Dairy consumption in adolescence and early adulthood and risk of breast cancer

Abstract

Background

Carcinogenic exposure in early life may be critical for subsequent breast cancer risk. Dairy consumption was examined during adolescence and early adulthood in relation to incident breast cancer in the Nurses’ Health Study II cohort.

Methods

For the analyses of early adulthood dairy consumption, we included 90,503 premenopausal women aged 27-44 years in 1991 who reported dairy consumption using a validated food-frequency questionnaire. From 1991-2013, 3,191 invasive breast cancer cases were identified. In 1998, 44,264 women recalled adolescent dairy consumption. This subgroup of women was followed up from 1998-2013, 1,318 invasive breast cancer cases were identified. Multivariate hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using the Cox proportional hazard regression.

Results

Adolescent and early adulthood total dairy consumption was not associated with overall breast cancer risk (each serving/day during adolescence, total dairy HR=1.02, 95%CI=0.97-1.07; for early adulthood total dairy HR=1.01, 95%CI=0.97-1.04), as were intakes of calcium, vitamin D, and lactose. Adolescent consumption of total and high-fat dairy was associated with higher risk of estrogen and progesterone receptor negative (each serving/day: total dairy HR = 1.11, 95% CI, 1.00–1.24; high-fat dairy HR = 1.17, 95% CI, 1.04–1.31). However, higher adolescent high-fat dairy consumption was associated with lower risk of estrogen and progesterone receptor positive tumors (each serving/day HR= 0.91, 95% CI, 0.86–0.97).

Conclusions

Our results suggest no overall association between dairy consumption during adolescence or early adulthood and breast cancer risk, but the findings may differ by hormone receptor status of tumors.

Impact

Dairy consumption in adolescence or early adulthood may not be a significant predictor of breast cancer incidence.

Introduction

Breast cancer remains the most common type of cancer in women. During 2016, 246,660 new cases of invasive breast cancer were estimated, with 40,450 breast cancer deaths in the U.S. women (1). Among numerous dietary components that have been related to breast cancer, dairy products have been hypothesized to play a role by increasing hormone levels such as estrogen and insulin-like growth factors (2–5). However, epidemiological studies assessing dairy intake and breast cancer risk have been inconsistent (6–23), reporting no (6–15), higher (16, 17), or even lower (18–23) breast cancer risk. Moreover, the findings vary across dairy products (6–10, 12–16, 18, 20–23). A meta-analysis of prospective cohort studies found an inverse association between total dairy intake and breast cancer risk (24). Notably, almost all of these studies used dietary assessments during mid-life and later, with little focus on diet earlier in life (9, 12). In early life, carcinogenic exposure may be critical for subsequent breast cancer risk. For example, the atomic bombings of Hiroshima and Nagasaki and radiotherapy for Hodgkin’s lymphoma demonstrated evidence for early life exposure and subsequent risk of breast cancer. In both cases, exposure to radiation in childhood and early adult life was associated with risk of breast cancer whereas exposure after age 30 had little effect when observed among women exposed to ionizing radiation (25–27). Moreover, our studies using data from the Nurses’ Health Study II (NHSII) indicated that a high red meat intake during adolescence and early adulthood was more strongly associated with breast cancer risk than in later life (28, 29). We also found a stronger inverse association with adolescent fruit intake as well as adolescent and early adulthood fiber intake with breast cancer risk, compared with consumption later in life (30, 31). In a previous analysis of the NHSII (12, 17), whereas dairy intake during adolescence was not significantly associated with subsequent breast cancer risk (12), premenopausal high-fat dairy intake was associated with higher risk of breast cancer (17). It is, however, not clear whether this increased risk was due to dietary assessment at early age or the relatively young age of women at diagnosis of breast cancer.

Dairy products are a diverse food group that consists of several nutrients potentially influencing breast cancer risk. Calcium and vitamin D components in dairy products may have anticarcinogenic activity (32). However, in most prospective studies, the association between intake of calcium or vitamin D and risk of breast cancer is inconsistent (19, 22, 33–38), lacking data from early adult life. Other components of dairy products such as lactose might also be responsible for the associations between dairy and breast cancer risk. Although a few studies have suggested that lactose intake is associated with an increased risk of ovarian cancer (39, 40), little is known about the relationship with breast cancer (41, 42). To date, the relationship between early life lactose intake and breast cancer has yet to be investigated.

Furthermore, breast cancer is a heterogeneous disease and breast tumors vary by estrogen and progesterone receptor status. Therefore, the relation between dairy foods and breast cancer may differ by hormone receptor status (14, 19, 23).

Therefore, based on our previous analyses (12, 17), but with longer follow up and a larger number of cases, the associations between consumption of adolescent and early adulthood dairy products and breast cancer were examined. We also evaluated the association between vitamin D, calcium, and lactose with breast cancer incidence. The associations between dairy consumption and breast cancer were also examined by menopausal and hormone receptor status.

Materials and methods

Study Population

The NHSII was established in 1989 with a total enrollment of 116,429 female registered nurses aged 25-42 years. From baseline enrollment, the participants have been followed up every two years to update lifestyle and medical information. In 1991, women reported dietary intake through a semi-quantitative food-frequency questionnaire (FFQ). Among the 97,813 women who returned the FFQ, we included the participants who were premenopausal in 1991 and had total energy intake between 600 and 3500 kcal/day. We excluded the participants who had missing information on age, or had left more than 70 food items blank, or had left all items on dairy foods blank, or had prevalent cancer (except non-melanoma skin cancer) in 1991 or before, leaving a total population of 90,503 women for early adulthood diet analysis. The follow-up rate was 96 percent of total potential person-years from 1991 through 2013.

In 1997, women were asked if they would complete a supplemental FFQ about diet during high school (HS-FFQ; 13-18 years). Among the 47,355 women who returned the HS-FFQ in 1998, women were excluded if they were diagnosed with cancer (except non-melanoma skin cancer) before 1998, or had total energy intake under 600 or over 5000 kcal/day, or left more than 70 food items blank, or left all items on dairy foods blank, leaving a total population of 44,264 women for adolescent diet analysis. Among women who provided data on adult diet, there were minimal differences in baseline demographic characteristics and breast cancer rate between those who completed the HS-FFQ compared to those who did not (12). The follow-up rate was 98 percent of total potential person-years from 1998 through 2013.

This analysis was approved by the Human Subjects Committee at Brigham and Women’s Hospital and the Harvard T.H. Chan School of Public Health (Boston, MA, United States).

Dietary Assessment

Usual dietary habits from the past year were evaluated in 1991 and every four years thereafter by validated semi-quantitative FFQs with approximately 130 food items (available at http://www.nurseshealthstudy.org/participants/questionnaires). Women reported the frequency of dairy consumption in nine possible responses ranging from “never or less than once per month” to “6 or more times per day” (Supplementary Table S1). The validity of the adult dietary questionnaire used in the NHS II has been extensively documented (43).

Administered in 1998, the adolescent diet was ascertained from the HS-FFQ with 124 food items. Women reported the foods typically consumed between 1960 and 1980 when participants attended high school (Supplemental Table S2). For validity, of the 47,355 women who completed the HS-FFQ, the mothers of 272 of these women also completed the HS-FFQ for diet comparison. The mean Pearson correlation for nutrients was 0.40 (range, 0.13-0.59) (44). The validity was also evaluated by comparing the responses of 80 women in high school from another study, using three, 24-hour recalls and two HS-FFQs with the same HS-FFQ administered 10 years later. The mean of corrected correlation coefficients for energy-adjusted nutrient intake was 0.58 (range, 0.40-0.88) calculated using the average of two HS-FFQs and the HS-FFQ from 10 years later, and 0.45 (range, 0.16-0.68) calculated using the average of three, 24-hour recalls and the HS-FFQ (10 years later) (45).

Nutrient values in foods were obtained from the United States Department of Agriculture, food manufacturers, and independent academic sources (46–48). The food composition database was updated every four years to account for changes in the food supply. The intake of calcium, vitamin D, and lactose was energy-adjusted using the residuals from the regression of nutrient intake on total energy intake (49).

Assessment of Breast Cancer Cases

In biennial questionnaires, participants reported the diagnosis of breast cancer and the date of diagnosis. When a case of breast cancer was identified, we obtained the medical records and pathology reports to confirm the breast cancer diagnosis. Because of the high accuracy of self-reporting (99%), diagnoses with unavailable medical records (n=384) were included in the analysis. Estrogen and progesterone receptor status of tumors was extracted from medical records. Deaths were identified by family members, the postal service, or the National Death Index.

Assessment of covariates

At baseline enrollment and every two years thereafter, we inquired about potential risk factors for breast cancer including age, weight, smoking, history of benign breast disease, family history of breast cancer, menopausal status, menopausal hormone use, and oral contraceptive use. Information on race, age at menarche, weight at age 18, adult height, and adolescent alcohol consumption was obtained from the 1989 questionnaire. Women were considered postmenopausal if they reported natural menopause or had undergone bilateral oophorectomy. We defined women of unknown menopausal status or who had hysterectomy without bilateral oophorectomy as premenopausal if they were under 46 years and smokers, or under 48 years and non-smokers; and as postmenopausal if they were 54 years or older and smokers, or 56 years or older and non-smokers (50).

Statistical Analysis

Dairy intake reported in the baseline FFQ (1991) was considered as early adulthood dietary intake (27-44 years). To evaluate early adulthood diet and breast cancer, we computed person-years of follow up for each participant from the date of return of the 1991 questionnaire until the date of any cancer diagnosis except non-melanoma skin cancer, death from any cause, or the end of follow up (June 1, 2013), whichever came first. For adolescent dairy consumption, similarly, person-years were calculated except that follow-up began with return of the adolescent diet questionnaire in 1998. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for breast cancer associated with dairy product, calcium, vitamin D, and lactose consumption. Participants were divided into quintiles according to food groups. Adolescent and adult intake of ice cream and adult intake of yogurt and cream were divided into tertiles. As teenagers, 74% of the women did not consume yogurt, and less than 2% consumed five or more servings/week. The adolescent yogurt intake was divided into two categories: women who reported “never or <1 serving/month” or “1 serving/month or more.” We examined quintiles of dairy consumption to allow for nonlinearity and modeled the median value in each quintile as a continuous term to test for linear trend. For yogurt, ice cream, and cream, we used the median value in each tertile as a continuous term to test for linear trend. All regression models were stratified by age in months and calendar year of the current questionnaire cycle. Multivariable models were also simultaneously adjusted for history of breast cancer in mother or sisters, history of benign breast disease, smoking, height, body mass index (BMI) at age 18, weight change since age 18, age at menarche, parity and age at first birth, oral contraceptive use, menopausal status, menopausal hormone use, age at menopause, physical activity, alcohol consumption, and energy intake. For adolescent dairy consumption and breast cancer risk, we further included adolescent intake of alcohol and energy, rather than early adulthood energy intake in the multivariable models. To better represent long-term diet and minimize the effect of random measurement errors by using repeated dietary assessments, we calculated premenopausal the cumulative average of dietary intake from our repeated FFQs in 1991, 1995, 1999, 2003, 2007, and 2011, terminating the update of dietary information when a woman reached menopause. In addition, the average of adolescent and early adulthood (1991) dairy consumption was calculated among participants with information from these two periods.

To address whether the observed associations were independent of other dietary factors, we controlled for the Alternate Healthy Eating Index (AHEI) (51), total red meat, fruits and vegetables, or animal fat intake. To determine whether associations with adolescent intake were independent of adulthood dietary intake, we adjusted for dietary intake during adult life (cumulative average of dietary intake). To address whether the associations between dairy consumption during adolescence or early adulthood and breast cancer risk were modified by age and BMI at age 18, a cross-product term of the ordinal score was included in the multivariable model. The tests for interactions were obtained from a likelihood ratio test. We used the Cox proportional cause-specific hazards regression model with a duplication method for competing risk data to calculate the HR of tumor subtypes, including both estrogen and progesterone receptors positive (ER+/PR−), both estrogen and progesterone receptors negative (ER−/PR−), and estrogen receptor positive and progesterone receptor negative (ER+/PR−) (52). Because estrogen receptor negative and progesterone receptor positive (ER−/PR+) is not a reproducible breast cancer subtype (53), we did not evaluate the association between dairy food intake and this subtype of breast cancer. The association between adolescent dairy intake and adult height was evaluated using regression models adjusted for age, race, and adolescent consumption of total red meat, and total fruit and vegetables. All P values were two-sided. SAS version 9.3 (SAS Institute, Inc., Cary, NC) was used for all analyses.

Results

Among women with early adulthood dietary intake, 3,191 cases of invasive breast cancer were identified from 1991 through 2013. Among women with adolescent dietary intake, we documented 1,318 cases of invasive breast cancer from 1998 through 2013. In early adulthood, higher total dairy consumption was associated with a lower prevalence of smoking, using oral contraceptives, and nulliparity, higher consumption of animal fat, red meat, fruit, and vegetables, and lower consumption of fiber (Table 1). Women with higher adolescent total dairy consumption were less likely to smoke, to be nulliparous, and to consume fiber, and more likely to consume animal fat, red meat, fruits, and vegetables (Table S3). Also, women who consumed an average of 5.4 servings/day of total dairy products during adolescence were 1.7 cm taller than those who consumed an average of 1.0 serving/day (Table S3). Moreover, in regression analysis, milk consumption during teenage years was significantly associated with attained height after adjusting for age, race, adolescent consumption of total red meat, and total fruit and vegetables; women were 0.41 cm taller on average for each additional serving/day of milk (P<0.0001).

Table 1.

Age and age-standardized characteristics in 1991 according to intake of total dairy products during early adulthood among women enrolled in the Nurses’ Health Study II

	Total dairy products, quintile
	1	2	3	4	5
Number	18,094	18,045	18,246	18,016	18,102
Mean±SD
Age, years	37.1±4.6	36.7±4.6	36.5±4.7	36.3± 4.6	35.7±4.6
Total dairy products intake, serving/day	0.7±0.3	1.3±0.2	1.9±0.2	2.9±0.3	4.5±1.2
Low-fat dairy intake, serving/day	0.3±0.2	0.8± 0.4	1.1±0.4	1.9±0.8	2.7±1.3
High-fat dairy intake, serving/day	0.4±0.2	0.6±0.4	0.9±0.4	1.0±0.8	1.8±1.5
Total energy intake, kcal	1443±477	1611±468	1798±471	1920±496	2183±513
Total fiber intake, g/day	18.6±6.3	18.6±5.5	18.6±5.2	18.1±5.4	17.4±4.9
Animal fat intake, % energy	16.4±5.1	17.0± 4.5	17.5±4.2	17.7±4.3	18.9±4.6
Total red meat intake, serving/day	0.7±0.5	0.8±0.5	0.8±0.5	0.8±0.6	0.9±0.6
Total fruit intake, serving/day	0.8±0.8	0.9±0.8	1.1±0.8	1.2±0.9	1.3±1.0
Total vegetable intake, serving/day	2.4±1.6	2.5±1.5	2.8±1.6	2.9±1.7	3.1±1.7
Adult body mass index, kg/m2	24.5±5.4	24.6±5.3	24.6±5.4	24.6±5.3	24.6±5.2
Height, cm	164.2±6.6	164.5±6.6	164.9±6.6	165.1±6.6	165.4±6.6
Body mass index at age 18, kg/m2	21.2± 3.4	21.3±3.3	21.4±3.4	21.3±3.3	21.2±3.2
Age at first birth, years	25.4±4.1	25.5±4.0	25.8±4.1	26.1±4.1	26.5±4.3
Age at menarche, years	12.4± 1.4	12.4±1.4	12.4±1.4	12.4±1.4	12.4±1.4
%
Alcohol intake
Never	46	41	39	43	43
<5 g/day	36	40	41	39	39
≥5 g/day	18	19	20	18	18
Current smokers	15	13	11	10	11
Ever oral contraceptive use	85	85	85	84	83
History of benign breast disease	10	9	10	9	9
Family history of breast cancer in mother or sisters	15	15	16	15	15
Nulliparous	31	29	27	25	22

Adolescent dairy consumption and breast cancer risk

Adolescent total dairy consumption was not associated with overall breast cancer risk (HR [highest vs lowest]=1.08, 95%CI=0.88-1.33; P_trend=0.46) nor with pre- or postmenopausal breast cancer (Table 2). No significant associations were noticed between breast cancer risk and adolescent intake of low-fat/high-fat dairy products, milk, cheese, ice cream, or yogurt (Tables 2 and S4). Results were similar after additional adjustment for adolescent red meat, fruit and vegetable, fiber, or animal fat intake or for adult total dairy intake.

Table 2.

Hazard ratios (HR) and 95% confidence intervals (95% CI) for breast cancer according to quintile of adolescent dairy product intake

	Quintile of intake
	1	2	3	4	5	P trend*	Per 1 serving/day
Adolescent total dairy products intake
All cases
Median intake, serving/day	1.1	2.0	2.9	3.8	5.1
No. of cases/person-years	255/134,666	262/135,121	258/133,447	276/134,883	267/135,002
Age-adjusted HR (95% CI)	1	1.05 (0.88-1.25)	1.03 (0.87-1.23)	1.09 (0.91-1.29)	1.08 (0.91-1.28)	0.37	1.02 (0.98-1.06)
Multivariable HR (95% CI)	1	1.07 (0.89-1.28)	1.04 (0.86-1.24)	1.10 (0.91-1.32)	1.08 (0.88-1.33)	0.46	1.02 (0.97-1.07)
Premenopausal cases
Median intake, serving/day	1.1	2.0	3.0	3.8	5.1
No. of cases/person-years	105/69,702	116/69,226	119/70,157	121/69,456	110/69,464
Age-adjusted HR (95% CI)	1	1.14 (0.87-1.49)	1.09 (0.83-1.42)	1.12 (0.86-1.45)	1.04 (0.79-1.36)	0.91	1.00 (0.95-1.07)
Multivariable HR (95% CI)	1	1.20 (0.91-1.59)	1.16 (0.88-1.54)	1.23 (0.92-1.65)	1.14 (0.83-1.57)	0.52	1.02 (0.95-1.10)
Postmenopausal cases
Median intake, serving/day	1.1	1.9	2.9	3.7	5.0
No. of cases/person-years	119/53,684	125/53,640	107/53,130	133/53,463	131/53,347
Age-adjusted HR (95% CI)	1	1.08 (0.83-1.39)	0.91 (0.70-1.19)	1.12 (0.87-1.44)	1.14 (0.88-1.46)	0.31	1.03 (0.97-1.09)
Multivariable HR (95% CI)	1	1.03 (0.79-1.34)	0.88 (0.67-1.17)	1.08 (0.82-1.42)	1.14 (0.85-1.53)	0.36	1.03 (0.96-1.11)
Adolescent low-fat dairy
All cases
Median intake, serving/day	0	0.07	0.3	0.8	2.6
No. of cases/person-years	184/87,906	420/200,430	229/116,769	247/134,092	238/133,922
Age-adjusted HR (95% CI)	1	1.02 (0.86-1.21)	0.98 (0.80-1.19)	0.97 (0.80-1.18)	0.99 (0.82-1.21)	0.87	1.00 (0.94-1.06)
Multivariable HR (95% CI)	1	1.02 (0.85-1.21)	0.98 (0.80-1.19)	0.99 (0.81-1.20)	1.00 (0.82-1.22)	0.96	1.00 (0.94-1.06)
Premenopausal cases
Median intake, serving/day	0.07	0.1	0.3	1.0	2.8
No. of cases/person-years	160/88,270	81/52,327	106/68,826	107/68,978	117/69,604
Age-adjusted HR (95% CI)	1	0.84 (0.64-1.10)	0.84 (0.66-1.08)	0.93 (0.72-1.19)	0.99 (0.78-1.27)	0.49	1.03 (0.95-1.12)
Multivariable HR (95% CI)	1	0.86 (0.65-1.12)	0.86 (0.67-1.11)	0.95 (0.74-1.22)	1.04 (0.80-1.34)	0.31	1.05 (0.96-1.14)
Postmenopausal cases
Median intake, serving/day	0	0.07	0.2	0.6	2.5
No. of cases/person-years	84/40,651	186/69,442	133/52,951	105/50,790	107/53,429
Age-adjusted HR (95% CI)	1	1.29 (0.99-1.67)	1.23 (0.93-1.62)	1.08 (0.81-1.44)	1.04 (0.78-1.39)	0.25	0.95 (0.87-1.04)
Multivariable HR (95% CI)	1	1.26 (0.97-1.64)	1.22 (0.92-1.62)	1.05 (0.78-1.42)	1.02 (0.76-1.38)	0.22	0.94 (0.86-1.04)
Adolescent high-fat dairy
All cases
Median intake, serving/day	0.6	1.2	1.8	2.9	4.2
No. of cases/person-years	264/132,526	246/140,206	282/131,707	256/133,575	270/135,104
Age-adjusted HR (95% CI)	1	0.89 (0.74-1.05)	1.06 (0.89-1.25)	0.89 (0.75-1.06)	0.94 (0.79-1.12)	0.51	0.99 (0.95-1.03)
Multivariable HR (95% CI)	1	0.87 (0.73-1.04)	1.03 (0.87-1.23)	0.86 (0.71-1.03)	0.90 (0.74-1.09)	0.26	0.97 (0.93-1.02)
Premenopausal cases
Median intake, serving/day	0.6	1.1	1.7	2.8	4.1
No. of cases/person-years	118/70,774	102/68,152	127/70,316	117/69,419	107/69,345
Age-adjusted HR (95% CI)	1	0.89 (0.68-1.17)	1.04 (0.81-1.34)	0.94 (0.73-1.22)	0.85 (0.65-1.11)	0.29	0.97 (0.90-1.03)
Multivariable HR (95% CI)	1	0.90 (0.68-1.18)	1.05 (0.81-1.37)	0.94 (0.72-1.24)	0.86 (0.64-1.16)	0.37	0.97 (0.90-1.04)
Postmenopausal cases
Median intake, serving/day	0.6	1.2	1.9	3.1	4.3
No. of cases/person-years	125/53,031	108/53,805	136/53,295	112/53,295	134/53,837
Age-adjusted HR (95% CI)	1	0.88 (0.68-1.14)	1.08 (0.85-1.38)	0.87 (0.67-1.12)	1.03 (0.81-1.32)	0.85	1.01 (0.95-1.07)
Multivariable HR (95% CI)	1	0.86 (0.66-1.13)	1.05 (0.81-1.36)	0.82 (0.62-1.07)	1.01 (0.77-1.34)	0.93	1.00 (0.93-1.07)

^*P_trend calculated with median intake of each variable in each quintile as a continuous variable.

Multivariable model was stratified by age in months at start of follow-up and calendar year of the current questionnaire cycle and was simultaneously adjusted for smoking (never, past, current 1 to 14/day, current 15 to 24/day, current ≥25/day), race (white, non-white), parity and age at first birth (nulliparous, parity ≤2 and age at first birth <25 years, parity≤2 and age at first birth 25 to <30 years, parity ≤2 and age at first birth ≥30 years, parity 3 to 4 and age at first birth <25 years, parity 3 to 4 and age at first birth 25 to <30 years, parity 3 to 4 and age at first birth ≥30 years, parity ≥5 and age at first birth <25 years, parity ≥5 and age at first birth ≥25 years), height (<62, 62 to <65, 65 to <68, ≥68 inches), BMI at age 18 years (<18.5, 18.5 to <20, 20 to <22.5, 22.5 to <25, 25.0 to <30, ≥30.0 kg/m2), weight change since age 18 (continuous, missing indicator), age at menarche (<12, 12, 13, ≥14 years), family history of breast cancer (yes, no), history of benign breast disease (yes, no), oral contraceptive use (never, ever), adolescent alcohol intake (nondrinker, <5, ≥5 g/day), adult alcohol intake (nondrinker, <5, 5 to <15, ≥15 g/day), physical activity (quintile), adolescent energy intake (quintile). In postmenopausal women, we additionally adjusted for hormone use (postmenopausal never users, postmenopausal past users, postmenopausal current users) and age at menopause (continuous, missing indicator). Among all women, we additionally adjusted for age at menopause (continuous, missing indicator), and menopausal status and postmenopausal hormone use (premenopausal, postmenopausal never users, postmenopausal past users, postmenopausal current users, postmenopausal unknown hormone use or unknown menopausal status).

Early adulthood dairy consumption and breast cancer risk

Early adulthood total dairy intake was not associated with overall breast cancer risk (HR [highest vs lowest]=1.04, 95%CI=0.92-1.18; P_trend=0.73) nor with pre- or postmenopausal breast cancer (Table 3). No association was found between risk of breast cancer and consumption of low-fat or high-fat dairy, milk, cheese, yogurt, ice cream, or cream (Tables 3 and S5). Results were similar after additionally adjusting for intake of fiber, total fruits and vegetables, total red meat, animal fat, or the AHEI score. The cumulative average of premenopausal total dairy intake was also not associated with risk of overall breast cancer (HR [highest vs lowest]=1.07, 95%CI=0.94-1.21; P_trend=0.74), premenopausal breast cancer (HR [highest vs lowest]=1.06, 95%CI=0.89-1.26; P_trend=0.66), or postmenopausal breast cancer (HR [highest vs lowest]=0.94, 95%CI=0.76-1.16; P_trend=0.26). No significant associations were found for the cumulative average of premenopausal low-fat dairy, high-fat dairy, milk, cheese, or yogurt intake and breast cancer risk.

Table 3.

Hazard ratios (HR) and 95% confidence intervals (95% CI) for breast cancer according to quintile of early adulthood dairy product intake

	Quintile of intake
	1	2	3	4	5	P trend*	Per 1 serving/day
Early adulthood total dairy products intake
All cases
Median intake, serving/day	0.7	1.3	1.9	2.9	4.1
No. of cases/person-years	647/375,726	649/375,863	664/380,088	626/376,361	605/377,580
Age-adjusted HR (95% CI)	1	1.04 (0.93-1.15)	1.07 (0.96-1.20)	1.03 (0.93-1.15)	1.04 (0.93-1.16)	0.61	1.01 (0.98-1.04)
Multivariable HR (95% CI)	1	1.03 (0.92-1.15)	1.05 (0.94-1.18)	1.02 (0.91-1.15)	1.04 (0.92-1.18)	0.73	1.01 (0.97-1.04)
Premenopausal cases
Median intake, serving/day	0.7	1.4	2.0	3.0	4.2
No. of cases/person-years	341/236,401	342/236,006	359/235,913	334/236,710	330/235,834
Age-adjusted HR (95% CI)	1	1.03 (0.88-1.19)	1.10 (0.95-1.28)	1.01 (0.87-1.17)	1.05 (0.90-1.22)	0.77	1.01 (0.97-1.05)
Multivariable HR (95% CI)	1	1.03 (0.88-1.19)	1.10 (0.94-1.28)	1.01 (0.86-1.19)	1.06 (0.89-1.26)	0.72	1.01 (0.96-1.05)
Postmenopausal cases
Median intake, serving/day	0.6	1.3	1.8	2.8	4.0
No. of cases/person-years	244/106,526	229/105,141	227/106,662	226/106,306	208/105,294
Age-adjusted HR (95% CI)	1	0.98 (0.81-1.17)	0.95 (0.79-1.14)	0.97 (0.81-1.16)	0.92 (0.77-1.11)	0.45	0.98 (0.93-1.03)
Multivariable HR (95% CI)	1	0.97 (0.80-1.16)	0.93 (0.77-1.12)	0.94 (0.77-1.13)	0.89 (0.73-1.10)	0.30	0.97 (0.92-1.03)
Early adulthood low-fat dairy
All cases
Median intake, serving/day	0.1	0.6	1.1	1.6	2.9
No. of cases/person-years	617/370,200	684/381,303	635/381,221	657/387,660	598/364,995
Age-adjusted HR (95% CI)	1	1.10 (0.98-1.22)	1.03 (0.92-1.15)	1.05 (0.94-1.17)	1.07 (0.95-1.20)	0.52	1.01 (0.98-1.05)
Multivariable HR (95% CI)	1	1.09 (0.97-1.21)	1.01 (0.90-1.13)	1.03 (0.92-1.16)	1.06 (0.94-1.20)	0.62	1.01 (0.97-1.05)
Premenopausal cases
Median intake, serving/day	0.1	0.6	1.1	1.7	2.9
No. of cases/person-years	346/232,954	332/234,767	362/245,037	320/224,263	346/243,749
Age-adjusted HR (95% CI)	1	0.96 (0.83-1.12)	1.01 (0.87-1.17)	0.97 (0.83-1.12)	0.99 (0.85-1.14)	0.91	1.00 (0.95-1.05)
Multivariable HR (95% CI)	1	0.96 (0.83-1.12)	1.01 (0.87-1.17)	0.97 (0.83-1.14)	1.01 (0.86-1.18)	0.87	1.00 (0.95-1.06)
Postmenopausal cases
Median intake, serving/day	0.1	0.6	1.0	1.5	2.8
No. of cases/person-years	215/105,697	249/104,275	224/105,077	223/110,176	223/104,600
Age-adjusted HR (95% CI)	1	1.18 (0.98-1.42)	1.07 (0.88-1.29)	1.01 (0.83-1.22)	1.10 (0.91-1.33)	0.81	1.01 (0.94-1.08)
Multivariable HR (95% CI)	1	1.18 (0.98-1.41)	1.05 (0.87-1.27)	0.99 (0.81-1.20)	1.08 (0.89-1.32)	0.94	1.00 (0.94-1.08)
Early adulthood high-fat dairy
All cases
Median intake, serving/day	0.2	0.4	0.6	1.0	1.9
No. of cases/person-years	697/401,858	509/308,304	703/413,946	663/389,246	618/371,494
Age-adjusted HR (95% CI)	1	0.99 (0.88-1.11)	1.05 (0.94-1.17)	1.07 (0.96-1.19)	1.06 (0.95-1.18)	0.18	1.04 (0.98-1.11)
Multivariable HR (95% CI)	1	0.98 (0.87-1.10)	1.04 (0.93-1.16)	1.07 (0.96-1.20)	1.06 (0.95-1.19)	0.19	1.04 (0.98-1.11)
Premenopausal cases
Median intake, serving/day	0.2	0.5	0.7	1.1	1.9
No. of cases/person-years	356/237,648	342/249,251	331/219,841	332/242,479	344/231,269
Age-adjusted HR (95% CI)	1	0.94 (0.81-1.09)	1.06 (0.91-1.23)	0.99 (0.85-1.15)	1.08 (0.93-1.26)	0.18	1.06 (0.97-1.15)
Multivariable HR (95% CI)	1	0.94 (0.81-1.09)	1.07 (0.91-1.24)	1.00 (0.85-1.16)	1.08 (0.92-1.27)	0.23	1.06 (0.97-1.15)
Postmenopausal cases
Median intake, serving/day	0.1	0.4	0.6	1.0	1.7
No. of cases/person-years	228/103,750	241/111,207	218/101,241	227/105,351	220/108,089
Age-adjusted HR (95% CI)	1	1.01 (0.84-1.21)	1.04 (0.86-1.25)	1.02 (0.85-1.23)	0.99 (0.82-1.20)	0.88	0.99 (0.89-1.11)
Multivariable HR (95% CI)	1	1.00 (0.83-1.20)	1.02 (0.84-1.24)	1.01 (0.84-1.23)	0.98 (0.81-1.20)	0.84	0.99 (0.88-1.11)

^*P_trend calculated with median intake of each variable in each quintile as a continuous variable.

Multivariable model was stratified by age in months at start of follow-up and calendar year of the current questionnaire cycle and was simultaneously adjusted for race (white, non-white), family history of breast cancer in mother or sisters (yes, no), history of benign breast disease (yes, no), smoking (never, past, current 1 to 14/day, current 15 to 24/day, current ≥25/day), height (<62, 62 to <65, 65 to <68, ≥68 inches), BMI at age 18 years (<18.5, 18.5 to <20, 20 to <22.5, 22.5 to <25, 25.0 to <30, ≥30.0 kg/m2), weight change since age 18 (continuous, missing indicator), age at menarche (<12, 12, 13, ≥14 years), parity and age at first birth (nulliparous, parity ≤2 and age at first birth <25 years, parity≤2 and age at first birth 25 to <30 years, parity ≤2 and age at first birth ≥30 years, parity 3 to 4 and age at first birth <25 years, parity 3 to 4 and age at first birth 25 to <30 years, parity 3 to 4 and age at first birth ≥30 years, parity ≥5 and age at first birth <25 years, parity ≥5 and age at first birth ≥25 years), oral contraceptive use (never, ever), alcohol intake (nondrinker, <5, 5 to <15, ≥15 g/day), physical activity (quintile), and energy intake (quintile). In postmenopausal women, we additionally adjusted for hormone use (postmenopausal never users, postmenopausal past users, postmenopausal current users) and age at menopause (continuous, missing indicator). Among all women, we additionally adjusted for age at menopause (continuous, missing indicator), and menopausal status and postmenopausal hormone use (premenopausal, postmenopausal never users, postmenopausal past users, postmenopausal current users, postmenopausal unknown hormone use or unknown menopausal status).

Average adolescent and early adulthood dairy consumption and breast cancer risk

Adolescent and early adult (1991) total dairy intake was modestly correlated (r=0.35). Among women with both early adulthood and adolescent dietary data (n=41,092), adolescent and early adulthood dairy intake was averaged. We observed no significant association with risk of pre- or postmenopausal breast cancer. However, an inverse association was noted between average adolescent and early adulthood yogurt intake and overall (for ≥1 serving/month vs never or <1 serving/month: HR=0.88, 95%CI=0.79-1.00) and premenopausal breast cancer risk (for ≥1 serving/month vs never or <1 serving/month: HR=0.82, 95%CI=0.68-0.99). This inverse association did not reach a significant level for postmenopausal breast cancer (for ≥1 serving/month vs never or <1 serving/month: HR=0.91, 95%CI=0.77-1.08).

Calcium, vitamin D, and lactose intake and breast cancer risk

We did not observe any significant association between breast cancer risk and calcium, vitamin D, or lactose intake during either adolescence or early adulthood (Tables S6 and S7).

Subgroup analyses

We had information on ER status for 82% (n = 2,617) of breast cancers and PR status for 82% (n = 2,604) of breast cancers. Associations between adolescent consumption of total dairy and high-fat dairy products and risk of breast cancer differed by ER/PR status (Table 4). High adolescent total dairy intake was associated with higher risk of ER−/PR− cancer (each serving/day for total dairy product HR = 1.11, 95% CI, 1.00–1.24; P_{for difference by receptor status} = 0.04). During adolescence, high intake of high-fat dairy products was associated with increased risk of ER−/PR− cancer (each serving/day HR = 1.17, 95% CI, 1.04–1.31; P_{for difference by receptor status} = 0.0004) and decreased risk of ER+/PR+ tumors (each serving/day HR = 0.91, 95% CI, 0.86–0.97). These associations were minimally changed after additional adjustment for animal or total fat intake. We did not observe significant heterogeneity between early adulthood dairy intake and tumor receptor status in either pre- or postmenopausal breast cancer (Table 4). To evaluate whether missing data on ER/PR status may impact the results, we examined the associations between dairy food intake and overall breast cancer incidence when only cases with ER/PR data were included. Compared to analyses including all cases of breast cancer, we observed similar results for adolescent and early adulthood dairy food intake when the analyses included only cases with ER/PR data.

Table 4.

Adolescent and early adulthood dairy products intake in relation to risk of breast cancer by estrogen and progesterone receptor status among women in the Nurses’ Health Study II

Breast cancer subtype	All cases		Premenopausal cases		Postmenopausal cases
	No. of cases	HR (95%CI)	No. of cases	HR (95%CI)	No. of cases	HR (95%CI)
Adolescent total dairy intake (HR per serving/day)
Estrogen and progesterone receptor positive	822	0.97 (0.92–1.03)	379	0.96 (0.88–1.04)	369	1.00 (0.91–1.09)
Estrogen and progesterone receptor negative	179	1.11 (1.00–1.24)	84	1.10 (0.94–1.29)	79	1.16 (0.97–1.37)
Estrogen receptor positive and progesterone receptor negative	119	1.08 (0.94–1.23)	35	1.04 (0.81–1.34)	70	1.12 (0.94–1.34)
Pfor difference by receptor status	0.04		0.24		0.17
Early adult total dairy intake (HR per serving/day)
Estrogen and progesterone receptor positive	1849	1.01 (0.97–1.05)	1028	1.01 (0.96–1.07)	643	0.98 (0.91–1.06)
Estrogen and progesterone receptor negative	451	0.99 (0.91–1.07)	255	1.03 (0.93–1.14)	153	0.92 (0.80–1.06)
Estrogen receptor positive and progesterone receptor negative	247	1.01 (0.91–1.12)	109	1.10 (0.95–1.29)	111	0.95 (0.80–1.12)
Pfor difference by receptor status	0.87		0.58		0.66
Adolescent high-fat dairy intake (HR per serving/day)
Estrogen and progesterone receptor positive	822	0.91 (0.86–0.97)	379	0.90 (0.83-0.99)	369	0.96 (0.88-1.04)
Estrogen and progesterone receptor negative	179	1.17 (1.04–1.31)	84	1.15 (0.97-1.37)	79	1.18 (0.99-1.39)
Estrogen receptor positive and progesterone receptor negative	119	0.99 (0.86–1.14)	35	1.01 (0.78-1.33)	70	0.97 (0.81-1.16)
Pfor difference by receptor status	0.0004		0.03		0.09
Early adult high-fat dairy intake (HR per serving/day)
Estrogen and progesterone receptor positive	1849	1.05 (0.97-1.14)	1028	1.07 (0.96–1.19)	643	1.00 (0.86–1.17)
Estrogen and progesterone receptor negative	451	0.95 (0.81-1.13)	255	1.02 (0.82–1.26)	153	0.78 (0.57–1.07)
Estrogen receptor positive and progesterone receptor negative	247	1.13 (0.91-1.41)	109	1.13 (0.82–1.56)	111	1.15 (0.82-1.62)
Pfor difference by receptor status	0.41		0.85		0.21

Multivariable model was stratified by age in months at start of follow-up and calendar year of the current questionnaire cycle and was simultaneously adjusted for race (white, non-white), family history of breast cancer in mother or sisters (yes, no), history of benign breast disease (yes, no), smoking (never, past, current 1 to 14/day, current 15 to 24/day, current ≥25/day), height (<62, 62 to <65, 65 to <68, ≥68 inches), BMI at age 18 years (<18.5, 18.5 to <20, 20 to <22.5, 22.5 to <25, 25.0 to <30, ≥30.0 kg/m²), weight change since age 18 (continuous, missing indicator), age at menarche (<12, 12, 13, ≥14 years), parity and age at first birth (nulliparous, parity ≤2 and age at first birth <25 years, parity≤2 and age at first birth 25 to <30 years, parity ≤2 and age at first birth ≥30 years, parity 3 to 4 and age at first birth <25 years, parity 3 to 4 and age at first birth 25 to <30 years, parity 3 to 4 and age at first birth ≥30 years, parity ≥5 and age at first birth <25 years, parity ≥5 and age at first birth ≥25 years), oral contraceptive use (never, ever), alcohol intake (nondrinker, <5, 5 to <15, ≥15 g/day), physical activity (quintile), and energy intake (quintile). In postmenopausal women, we additionally adjusted for hormone use (postmenopausal never users, postmenopausal past users, postmenopausal current users) and age at menopause (continuous, missing indicator). Among all women, we additionally adjusted for age at menopause (continuous, missing indicator), and menopausal status and postmenopausal hormone use (premenopausal, postmenopausal never users, postmenopausal past users, postmenopausal current users, postmenopausal unknown hormone use or unknown menopausal status). For adolescent dairy food intake, we additionally adjusted for adolescent alcohol intake (nondrinker, <5, ≥5 g/day) and adolescent energy intake (quintile) (instead of adult energy intake).

Note: The 56 cases of ER+ and PR− were not included in the table and 588 women did not have data for ER/PR status.

In addition, we examined whether the association between total dairy and high-fat dairy consumption during adolescence and early adulthood, and risk of breast cancer differed by BMI at age 18 (<21 or >= 21 kg/m²). No significant interaction was observed. Because we found a significant positive association between high-fat dairy and breast cancer in a previous analysis using NHSII data and we did not find this result in the current analysis, we examined whether the positive association was due to the younger age of participants at diagnosis, we looked at the association in 2 groups of women: younger than 45 years and 45 years or more (age updated during follow-up). We observed a significant positive association between early adulthood high-fat dairy consumption and breast cancer risk only among women younger than 45 years (each serving/day HR = 1.15, 95% CI, 1.01–1.30).

Discussion

Adolescent or early adulthood dairy intake was not associated with overall breast cancer risk. Although analysis of two time periods (adolescence and early adulthood) separately did not support the beneficial effects of yogurt for breast cancer prevention, the average adolescent and early adulthood yogurt consumption was associated with lower risk of breast cancer, specially before menopause. Moreover, higher dairy consumption, especially high-fat dairy during adolescence, was associated with a higher risk of ER/PR negative and lower risk of ER/PR positive breast cancer. Adolescent or early adulthood calcium, vitamin D, and lactose intake was not associated with incident breast cancer.

Prospective studies have been inconsistent concerning a role of dairy consumption on breast cancer incidence. Although a few studies reported higher (16, 17) or lower (18–23) breast cancer risk, most studies have not reported significant relationships between dairy consumption and breast cancer risk (6–15). Similar to the current study, in an earlier analysis of the NHSII, adolescent dairy intake was not associated with breast cancer risk (12). Although, we did not observe a significant association between early adulthood high-fat dairy foods and risk of breast cancer overall, a significant positive association was noted between high-fat dairy and breast cancer among women younger than 45 years. Therefore, it is possible that the positive association observed in Cho et al. (17) study was primarily due to the young age of participants (mean age at diagnosis=43 years) rather than the early life dietary evaluation.

Fewer studies evaluated whether the association between dairy products and breast cancer varied by hormone receptor status (14, 19, 23). While lower risk of ER positive breast cancer was observed with higher dairy intake among postmenopausal women in the Cancer Prevention Study II Nutrition Cohort (23), Lin et al. (19) and Genkinger et al. (14) did not observe any difference by ER/PR status. In our study, high adolescent intake of total and high-fat dairy products was associated with higher risk of ER/PR negative, but not ER/PR positive breast cancer. The biological mechanisms are not clear for dairy products by hormone receptor status. Dairy products naturally contain endogenous estrogens and estrogen metabolites (54), which account for approximately 50% of the estrogens consumed (55). In one study, higher dairy consumption was associated with higher total and free estradiol concentrations among postmenopausal women (2). Because factors related to estrogen metabolism are more strongly related to ER positive tumors, our a priori hypothesis was that development of hormone receptor positive tumors might be more sensitive to dairy consumption. Further, insulin-like growth factors likely play an important role in the etiology of breast cancer (56–58), and dairy intake may promote neoplasms by raising insulin-like growth factor I concentrations (3–5, 59). Plasma levels of insulin-like growth factor I were mainly associated with higher ER positive tumor risk, but not ER negative tumors (60, 61). In addition, N-glycolylneuraminic acid found in dairy foods may play a role in breast tumors (62, 63), however, its role in relation to tumor subtypes is not clear. Therefore, the variation in associations by ER/PR status might have occurred by chance and needs confirmation.

Although prospective cohort studies have not shown any significant association between either yogurt or fermented milk intake and incident breast cancer (8, 14, 20, 22), a recently published meta-analysis with case-control and cohort studies (64) reported a 9% lower breast cancer risk with high yogurt intake. Our study suggested that the average of adolescent and early adulthood yogurt consumption might reduce risk of breast cancer, but this finding should be interpreted cautiously as an association with yogurt was not seen when adolescent and adult intakes were examined separately. Lactic acid bacteria that are found in yogurt may play a role in decreasing breast cancer risk, at least partially through immunomodulatory mechanisms (65).

Our study has several strengths. We were able to evaluate the role of dairy intake in specific life periods including adolescence, early adulthood, and the cumulative average of the premenopausal time span. The large number of cases showed modest differences in risk and examined breast cancer by menopausal and hormone receptor status.

There are several limitations to our study. The participants were predominantly white nurses who do not represent a random sample of U.S. women, however, biological mechanisms underlying these associations might not differ by race or education. In previous studies, we observed that the associations for breast cancer and other diseases were very similar to those found in the other broadly based U.S. populations. Because women aged 33-52 years were asked to recall high school diet, the assessment of adolescent dietary intake might be imprecise. Nevertheless, the HS-FFQ showed reasonable validity (45). In addition, adolescent milk intake was positively associated with increased adult height in the current study, as observed prospectively in the Growing Up Today Study, supporting the validity of our measurement of adolescent milk intake (66). Finally, residual confounding is always of concern in observational studies. With the detailed NHSII questionnaires, we adjusted for all known breast cancer risk factors.

In summary, we found no association between dairy consumption during adolescence or early adulthood with overall breast cancer risk. However, our findings suggested that adolescent high dairy intake might be associated with higher ER/PR negative and lower ER/PR positive cancer risk. Intake of calcium, vitamin D, and lactose during adolescence or early adulthood was not associated with breast cancer incidence. Further studies are warranted to investigate these relationships, especially the associations between dairy intake and risk of breast cancers classified by hormone receptor status.

Abbreviation list

AHEI

Alternate Healthy Eating Index

CIs

confidence intervals

ER

estrogen receptor

FFQ

food-frequency questionnaire

HRs

hazard ratios

HS-FFQ

high school food-frequency questionnaire

NHSII

Nurses’ Health Study II

PR

progesterone receptor