FW: Dairy, calcium, vitamin D and breast cancer

October 22, 2002

-----Original Message-----

From: Alan Pater [mailto:apater@...]

Sent: Monday, October 21, 2002 6:02 PM

'CR List'

Subject: Dairy, calcium, vitamin D and breast cancer

Hi All, especially the ladies. The attached paper is on dairy and

especially low-fat milk as a diet risk reduction factor for development of

breast cancer. The PDF is available. Willett is senior author and his work

is well known. See the archives for a much better representation of the

tables. It comes up there before it reaches your mailbox.

I first below put in a few excerpts I found were interesting.

“Because vitamin D modulates calcium metabolism, effects of dairy calcium

might be modified by vitamin D intake. When we stratified the data by

tertiles of total vitamin D intake, dairy calcium appeared to be associated

with reduced risk of premenopausal breast cancer in women at all levels of

vitamin D intake (Pinteraction = .85). According to the calcium–high fat

hypothesis (25,26), the effect of calcium should be stronger in the

high-fat-diet group. However, we observed an inverse association between

dairy calcium intake and premenopausal breast cancer in all tertiles of

total fat intake. Similarly, the association between total vitamin D intake

and premenopausal breast cancer was not modified by total fat intake. The

inverse association between dairy calcium and breast cancer also was not

modified by height, current BMI, or alcohol intake.”

“According to the calcium–high fat hypothesis (25,26), the effect of calcium

should be stronger in the high-fat-diet group. However, we observed an

inverse association between dairy calcium intake and premenopausal breast

cancer in all tertiles of total fat intake. Similarly, the association

between total vitamin D intake and premenopausal breast cancer was not

modified by total fat intake. The inverse association between dairy calcium

and breast cancer also was not modified by height, current BMI, or alcohol

intake.”

“vitamin D intake appears to offer a possible protective association apart

from the " milk effect. " ”

“Lactose can aid the absorption of dietary calcium as well as promote the

growth of lactic acid-producing bacteria in the large intestine. Although

lactose intake is suspected to be associated with an increased risk of

ovarian cancer (46) and decreased risk of colon cancer (47), little is known

about its relationship with breast cancer. Lactose has been hypothesized to

increase ovarian cancer risk by direct toxicity to oocytes and by inducing

premature ovarian failure (48). This effect could reduce exposure of breast

tissue to estrogen. Some epidemiologic studies reported an inverse

association between fermented milk (6) and yogurt (12) and risk of breast

cancer, interpreting this as an effect of lactose or lactic acid.”

“Conjugated linoleic acid (CLA), a mixture of positional and geometric

isomers of linoleic acid, comes from dairy (60%) and beef (32%) products

(49) and is a potent anticarcinogen in animal models (50). However, the

inverse association we saw with dairy foods was probably not due to CLA

because it was strongest for low-fat dairy products, which should have low

CLA content.”

Cheers, Al.

Alan Pater, Ph.D.; Faculty of Medicine; Memorial University; St. 's, NL

A1B 3V6 Canada; Tel. No.: (709) 777-6488; Fax No.: (709) 777-7010; email:

apater@...

J Natl Cancer Inst 2002 Sep 4;94(17):1301-11

Intake of dairy products, calcium, and vitamin d and risk of breast cancer.

Shin MH, Holmes MD, Hankinson SE, Wu K, Colditz GA, Willett WC.

BACKGROUND: Laboratory data suggest that calcium and vitamin D, found at high

levels in dairy products, might reduce breast carcinogenesis. However,

epidemiologic studies regarding dairy products and breast cancer have yielded

inconsistent results. We examined data from a large, long-term cohort study to

evaluate whether high intake of dairy products, calcium, or vitamin D is

associated with reduced risk of breast cancer. METHODS: We followed 88 691 women

in the Nurses' Health Study cohort from the date of return of their

food-frequency questionnaire in 1980 until May 31, 1996. Dietary information was

collected in 1980 and updated in 1984, 1986, 1990, and 1994. We identified 3482

women (premenopausal = 827, postmenopausal = 2345, and uncertain menopausal

status = 310) with incident invasive breast cancer. We used pooled logistic

regression to estimate multivariable relative risks (RRs) using 2-year time

increments. The RRs and 95% confidence intervals (CIs) were calculated for each

category of intake compared with the lowest intake group. All statistical tests

were two-sided. RESULTS: Intakes of dairy products, calcium, or vitamin D were

not statistically significantly associated with breast cancer risk in

postmenopausal women. In premenopausal women, however, consumption of dairy

products, especially of low-fat dairy foods and skim/low-fat milk, was inversely

associated with risk of breast cancer. The multivariable RRs comparing highest

(>1 serving/day) and lowest (<or=3 servings/month) intake categories were 0.68

(95% CI = 0.55 to 0.86) for low-fat dairy foods and 0.72 (95% CI = 0.56 to 0.91)

for skim/low-fat milk. Dairy calcium (>800 mg/day versus <or=200 mg/day; RR =

0.69, 95% CI = 0.48 to 0.98), total vitamin D (>500 IU/day versus <or=150

IU/day; RR = 0.72, 95% CI = 0.55 to 0.94), and lactose (quintile 5 versus

quintile 1; RR = 0.68, 95% CI = 0.54 to 0.86] also had inverse associations with

premenopausal breast cancer risk. By taking into account supplemental calcium

and vitamin D intake, we found that association with calcium was due mainly to

dairy sources whereas the association with vitamin D may be independent of dairy

intake. CONCLUSIONS: We found no association between intake of dairy products

and breast cancer in postmenopausal women. Among premenopausal women, high

intake of low-fat dairy foods, especially skim/low-fat milk, was associated with

reduced risk of breast cancer. Similar inverse associations were seen with

components (calcium and vitamin D) of dairy foods, but their independent

associations with breast cancer are difficult to distinguish.

PMID: 12208895 [PubMed - indexed for MEDLINE]

------------------------------------------------------------------------

INTRODUCTION

Milk and dairy products have been suspected to

increase the risk of breast cancer. International

comparative studies have shown a positive

association between milk and breast cancer

mortality (1,2). The association between milk and

breast cancer, however, has been inconsistent in

case–control studies, with reports of no

association (3–5), inverse association (6–10), and

positive association (11–15). Cohort studies of

dairy foods and breast cancer have yielded

similarly conflicting findings (16,17), with

inverse associations between milk and breast cancer found in several

recent studies (18–20). In some studies, different associations between

milk and breast cancer were found, depending on the type of milk

(7,17,21). In a 1993 meta-analysis, a small increase in breast cancer risk

with higher milk intake was observed (22), but the more recent findings

showing inverse associations were not part of that meta-analysis.

Components in milk that might be anticarcinogenic include calcium and

vitamin D, and some studies have suggested protective effects of calcium

and vitamin D against colon cancer (23,24). The hypothesized effect of

calcium on colon cancer is intraluminal binding with bile acids and fatty

acids, thus reducing the proliferative stimulus of these compounds. With

breast cancer, calcium has been proposed to reduce fat-induced cell

proliferation by maintaining intracellular calcium concentrations (25,26).

Vitamin D modulates calcium metabolism (27) and has calcium-independent

antiproliferative actions (26). Some suggest that only vitamin D, not

calcium, inhibits mammary tumorigenesis (28), but an independent

anticancer effect of higher calcium intake in rats has also been reported

(29).

Epidemiologic evidence relating calcium and vitamin D intakes to breast

cancer risk is limited. Breast cancer rates in white women are highest in

areas with the least winter sunlight and longest winters, which has been

interpreted to support an association with vitamin D (30), although we did

not find this association in the Nurses' Health Study (NHS) (31). A few

epidemiologic studies have reported a statistically significant inverse

association between calcium intake and breast cancer (19,32–34), while

others reported no association (35,36). However, intake of calcium and

dairy foods are strongly correlated, so the observed associations with

calcium are difficult to separate from those with milk, dairy products

and, consequently, other components of milk and dairy products. To our

knowledge, there is no epidemiologic study of dietary vitamin D and breast

cancer.

We examined data from a large, long-term cohort study to evaluate the

hypotheses that higher intakes of dairy products, calcium, or vitamin D

are associated with reduced risk of breast cancer. By taking into account

supplemental intake of calcium and vitamin D, we hoped to dissociate the

effects of calcium and vitamin D from those of milk and dairy products.

METHODS

The NHS cohort was established in 1976, when 121

700 registered nurses from 11 states in the United

States answered a mailed questionnaire on risk

factors for cancer and cardiovascular disease. ......... The

participants included in this analysis were the 88 691 women who

........... had not been diagnosed with cancer by 1980.

Semiquantitative Food-Frequency Questionnaires and Calculation of Nutrient

Intake

..........

The dairy food group included skim/low-fat milk, whole milk, cream, sour

cream, sherbet, ice cream, yogurt, cottage cheese, cream cheese, other

(hard) cheese, and butter. Total dairy food intake ........, except

butter because it was composed almost entirely of fat and was therefore

unlike the other dairy foods. When we calculated dairy fat intake,

however, we took into account all the foods in the dairy group, as well as

dairy ingredients from other foods. Low-fat dairy food intake was

calculated by summing the daily servings of skim/low-fat milk, sherbet,

yogurt, and cottage cheese. High-fat dairy food intake was calculated by

summing the daily servings of whole milk, cream, sour cream, ice cream,

cream cheese, other cheese, and butter. .......... Total

fermented milk intake was calculated by summing the daily intakes of sour

cream, yogurt, cottage cheese, cream cheese, and other cheese.

............ Nutrient intakes were energy-adjusted by using the residuals

from the regression of nutrient intake on total caloric intake (40).

Residuals were adjusted to 1600 kcal/day, the approximate median caloric

intake of all the participants with acceptable diet data, to have

meaningful nutrient values.

.................

............ Correlation coefficients between intake and plasma concentration of

vitamin D in 57 men and 82 women were 0.35 with supplements and 0.25

without supplements (41).

..........

Statistical Analysis

..... We simultaneously adjusted for age in

5-year categories, time period, physical activity in metabolic

equivalent-hours (METs, with activity at rest = 1.0) values, history of

benign breast disease, family history of breast cancer, height, weight

change since age 18 years, body mass index (BMI; kg/m2) at age 18 years,

age at menarche, parity, age at first birth, alcohol intake, total energy

intake, total fat intake, glycemic index value (= [glycemic index x

carbohydrate intake for each food]/total carbohydrate intake),

[{beta}]-carotene intake, and total vitamin E intake. .........

For vitamin D analyses, we added history of outdoor

sun exposure and participant's residential area. These covariates were

either known or suspected risk factors for breast cancer or had been found

to be associated with dairy/calcium/vitamin D intake and with breast

cancer risk in the NHS data. RRs were adjusted for glycemic index value

because blood glucose level could affect the active cellular uptake of

calcium. .........

RESULTS

During 16 years of follow-up, 827 premenopausal

women and 2345 postmenopausal women of the 88 691

women in the cohort were diagnosed with breast

cancer. An additional 310 women who developed

breast cancer were of uncertain menopausal status

and were excluded from analyses.

At baseline, most of the known breast cancer risk

factors did not vary appreciably across categories

of total milk, total calcium, and total vitamin D

intake (Table 1). Calcium, vitamin D, and

multivitamin supplement users were more frequent in the high total calcium

and vitamin D intake groups. Postmenopausal hormone use and history of

osteoporosis were not strongly associated with total milk intake or total

calcium intake. Women who consumed more total milk, total calcium, or

total vitamin D exercised more, smoked less, and drank less alcohol.

Table 1. Age-adjusted characteristics of

participants in the Nurses' Health Study (1980),

according to total milk (servings/day), calcium

(mg/day), and vitamin D (IU/day) intake*

Milk and Dairy Products

In postmenopausal women, none of the dairy products had any appreciable

association with breast cancer risk (Table 2). However, in

premenopausal women, a statistically significant inverse association

between low-fat dairy food intake and breast cancer risk was observed

(Table 2). The multivariable RR comparing the highest with the

lowest categories of consumption was 0.68 (95% CI = 0.55 to 0.86; Ptrend =

.003). Skim/low-fat milk intake accounted for 49% of low-fat dairy food

intake in the 1984 data and was the dairy food most strongly related to

breast cancer risk (>1 serving/day versus never; RR = 0.72, 95% CI = 0.56

to 0.91; Ptrend = .007). High-fat dairy food and whole milk, which

accounted for 12% of high-fat dairy food intake in 1984, showed

statistically nonsignificant inverse associations with premenopausal

breast cancer risk (for high-fat dairy food, >2.5 servings/day versus

[<=]3 servings/week; RR = 0.83, 95% CI = 0.62 to 1.10). When we included

the intakes of skim/low-fat milk and whole milk simultaneously in the same

model, the RRs were 0.68 (95% CI = 0.53 to 0.88) for skim/low-fat milk and

0.71 (95% CI = 0.49 to 1.05) for whole milk. Total milk intake showed a

statistically significant linear inverse association with premenopausal

breast cancer (>1 serving/day versus [<=]3 servings/month; RR = 0.69, 95%

CI = 0.54 to 0.87; Ptrend<.001).

Table 2. See end of paper.

.......... Yogurt, other cheese, and total fermented dairy foods did not have

any association with risk. Additional adjustment for total calcium or

total vitamin D slightly attenuated the associations of dairy foods with

premenopausal breast cancer.

There was no qualitative difference between age-adjusted and multivariable

RRs. For example, the age-adjusted RR for highest versus lowest intake of

low-fat dairy food was 0.77 (95% CI = 0.63 to 0.95) and that for

skim/low-fat milk was 0.82 (95% CI = 0.66 to 1.01). ...... Also, premenopausal

intakes of dairy foods were not associated with postmenopausal breast

cancer risk.

Calcium and Vitamin D

Calcium and vitamin D intakes were not associated with postmenopausal

breast cancer risk (Table 3). Dairy and total nondairy calcium

also had no association with risk in postmenopausal women. In

premenopausal women, most of the calcium- and vitamin D-related variables

were inversely associated with breast cancer incidence (Table 3).

The multivariable RR for highest versus lowest total calcium intake was

0.80 (95% CI = 0.58 to 1.12; Ptrend = .05) and that for dietary calcium

intake was 0.67 (95% CI = 0.49 to 0.92; Ptrend = .02). When we further

divided dietary calcium into dairy and nondairy calcium, dairy calcium was

inversely associated with risk (>800 mg/day versus [<=]200 mg/day; RR =

0.69, 95% CI = 0.48 to 0.98; Ptrend = .01); nondairy dietary calcium had

no association, although the range in intake was much smaller (>350 mg/day

versus [<=]275 mg/day; RR = 1.12, 95% CI = 0.78 to 1.60). Total nondairy

calcium also had no appreciable association with risk. Simultaneous

inclusion of dairy and nondairy calcium in the model did not change the

results appreciably.

Table 3. See end of paper.

Total vitamin D intake was associated with lower risk of premenopausal

breast cancer (highest versus lowest intake; RR = 0.72, 95% CI = 0.55 to

0.94; Ptrend = .01), while dietary vitamin D intake was associated with a

similar but marginally statistically significant risk reduction (highest

versus lowest intake; RR = 0.66, 95% CI = 0.43 to 1.00. Adjusting for

residential area and history of outdoor sun exposure did not affect the

associations of total and dietary vitamin D with premenopausal breast

cancer, nor were these variables themselves associated with breast cancer

incidence.

No qualitative difference was observed between age-adjusted and

multivariable RRs for the associations of vitamin D and calcium with

premenopausal breast cancer risk. The age-adjusted RR for highest versus

lowest intake of dietary calcium was 0.74 (95% CI = 0.55 to 0.98) and that

for dietary vitamin D was 0.78 (95% CI = 0.52 to 1.18). When we used 1980

baseline intakes of calcium from various sources in the analyses, inverse

associations with premenopausal breast cancer were still seen, but the

magnitude and statistical significance of trends were attenuated compared

with the use of cumulative average intakes (Table 3). Baseline

total and dietary vitamin D intakes were not associated with premenopausal

breast cancer risk. Similar attenuation was observed when a 4-year time

lag was applied between calcium and vitamin D intakes and premenopausal

breast cancer. The RR for dairy calcium (>800 mg/day) was 0.78 (95% CI =

0.57 to 1.07; Ptrend = .06). When we included supplement users in the

analyses, the associations of calcium and vitamin D intakes with

premenopausal breast cancer were slightly attenuated but were not changed

substantially. Again, the premenopausal intakes of calcium and vitamin D

were not associated with postmenopausal breast cancer risk.

Supplemental calcium had no apparent linear association with breast cancer

risk in either premenopausal or postmenopausal women (Tables 4 and 5).

In the stratified analysis by tertiles of dietary

calcium among premenopausal women, women who used high-dose calcium

supplements ([>=]900 mg/day) had a lower risk only if they were in the

high dietary calcium intake group (RR = 0.44, 95% CI = 0.19 to 1.01)

although the number of case subjects in this analysis was very small.

Supplemental vitamin D had a weak, statistically nonsignificant inverse

association with premenopausal breast cancer risk, and this association

was more prominent among women in the low dietary vitamin D intake group

(for [>=]400 IU/day; RR = 0.80, 95% CI = 0.57 to 1.14). Most of the

supplemental vitamin D use was determined by multivitamin use.

Postmenopausal hormone use did not modify the associations between calcium

or vitamin D supplement intake and breast cancer.

Table 4. See end of paper.

Table 5. See end of paper.

Other Constituents of Dairy Foods and Their Correlations With Dairy Food

Intake

The intake of other constituents of dairy foods had associations similar

to those with dairy calcium. Lactose and phosphorus intakes, which were

highly correlated with intake of low-fat dairy foods (r = 0.75 and 0.71,

respectively), were inversely associated with breast cancer risk in

premenopausal women (quintile 5 versus quintile 1; RR = 0.68, 95% CI =

0.54 to 0.86; Ptrend<.001 for lactose and RR = 0.73, 95% CI = 0.56 to

0.96; Ptrend = .01 for phosphorus). Dairy fat intake was associated with

lower risk in the highest quintile relative to the lowest, but the trend

was not statistically significant (quintile 5 versus quintile 1; RR =

0.78, 95% CI = 0.62 to 0.98; Ptrend = .13).

These inverse associations between the constituents of dairy food intake

and premenopausal breast cancer disappeared rapidly after menopause. In

early menopause, i.e., within 10 years after menopause, the RRs for dairy

calcium, lactose, phosphorus, and dairy fat were already attenuated and

statistically nonsignificant. In late menopause, i.e., beyond 10 years

after menopause, the RRs were virtually null. For example, for dairy

calcium, the RR for the highest versus lowest quintiles was 0.67 (95% CI =

0.52 to 0.88) in premenopausal women, 0.85 (95% CI = 0.65 to 1.11) during

early menopause, and 1.05 (95% CI = 0.83 to 1.34) in late menopause. Also,

the associations between the constituents of dairy foods with

premenopausal breast cancer were more pronounced in women of even younger

ages. For example, for dairy calcium (highest versus lowest quintile), the

RR of premenopausal breast cancer occurring 6 years or more before

menopause was 0.66 (95% CI = 0.38 to 1.12), and within 5 years of

menopause, the RR was 0.86 (95% CI = 0.68 to 1.09).

The inverse association between low-fat dairy food intake and

premenopausal breast cancer risk was attenuated when it was further

adjusted for lactose, dairy calcium, total vitamin D, and phosphorus

intakes, but only the adjustment for lactose was strong enough to make the

association not statistically significant (highest versus lowest intake of

low-fat dairy products; RR = 0.81, 95% CI = 0.61 to 1.08).

Because vitamin D modulates calcium metabolism, effects of dairy calcium

might be modified by vitamin D intake. When we stratified the data by

tertiles of total vitamin D intake, dairy calcium appeared to be

associated with reduced risk of premenopausal breast cancer in women at

all levels of vitamin D intake (Pinteraction = .85). According to the

calcium–high fat hypothesis (25,26), the effect of calcium should be

stronger in the high-fat-diet group. However, we observed an inverse

association between dairy calcium intake and premenopausal breast cancer

in all tertiles of total fat intake. Similarly, the association between

total vitamin D intake and premenopausal breast cancer was not modified by

total fat intake. The inverse association between dairy calcium and breast

cancer also was not modified by height, current BMI, or alcohol intake.

DISCUSSION

In this large prospective cohort study, intakes of

dairy foods, calcium, or vitamin D were not

associated with the risk of breast cancer among

postmenopausal women. Among premenopausal women,

however, most of the dairy-related variables (i.e.,

total dairy, low-fat dairy, total milk,

skim/low-fat milk, dietary and dairy calcium, total

vitamin D, lactose, total phosphorus, and dairy

fat) were inversely associated with breast cancer.

The associations were mostly related to the low-fat

dairy variables (e.g., intake of skim/low fat milk)

but it is unlikely that these variables were merely acting as markers for

a low-fat diet in general, because total fat itself was not associated

with breast cancer in premenopausal women. The weaker association for

whole milk intake with premenopausal cancer might be due to fewer numbers

of women who drank sufficiently large amounts. Calcium intake and total

dairy product intake have also been associated with reduced mortality

among breast cancer patients in this cohort (44).

We hypothesized that if milk intake is associated with reduced risk of

breast cancer, calcium or vitamin D might be the responsible nutrient. In

the present study, intake of calcium and vitamin D indeed had

statistically significant inverse associations with premenopausal breast

cancer. Detailed analyses for calcium, however, suggested that the inverse

association with calcium was due mostly to dairy sources rather than to

nondairy sources or supplements. Low-fat dairy foods remained associated

with premenopausal breast cancer risk when total calcium was included in

the same model, whereas total calcium was no longer associated with risk

(RR for >1250 mg/day versus [<=]500 mg/day of total calcium = 0.95, 95% CI

= 0.66 to 1.35). This suggests that dairy calcium is not likely to be

responsible for the association of low-fat dairy food and skim/low-fat

milk intake with reduced risk of premenopausal breast cancer.

Vitamin D intake, by contrast, was most strongly related to risk when it

was analyzed as total intake rather than as dietary or supplemental

intake. Unlike calcium, vitamin D intake was largely accounted for by

multivitamin supplementation (35% of total intake; 1984 data). Summation

of dietary and supplement intake increases the range of intake and, hence,

the power to detect an association. Although vitamin D did not contribute

substantially to the association between low-fat dairy foods and

premenopausal breast cancer risk when both terms were included in a

multivariable model, the inverse association with vitamin D was sustained

(RR for >500 IU/day versus [<=]150 IU/day of total vitamin D = 0.78, 95%

CI = 0.59 to 1.02). Therefore, vitamin D intake appears to offer a

possible protective association apart from the " milk effect. " Residual

confounding by the level of sun exposure could still be possible, because

our measures of sun exposure (i.e., outdoor sun exposure and site of

residence) were rather crude.

Knekt et al. (19) reported a strong inverse association between milk

intake and subsequent incidence of breast cancer in a Finnish cohort

study. They also found statistically significant inverse associations of

breast cancer with calcium and lactose intakes. Their study was based on

only 88 case subjects, but the observed decrease in risk among the highest

tertile of total milk intake compared with the lowest was quite strong (RR

= 0.42, 95% CI = 0.24 to 0.74). The fact that their cohort included more

younger person-years (mean age at baseline = 39 years, with 25 years of

follow-up) and consumed more than twice the amount of milk (531 g/day)

than was consumed in our cohort (215 g/day) might account for the strength

of the association. Two cohort studies conducted in Norway, where people

also consume milk frequently (>1.7 glasses/day), reported both positive

(17) and negative (20) associations between milk intake and breast cancer.

The former study included older person-years (mean age = 43 years, with

10.4 years of follow-up) than the latter study (mean age = 40.7 years,

with 6.2 years of follow-up, which was similar to our premenopausal

analysis). In addition, the main type of milk consumed in the former study

was whole milk, whereas in the latter study, it was skim and low-fat milk.

Other cohort studies conducted in the United States, where people consume

less than one glass of milk per day, reported either decreased risk with

greater intake of milk (18) (age range = 35–65 years, with <5 years of

follow-up) or no association (16) (median age = 55 years, with 20 years of

follow-up). Most of the case–control studies with positive associations

between milk intake and breast cancer risk also had the common components

of older age and consumption of whole milk (12,14, 15,21).

Validity of the dietary measurement should be considered in the

interpretation of these conflicting results between studies. However,

intake assessments of commonly consumed beverages, such as milk or coffee,

have high validity and reproducibility (38). Furthermore, by updating and

averaging the repeated measurements of diet five times, we reduced

within-person fluctuations and took into account changes over time, which

should improve validity compared with most previous studies.

Confounding might be another reason for the conflicting results in

previous studies. In the present study, we adjusted all food and nutrient

items for total energy intake, so that the relative rather than the

absolute amount of intake could be evaluated (40). We also controlled for

a wide range of potential confounders. Adjustment for other nutrient

factors changed the result meaningfully in this study. For example, the RR

of premenopausal breast cancer for the highest intake of total milk

relative to the lowest was 0.78 (95% CI = 0.64 to 0.96) in the

age-adjusted model, 0.77 (95% CI = 0.62 to 0.95) in a multivariable model

without other dietary factors, and 0.69 (95% CI = 0.54 to 0.87) in the

fully adjusted model. Changes in the RRs for calcium and vitamin D were

even greater than those for total milk.

The apparent association of intake of milk and its related nutrients with

reduced risk of breast cancer disappeared quickly after menopause. This

diminishing association with increasing age was also observed in an

Italian case–control study (45). It is not clear why milk and its related

nutrients might show different associations with pre- and postmenopausal

breast cancer.

Components of milk other than vitamin D and calcium might be responsible

for the associations we observed. Lactose can aid the absorption of

dietary calcium as well as promote the growth of lactic acid-producing

bacteria in the large intestine. Although lactose intake is suspected to

be associated with an increased risk of ovarian cancer (46) and decreased

risk of colon cancer (47), little is known about its relationship with

breast cancer. Lactose has been hypothesized to increase ovarian cancer

risk by direct toxicity to oocytes and by inducing premature ovarian

failure (48). This effect could reduce exposure of breast tissue to

estrogen. Some epidemiologic studies reported an inverse association

between fermented milk (6) and yogurt (12) and risk of breast cancer,

interpreting this as an effect of lactose or lactic acid.

Other components of milk have the potential to explain the apparent

protective association with breast cancer. Conjugated linoleic acid (CLA),

a mixture of positional and geometric isomers of linoleic acid, comes from

dairy (60%) and beef (32%) products (49) and is a potent anticarcinogen in

animal models (50). However, the inverse association we saw with dairy

foods was probably not due to CLA because it was strongest for low-fat

dairy products, which should have low CLA content.

In conclusion, high intakes of dairy products, especially low-fat dairy

and skim/low-fat milk, may be associated with a modest reduction in the

risk of breast cancer in premenopausal women but not in postmenopausal

women. Other constituents of dairy foods, such as calcium, total vitamin

D, lactose, and phosphorus, also showed inverse associations with risk of

premenopausal breast cancer, but their independent associations with

breast cancer are difficult to distinguish. Further study of the

relationship between dairy product consumption and breast cancer is

warranted, with a specific focus on premenopausal women.

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Table 2. Multivariable relative risks (RRs) and 95% confidence intervals

(CIs) of invasive breast cancer by menopausal status according to dairy

food intakes in the Nurses' Health Study (1980–1996)

Postmenopausal

Premenopausal women

women

-------------------------------------------------

-------------------

No. of No. of

case RR1* (95% RR2[{dagger}] RR3[{ddagger}] case

RR1*[§]

women CI) (95% CI) (95% CI) women

(95% CI)

------------------------------------------------------------------------

Total No. of

case women 827 2345

Total dairy,

servings

[<=]1/day 1.00 1.00 1.00

1.00

202 (referent) (referent) (referent) 439

(referent)

>1/day –

[<=]3/day 0.87 (0.73 0.87 (0.70 to 0.90 (0.75 to

0.95 (0.85

433 to 1.04) 1.08) 1.09) 1239

to 1.07)

0.73 (0.58 0.76 (0.56 to 0.80 (0.63 to

0.97 (0.85

>3/day 192 to 0.92) 1.03) 1.03) 667

to 1.12)

Ptrend [[{beta}]

±

SE([{beta}])]|| .009 [-0.11 .10 [-0.09 ± .10 [-0.08 ±

..97 [-0.001

± 0.04] 0.05] 0.05]

± 0.02]

Low-fat dairy,

servings

[<=]3/month 1.00 1.00 1.00

1.00

155 (referent) (referent) (referent) 226

(referent)

>3/month –

[<=]4/week 0.83 (0.67 0.83 (0.67 to 0.83 (0.67 to

0.98 (0.84

201 to 1.03) 1.03) 1.03) 486

to 1.16)

>4/week –

[<=]1/day 0.75 (0.60 0.74 (0.58 to 0.76 (0.61 to

1.00 (0.86

207 to 0.93) 0.93) 0.95) 658

to 1.18)

0.68 (0.55 0.70 (0.55 to 0.73 (0.57 to

1.01 (0.86

>1/day 264 to 0.86) 0.91) 0.92) 975

to 1.19)

Ptrend [[{beta}]

±

SE([{beta}])]|| .003 [-0.20 .02 [-0.18 ± .03 [-0.15 ±

..67 [0.02 ±

± 0.06] 0.07] 0.07]

0.04]

High-fat dairy,

servings

[<=]4/week 1.00 1.00 1.00

1.00

123 (referent) (referent) (referent) 409

(referent)

>4/week –

[<=]1/day 1.08 (0.87 1.09 (0.88 to 1.08 (0.87 to

0.95 (0.84

291 to 1.34) 1.36) 1.33) 832

to 1.07)

>1/day –

[<=]2.5/day 1.05 (0.84 1.08 (0.86 to 1.05 (0.84 to

0.97 (0.85

313 to 1.31) 1.35) 1.32) 834

to 1.10)

0.83 (0.62 0.86 (0.65 to 0.84 (0.63 to

1.01 (0.85

>2.5/day 100 to 1.10) 1.16) 1.12) 270

to 1.20)

Ptrend [[{beta}]

±

SE([{beta}])]|| .06 [-0.07 .13 [-0.06 ± .09 [-0.07 ±

..59 [0.01 ±

± 0.04] 0.04] 0.04]

0.03]

Total milk, 8-oz

glasses

[<=]3/month 1.00 1.00 1.00

1.00

169 (referent) (referent) (referent) 327

(referent)

>3/month –

[<=]4/week 1.00 (0.81 0.99 (0.80 to 1.00 (0.82 to

1.08 (0.94

216 to 1.22) 1.22) 1.23) 526

to 1.24)

>4/week –

[<=]1/day 0.84 (0.68 0.81 (0.64 to 0.85 (0.69 to

1.06 (0.92

253 to 1.03) 1.02) 1.06) 783

to 1.21)

0.69 (0.54 0.66 (0.50 to 0.73 (0.56 to

1.01 (0.87

>1/day 189 to 0.87) 0.88) 0.94) 709

to 1.17)

Ptrend [[{beta}]

± <.001

SE([{beta}])]|| [-0.16 ± .002 [-0.17 ± .007 [-0.14 ±

..59 [-0.01

0.04] 0.06] 0.05]

± 0.03]

Skim/low-fat

milk, 8-oz

glasses

1.00 1.00 1.00

1.00

Never 247 (referent) (referent) (referent) 431

(referent)

[<=]1/week 0.91 (0.72 0.91 (0.72 to 0.90 (0.71 to

1.09 (0.93

101 to 1.16) 1.16) 1.15) 248

to 1.28)

>Never –

[<=]6/week 0.90 (0.74 0.90 (0.74 to 0.91 (0.75 to

1.07 (0.94

241 to 1.09) 1.10) 1.10) 811

to 1.21)

>6/week –

[<=]1/day 0.80 (0.63 0.81 (0.64 to 0.83 (0.65 to

1.14 (0.98

112 to 1.01) 1.04) 1.06) 338

to 1.32)

0.72 (0.56 0.76 (0.57 to 0.78 (0.60 to

1.05 (0.91

>1/day 126 to 0.91) 1.00) 1.01) 517

to 1.22)

Ptrend [[{beta}]

±

SE([{beta}])]|| .007 [-0.13 .06 [-0.10 ± .08 [-0.09 ±

..85 [0.005

± 0.05] 0.06] 0.05]

± 0.03]

Whole milk, 8-oz

glasses

1.00 1.00 1.00

1.00

Never 461 (referent) (referent) (referent) 1248

(referent)

[<=]1/week 1.05 (0.87 1.04 (0.86 to 1.04 (0.86 to

0.96 (0.86

151 to 1.26) 1.25) 1.25) 421

to 1.08)

>1/week –

[<=]6/week 0.99 (0.81 0.99 (0.81 to 1.00 (0.82 to

1.05 (0.94

136 to 1.21) 1.21) 1.22) 490

to 1.17)

>6/week –

[<=]1/day 1.00 (0.74 1.02 (0.75 to 1.04 (0.77 to

1.03 (0.84

49 to 1.36) 1.38) 1.41) 107

to 1.26)

0.80 (0.54 0.86 (0.58 to 0.87 (0.59 to

0.87 (0.69

>1/day 30 to 1.16) 1.26) 1.28) 79

to 1.10)

Ptrend [[{beta}]

±

SE([{beta}])]|| .26 [-0.08 .48 [-0.05 ± .56 [-0.04 ±

..43 [-0.03

± 0.07] 0.07] 0.07]

± 0.04]

Milk intake

during high

school years,

8-oz glasses¶

[<=]0.5/day 1.00 1.00 1.00

1.00

85 (referent) (referent) (referent) 383

(referent)

>0.5/day –

[<=]1/day 0.93 (0.69 0.93 (0.69 to 0.95 (0.70 to

1.04 (0.91

81 to 1.27) 1.27) 1.29) 406

to 1.20)

>1/day –

[<=]3/day 0.99 (0.75 1.00 (0.75 to 1.03 (0.77 to

1.08 (0.94

136 to 1.31) 1.32) 1.37) 606

to 1.23)

0.76 (0.48 0.77 (0.48 to 0.81 (0.51 to

1.02 (0.82

>3/day 25 to 1.21) 1.22) 1.28) 114

to 1.26)

Ptrend [[{beta}]

±

SE([{beta}])]|| .45 [-0.03 .47 [-0.03 ± .66 [-0.02 ±

..47 [0.02 ±

± 0.04] 0.05] 0.05]

0.02]

Yogurt, servings

1.00 1.00 1.00

1.00

Never 390 (referent) (referent) (referent) 1049

(referent)

[<=]3/month 0.97 (0.82 0.98 (0.82 to 0.97 (0.82 to

0.93 (0.84

213 to 1.15) 1.16) 1.16) 565

to 1.04)

>3/month –

[<=]4/week 0.92 (0.76 0.93 (0.77 to 0.93 (0.77 to

0.96 (0.87

189 to 1.10) 1.13) 1.12) 609

to 1.08)

0.95 (0.66 1.00 (0.69 to 0.98 (0.68 to

0.94 (0.77

>4/week 35 to 1.37) 1.44) 1.41) 122

to 1.14)

Ptrend [[{beta}]

±

SE([{beta}])]|| .77 [-0.06 .97 [-0.007 ± .90 [-0.02 ±

..58 [-0.06

± 0.19] 0.19] 0.19]

± 0.10]

Other cheese,

servings

[<=]1/week 1.00 1.00 1.00

1.00

201 (referent) (referent) (referent) 502

(referent)

>1/week –

[<=]4/week 1.00 (0.84 1.02 (0.85 to 1.00 (0.83 to

0.94 (0.84

328 to 1.20) 1.23) 1.20) 979

to 1.05)

1.02 (0.84 1.07 (0.87 to 1.01 (0.83 to

0.99 (0.88

>4/week 298 to 1.24) 1.30) 1.23) 864

to 1.12)

Ptrend [[{beta}]

±

SE([{beta}])]|| .52 [-0.04 .96 [0.006 ± .67 [-0.05 ±

..88 [0.01 ±

± 0.12] 0.12] 0.12]

0.07]

------------------------------------------------------------------------

*RR1 was adjusted for age in 5-year categories, time period, physical

activity in METs

(metabolic equivalent-hours [with activity at rest = 1.0]), history of benign

breast

disease, family history of breast cancer, height, weight change since age 18,

body

mass index at age 18, age at menarche, parity, age at first birth, alcohol

intake,

total energy intake, total fat intake, glycemic index, [{beta}]-carotene

intake, and

total active vitamin E intake.

[{dagger}]RR2 was adjusted for all the covariates in the RR1 model plus total

calcium

intake.

[{ddagger}]RR3 was adjusted for all the covariates in the RR1 model plus

total vitamin

D intake.

[§]For the analysis of postmenopausal women, age at menopause and

postmenopausal

hormone use (e.g., hormone replacement therapy) were added to the

multivariable model.

||P values for trend were calculated with the Wald statistic using median

values for

each category of intake. The estimator ([{beta}]) is an increment of the log

of odds

for an increase of one serving/day, and SE is the standard error of [{beta}].

¶Milk intake during high school years was first measured in 1986, and

follow-up for

this variable started in 1986. Thus, there are fewer case subjects in this

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