Dairy Intake and Mortality After Breast Cancer Diagnosis
The LACE Study cohort includes 2264 women diagnosed with early-stage invasive breast cancer from 1997 to 2000 who were recruited primarily from the Kaiser Permanente Northern California (KPNC) Cancer Registry (83%) and the Utah Cancer Registry (12%) from 2000 to 2002. Further details have been provided elsewhere. In brief, eligibility criteria included 1) aged 18 to 70 years at enrollment; 2) diagnosis of early-stage primary breast cancer (stage I ≥ 1cm, II, or IIIA); 3) enrollment between 11 and 39 months postdiagnosis; 4) completion of breast cancer treatment (except adjuvant hormonal therapy); 5) no evidence of recurrence; and 6) no history of other cancers within 5 years prior to enrollment.
Of the total sample, 1893 women provided complete information on baseline diet. Of these, 1513 women provided dietary data at follow-up 6 years later. Of the total sample, 349 women had a recurrence and 372 died of any cause, with 189 (50.8%) dying from breast cancer. Women provided passive consent when they responded to surveys; the study was approved by the institutional review boards of KPNC and the University of Utah.
Breast Cancer Ascertainment. Information on clinical factors was obtained through electronic data sources available from KPNC or from medical chart review for the non-KPNC participants. Data included tumor size, number of positive lymph nodes, hormone receptor status, and treatment (ie, chemotherapy, radiation therapy, and hormonal therapy). Tumor stage was calculated according to criteria of the American Joint Committee on Cancer (4th edition).
Recurrences were ascertained by a mailed semiannual or annual (after April 2005) health status questionnaire asking participants to report events occurring in the preceding 6 or 12 months, respectively. Recurrences included a locoregional cancer recurrence, distant recurrence/metastasis, or development of a contralateral breast primary. Nonrespondents were called by telephone to complete questionnaires. Medical records were reviewed to verify reported outcomes.
Mortality. Participant deaths were determined through KPNC electronic data sources, a family member responding to a mailed questionnaire, or a phone call to the family. Copies of death certificates were obtained to verify primary and underlying causes of death (International Classification of Diseases, Ninth revision). All-cause mortality included death from any cause including breast cancer. Breast cancer–specific death included death attributable to breast cancer as a primary or underlying cause on the death certificate. Death from causes other than breast cancer included all other deaths. A physician reviewer was consulted when the cause of death was unclear.
Assessment of Dairy Intake. Dietary intake during the previous 12 months was assessed using the Fred Hutchinson Cancer Research Center Food Frequency Questionnaire (FHCRC-FFQ) at both the baseline and 6-year follow-up surveys. The FHCRC-FFQ questionnaire is a validated, self-administered, semiquantitative food frequency questionnaire with approximately 120 items and is an adaptation of the 95-item Health Habits and Lifestyle Questionnaire developed by Block and colleagues at the National Cancer Institute.
Specifically, women were asked how often they consumed dairy foods during the previous year. The portion size of a medium serving was provided, and women were asked whether they consumed a small, medium, or large serving. Dairy products included milk (milk on cereal; milk not on cereal; milk, cream or creamer in coffee or tea), cheese (low-fat cottage cheese; nonfat cheese; part skim or reduced-fat cheese; other cheese), dairy desserts (ice cream; pudding; custard or flan; low-fat or nonfat frozen desserts), and yogurt (nonfat; other). To assess fat level in milk, women were asked, "Did you drink milk or beverages made with milk, such as hot chocolate, during this time period? When you drank milk or milk beverages, was it usually: whole milk, 2% milk, 1% milk or butter milk, nonfat or skim milk, evaporated or condensed milk, soy milk, or don't know?" Women were asked similar questions separately for milk, cream, or creamer used on cereal and milk, cream, or creamer in tea or coffee. Servings per day of dairy were computed as the sum of the number of servings of each of these foods consumed each day multiplied by a factor related to the serving size reported (0.5 = small, 1.0 = medium, 1.5 = large) for each item. Servings per day of low-fat dairy were computed as the sum of servings per day of low-fat (1%, 2%) and nonfat (skim) items, including milk, cheese, desserts, and yogurt. Servings per day of high-fat dairy were computed as the sum of high-fat items, including cream, whole milk, condensed or evaporated milk, other cheese, other yogurt, pudding, ice cream, custard, and flan. Total servings per day of dairy were computed as the sum of servings of all dairy.
To maximize power, to capitalize on the availability of dietary data assessed at more than one time point, and to avoid issues of interpretation if recurrence causes women to alter subsequent diet, we analyzed dietary intake in the following way. For those with recurrence events between baseline and the 6-year follow-up, we assigned dietary intake based on women's self-reported diet at baseline. For women who were free of recurrence at follow-up and who provided dietary data at follow-up, we computed diet as the cumulative average of self-reported intake at baseline and follow-up. If women were free of recurrence by follow-up but were missing dietary data at follow-up, we assigned them baseline dietary intake. We also conducted analyses assigning person-time to the updated cumulative average of previously assessed diet.
We used the following categories: 0 to less than 1.0, 1.0 to less than 2.0, and 2.0 or more servings per day, to analyze total dairy consumption and outcomes and ensure a reasonable distribution across categories. To ensure reasonable distributions and consistency in analyses of low-fat and high-fat dairy, we generated the following categories: 0 to less than 0.5, 0.5 to less than 1.0, and 1.0 or more servings per day. These categories were reasonably consistent with previous analyses of levels of dairy in US postmenopausal women.
Other Covariates. Information on other covariates was self-reported at baseline. Data on race, education, smoking, menopausal status, reproductive factors, and body mass index were obtained from the mailed baseline questionnaire.
Using analysis of covariance, we regressed potential confounding variables against categories of high-fat dairy food consumption, adjusted for continuous age.
We employed delayed entry Cox proportional hazards models (SAS PROC PHREG; SAS Institute, Cary, NC) for failure-time data to assess associations of categories of dairy as well as high- and low-fat dairy intake with time to event. Person-years of follow-up were counted from the date of study entry until the date of recurrence, death, or end of follow-up, whichever came first. Time between diagnosis and dietary assessment was updated in analyses for those with dietary data at baseline and follow-up. We conducted tests for linear trend or continuous variables, as indicated, computing Wald statistics and tests of proportionality with variable by time interactions. Tests of statistical significance were two-sided. Statistically significant results denote P values less than or equal to.05.
Minimally adjusted results were compared with those adjusted for multiple covariates. Initial analyses were adjusted for age and time between dietary assessment and prior breast cancer diagnosis. Analyses were adjusted additionally for factors considered a priori to be important potential confounding variables of the relationship between dairy intake and breast cancer outcomes, including disease severity (stage, tumor size, grade, nodal status, estrogen receptor status, and human epidermal growth factor receptor 2 [HER-2] status), treatment (radiation, chemotherapy, tamoxifen), education, ethnicity, and behavioral and related factors (energy intake, red meat, fiber, and fruit intake, body mass index, physical activity, alcohol intake, smoking status). Reproductive variables were not related to dairy consumption, and their inclusion as covariates did not influence associations, so they were dropped from final models. Covariates for which we had data at follow-up, including time between diagnosis and follow-up, tamoxifen, menopausal status, body mass index, smoking, and alcohol, were updated in analyses using the most recent covariate information.
We also evaluated a model adjusted additionally for nutrients found in dairy, including vitamin D, calcium, potassium, and saturated fat intake, to ascertain whether these explained associations of dairy intake and outcomes.
We did not evaluate associations by race/ethnicity because we did not have adequate power.
Methods
Study Population
The LACE Study cohort includes 2264 women diagnosed with early-stage invasive breast cancer from 1997 to 2000 who were recruited primarily from the Kaiser Permanente Northern California (KPNC) Cancer Registry (83%) and the Utah Cancer Registry (12%) from 2000 to 2002. Further details have been provided elsewhere. In brief, eligibility criteria included 1) aged 18 to 70 years at enrollment; 2) diagnosis of early-stage primary breast cancer (stage I ≥ 1cm, II, or IIIA); 3) enrollment between 11 and 39 months postdiagnosis; 4) completion of breast cancer treatment (except adjuvant hormonal therapy); 5) no evidence of recurrence; and 6) no history of other cancers within 5 years prior to enrollment.
Of the total sample, 1893 women provided complete information on baseline diet. Of these, 1513 women provided dietary data at follow-up 6 years later. Of the total sample, 349 women had a recurrence and 372 died of any cause, with 189 (50.8%) dying from breast cancer. Women provided passive consent when they responded to surveys; the study was approved by the institutional review boards of KPNC and the University of Utah.
Data Collection
Breast Cancer Ascertainment. Information on clinical factors was obtained through electronic data sources available from KPNC or from medical chart review for the non-KPNC participants. Data included tumor size, number of positive lymph nodes, hormone receptor status, and treatment (ie, chemotherapy, radiation therapy, and hormonal therapy). Tumor stage was calculated according to criteria of the American Joint Committee on Cancer (4th edition).
Recurrences were ascertained by a mailed semiannual or annual (after April 2005) health status questionnaire asking participants to report events occurring in the preceding 6 or 12 months, respectively. Recurrences included a locoregional cancer recurrence, distant recurrence/metastasis, or development of a contralateral breast primary. Nonrespondents were called by telephone to complete questionnaires. Medical records were reviewed to verify reported outcomes.
Mortality. Participant deaths were determined through KPNC electronic data sources, a family member responding to a mailed questionnaire, or a phone call to the family. Copies of death certificates were obtained to verify primary and underlying causes of death (International Classification of Diseases, Ninth revision). All-cause mortality included death from any cause including breast cancer. Breast cancer–specific death included death attributable to breast cancer as a primary or underlying cause on the death certificate. Death from causes other than breast cancer included all other deaths. A physician reviewer was consulted when the cause of death was unclear.
Assessment of Dairy Intake. Dietary intake during the previous 12 months was assessed using the Fred Hutchinson Cancer Research Center Food Frequency Questionnaire (FHCRC-FFQ) at both the baseline and 6-year follow-up surveys. The FHCRC-FFQ questionnaire is a validated, self-administered, semiquantitative food frequency questionnaire with approximately 120 items and is an adaptation of the 95-item Health Habits and Lifestyle Questionnaire developed by Block and colleagues at the National Cancer Institute.
Specifically, women were asked how often they consumed dairy foods during the previous year. The portion size of a medium serving was provided, and women were asked whether they consumed a small, medium, or large serving. Dairy products included milk (milk on cereal; milk not on cereal; milk, cream or creamer in coffee or tea), cheese (low-fat cottage cheese; nonfat cheese; part skim or reduced-fat cheese; other cheese), dairy desserts (ice cream; pudding; custard or flan; low-fat or nonfat frozen desserts), and yogurt (nonfat; other). To assess fat level in milk, women were asked, "Did you drink milk or beverages made with milk, such as hot chocolate, during this time period? When you drank milk or milk beverages, was it usually: whole milk, 2% milk, 1% milk or butter milk, nonfat or skim milk, evaporated or condensed milk, soy milk, or don't know?" Women were asked similar questions separately for milk, cream, or creamer used on cereal and milk, cream, or creamer in tea or coffee. Servings per day of dairy were computed as the sum of the number of servings of each of these foods consumed each day multiplied by a factor related to the serving size reported (0.5 = small, 1.0 = medium, 1.5 = large) for each item. Servings per day of low-fat dairy were computed as the sum of servings per day of low-fat (1%, 2%) and nonfat (skim) items, including milk, cheese, desserts, and yogurt. Servings per day of high-fat dairy were computed as the sum of high-fat items, including cream, whole milk, condensed or evaporated milk, other cheese, other yogurt, pudding, ice cream, custard, and flan. Total servings per day of dairy were computed as the sum of servings of all dairy.
To maximize power, to capitalize on the availability of dietary data assessed at more than one time point, and to avoid issues of interpretation if recurrence causes women to alter subsequent diet, we analyzed dietary intake in the following way. For those with recurrence events between baseline and the 6-year follow-up, we assigned dietary intake based on women's self-reported diet at baseline. For women who were free of recurrence at follow-up and who provided dietary data at follow-up, we computed diet as the cumulative average of self-reported intake at baseline and follow-up. If women were free of recurrence by follow-up but were missing dietary data at follow-up, we assigned them baseline dietary intake. We also conducted analyses assigning person-time to the updated cumulative average of previously assessed diet.
We used the following categories: 0 to less than 1.0, 1.0 to less than 2.0, and 2.0 or more servings per day, to analyze total dairy consumption and outcomes and ensure a reasonable distribution across categories. To ensure reasonable distributions and consistency in analyses of low-fat and high-fat dairy, we generated the following categories: 0 to less than 0.5, 0.5 to less than 1.0, and 1.0 or more servings per day. These categories were reasonably consistent with previous analyses of levels of dairy in US postmenopausal women.
Other Covariates. Information on other covariates was self-reported at baseline. Data on race, education, smoking, menopausal status, reproductive factors, and body mass index were obtained from the mailed baseline questionnaire.
Statistical Analyses
Using analysis of covariance, we regressed potential confounding variables against categories of high-fat dairy food consumption, adjusted for continuous age.
We employed delayed entry Cox proportional hazards models (SAS PROC PHREG; SAS Institute, Cary, NC) for failure-time data to assess associations of categories of dairy as well as high- and low-fat dairy intake with time to event. Person-years of follow-up were counted from the date of study entry until the date of recurrence, death, or end of follow-up, whichever came first. Time between diagnosis and dietary assessment was updated in analyses for those with dietary data at baseline and follow-up. We conducted tests for linear trend or continuous variables, as indicated, computing Wald statistics and tests of proportionality with variable by time interactions. Tests of statistical significance were two-sided. Statistically significant results denote P values less than or equal to.05.
Minimally adjusted results were compared with those adjusted for multiple covariates. Initial analyses were adjusted for age and time between dietary assessment and prior breast cancer diagnosis. Analyses were adjusted additionally for factors considered a priori to be important potential confounding variables of the relationship between dairy intake and breast cancer outcomes, including disease severity (stage, tumor size, grade, nodal status, estrogen receptor status, and human epidermal growth factor receptor 2 [HER-2] status), treatment (radiation, chemotherapy, tamoxifen), education, ethnicity, and behavioral and related factors (energy intake, red meat, fiber, and fruit intake, body mass index, physical activity, alcohol intake, smoking status). Reproductive variables were not related to dairy consumption, and their inclusion as covariates did not influence associations, so they were dropped from final models. Covariates for which we had data at follow-up, including time between diagnosis and follow-up, tamoxifen, menopausal status, body mass index, smoking, and alcohol, were updated in analyses using the most recent covariate information.
We also evaluated a model adjusted additionally for nutrients found in dairy, including vitamin D, calcium, potassium, and saturated fat intake, to ascertain whether these explained associations of dairy intake and outcomes.
We did not evaluate associations by race/ethnicity because we did not have adequate power.
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