005;293:135.

Diet and Cancer Risk

Many studies have assessed possible associations of dietary

components with cancer risk, often with inconclusive results. Two

articles in this issue of JAMA add additional insight. First, Chao

and colleagues (SEE ARTICLE) examined the association of recent and

long-term meat consumption and risk of incident colon and rectal

cancer in a large cohort of US adults. They found that prolonged high

consumption of red and processed meat is associated with an increased

risk of cancer in the distal colon. In a second article, van Gils and

colleagues (SEE ARTICLE) examined the relationship between total and

specific vegetable and fruit intake and the incidence of breast

cancer in a large cohort of European women. During a median 5.4 years

of follow-up, the authors found no association between vegetable and

fruit intake and incident breast cancer. In an editorial, Willett

(SEE ARTICLE) discusses these findings and the benefits of a

healthful diet.

Diet and Cancer: An Evolving Picture

Walter C. Willett

JAMA. 2005;293:233-234.

In a 1981 landmark report, Doll and Peto1 estimated that 35% of US

cancer deaths were attributable to dietary factors. This estimate was

primarily based on the large differences in rates of specific cancers

among countries and observations that these rates were strongly

correlated with aspects of national food supplies. However, these

authors acknowledged major uncertainties in responsible aspects of

diet and the magnitude of impact.

Since the early 1980s many detailed investigations including

mechanistic studies, animal experiments, epidemiological

observations, and clinical trials have addressed the potential

effects of diet on cancer incidence. Although much has been learned,

progress has been slower and more difficult than was anticipated. At

the beginning of this period, high total fat consumption was widely

believed to be the primary reason for the high rates of breast,

colon, prostate, and several other cancers.2 National dietary

recommendations and policy were largely driven by this presumed

relation. However, little relation between total fat intake and risk

of breast cancer and risk of colon cancer has been found in large

prospective studies.3-4 Although a weak effect is impossible to

exclude, evidence is strong that simply reducing the percentage of

energy intake from fat during midlife will not have a major impact on

breast and colon cancer.5 Prospective studies of prostate cancer are

far fewer, but no clear role for dietary fat per se has been seen.

The Women's Health Initiative trial, primarily justified to test the

hypothesis that reducing total fat would decrease breast cancer

incidence, will be concluding soon, but even if a modest effect is

seen, this would be difficult to interpret because many aspects of

diet have been changed simultaneously.6

As evidence to support the dietary fat hypothesis has waned,

enthusiasm increased during the 1990s for increasing fruit and

vegetable consumption to prevent cancer; the national Five-a Day

program was launched on this basis. Although inverse associations

between intakes of fruits or vegetables and incidence of various

cancers were reported in numerous case-control studies,7 the findings

from more recent large prospective studies have been far less

supportive of a benefit. In a recent report combining 2 large

cohorts, no relation was observed between total fruit and vegetable

consumption and overall cancer incidence.8 Randomized trials using

high doses of single constituents of fruits and vegetables, and beta

carotene in particular, also failed to show benefits and some even

suggested harm.9

One lesson from this experience has been that case-control studies

of diet, in which patients with cancer and a control group are asked

about their diet years in the past, can be misleading. Recall of diet

might be biased by the diagnosis of cancer, but in typical case-

control studies selection bias may be even more problematic.

Participation rates of patients with cancer are usually high, but

participation of population controls is often only 50% or 60%.10

Those who participate are likely to be more health conscious and

therefore consume more fruits and vegetables and less fat than those

who do not. When cases and controls are compared, this would lead to

apparent inverse associations with fruits and vegetables and positive

associations with fat.

The 2 reports in this issue of JAMA from large and well-conducted

prospective studies provide valuable increments to current knowledge

about diet and cancer.11-12 The lack of association between fruit and

vegetable intake and incidence of breast cancer seen in the European

Prospective Investigation Into Cancer and Nutrition (EPIC) study11 is

consistent with the pooled data from other large prospective studies

that included 351 825 women and 7377 cases of breast cancer.13 The

authors provide the caveats that necessarily attend any negative

study: a small benefit can never be excluded and a modest benefit

could exist for a subgroup of women (perhaps defined by genetic

factors) or a subset of cases (for example, defined by estrogen

receptor status). Measurement of diet will always be imperfect, which

will tend to attenuate a true association. However, assessments of

fruits and vegetables are informative because they predict blood

levels of micronutrients provided by these foods and correlate

reasonably well with intakes measured by more detailed approaches.14

The most important limitation of these studies is the lack of data

on diet during childhood. Studies on cancer risk among survivors of

the American bombing of Japan suggest that radiation exposure during

childhood most strongly increases risk of breast cancer and little

effect is seen for exposure after age 40 years.15 Thus, if

constituents of fruits and vegetables are acting to protect DNA from

damage, published studies could have entirely missed the critical

periods. Despite the caveats, the current body of evidence clearly

indicates that increasing fruit and vegetable consumption during

midlife will not have a major effect on overall incidence of breast

cancer. Such results are valuable because they prevent a false sense

of security and stimulate the exploration of alternative means for

prevention; for breast cancer these alternatives will probably need

to include pharmacological methods.

The positive findings of Chao et al12 relating intake of red meat

to risk of colon cancer contrast with the results for breast cancer.

Among the international correlations between dietary factors and

various cancers, the relation between meat consumption and colon

cancer has been the strongest. There is no shortage of plausible

mechanisms; heterocyclic amines formed in cooking, nitroso compounds

in processed meats, and heme iron have been among the proposed

agents,11 and these could act in combination. Positive associations

with intake of red meat have been seen consistently in case-control

studies, and a similar relationship was reported earlier in the

prospective Nurses' Health Study.16 In subsequent cohort studies,

this relationship has been observed only inconsistently, but in a

recent meta-analysis of cohort studies an overall positive

association was seen; this was strongest for processed meats.17 The

report by Chao et al12 adds further support for this relationship and

emphasizes the value of long follow-up and multiple measurements of

diet.

The rapid changes in colon cancer risk among migrants from low to

high incidence regions (or vice versa) indicate an important role of

exposures during adult life in colon carcinogenesis. However, the

relevant period between the assessment of diet and diagnosis could

still range from a few years to several decades; for smoking this

appears to be roughly 40 years.18 A single assessment of diet would

not be problematic if individuals' diets remained constant over time,

but intake of red meat has fluctuated greatly during the last 25

years in the United States.19 Thus, only one measure of intake could

seriously misrepresent an individual's intake during the critical

period. Added to the differences among studies in the population

characteristics, the amounts of red meat consumed, and methods of

cooking, some inconsistencies in findings are not surprising.

Although the overall data for red meat and colon cancer are strongly

suggestive of an important relation, they are not conclusive. Further

studies with long follow-up, repeated measures of diet, genetic

markers of susceptibility, more detailed measures of cooking methods,

and molecular characterization of colon cancer cases may be helpful.

Although recent findings on fruit and vegetable consumption and

cancer may be disappointing, reductions in blood pressure and

epidemiological evidence for lower risks of cardiovascular disease

provide sufficient reason to consume these foods in abundance. The

relation between red meat consumption and colorectal cancer may not

be conclusive, but prudence would suggest that red meat, and

processed meats in particular, should be eaten sparingly to minimize

risk. When combined with other healthful diet and lifestyle factors,

it appears that approximately 70% of colon cancer can potentially be

avoided.20 Replacing red meat with a combination of fish, nuts,

poultry, and legumes will also reduce risk of coronary heart disease,

in part, because some of these foods have positive benefits.21 This

substitution is an important part of the Mediterranean dietary

pattern, which improves blood lipids and other metabolic parameters22

and has been related to lower rates of total mortality.23 Thus,

keeping red meat consumption low is best viewed, not as an isolated

goal, but as part of an overall dietary and lifestyle strategy to

optimize health and well-being. Fortunately, substituting pistachio-

encrusted salmon and gingered brown basmati pilaf for roast beef with

mashed potatoes and gravy is not a culinary sacrifice.

Consumption of Vegetables and Fruits and Risk of Breast Cancer

Carla H. van Gils; Petra H. M. Peeters; H. Bas Bueno-de-Mesquita;

Hendriek C. Boshuizen; Petra H. Lahmann; Françoise Clavel-Chapelon;

Anne Thiébaut; Emmanuelle Kesse; Sabina Sieri; Domenico Palli;

rio Tumino; Salvatore Panico; Paolo Vineis; A. ;

Eva Ardanaz; -José Sánchez; Pilar Amiano; Carmen Navarro; José

R. Quirós; J. Key; Naomi ; Kay-Tee Khaw; Sheila A.

Bingham; Theodora Psaltopoulou; Koliva; Antonia Trichopoulou;

Gabriële Nagel; Jakob Linseisen; Heiner Boeing; Göran Berglund;

bet Wirfält; Göran Hallmans; Per Lenner; Kim Overvad; Anne

Tjønneland; Anja Olsen; Eiliv Lund; Dagrun Engeset; Elin Alsaker;

Norat; Rudolf Kaaks; Nadia Slimani; Elio Riboli

JAMA. 2005;293:183-193.

ABSTRACT

Context The intake of vegetables and fruits has been thought to

protect against breast cancer. Most of the evidence comes from case-

control studies, but a recent pooled analysis of the relatively few

published cohort studies suggests no significantly reduced breast

cancer risk is associated with vegetable and fruit consumption.

Objective To examine the relation between total and specific

vegetable and fruit intake and the incidence of breast cancer.

Design, Setting, and Participants Prospective study of 285 526

women between the ages of 25 and 70 years, participating in the

European Prospective Investigation Into Cancer and Nutrition (EPIC)

study, recruited from 8 of the 10 participating European countries.

Participants completed a dietary questionnaire in 1992-1998 and were

followed up for incidence of cancer until 2002.

Main Outcome Measures Relative risks for breast cancer by total

and specific vegetable and fruit intake. Analyses were stratified by

age at recruitment and study center. Relative risks were adjusted for

established breast cancer risk factors.

Results During 1 486 402 person-years (median duration of follow-

up, 5.4 years), 3659 invasive incident breast cancer cases were

reported. No significant associations between vegetable or fruit

intake and breast cancer risk were observed. Relative risks for the

highest vs the lowest quintile were 0.98 (95% confidence interval

[CI], 0.84-1.14) for total vegetables, 1.09 (95% CI , 0.94-1.25) for

total fruit, and 1.05 (95% CI , 0.92-1.20) for fruit and vegetable

juices. For 6 specific vegetable subgroups no associations with

breast cancer risk were observed either.

Conclusion Although the period of follow-up is limited for now,

the results suggest that total or specific vegetable and fruit intake

is not associated with risk for breast cancer.

INTRODUCTION

It is biologically plausible that diets high in vegetable and

fruit intake protect against cancer. Many vegetables and fruits are

high in candidate protective substances, such as fiber, antioxidant

vitamins and minerals, and other potentially anticarcinogenic

compounds including dithiolthiones, isothiocyanates, indole-3-

carbinol, flavonols, and lignans, to name a few.

Associations between vegetable and fruit intake and breast cancer

risk have been the subject of a large number of case-control studies

and a limited number of cohort studies. An extensive summary by the

World Cancer Research Fund1 of articles published to 1996 observed

that 8 of 11 studies on total vegetable intake and breast cancer risk

found protective associations. The same was true for only 4 of 12

studies on fruits. In a meta-analysis of 16 case-control studies and

3 cohort studies a 25% lower breast cancer risk was found for high vs

low consumption of vegetables and a 6% lower risk for high vs low

consumption of fruits.2 In contrast, a recent pooled analysis of 8

cohort studies showed no evidence for a protective effect of the

intake of vegetables and fruits as a whole nor for specific vegetable

and fruit groups.3 For comparisons of the highest vs the lowest

quartiles of intake, a statistically nonsignificant 4% lower risk was

observed for total vegetables and a 7% lower risk for total fruits.

In yet another meta-analysis, 15 case-control studies and 10 cohort

studies were analyzed separately.4 From the analysis of case-control

studies it was concluded that the relative risk of breast cancer was

14% lower for each additional 100-g/d intake of vegetables and 8%

(statistically nonsignificant) lower for each additional 100-g/d

intake of fruits. The analysis of cohort studies did not show any

relationship between vegetable or fruit intake and breast cancer

risk. The most recent meta-analysis evaluating a slightly different

selection of cohort and case-control studies showed a slightly lower

risk for high vs low vegetable intake in the 20 case-control studies

but not in the 7 cohort studies.5 Total fruit consumption, on the

other hand, was associated with a slightly lower breast cancer risk

in cohort studies but not in case-control studies.5

Discrepancies in results may be explained by differences in study

design, case-control studies being more susceptible to recall and

selection bias. On the other hand, most cohort studies examining diet

and breast cancer have been carried out in single populations in whom

dietary habits are relatively homogeneous, so that the extent of

measurement error would have obscured anything but very large

underlying diet disease associations.6-7 One way of reducing the

impact of measurement error is to study different populations with

diverse dietary practices, thus increasing the between-person

variance in diet and enabling the impact of measurement error to be

minimized.6

We describe herein how the intake of total and specific vegetable

and fruit groups is related to breast cancer risk among participants

in the European Prospective Investigation Into Cancer and Nutrition

(EPIC) study, a large prospective collaboration project carried out

in 10 European countries. This project, currently including 519 978

individuals, is the largest ever conducted specifically to

investigate the relationship between diet and cancer.8 It includes

participants living in countries from the north to the south of

Europe, spanning a wide range of vegetable and fruit consumption.9

........

RESULTS

In the 1 486 402 person-years of follow-up since 1992, 3659

invasive incident breast cancer cases with complete and satisfactory

data as described in the " Methods " section had been included in the

International Agency for Research on Cancer database by November

2002. Ninety percent of the tumors had been histologically confirmed.

The median duration of follow-up was 5.4 years (2.9 years in the

breast cancer cases). Thirty percent of the women were premenopausal,

18% perimenopausal, and 45% postmenopausal at recruitment. Menopausal

status was uncertain in 6%. The median age at breast cancer diagnosis

was 57 years. Table 1 shows the numbers of invasive breast cancers

included in the analysis according to country and age, the cohort

sizes and the corresponding numbers of person-years. On average,

breast cancer incidence rates were higher in northern than in

southern European countries.

Table 4 presents the number of cases and person-years and the

estimated RRs per EPIC-wide quintile of total vegetable and fruit

groups. Only invasive breast tumors are included. Different RRs are

presented: first unadjusted RRs (only stratified by center and age at

recruitment), followed by adjusted RRs for which all the breast

cancer risk factors listed in the Table 4 footnote were taken into

account.

No significant associations between intake of total vegetable and

fruit groups and breast cancer risk were observed. Relative risk

estimates for comparisons of the highest vs the lowest quintile were

0.98 (95% CI, 0.84-1.14) for total vegetables, 1.09 (95% CI, 0.94-

1.25) for total fruit, and 1.05 (95% CI, 0.92-1.20) for fruit and

vegetable juices. Looking at vegetable subtypes (Table 5), there was

no evidence for inverse associations between intake and breast cancer

risk either.

To ensure that the complete-subject approach we used in the

multivariate analyses did not lead to selection bias, we calculated

the crude risk estimates for the persons with complete data on all

potential confounding variables and compared these with the crude

risk estimates in the total cohort, as presented in Table 4. The

crude risk estimates in the persons with complete data for the

highest vs the lowest quintile were 0.96 (95% CI, 0.83-1.10) for

total vegetables, 1.04 (95% CI, 0.91-1.19) for total fruit, and 1.05

(95% CI, 0.93-1.20) for fruit and vegetable juices, which is hardly

different from the crude risk estimates in the total cohort.

Figure 1 shows country-specific RRs for breast cancer in relation

to total vegetable intake and Figure 2 in relation to total fruit

intake. On average, there was no evidence for protective effects of

either vegetable or fruit intake. Only Sweden showed a slight, but

nonsignificant, trend of a protective effect of vegetables and

fruits. In Spain slightly increased risks were observed.

Figure 3 shows the continuous original (uncalibrated) and

deattenuated (regression-calibrated) risks for breast cancer

according to total vegetable intake and according to total fruit

intake. The uncalibrated analysis is the analysis with the original

values as obtained from the dietary questionnaires. The regression-

calibrated analysis is the analysis with the predicted values based

on the calibration models that were built by regressing the 24-hour

recall values on the dietary questionnaire values. The predicted

values are believed to better reflect real intake because these

values are adjusted for systematic and random within-person errors as

well as between-center errors. The coefficient for total vegetable

intake (per 100 g/d) based on the food-frequency questionnaire

(uncalibrated) was 0.0129 (SE, 0.0187; P = .49), whereas that for the

calibrated values was 0.0210 (SE, 0.0580; P = .72). For total fruit

intake (per 100 g/d) the uncalibrated coefficient was 0.0130 (SE,

0.0124; P = .29) and the calibrated coefficient was 0.0281 (SE,

0.0271; P = .30). The SEs of the deattenuated estimates presented

herein are in fact too small because the uncertainty related to

measurement error correction has not been taken into account. Since

we could not find evidence for a relationship in the first place, the

calculation of SEs with bootstrap sampling, which is normally done to

obtain more conservative SEs, seems not relevant in this case.

The main analyses on total vegetable and fruit consumption in

EPIC-wide quintiles were repeated, restricting to younger women,

diagnosed with breast cancer at age 50 or younger, as a proxy for

hereditary breast cancer, but this made no essential difference to

our conclusion (highest vs lowest quintile for total vegetables RR,

1.25; 95% CI, 0.86-1.82 and total fruits RR, 1.17; 95% CI, 0.84-

1.64). Stratification by body mass index (below vs above median

value) did not lead to different conclusions either (for interaction

of body mass index with total vegetables, P = .60; with total fruits,

P = .58). In addition, to investigate whether cancers diagnosed soon

after recruitment may have influenced our findings, we repeated our

analyses excluding the first 2 years of follow-up. For vegetables,

this led to a slightly lower risk for the highest vs lowest quintile

(RR, 0.91; 95% CI, 0.75-1.11), but there was no evidence for a dose-

response relationship: P for trend = .62). Total fruits excluding the

first 2 years of follow-up did not lead to different findings

(highest vs lowest quintile RR, 1.15; 95% CI, 0.96-1.38).

To examine whether the type of food-frequency questionnaire could

have influenced our results, we ran separate analyses for centers

with extensive questionnaires, estimating individual average portion

sizes systematically, excluding those with semiquantitative food-

frequency questionnaires (Denmark, Naples, Italy, and Umea, Sweden),

with the same standard portion assigned to all participants. After

this restriction, results remained essentially the same (highest vs

lowest quintile for total vegetables RR, 0.99 [95% CI, 0.84-1.17] and

total fruits RR, 1.06 [95% CI, 0.91-1.23]).

COMMENT

In this prospective study with more than 3500 invasive breast

cancer cases, we observed no association of risk with either total

consumption of vegetables and fruits or with vegetable subgroups.

This absence of a protective association was observed among almost

all of the participating countries.

A protective effect is supported by a vast number of case-control

studies.1-2,4 It is possible, however, that the inverse relationships

reported from case-control studies may have been overstated, because

of recall bias and possibly because early symptoms in patients may

have led to a change in dietary habits. In addition, selection bias

is a problem in situations where control participation is less than

complete because those controls who participate are likely to be more

health conscious and consume greater amounts of vegetables and

fruits.

Our null findings are in agreement with a recent pooled analysis

of the cohort studies on vegetable and fruit intake and the risk of

breast cancer.3 One of the advantages of the Pooling Project is its

large sample size. Limitations are a potential for publication bias

and the fact that although all analyses were performed with the

original data in a standardized way, dietary questionnaires were very

different in design.

The advantages of our cohort study are its size and the wide range

of vegetable and fruit intake, caused by the inclusion of

participants living in countries from the North to the South of

Europe. The mean 24-hour-recall intake of total vegetables in the

fifth quintile was more than 2 times higher than that in the first

quintile. For total fruit intake the 24-hour-recall mean in the fifth

quintile was more than 3 times higher than that in the first

quintile. It thus seems unlikely that the range of intakes of these

foods was too narrow to detect an association, if there was one. This

study had 80% power to detect a relative risk of 0.84 for the highest

vs the lowest quintiles, tested with a 2-sided of.05.

Comparable with the pooled analysis by -Warner et al3 a

potential limitation of our study is that although a similar type of

dietary questionnaire is used in the various EPIC study centers, the

number and detail of questions about consumption of specific foods

was adapted to local habits, for dietary habits vary substantially

between countries. To adjust for possible systematic overestimation

or underestimation in dietary intake measurements, a calibration

approach was used.12 The calibration method assumes that the 24-hour

recall method measures the intake without bias and that the

measurement error of the 24-hour recalls is independent of that of

the dietary questionnaires. Because this might not be true, it could

be argued that the absence of any association of vegetable and fruit

intake with breast cancer risk in EPIC could be because the methods

for measuring diet are insufficiently accurate. Arguing against this

interpretation is the fact that EPIC has detected significant

associations of fruit intake with lung cancer, based on 860 cases.22

This suggests that the methods used by EPIC to estimate diet,

together with the wide range in dietary intakes, are sufficient to

detect associations of these foods with cancer risk.

Another critical issue is the fact that some of the cohorts were

not based on the general population but were school teachers, breast

cancer screening participants, members of blood donor organizations,

or vegetarian and health-conscious volunteers, which may lead to

differences in mode of detection between centers. Also, the fact that

in some countries national or regional breast cancer screening

programs (with varying coverage percentages) are organized, whereas

in others individual women may request a routine mammography, could

possibly lead to higher detection rates in some centers than in

others. Since all our analyses were stratified by center, however, it

is unlikely that this would have biased our results. Also, when

studying the results at country level, no clear protective effects

can be observed in any of the countries.

It has been suggested that only certain types of vegetables and

fruits confer protection against breast cancer risk. In our analysis

we were able to study the intake of a number of vegetable subgroups,

which did not appear to protect against breast cancer. It remains

possible, however, that there may be an association with specific

types of vegetables and fruits and their related nutrients. There may

be a protective effect of specific antioxidant or anticarcinogenic

food constituents that is diluted by looking at food groups as a

whole. Future analyses of breast cancer incidence in EPIC will

therefore aim to examine the associations of risk with specific

nutrients.

In addition, there is some evidence that protective effects of

vegetables and fruits would be stronger in women with a family

history of breast cancer23 or women with estrogen receptor positive

tumors.24 This information is not available from the EPIC cohort,

therefore, we were not able to confirm this.

Lastly, it should be noted that the duration of follow-up in EPIC

is still relatively short and that the dietary information collected

at baseline may not be the best reflection of what is etiologically

relevant. We cannot exclude that associations will be found after

more years of follow-up. However, the cohort studies as summarized in

the pooled analysis of -Warner et al,3 which varied in duration

of follow-up from 5 to 10 years, did not show stronger effects with

longer duration of follow-up. For now, the findings from this study

confirm the data from the largest pooled analysis to date,3 in that

no large protective effects for vegetable or fruit intake in relation

to breast cancer can be observed. This does not exclude the

possibility that protective effects may be observed for specific

nutrients or in specific subgroups of women, such as those with a

family history of breast cancer or estrogen-receptor positive tumors.

Meat Consumption and Risk of Colorectal Cancer

Ann Chao; J. Thun; Cari J. Connell; Marjorie L. McCullough;

J. s; W. Dana Flanders; Carmen ; Rashmi Sinha;

Eugenia E. Calle

JAMA. 2005;293:172-182.

ABSTRACT

Context Consumption of red and processed meat has been associated

with colorectal cancer in many but not all epidemiological studies;

few studies have examined risk in relation to long-term meat intake

or the association of meat with rectal cancer.

Objective To examine the relationship between recent and long-

term meat consumption and the risk of incident colon and rectal

cancer.

Design, Setting, and Participants A cohort of 148 610 adults aged

50 to 74 years (median, 63 years), residing in 21 states with

population-based cancer registries, who provided information on meat

consumption in 1982 and again in 1992/1993 when enrolled in the

Cancer Prevention Study II (CPS II) Nutrition Cohort. Follow-up from

time of enrollment in 1992/1993 through August 31, 2001, identified

1667 incident colorectal cancers. Participants contributed person-

years at risk until death or a diagnosis of colon or rectal cancer.

Main Outcome Measure Incidence rate ratio (RR) of colon and

rectal cancer.

Results High intake of red and processed meat reported in

1992/1993 was associated with higher risk of colon cancer after

adjusting for age and energy intake but not after further adjustment

for body mass index, cigarette smoking, and other covariates. When

long-term consumption was considered, persons in the highest tertile

of consumption in both 1982 and 1992/1993 had higher risk of distal

colon cancer associated with processed meat (RR, 1.50; 95% confidence

interval [CI], 1.04-2.17), and ratio of red meat to poultry and fish

(RR, 1.53; 95% CI, 1.08-2.18) relative to those persons in the lowest

tertile at both time points. Long-term consumption of poultry and

fish was inversely associated with risk of both proximal and distal

colon cancer. High consumption of red meat reported in 1992/1993 was

associated with higher risk of rectal cancer (RR, 1.71; 95% CI, 1.15-

2.52; P = .007 for trend), as was high consumption reported in both

1982 and 1992/1993 (RR, 1.43; 95% CI, 1.00-2.05).

Conclusions Our results demonstrate the potential value of

examining long-term meat consumption in assessing cancer risk and

strengthen the evidence that prolonged high consumption of red and

processed meat may increase the risk of cancer in the distal portion

of the large intestine.

Meat consumption has been associated with colorectal neoplasia in

the epidemiological literature, but the strength of the association

and types of meat involved have not been consistent. Few studies have

evaluated long-term meat consumption or the relationship between meat

consumption and the risk of rectal cancer. Studies of red meat

consumption and colorectal adenoma have reported odds ratios in the

range of 1.2 to 1.3.1-3 Case-control studies4-25 of colorectal cancer

conducted in the United States and Europe have generally reported

increased risk associated with red or processed meat intake in

analyses of men,4-9,13-14 and men and women combined,10-12,15-25 but

not in analyses that included only women.5-9,13 Case-control

studies26-32 of colorectal cancer among Asians in the United States

or Asia have more consistently reported a positive association with

red, processed, or total meats.

Five33-37 of 1033-42 US prospective studies of colorectal cancer

reported positive associations with red or processed meat intake,

although some associations35-37 did not reach statistical

significance. European prospective studies43-49 have generally

reported no association with fresh or total meat but positive

associations with cured or processed meat,43, 45-46 sausages,47 or

smoked/salted fish.45 High consumption of poultry or fish has been

inconsistently associated with higher36-37,46 or lower34, 40-41,47,

49 risk of colorectal cancer; some studies have found no

association.33, 39, 42-43,45, 48 Only 2 prospective studies38, 49

have reported on rectal cancer in relation to meat consumption. The

results were conflicting but were limited by the small number of

cases.

A meta-analysis50 of case-control and prospective studies

estimated the mean relative risk comparing the highest to lowest

categories of meat consumption to be 1.35 (95% confidence interval

[CI], 1.21-1.51) for red meat and 1.31 (95% CI, 1.13-1.51) for

processed meat and colorectal cancer. A review of prospective

studies51 concluded that a daily increment of 100 g of red or total

meat consumption was associated with a 12% to 17% higher risk of

colorectal cancer, and that an increment of 25 g of processed meat

was associated with a 49% higher risk. Not all risk estimates

included in these review articles were adjusted for potential

confounders beyond age and energy intake, so residual confounding may

influence the summary risk estimates.

Clarifying the role of meat consumption in colorectal

carcinogenesis is important. Meat is an integral component of diet in

the United States and many other countries in which colorectal cancer

is common. Per capita annual consumption of beef has increased in the

United States since 1993, reversing a previous decrease since 1976.

Poultry consumption has surpassed beef consumption since the late

1980s.52-53

An earlier analysis of the Cancer Prevention Study II (CPS II)

Mortality Cohort, based on deaths from colorectal cancer from 1982 to

August 1988, found no association between colorectal cancer mortality

and high consumption of red meat, but suggested lower risk associated

with higher intake of chicken and fish in women.41 We examined the

relationship between meat consumption and incident colon and rectal

cancers among 148 610 men and women enrolled in the CPS II Nutrition

Cohort in 1992/1993.

This analysis was based on 1667 incident cases of colon or rectal

cancer diagnosed from the time of enrollment in 1992/1993 through

August 31, 2001. Participants contributed person-years at risk until

death or a diagnosis of colon or rectal cancer. Excluded from the

analysis were persons who were not known to be deceased but failed to

respond to the 1997, 1999, and 2001 questionnaires (3.7%); reported a

colon or rectal cancer not verified by pathology report or death

certificate (0.3%); reported at baseline a personal history of colon

or rectal cancer (1.5%); reported uninterpretable or missing data on

meat consumption in 1982 (4.7%); completed less than 85% of the food

section of the 1992/1993 questionnaire; or reported implausibly high

or low energy intake (9.1%). After exclusions, the analytic cohort

included 69 664 men and 78 946 women, representing 81% of the CPS II

Nutrition Cohort.

....

Incident Colon and Rectal Cancer

A total of 1197 incident cancers of the colon (International

Classification of Diseases codes: C18.0, C18.2-C18.9)56-57 and 470

cancers of the rectosigmoid junction (C19.0)56-57 or rectum (C20.9)56-

57 were identified. Of these, 665 colon and 291 rectal cancers were

diagnosed in men, and 532 colon and 179 rectal cancers in women. A

total of 1335 (80%) of 1667 colorectal cancers were self-reported on

the 1997, 1999, or 2001 questionnaires and subsequently verified by

medical record abstraction or linkage with state cancer registries;

another 43 (3%) were identified while verifying a different reported

cancer; and 289 (17%) were identified as interval deaths, defined as

persons who died with colon or rectal cancer recorded on death

certificate but not reported on the questionnaire. Linkage with state

cancer registries confirmed the diagnosis of colon or rectal cancer

in 74% of interval deaths. Subsite-specific analyses were conducted

on 667 proximal (cecum to splenic flexure) and 408 distal (descending

to sigmoid colon) colon cancers, excluding those with overlapping or

unspecified site codes. We also present the results from analyses of

470 cancers of the rectosigmoid and rectum combined but not from

separate analyses of the rectosigmoid junction (214 cases) or rectum

(246 cases). The remaining 10 cases were unspecified (not able to

distinguish as rectum or rectosigmoid junction).

Meat Consumption

Dietary assessment in 1992/1993 was based on a 68-item modified

Block58 food-frequency questionnaire (FFQ); nutrient values were

estimated using the Dietary Analysis System version 3.8a.59

Participants were asked to report their usual eating habits during

the past year, including average frequency and serving size (small,

medium, or large) of each food and beverage listed. Consumption of

each meat item in grams per week was estimated by taking the product

of average frequency per week, number of grams in a medium serving,

and serving size (0.5 for small, 1.0 for medium, and 1.5 for large).

Intake of red meat, poultry and fish, and processed meat (g/wk) was

computed by summing across meat items that contributed to each meat

group and categorizing by quintile. The lowest quintile of intake

served as the referent group for analyses.

We considered red meat to include the following individual or

grouped items on the questionnaire: bacon; sausage; hamburgers,

cheeseburgers, meatloaf, or casserole with ground beef; beef (steaks,

roasts, etc, including sandwiches); beef stew, or pot pie with

carrots or other vegetables; liver, including chicken livers; pork,

including chops, roast; hot dogs; and ham, bologna, salami, or

lunchmeat. Food items classified as poultry and fish included chicken

or turkey (roasted, stewed, broiled, ground, including sandwiches);

fried chicken; fried fish or fish sandwich; tuna, tuna salad, tuna

casserole; and other fish (broiled or baked). We considered processed

meat to include bacon; sausage; hot dogs; and ham, bologna, salami,

or lunchmeat. We computed the ratio of red meat-to-poultry and fish

by dividing red meat intake by intake of poultry and fish (g/wk);

individuals were assigned to the lowest or highest quintile when

either value was 0. An additional question, " How often did you eat

beef, pork, or lamb as a main dish, eg, steak, roast ham, etc (4-6

ounces)? " was included for comparison with other studies that

included this question. Participants were also asked, " When you eat

red meat such as beef, pork, or lamb, how well done is it cooked? "

with the following possible responses on the questionnaire, " well-

done, medium well done, medium rare, rare, and don't eat red meat. "

The 1992/1993 FFQ was validated among 441 Nutrition Cohort members

who completed four 24-hour dietary recall interviews and a repeat

FFQ.60 For red meat, the correlation coefficient between the FFQ and

dietary recall interview was 0.55 among men and 0.78 in women;

between the initial FFQ and the repeat FFQ, the correlation

coefficient was 0.81 in men and 0.78 in women.

The 1982 questionnaire asked participants to report the average

number of days per week they ate each of the 11 meat items. Intake

frequencies of red meat, poultry and fish, and processed meat were

computed by summing the number of days per week across individual

meat items that contributed to each meat group, and categorizing into

quintiles. Foods categorized as red meat were beef, pork, ham, liver,

smoked meats, frankfurters/sausage, fried bacon, and fried hamburger;

poultry and fish included chicken, fish, and fried chicken/fish; and

processed meats included ham, smoked meats, frankfurters/sausage, and

fried bacon. Turkey was not included on the 1982 questionnaire but

was included on the 1992/1993 questionnaire.

We examined long-term meat consumption by considering consumption

reported in 1982 and in 1992/1993. Consumption at each time point was

categorized into tertiles (low, moderate, high) and participants were

classified as low intake in 1982 and 1992/1993 (referent group), high

intake in 1982 and 1992/1993, and all other combinations of intake

over time.

Statistical Analysis

Colon and rectal cancer incidence rate ratios (RRs) and 95% CIs by

meat intake were estimated using proportional hazards regression

modeling. P values for linear trend were estimated by modeling meat

intake (g/wk) using the median value within quintiles; these results

were similar when modeled as continuous variables. This study was

observational, not randomized, so P values were interpreted as

approximate.61 To obtain P values and confidence limits, we treated

the disease outcome as though it were a random variable that changed

over time. Potential confounders were chosen based on a priori

considerations and on the observed association with colon or rectal

cancer and meat intake.

For each meat variable, we constructed 3 models stratified by

single year of age, controlling for other covariates. Model 1 also

included total energy (continuous); model 2 included total energy,

education (some high school, high school graduate, some college or

trade school, college graduate or postgraduate work, or unknown),

body mass index calculated as weight in kilograms divided by the

square of height in meters in 1992/1993 (<18.5, 18.5-24.9, 25.0-29.9,

30.0-39.9, 40.0, or unknown), cigarette smoking in 1992/1993 (never,

former, current, ever smoker not specified, or unknown), recreational

physical activity in 1992/1993 (none, hours per week of walking, or

walking plus other activities), multivitamin use in 1982 (none,

current user, or unknown), aspirin use in 1982 and in 1992 (nonuser

in 1982 and 1992, 15 days per month in 1982 and 1992, <15 days per

month in 1982 or 1992, or unknown at either time point), intake of

wine (none, any), beer (none, any), and liquor (none, any), and

hormone therapy use in 1992/1993 among women (nonuser, former user,

current user, ever user not specified, or unknown). Model 3 included

all covariates in model 2 plus intake of fruits in 1992/1993

(quintiles), vegetables in 1982 (quintiles), and high-fiber grain

foods in 1982 (quintiles). Models of men and women combined also

included a term for sex. Family history of colorectal cancer reported

in 1982 was examined and excluded as a potential confounder; no

information on family history of colorectal cancer was available in

1992/1993. Results of models including age and energy were similar to

those from models including only age or age plus energy in quintiles.

In a subanalysis of meat consumption reported in 1992/1993, we

examined quintiles of energy-adjusted intake of red meat, poultry and

fish, and processed meat based on the residual method.62 We also

examined how the association with each type of meat was affected when

controlling for other types of meat; no substantial difference was

observed in these analyses (results not shown).

We tested the proportional hazard assumption for each meat intake

variable in relation to colon or rectal cancer using the likelihood

ratio test, comparing models with and without product terms for meat

consumption (quintiles) and follow-up time (years). We evaluated

effect modification of the RR for colon and rectal cancer in relation

to meat consumption by other covariates using the likelihood ratio

test comparing models with and without interaction terms. The Wald

statistic was used to test for homogeneity of the RR for proximal and

distal colon cancers.63 All P values were 2-sided and considered

significant at P<.05. All analyses were conducted using SAS version

9.0 (SAS Institute Inc, Cary, NC).

Participant Characteristics by Meat Consumption

Men and women reported a wide range in consumption of red and

processed meat in 1992/1993. A 10-fold difference was observed

between the lowest and highest quintiles of red meat in men and a 17-

fold difference in women (Table 1). Men reported greater consumption

of red and processed meat than did women; median intake was 427 g/wk

and 274 g/wk for red meat among men and women, respectively, and 95

g/wk and 43 g/wk for processed meat, respectively. There was little

variation in the consumption of poultry and fish by quintiles of red

meat intake. Men also reported substantially higher intake of red and

processed meats in 1982 than did women (data not shown).

Approximately half of the men and women in the top tertile for

consumption of red or processed meat in 1982 were also in the highest

tertile in 1992/1993 (data not shown). The absolute levels of meat

consumption in 1982 could not be compared with consumption in

1992/1993 due to differences in the questionnaires.

Men and women who reported higher intake of red meat in 1992/1993

(Table 1) were more likely to report lower educational attainment, no

recreational physical activity, higher body mass index, current

cigarette smoking, beer and liquor drinking, higher total daily

energy intake, low fruit intake in 1992/1993, and little or no intake

of vegetables or high-fiber grain foods in 1982 compared with those

with lower red meat intake. Men and women who reported lower red meat

intake tended to report multivitamin use in 1982, wine drinking, and

(in women) use of hormone therapy in 1992/1993.

Meat Consumption and Colon Cancer Incidence

Table 2 shows the relationship between colon cancer incidence and

meat consumption as reported in 1992/1993. Higher intake of red and

processed meat was associated with higher colon cancer risk in men

and women in models that adjusted only for age and energy intake

(model 1). However, the positive associations were attenuated in

analyses (model 2) that further adjusted for nondietary factors,

including education, body mass index, cigarette smoking, recreational

physical activity, use of multivitamins or aspirin, and (in women)

use of hormone therapy. Further adjustment for dietary factors (model

3) had little effect on the RR estimates. No association was observed

between colon cancer incidence and consumption frequency of beef,

pork, or lamb as a main dish, or with reported preference for red

meat doneness (data not shown).

Higher consumption of poultry and fish was inversely associated

with colon cancer risk in women but not men (Table 2). Further

adjustment for additional covariates other than energy attenuated the

association. Among women, the inverse relationship remained

statistically significant (P = .03 for trend). The positive

association between colon cancer risk and ratio of red meat-to-

poultry and fish intake was also stronger in women than men. The

trend test for the ratio of red meat-to-poultry and fish intake was

statistically significant in men, women, and both sexes combined. The

inverse, marginally significant, association between high consumption

of poultry and fish and colon cancer risk in men and women remained

unchanged when adjusting simultaneously for red meat (data not

shown).

Proximal and Distal Colon Cancer, and Rectal Cancer

Table 3 shows the relationship between meat consumption reported

in 1992/1993 and incident colon cancer by subsite and rectal cancer

in men and women combined. After covariate adjustment, no consistent

association was observed between consumption of red meat, poultry and

fish, or processed meat as reported at a single time point and cancer

of either subsite of the colon. Men and women in the second to fifth

quintiles of red meat intake had higher risk of rectal cancer

compared with those in the lowest quintile, particularly those

individuals in the highest quintile (RR, 1.71; 95% CI, 1.15-2.52; P

= .007 for trend). This association was observed primarily with

cancers of the rectosigmoid junction (RR, 2.40; 95% CI, 1.30-4.43)

with risk increasing significantly with the amount of red meat

consumed (P = .002 for trend). No significant association was

observed between red meat consumption and cancers of the rectum (data

not shown). No clear association was observed between rectal cancer

risk and other measures of meat consumption reported in 1992/1993.

Energy-Adjusted Meat Intake

Analyses using energy-adjusted meat intake reported in 1992/1993

yielded results similar to those using meat intake (g/wk) with few

exceptions. Compared with risk estimates derived from nonenergy-

adjusted meat intake, the association between colon cancer and

consumption of processed meat (RR, 1.35; 95% CI, 1.04-1.77; highest

to lowest quintile, P = .02 for trend) became stronger in men,

although the association between rectal cancer and red meat intake

(RR, 1.31; 95% CI, 0.96-1.79; P = .03 for trend) was attenuated in

men and women combined. Other risk estimates for red meat, poultry

and fish, and processed meat remained unchanged.

Long-term Meat Consumption

Table 4 presents multivariate-adjusted RRs for colon cancer by

subsite and rectal cancer among persons who were in the highest

tertile of meat consumption in both 1982 and 1992/1993 compared with

those in the lowest tertile at both time points. Prolonged high

consumption of red meat was associated with a statistically

nonsignificant increased risk of distal colon cancer (RR, 1.29; 95%

CI, 0.88-1.89). The most consistent associations were observed

between distal colon cancer and prolonged high intake of processed

meat (RR, 1.50; 95% CI, 1.04-2.17), and ratio of red meat to poultry

and fish (RR, 1.53; 95% CI, 1.08-2.18) compared with persons with

prolonged low intake. These associations were not observed with

cancer of the proximal colon. The association between distal colon

cancer and consumption of processed meat was stronger in analyses

based on long-term consumption than on that reported only in 1982

(data not shown). Long-term high intake of poultry and fish was

marginally associated with lower risk of proximal (RR, 0.77; 95% CI,

0.59-1.02) and distal (RR, 0.70; 95% CI, 0.50-0.99) colon cancer.

Red meat consumption was marginally associated with higher risk of

rectal cancer (RR, 1.43; 95% CI, 1.00-2.05); this association was

somewhat stronger for cancers of the rectosigmoid junction (RR, 1.75;

95% CI, 1.04-2.96) than for cancer of the rectum (RR, 1.31; 95% CI,

0.79-2.15). The relationship between long-term consumption of red

meat, poultry and fish, and risk of colon or rectal cancer remained

unchanged when all were included in the same model (data not shown).

Effect Modification

No statistically significant interaction was observed between meat

consumption and other known risk factors for colon or rectal cancer

on a multiplicative scale.

The association between processed meat consumption and colon

cancer risk was independent of other covariates only when intake was

measured at 2 time points during a 10-year interval. Moreover, the

association was observed consistently only for cancers of the distal

colon. Prolonged high consumption of red meat was associated with

higher risk of rectal cancer, particularly cancers of the

rectosigmoid junction. Prolonged high consumption of poultry and fish

was marginally associated with lower risk of proximal and distal

colon cancer but not rectal cancer.

A strength of our study was the ability to control for several

factors known to influence colon cancer risk. Inadequate control for

potential confounding may partly explain the inconsistently observed

positive associations between red meat and colon cancer risk in other

studies, since some positive articles included in the quantitative

reviews50-51 have adjusted for only age and energy. In our analyses,

the association between colon cancer risk and high intake of red (RR,

1.41; 95% CI, 1.12-1.78) and processed meat (RR, 1.33; 95% CI, 1.08-

1.64) measured at a single time point is consistent with meta-

analysis results,50 adjusting for age and energy intake. However, the

association was substantially attenuated with further adjustment for

educational attainment, cigarette smoking, physical activity, and

other lifestyle factors associated with red meat intake.

To our knowledge, no study has addressed the relationship between

long-term meat consumption and risk of colon and rectal cancer. The

association with distal colon cancer was stronger among persons who

reported greater consumption of processed meat at 2 time points

during a 10-year interval, as was the risk of cancer of the

rectosigmoid junction among those persons who consistently reported

high red meat intake. It is possible that true high consumers of red

or processed meat were better defined with less measurement error

when assessed twice during a 10-year period. It is also plausible

that long-term high consumption of red and processed meat may be more

strongly associated with colorectal carcinogenesis than short-term or

sporadic consumption of meat. Certain components of red meat may

affect both early and late stages in the development of neoplasia.

Animal studies show that diets high in red meat tend to affect the

early aberrant crypt stage of carcinogenesis.64 To our knowledge, no

study has evaluated the importance of continued high exposure to red

meat in animal models.

The higher risk associated with prolonged consumption of red meat

but not poultry and fish is consistent with other epidemiological

studies.33-34,38, 40 The cytotoxic effect of dietary heme has been

proposed as a potential mechanism by which red meat increases

colorectal cancer risk because of higher heme content in red meat

compared with poultry and fish.65-66 Heme damages the colonic mucosa

and stimulates epithelial proliferation in animal studies.66 Both

ingestion of red meat and heme iron supplementation have been shown

to increase fecal concentrations of N-nitroso compounds65 and DNA-

adducts in human colonocytes.67-68

We found that consistently high consumption of processed meat was

associated with increased risk of distal colon cancer. Results of

prospective studies of colorectal cancer and processed meat have been

more consistently positive in Europe43, 45, 47 than in the United

States.33-34,39-40,42 Processed meat includes foods preserved by

salting, smoking, or the addition of nitrites or nitrates, and high

consumption of these foods can increase exposure to nitrosamines and

their precursors. The amount of these substances in processed meat

likely varied by region and over time but we had no information to

assess the impact of these differences in our study results.

Several prospective studies have reported an inverse association

between colon cancer risk and prolonged high consumption of poultry

and fish.34, 40-41,47, 49 However, other studies have found either no

association33, 39, 42-43,45, 48 or increased risk36-37,46 associated

with poultry and fish consumption. The lower risk associated with

high consumption of poultry and fish or a low ratio of red meat-to-

poultry and fish could be attributed to a displacement of red meat in

the diet, but in our study high consumption of poultry and fish

remained independently associated with lower risk of colon cancer

even when controlling for red meat intake. It is also possible that

poultry and fish contain factors that may protect against colon

cancer. Poultry contains small amounts of nutrients such as selenium

and calcium that have been associated with lower risk of colorectal

neoplasia,69-71 but it is a relatively minor source of these

nutrients. Fish is a primary source of omega-3 fatty acids and high

intake of fish or fish oil has been inversely associated with

colorectal cancer risk in some epidemiological studies.40, 47, 72 In

experimental studies, omega-3 fatty acids have been shown to inhibit

tumor growth and to modulate the expression of proinflammatory

genes.73-74 However, the poultry and fish consumed by CPS II

Nutrition Cohort participants consisted mostly of chicken.

Our findings add to the limited prospective data38, 49, 75 on meat

consumption in relation to rectal cancer. Consumption of red meat, as

reported in 1992/1993, was more strongly associated with rectal than

colon cancer in our study, as has been reported in some4-5,20-21 but

not all17-18,23-24,28-29 case-control studies. One recent case-

control study found no association between rectal cancer and red

meat, poultry and fish, or processed meat consumption but reported

increased risk associated with greater doneness of red meat among

men.76 In our study, the positive association and significant dose-

response relationship was observed mostly with tumors of the

rectosigmoid junction rather than the rectum. Taken together with the

higher risk of cancer observed in the distal colon, our results

suggest that tumors in the distal portion of the large intestine may

be particularly associated with meat consumption. It is possible that

concentration of stool in the distal portion of the large intestine

may contribute to higher cancer risk by increasing exposure to

carcinogens as a result of water resorption during transit through

the large intestine.

Our study had several limitations in addition to the measurement

error inherent in studies based on FFQs.77 The 1982 questionnaire did

not assess the number of servings of meat per day and could not

differentiate persons who ate multiple servings from those who ate

meat only once per day; we were also unable to estimate total energy

intake from the 1982 diet questionnaire. We had no information on

meat cooking methods to estimate exposure to heterocyclic amines or

other specific carcinogens produced from pyrolysis of meat78-82; our

reliance on self-reported data on preference for doneness of meat was

likely a crude proxy of the relevant exposures. Although heterocyclic

amines are potent mutagens in the Ames assay and are carcinogenic in

animal studies, the impact of these compounds on colorectal

carcinogenesis in humans is less clear,81-83 primarily due to the

difficulties in measuring exposure and possible interactions between

meat and other dietary constituents or genetic susceptibility.9, 84

We had no information on family history of colorectal cancer from the

1992/1993 questionnaire to update this important variable, which

could potentially modify the association between meat intake and risk

of colorectal cancer. No information was collected on examination by

sigmoidoscopy, colonoscopy, or fecal occult blood test in either the

1982 or 1992/1993 questionnaires. However, in 1997, persons who

reported long-term high consumption of red meat were less likely

(23%) to have had endoscopy for screening than those persons who

reported long-term low intake of red meat (34%). It is difficult to

predict the net effect of endoscopy on colorectal cancer incidence.

On the one hand, endoscopic removal of precancerous lesions could

contribute to lower risk; however, endoscopy could accelerate the

diagnosis of some tumors that might not otherwise have been

identified during the follow-up period.

The main strengths of this study are its size, the availability of

dietary and other exposure information collected prospectively from

respondents at 2 time points, and information on major potential

confounders. The sample size allowed us to obtain stable estimates of

risk and to show differences by colorectal subsite. Our results

demonstrate the potential value of examining long-term meat

consumption in assessing risk and strengthen the evidence that

prolonged high consumption of red and processed meat may increase the

risk of cancer in the distal portion of the large intestine.

Cheers, Al Pater.