ABSTRACT
Background
To evaluate the association between postdiagnostic dairy intake and survival among patients with colorectal cancer (CRC).
Methods
This study analyzed data from the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). Postdiagnostic dairy intake and other dietary and lifestyle factors were obtained from validated questionnaires. Individual dairy items including milk, cheese, yogurt, and so on were reported, and total, high-fat, and low-fat dairy intakes were derived.
Results
A total of 1753 eligible CRC cases were identified until 2012, from which 703 deaths were documented after a median follow-up time of 8.2 y, and 242 were due to CRC. Overall, when comparing those who consumed 21+ servings/wk with <7 servings/wk, postdiagnostic total dairy intake did not show significant associations with CRC-specific mortality (HR: 1.35; 95% CI: 0.85, 2.13) or overall mortality (HR: 1.28; 95% CI: 0.98, 1.67). However, high-fat dairy, including whole milk and cream cheese, was positively associated with overall mortality (HR: 1.33; 95% CI: 1.08, 1.65) but not significantly with CRC-specific mortality (HR: 1.31; 95% CI: 0.91, 1.90) when comparing those who consumed 10.5+ servings/wk with <3.5 servings/wk. For the same comparison, low-fat dairy, including skim or nonfat milk and cottage cheese, was inversely associated with overall mortality (HR: 0.74; 95% CI: 0.59, 0.92) but not CRC-specific mortality (HR: 0.91; 95% CI: 0.63, 1.29).
Conclusions
Total dairy products intake did not show significant association with CRC-specific or overall mortality. However, high intake of high-fat dairy products was associated with increased mortality, whereas low-fat dairy was associated with lower risk of overall mortality.
Keywords: dairy, high-fat dairy, low-fat dairy, colorectal cancer, survival
See corresponding editorial on page 1388 and article on pages 1447 and 1458.
Background
Colorectal cancer (CRC) is ranked third in incidence and second in mortality among cancers worldwide in 2020, with more than 1.9 million new cases diagnosed annually (1). The high incidence is partially due to unhealthy dietary patterns and lifestyle factors and obesity, whereas mortality was improved in more developed countries by early detection of CRC and precursor lesions from screening and treatment in time (2, 3). As the number of people with CRC is growing, many are seeking advice for effective dietary and lifestyle modifications, which requires a better understanding of the relevant factors (4).
Dairy products are among the most commonly consumed food in Western countries, including the United States (5, 6). They provide important nutrients, including protein; calcium; potassium; phosphorus; vitamins A, D, and B-12; riboflavin; and niacin. However, the high content of saturated fat may have some deleterious health consequences (7). Previous studies have examined the associations of nutrients from dairy products, including calcium and vitamin D, with CRC survival. For example, higher calcium intake was associated with lower mortality after CRC diagnosis (8, 9). Although no clear association has been found between vitamin D intakes and CRC survival (9), plasma 25(OH) vitamin D concentration was inversely associated with CRC mortality (10, 11). Recent randomized controlled clinical trials reported benefits from high-dose vitamin D intake for survival among patients with advanced CRC (12) and suggestively with digestive cancer survival (13). Three prospective studies have examined the associations between dairy food intake and CRC-specific survival and overall survival. Null associations have been reported for total dairy intake (HR: 0.73–1.17), yogurt (HR: 1.08–1.09), and cheese (HR: 0.87–0.93), whereas null or positive associations have been reported for milk (HR: 0.72–1.21) (9, 14, 15). Two of the studies used baseline dietary information before cancer diagnosis, and limited dairy items were examined. Dairy products are diverse, and the nutrient compositions vary, which may have different effects. One systematic review indicated an inverse association between total dairy products intake and CRC incidence, but the associations varied across types of dairy products (16). Thus, we examined both total intake of dairy products and individual dairy items after CRC diagnosis in relation to survival of patients with CRC.
We used 2 large cohorts that had comprehensive data collected on dietary and lifestyle factors and sufficient CRC cases to investigate postdiagnostic intake of dairy products and CRC-specific survival and overall survival in the US population.
Methods
Study cohorts
Participants were from the Nurses’ Health Study (NHS) established in 1976 with 121,700 female registered nurses aged 30–55 y at baseline and the Health Professionals Follow-up Study (HPFS) established in 1986 with 51,529 male dentists, veterinarians, pharmacists, optometrists, osteopath physicians, and podiatrists aged 40–75 y. A questionnaire collecting detailed information on demographic characteristics, lifestyle factors, and medical history was returned by participants at baseline and biennially during follow-up in both cohorts. The response rates were >90% for both cohorts throughout the years.
Study participants
During follow-up, the incident CRC cases were identified by report from returned biennial questionnaires. Patients were then asked for written permission to access their medical records, including pathologic reports. For those participants who did not respond, the state cancer registries and the National Death Index (NDI) were searched to identify CRC diagnosis or CRC-related death (17). For CRC-related deaths identified from the NDI, we requested the permission for medical records review from next-of-kin of the participants. CRC was defined as a primary tumor with International Classification of Diseases, Ninth Revision codes of 153 (malignant neoplasm of colon) and 154 (malignant neoplasm of rectum and rectosigmoid junction). The obtained medical and pathologic records were reviewed carefully to confirm CRC diagnoses. Tumor-related information, including anatomic location, stage, differentiation, and histologic type, was extracted by study physicians with no idea of potential exposure data.
By June 1, 2012, for the NHS and January 31, 2012, for the HPFS, a total of 3924 CRC cases were identified. We set these cutoffs to allow time to assess mortality after diagnosis. Exclusion criteria included the following: participants died before 1980 for NHS or 1986 for HPFS, cancer diagnoses before 1980 for NHS or 1986 for HPFS, cancer diagnosed after the end of this study period, participants died before cancer diagnosis, CRC cases at stage IV, missing data on dietary report, missing data on dairy intake, and dairy information assessed <6 mo or >4 y after CRC diagnosis (Supplemental Figure 1). The study protocol was approved by the institutional review boards of the Brigham and Women's Hospital and Harvard T. H. Chan School of Public Health, as well as those of participating registries as required.
Assessment of outcome
Death and cause of death were identified by reviewing the NDI and the postal office or the next-of-kin in response to the follow-up questionnaires. Death information was reviewed by cohort investigators, and the primary cause of death was determined.
Assessment of dairy product consumption
A 116-item FFQ for food intake was administered to participants from the NHS in 1984 and was expanded to a 131-item FFQ in 1986 to collect updated diet information every 4 y thereafter. A similar FFQ was used for HPFS participants every 4 y since 1986.
In FFQs, participants were asked how often, on average, they consumed a standard serving of each dairy product item in the previous year. The frequency was described in 9 categories, ranging from “never or less than once per month” to “6 or more times per day.” The dairy product items and their standard serving sizes included “skim or low-fat milk” (8-oz glass, 1 oz = 25.57 mL), “whole milk” (8-oz glass, 1 oz = 25.57 mL), “cottage or ricotta cheese” (1/2 cup), “cream cheese” (1 oz, 25.57 mL), “other cheese (including American, cheddar)” (1 slice or 1 oz, 25.57 mL), “yogurt” (4–6 oz, 1 oz = 25.57 mL), “cream” (1 tablespoon), “ice cream” (1 cup), “sherbet” (1 cup), and “butter” (spread). Consistent with previous studies from the same cohorts (18, 19), consumption of total dairy products was calculated as the sum of intakes of each individual item. Moreover, intake of “skim or low-fat milk” and “whole milk” was summed up to “milk.” “Cottage or ricotta cheese,” “cream cheese,” and “other cheese” were summed up to “total cheese.” We also calculated total consumption of low-fat dairy products, including “sherbet,” “skim or low-fat milk,” “yogurt,” and “cottage or ricotta cheese,” and total consumption of high-fat dairy products, including “whole milk,” “cream,” “ice cream,” “cream cheese,” “other cheese,” and “butter.” The evaluation of the validity and precision of the FFQ has been described in detail in previous publications (20–23). Briefly, the correlation coefficients of intakes based on four 1-wk dietary records from 1 y with the FFQ for each dairy product item ranged from 0.57 for other cheese to 0.97 for yogurt (21). To facilitate future comparisons across studies from different populations, absolute categories of dairy intake were used instead of relative cutoffs such as quintiles in this analysis.
Assessment of covariates
Information on BMI (in kg/m2), physical activity (metabolic equivalents from recreational and leisure-time activities, METs h/wk), current cigarette smoking status, pack-year of smoking, alcohol intake (g/d), regular aspirin use (≥2 tablet/wk), family history of CRC, and postmenopausal hormone use (only for nurses) were obtained from the biennial questionnaires for participants from both cohorts. Other dietary factors, including red meat and processed meat intake, and dietary components including fiber, fat, folate, calcium, vitamin D, total energy intake (kcal/d), Alternative Healthy Eating Index (AHEI), and so on were collected or derived from the FFQ every 4 y.
Statistical analysis
Person-years to event was calculated for each participant from the date of FFQ return for postdiagnostic assessment to death or the end of this observation (June 1, 2012, for the NHS and January 31, 2012, for the HPFS), whichever came first. Because active treatment right after diagnosis might affect diet, postdiagnostic intake was defined as dietary intake from the first FFQ collected at least 6 mo and no more than 4 y after diagnosis, as consistent with previous studies from the same cohorts (8). Cox proportional hazard regression models were used to estimate HRs and 95% CIs for death comparing different levels of dairy product intake. Cox regressions were stratified by age, tumor stage, and study cohort, and were adjusted for tumor differentiation, tumor subsite, year of diagnosis, time between CRC diagnosis and measurement of dairy food intake assessment, and prediagnostic total dairy intake. The covariates further included in the models were postdiagnostic BMI, physical activity, pack-year of smoking, alcohol drinking, total energy intake, family history of CRC, and postmenopausal hormone use (only for females). Data were analyzed all together first because there was no statistically heterogeneity by sex (P-heterogeneity = 0.99 for total dairy intake and overall survival), and then stratified analyses were conducted by sex and other important covariates.
We excluded participants if they missed information on all items regarding dairy intake. For dairy categories, they were the sum of individual items in that category. If a participant missed information on 1 item, the category variable was still calculated from all other items available in that category. Previous studies in our cohorts had shown that most missing individual items in the FFQs were from individuals not consuming that item (24). The proportions of participants missing information on dairy items ranged from 0 for yogurt to 0.6% for cream cheese. For those who missed information for covariates on 1 round of follow-up, the data from the previous round were carried forward. The proportions of missing for covariates ranged from 0% to 6.6%, except that the proportion of missing for cancer stage was 13%. For those who missed information on covariates, a missing category was assigned and entered into the regression analyses.
In sensitivity analyses, more covariates were added to the model, including postdiagnostic AHEI, intake of vitamin D, folate, total fat, ω-3 fatty acids, ω-6 fatty acids, fiber, red meat, and multivitamin. Although the AHEI includes dairy foods as one of the components, it serves here as an index for overall dietary quality (25). Sensitivity analysis was also conducted by excluding those patients with unknown stage for cancer diagnosis, including stage IV patients, and excluding those who died within 3 mo of FFQ return.
SAS 9.4 software was used for all analyses (SAS Institute).
Results
A total of 1753 CRC cases, including 1074 from the NHS and 679 from the HPFS, were included in this study. The median follow-up time was 8.2 y from the date of returning the FFQ after diagnosis of CRC to the end of the observation. During follow-up, 703 deaths occurred (391 from the NHS and 312 from the HPFS), including 242 deaths due to CRC (159 from the NHS and 83 from the HPFS). The median intake of postdiagnostic total dairy was 13.5 servings/wk (IQR: 8.5, 22.5 servings/wk) for females and 11.6 servings/wk (IQR: 7.5, 19.0 servings/wk) for males. The level of postdiagnostic total dairy product intake was categorized and analyzed in 4 groups (<7, 7 to <14, 14 to <21, 21+ servings/wk), and participants with higher total dairy intake tended to have higher BMI, had a lower AHEI, and were less likely to smoke, drink alcohol, or use aspirin (Table 1). Similar patterns were observed for male and female participants (Supplemental Table 1).
TABLE 1.
Characteristics of patients with colorectal cancer according to postdiagnostic weekly dairy intake in the Nurses’ Health Study and Health Professionals Follow-up Study cohorts1
| Postdiagnostic dairy intake, servings/wk | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Total dairy | Low-fat dairy | High-fat dairy | ||||||||||
| Characteristic | <7 (n = 324) | 7 to <14 (n = 614) | 14 to <21 (n = 359) | 21+ (n = 456) | <3.5 (n = 509) | 3.5 to <7 (n = 328) | 7 to <10.5 (n = 423) | 10.5+ (n = 493) | <3.5 (n = 686) | 3.5 to <7 (n = 405) | 7 to <10.5 (n = 284) | 10.5+ (n = 378) |
| Age, y | 67.7 | 68.4 | 68.2 | 67.9 | 67.9 | 68.1 | 68.4 | 68.2 | 68.4 | 68.6 | 66.8 | 68.0 |
| White, % | 95.8 | 97.7 | 98.3 | 98.3 | 97.9 | 96.6 | 97.1 | 98.6 | 96.9 | 97.9 | 97.5 | 99.0 |
| BMI, kg/m2 | 25.6 | 26.3 | 26.4 | 26.6 | 26.0 | 26.5 | 26.5 | 26.2 | 25.8 | 26.3 | 26.7 | 26.7 |
| Physical activity, METs2 h/wk | 17.6 | 21.9 | 19.1 | 17.8 | 16.7 | 20.9 | 20.4 | 20.3 | 20.9 | 18.5 | 20.8 | 16.7 |
| Current smoking, % | 11.6 | 11.1 | 7.6 | 9.2 | 15.5 | 9.5 | 8.6 | 5.9 | 7.6 | 9.5 | 12.8 | 12.9 |
| Pack-years of smoking | 17.0 | 16.4 | 15.8 | 16.8 | 20.1 | 15.3 | 15.5 | 14.5 | 14.9 | 16.7 | 17.4 | 18.8 |
| Alcohol, g/d | 8.8 | 8.4 | 7.9 | 5.9 | 9.2 | 8.3 | 7.4 | 5.9 | 7.2 | 8.7 | 8.0 | 7.3 |
| Regular aspirin use (2 or more tablets/wk), % | 38.2 | 34.6 | 33.4 | 32.7 | 35.2 | 34.4 | 34.1 | 34.2 | 37.0 | 35.9 | 32.2 | 30.9 |
| Family history of colorectal cancer, % | 16.8 | 21.8 | 22.5 | 21.3 | 18.7 | 20.0 | 20.7 | 24.3 | 19.1 | 21.4 | 26.5 | 19.3 |
| Alternate Healthy Eating Index | 52.3 | 51.2 | 51.8 | 49.2 | 48.7 | 51.5 | 51.9 | 52.4 | 53.9 | 50.7 | 48.8 | 47.9 |
| Prediagnosis total dairy intake, servings/wk | 8.2 | 12.5 | 16.3 | 23.9 | 11.9 | 12.9 | 15.3 | 21.0 | 12.4 | 14.9 | 15.8 | 21.6 |
| Postdiagnosis total dairy intake, servings/wk | ||||||||||||
| Total | 3.8 | 10.1 | 17.0 | 30.5 | 10.0 | 11.4 | 14.8 | 25.2 | 10.3 | 13.3 | 16.7 | 27.1 |
| Low fat | 2.0 | 5.8 | 9.4 | 16.0 | 1.2 | 4.9 | 8.2 | 18.7 | 9.1 | 8.4 | 8.4 | 7.5 |
| High fat | 1.9 | 4.3 | 7.6 | 14.5 | 8.8 | 6.5 | 6.6 | 6.6 | 1.2 | 4.9 | 8.3 | 19.6 |
| Milk | 1.0 | 3.8 | 6.4 | 11.9 | 1.5 | 3.0 | 5.8 | 12.5 | 5.6 | 5.7 | 6.0 | 6.6 |
| Skim or low-fat milk | 0.8 | 3.3 | 5.7 | 10.6 | 0.4 | 2.6 | 5.3 | 11.9 | 5.4 | 5.2 | 5.1 | 5.0 |
| Whole milk | 0.1 | 0.3 | 0.4 | 0.9 | 1.0 | 0.3 | 0.2 | 0.2 | 0.0 | 0.1 | 0.5 | 1.5 |
| Yogurt | 0.2 | 0.7 | 1.1 | 1.6 | 0.2 | 0.7 | 0.8 | 1.9 | 0.9 | 0.8 | 1.0 | 0.9 |
| Total cheese | 1.5 | 2.9 | 4.3 | 5.9 | 2.9 | 3.4 | 3.5 | 4.9 | 2.3 | 3.7 | 4.3 | 5.8 |
| Cottage or ricotta cheese | 0.3 | 0.6 | 0.9 | 1.3 | 0.3 | 0.6 | 0.7 | 1.4 | 0.7 | 0.7 | 0.8 | 0.8 |
| Cream cheese | 0.2 | 0.4 | 0.6 | 0.7 | 0.4 | 0.4 | 0.3 | 0.6 | 0.2 | 0.4 | 0.6 | 0.8 |
| Other cheese (American, cheddar) | 1.0 | 1.9 | 2.8 | 4.0 | 2.1 | 2.3 | 2.5 | 3.0 | 1.4 | 2.6 | 2.9 | 4.1 |
| Cream | 0.2 | 0.4 | 1.0 | 2.6 | 1.1 | 0.9 | 1.2 | 1.0 | 0.1 | 0.5 | 1.1 | 3.3 |
| Regular ice cream | 0.4 | 0.8 | 1.3 | 1.5 | 1.2 | 1.1 | 0.9 | 1.0 | 0.3 | 1.0 | 1.5 | 2.0 |
| Sherbet, frozen yogurt, or nonfat ice cream | 0.3 | 0.6 | 0.9 | 1.2 | 0.2 | 0.5 | 0.6 | 1.6 | 1.0 | 0.9 | 0.6 | 0.4 |
| Butter | 0.3 | 0.9 | 2.1 | 5.8 | 3.1 | 2.0 | 2.0 | 2.2 | 0.2 | 0.9 | 2.1 | 8.0 |
| Processed meat, servings/wk | 4.6 | 5.2 | 5.8 | 5.9 | 6.1 | 5.3 | 5.1 | 5.0 | 4.0 | 5.9 | 6.0 | 6.8 |
| Red meat, servings/wk | 1.5 | 1.8 | 1.9 | 2.1 | 2.3 | 1.9 | 1.7 | 1.6 | 1.2 | 2.0 | 2.1 | 2.6 |
| Total fiber, g/d | 23.2 | 21.7 | 21.1 | 19.5 | 20.4 | 21.7 | 21.6 | 21.7 | 24.0 | 20.3 | 19.8 | 18.4 |
| Total fat, g/d | 58.2 | 59.2 | 60.0 | 60.0 | 64.8 | 60.3 | 57.8 | 54.7 | 53.2 | 61.4 | 61.9 | 66.4 |
| Total ω-3 fat, mg/d | 32.8 | 30.1 | 28.1 | 24.9 | 28.3 | 31.1 | 29.1 | 27.5 | 33.2 | 27.3 | 27.3 | 23.9 |
| Total folate intake, μg/d | 688 | 675 | 661 | 643 | 632 | 666 | 669 | 698 | 726 | 645 | 646 | 605 |
| Total vitamin D, IU/d | 473 | 510 | 530 | 591 | 455 | 494 | 527 | 624 | 564 | 501 | 534 | 492 |
| Total calcium intake, mg/d | 664 | 837 | 910 | 1093 | 681 | 812 | 886 | 1148 | 900 | 865 | 900 | 874 |
| Calcium supplement intake, mg/d | 388 | 344 | 325 | 326 | 343 | 356 | 323 | 355 | 368 | 344 | 359 | 296 |
| Tumor subsite, % | ||||||||||||
| Proximal colon | 39.5 | 37.9 | 41.4 | 44.7 | 37.7 | 42.3 | 40.0 | 43.1 | 41.7 | 36.4 | 42.9 | 42.3 |
| Distal colon | 28.5 | 34.6 | 30.0 | 29.4 | 32.5 | 33.0 | 29.7 | 29.9 | 30.9 | 31.0 | 29.6 | 32.5 |
| Rectum | 26.6 | 21.0 | 21.5 | 21.3 | 24.0 | 18.0 | 23.2 | 22.2 | 21.5 | 25.3 | 21.3 | 20.3 |
| Unspecified | 5.3 | 6.5 | 7.1 | 4.6 | 5.9 | 6.7 | 7.2 | 4.7 | 5.9 | 7.4 | 6.2 | 4.9 |
| Tumor grade, % | ||||||||||||
| Grade 1 well differentiated | 14.7 | 14.4 | 16.6 | 15.0 | 15.9 | 16.4 | 12.6 | 15.5 | 16.8 | 14.0 | 10.7 | 16.1 |
| Grade 2 moderately differentiated | 59.7 | 60.2 | 50.1 | 54.1 | 58.6 | 56.5 | 57.9 | 52.9 | 55.1 | 58.8 | 57.3 | 54.8 |
| Grade 3 poorly differentiated | 11.2 | 10.4 | 16.4 | 15.2 | 10.5 | 11.2 | 13.6 | 16.1 | 13.9 | 10.5 | 15.1 | 13.2 |
| Unspecified | 14.4 | 15.0 | 16.9 | 15.6 | 15.0 | 15.9 | 15.8 | 15.6 | 14.3 | 16.6 | 16.9 | 15.9 |
| Tumor stage, % | ||||||||||||
| Stage I | 32.3 | 33.5 | 34.3 | 34.7 | 33.2 | 32.5 | 34.0 | 34.8 | 34.7 | 31.8 | 32.3 | 35.1 |
| Stage II | 28.8 | 31.5 | 25.8 | 28.7 | 29.9 | 29.2 | 30.2 | 26.9 | 29.2 | 27.6 | 29.7 | 28.8 |
| Stage III | 25.2 | 23.4 | 23.6 | 24.8 | 22.2 | 25.8 | 22.4 | 26.5 | 24.0 | 26.9 | 24.7 | 21.6 |
| Unspecified | 13.6 | 11.6 | 16.3 | 11.8 | 14.7 | 12.6 | 13.4 | 11.8 | 12.1 | 13.6 | 13.3 | 14.5 |
Values are means for continuous variables; percentages are calculated for categorical variables and are standardized to the age distribution of the study population. Values of polytomous variables may not sum to 100% due to rounding.
METs, metabolic equivalents from recreational and leisure-time activities.
Postdiagnostic intake of total dairy products did not show significant associations with CRC-specific mortality (HR: 1.35; 95% CI: 0.85, 2.13; 21+ compared with <7 servings/wk) and overall mortality (HR: 1.28; 95% CI: 0.98, 1.67; 21+ compared with <7 servings/wk) in multivariable models (Table 2). Higher intake of high-fat dairy showed positive association with overall mortality (HR: 1.33; 95% CI: 1.08, 1.65; 10.5+ compared with <3.5 servings/wk) but not CRC-specific mortality (HR: 1.31; 95% CI: 0.91, 1.90; 10.5+ compared with <3.5 servings/wk). Higher intake of low-fat dairy showed an inverse association with overall mortality (HR: 0.74; 95% CI: 0.59, 0.92; 10.5+ compared with <3.5 servings/wk) but not CRC-specific mortality (HR: 0.91; 95% CI: 0.63, 1.29; 10.5+ compared with <3.5 servings/wk). Associations between individual items of dairy product with survival were also shown in Table 2. The overall results were similar for males and females, although the associations slightly varied across sexes for different dairy items (Supplemental Tables 2 and 3).
TABLE 2.
Postdiagnostic dairy intake and colorectal cancer–specific and overall survival in the NHS and HPFS cohorts1
| Dairy items (servings/wk) | No. of subjects | No. of CRC deaths | CRC-specific survival, HR (95% CI) | No. of overall deaths | Overall survival, HR (95% CI) | ||
|---|---|---|---|---|---|---|---|
| Model 12 | Model 23 | Model 12 | Model 23 | ||||
| Total dairy | |||||||
| <7 | 324 | 44 | Reference | Reference | 134 | Reference | Reference |
| 7 to <14 | 614 | 75 | 0.91 (0.60, 1.36) | 0.96 (0.62, 1.47) | 237 | 0.96 (0.76, 1.21) | 0.92 (0.73, 1.17) |
| 14 to <21 | 359 | 48 | 1.02 (0.64, 1.62) | 1.01 (0.61, 1.68) | 141 | 0.97 (0.74, 1.27) | 0.93 (0.70, 1.23) |
| 21+ | 456 | 75 | 1.35 (0.85, 2.13) | 1.38 (0.84, 2.28) | 191 | 1.28 (0.98, 1.67) | 1.19 (0.90, 1.59) |
| P-trend | 0.65 | 0.80 | 0.16 | 0.35 | |||
| High-fat dairy | |||||||
| <3.5 | 686 | 80 | Reference | Reference | 273 | Reference | Reference |
| 3.5 to <7 | 405 | 67 | 1.36 (0.97, 1.90) | 1.39 (0.98, 1.96) | 159 | 1.02 (0.83, 1.25) | 1.00 (0.81, 1.23) |
| 7 to <10.5 | 284 | 37 | 0.99 (0.66, 1.49) | 0.99 (0.65, 1.51) | 106 | 0.97 (0.77, 1.23) | 0.94 (0.74, 1.20) |
| 10.5+ | 378 | 58 | 1.31 (0.91, 1.90) | 1.30 (0.88, 1.92) | 165 | 1.33 (1.08, 1.65) | 1.23 (0.99, 1.54) |
| P-trend | 0.27 | 0.36 | <0.01 | 0.01 | |||
| Low-fat dairy | |||||||
| <3.5 | 509 | 79 | Reference | Reference | 235 | Reference | Reference |
| 3.5 to <7 | 328 | 42 | 0.85 (0.57, 1.25) | 0.91 (0.61, 1.36) | 130 | 0.79 (0.63, 0.99) | 0.89 (0.71, 1.13) |
| 7 to <10.5 | 423 | 47 | 0.66 (0.45, 0.97) | 0.74 (0.50, 1.09) | 155 | 0.69 (0.56, 0.85) | 0.76 (0.61, 0.94) |
| 10.5+ | 493 | 74 | 0.91 (0.63, 1.29) | 0.95 (0.65, 1.38) | 183 | 0.74 (0.59, 0.92) | 0.78 (0.62, 0.98) |
| P-trend | 0.52 | 0.47 | 0.07 | 0.11 | |||
| Milk | |||||||
| <3.5 | 855 | 116 | Reference | Reference | 356 | Reference | Reference |
| 3.5 to <7 | 183 | 22 | 0.86 (0.53, 1.38) | 0.89 (0.55, 1.45) | 61 | 0.73 (0.55, 0.97) | 0.77 (0.58, 1.03) |
| 7+ | 715 | 104 | 0.94 (0.69, 1.26) | 0.95 (0.69, 1.29) | 286 | 0.84 (0.70, 0.99) | 0.82 (0.69, 0.98) |
| P-trend | 0.99 | 0.71 | 0.54 | 0.43 | |||
| Skim or low-fat milk | |||||||
| 0 | 464 | 75 | Reference | Reference | 233 | Reference | Reference |
| >0 to <7 | 647 | 77 | 0.80 (0.57, 1.12) | 0.90 (0.63, 1.27) | 233 | 0.72 (0.60, 0.87) | 0.82 (0.67, 1.00) |
| 7+ | 642 | 90 | 0.80 (0.57, 1.13) | 0.89 (0.62, 1.27) | 237 | 0.66 (0.55, 0.81) | 0.73 (0.60, 0.89) |
| P-trend | 0.49 | 0.40 | 0.02 | 0.03 | |||
| Whole milk | |||||||
| 0 | 1534 | 194 | Reference | Reference | 582 | Reference | Reference |
| >0 to <7 | 170 | 38 | 1.42 (0.98, 2.06) | 1.29 (0.88, 1.89) | 89 | 1.48 (1.16, 1.88) | 1.45 (1.14, 1.84) |
| 7+ | 49 | 10 | 1.40 (0.71, 2.75) | 1.26 (0.63, 2.51) | 32 | 1.73 (1.18, 2.52) | 1.36 (0.92, 2.01) |
| P-trend | 0.01 | 0.03 | <0.01 | <0.01 | |||
| Total cheese | |||||||
| <3.5 | 899 | 123 | Reference | Reference | 366 | Reference | Reference |
| 3.5 to <7 | 614 | 81 | 0.88 (0.66, 1.18) | 0.88 (0.64, 1.20) | 241 | 0.99 (0.84, 1.18) | 0.97 (0.81, 1.16) |
| 7+ | 239 | 38 | 1.22 (0.83, 1.78) | 1.23 (0.82, 1.86) | 96 | 1.08 (0.85, 1.38) | 1.04 (0.81, 1.34) |
| P-trend | 0.81 | 0.64 | 0.39 | 0.67 | |||
| Cottage or ricotta cheese | |||||||
| 0 | 761 | 110 | Reference | Reference | 302 | Reference | Reference |
| >0 to <2 | 758 | 96 | 0.69 (0.52, 0.92) | 0.76 (0.57, 1.03) | 300 | 0.80 (0.67, 0.95) | 0.85 (0.72, 1.02) |
| 2+ | 234 | 36 | 0.73 (0.49, 1.10) | 0.83 (0.55, 1.26) | 101 | 0.87 (0.68, 1.11) | 0.90 (0.71, 1.16) |
| P-trend | 0.29 | 0.63 | 0.40 | 0.53 | |||
| Cream cheese | |||||||
| 0 | 1033 | 146 | Reference | Reference | 419 | Reference | Reference |
| >0 to <2 | 598 | 75 | 0.78 (0.58, 1.04) | 0.81 (0.60, 1.10) | 228 | 0.91 (0.77, 1.08) | 0.96 (0.80, 1.14) |
| 2+ | 112 | 13 | 0.77 (0.43, 1.37) | 0.71 (0.39, 1.29) | 47 | 0.98 (0.72, 1.34) | 0.91 (0.66, 1.26) |
| P-trend | 0.12 | 0.12 | 0.78 | 0.87 | |||
| Other cheese (American, cheddar, etc.) | |||||||
| <3.5 | 1468 | 193 | Reference | Reference | 590 | Reference | Reference |
| 3.5 to <7 | 156 | 21 | 1.06 (0.67, 1.68) | 1.07 (0.66, 1.73) | 61 | 1.07 (0.81, 1.40) | 1.11 (0.83, 1.47) |
| 7+ | 119 | 20 | 1.69 (1.05, 2.73) | 1.64 (0.99, 2.73) | 43 | 1.09 (0.79, 1.50) | 0.93 (0.66, 1.31) |
| P-trend | 0.43 | 0.43 | 0.44 | 0.87 | |||
| Cream | |||||||
| 0 | 1113 | 138 | Reference | Reference | 455 | Reference | Reference |
| >0 to <2 | 419 | 65 | 1.02 (0.75, 1.40) | 1.06 (0.76, 1.47) | 161 | 0.91 (0.75, 1.11) | 0.95 (0.78, 1.16) |
| 2+ | 211 | 31 | 1.14 (0.76, 1.71) | 1.18 (0.78, 1.80) | 78 | 0.90 (0.70, 1.16) | 0.97 (0.75, 1.26) |
| P-trend | 0.52 | 0.53 | 0.26 | 0.35 | |||
| Regular ice cream | |||||||
| 0 | 662 | 77 | Reference | Reference | 255 | Reference | Reference |
| >0 to <2 | 753 | 105 | 1.04 (0.76, 1.40) | 1.08 (0.79, 1.48) | 291 | 0.85 (0.71, 1.01) | 0.93 (0.78, 1.12) |
| 2+ | 338 | 60 | 1.39 (0.97, 1.98) | 1.51 (1.04, 2.20) | 157 | 1.19 (0.96, 1.46) | 1.24 (1.00, 1.54) |
| P-trend | <0.01 | <0.01 | <0.01 | <0.01 | |||
| Sherbet, frozen yogurt, or nonfat ice cream | |||||||
| 0 | 984 | 135 | Reference | Reference | 410 | Reference | Reference |
| >0 to <2 | 530 | 69 | 0.83 (0.62, 1.13) | 0.90 (0.66, 1.23) | 193 | 0.79 (0.66, 0.94) | 0.84 (0.70, 1.01) |
| 2+ | 229 | 30 | 0.99 (0.66, 1.50) | 1.06 (0.69, 1.62) | 91 | 0.87 (0.68, 1.10) | 0.91 (0.72, 1.17) |
| P-trend | 0.80 | 0.72 | 0.46 | 0.46 | |||
| Yogurt | |||||||
| 0 | 1025 | 144 | Reference | Reference | 439 | Reference | Reference |
| >0 to <2 | 432 | 61 | 0.93 (0.69, 1.27) | 0.99 (0.72, 1.36) | 161 | 0.91 (0.76, 1.10) | 1.01 (0.83, 1.22) |
| 2+ | 296 | 37 | 1.00 (0.69, 1.47) | 0.99 (0.67, 1.46) | 103 | 1.06 (0.85, 1.33) | 1.10 (0.87, 1.38) |
| P-trend | 0.89 | 0.84 | 0.96 | 0.89 | |||
| Butter | |||||||
| 0 | 966 | 137 | Reference | Reference | 387 | Reference | Reference |
| >0 to <7 | 567 | 68 | 0.91 (0.68, 1.23) | 0.97 (0.71, 1.32) | 216 | 1.09 (0.92, 1.30) | 1.10 (0.92, 1.31) |
| 7+ | 220 | 37 | 1.26 (0.85, 1.85) | 1.28 (0.86, 1.92) | 100 | 1.48 (1.17, 1.87) | 1.44 (1.13, 1.83) |
| P-trend | 0.73 | 0.95 | <0.01 | 0.01 | |||
Postdiagnostic intake at least 6 mo (to avoid potential influence of active treatment) but no more than 4 y after diagnosis of colorectal cancer. CRC, colorectal cancer.
Cox model stratified by age at diagnosis (<55, 55–59, 60–64, 65–69, 70–74, and ≥75 y), cancer stage (I, II, III, and unspecified), and study [Nurses’ Health Study (NHS) and Health Professionals Follow-up Study (HPFS)], with additional adjustments for tumor grade of differentiation (well differentiated, moderately differentiated, poorly differentiated, and unspecified), tumor subsite (proximal colon, distal colon, rectum, and unspecified), year of diagnosis (continuous), time between CRC diagnosis and measurement of dairy food intake assessment (continuous), and prediagnostic intake of total dairy (in quartiles).
Model 1 + postdiagnostic BMI (<23, 23–24.9, 25–27.4, 27.5–29.9, ≥30 kg/m2), postdiagnostic physical activity (<3, 3–8.9, 9–11.9, 12–17.9, ≥18 metabolic equivalents, h/wk), postdiagnostic regular use of aspirin (yes or no), postdiagnostic smoking (0, 1–9, 10–19, 20–39, ≥40 pack-years), postdiagnostic alcohol consumption (<5, 5–14.9, ≥15 g/d), postdiagnostic intake of total energy (in quartiles), and family history of colorectal cancer (yes or no).
In stratified analyses, total dairy intake of 21+ servings/wk compared with <7 servings/wk was positively associated with CRC-specific mortality among those aged <65 y (HR: 2.42; 95% CI: 1.23, 4.78; P-interaction < 0.01) and among those females who never used postmenopausal hormone (HR: 3.05; 95% CI: 1.45, 6.41; P-interaction = 0.07). It was also positively associated with overall mortality among those females who never used postmenopausal hormone (HR: 1.76; 95% CI: 1.12, 2.77; P-interaction = 0.03) (Table 3). Stratified analyses were also performed for high-fat (Supplemental Table 4) and low-fat dairy (Supplemental Table 5).
TABLE 3.
Stratified analyses of postdiagnostic total dairy intake with survival among patients with colorectal cancer1
| CRC-specific survival | Overall survival | |||||
|---|---|---|---|---|---|---|
| Servings/wk, HR (95% CI) | Servings/wk, HR (95% CI) | |||||
| Characteristic | 7 to <14 | 14 to <21 | 21+ | 7 to <14 | 14 to <21 | 21+ |
| Study | ||||||
| HPFS | 1.02 (0.60, 1.73) | 0.77 (0.39, 1.52) | 0.91 (0.47, 1.77) | 0.99 (0.75, 1.32) | 0.99 (0.70, 1.41) | 1.32 (0.95, 1.85) |
| NHS | 0.91 (0.57, 1.44) | 1.17 (0.70, 1.97) | 1.58 (0.97, 2.57) | 0.85 (0.65, 1.12) | 0.94 (0.69, 1.28) | 1.10 (0.82, 1.48) |
| Age, y | ||||||
| <65 | 0.91 (0.45, 1.83) | 1.36 (0.65, 2.86) | 2.42 (1.23, 4.78) | 0.87 (0.57, 1.35) | 0.93 (0.57, 1.52) | 1.48 (0.96, 2.29) |
| 65+ | 0.99 (0.59, 1.67) | 0.85 (0.47, 1.55) | 0.89 (0.49, 1.63) | 0.94 (0.71, 1.25) | 0.93 (0.67, 1.27) | 1.06 (0.77, 1.47) |
| Smoking | ||||||
| Never | 2.01 (0.21, 19.6) | 1.89 (0.17, 21.4) | 2.69 (0.27, 26.6) | 1.07 (0.43, 2.69) | 0.90 (0.32, 2.54) | 0.83 (0.29, 2.42) |
| Ever | 0.98 (0.64, 1.50) | 0.96 (0.59, 1.57) | 1.42 (0.88, 2.30) | 1.04 (0.81, 1.33) | 0.99 (0.74, 1.31) | 1.35 (1.02, 1.80) |
| Alcohol consumption, g/d | ||||||
| <10 | 0.96 (0.58, 1.59) | 1.13 (0.64, 2.00) | 1.40 (0.81, 2.42) | 0.97 (0.73, 1.29) | 0.93 (0.68, 1.29) | 1.19 (0.87, 1.63) |
| 10+ | 0.84 (0.36, 1.95) | 0.78 (0.27, 2.19) | 1.46 (0.60, 3.56) | 0.88 (0.57, 1.38) | 1.09 (0.64, 1.84) | 1.37 (0.83, 2.27) |
| AHEI | ||||||
| <50 | 0.86 (0.52, 1.43) | 1.07 (0.59, 1.92) | 0.99 (0.56, 1.74) | 0.87 (0.66, 1.15) | 0.92 (0.66, 1.28) | 1.03 (0.75, 1.41) |
| 50+ | 1.08 (0.64, 1.81) | 1.03 (0.55, 1.90) | 1.83 (1.02, 3.25) | 0.93 (0.68, 1.26) | 0.92 (0.65, 1.31) | 1.27 (0.89, 1.80) |
| BMI, kg/m2 | ||||||
| <25 | 1.23 (0.67, 2.27) | 1.20 (0.60, 2.37) | 1.94 (1.00, 3.75) | 0.98 (0.69, 1.39) | 0.95 (0.64, 1.42) | 1.28 (0.87, 1.89) |
| 25+ | 0.69 (0.38, 1.22) | 0.68 (0.34, 1.36) | 0.92 (0.49, 1.71) | 0.89 (0.63, 1.24) | 0.90 (0.61, 1.31) | 1.04 (0.73, 1.50) |
| Physical activity (METs, h/wk) | ||||||
| <9 | 1.41 (0.77, 2.56) | 1.53 (0.78, 3.03) | 1.98 (1.03, 3.81) | 1.09 (0.78, 1.51) | 1.11 (0.76, 1.63) | 1.37 (0.95, 1.98) |
| 9+ | 0.57 (0.30, 1.09) | 0.78 (0.38, 1.58) | 0.98 (0.50, 1.92) | 0.74 (0.52, 1.06) | 0.79 (0.53, 1.18) | 1.06 (0.72, 1.57) |
| Regular aspirin use | ||||||
| No | 0.90 (0.54, 1.49) | 0.98 (0.56, 1.74) | 1.30 (0.76, 2.24) | 0.91 (0.68, 1.23) | 0.88 (0.63, 1.24) | 1.06 (0.77, 1.47) |
| Yes | 1.09 (0.54, 2.18) | 1.05 (0.46, 2.40) | 1.56 (0.73, 3.34) | 0.93 (0.63, 1.37) | 1.01 (0.65, 1.57) | 1.50 (0.99, 2.27) |
| Family history of CRC | ||||||
| No | 0.89 (0.56, 1.41) | 1.11 (0.66, 1.85) | 1.43 (0.86, 2.37) | 0.86 (0.66, 1.11) | 0.96 (0.71, 1.30) | 1.15 (0.86, 1.55) |
| Yes | 1.19 (0.46, 3.09) | 0.62 (0.19, 2.02) | 1.12 (0.40, 3.12) | 1.29 (0.75, 2.25) | 0.89 (0.48, 1.65) | 1.45 (0.81, 2.60) |
| Cancer subsite | ||||||
| Colon | 1.10 (0.65, 1.86) | 1.28 (0.71, 2.32) | 1.60 (0.90, 2.83) | 0.98 (0.74, 1.29) | 0.95 (0.68, 1.32) | 1.20 (0.87, 1.64) |
| Rectum | 0.77 (0.37, 1.60) | 0.68 (0.29, 1.63) | 1.06 (0.50, 2.25) | 0.71 (0.44, 1.15) | 0.64 (0.38, 1.08) | 0.86 (0.52, 1.40) |
| Cancer stage | ||||||
| Stage I/II | 0.74 (0.45, 1.24) | 0.52 (0.26, 1.05) | 1.03 (0.57, 1.86) | 0.89 (0.68, 1.16) | 0.75 (0.54, 1.04) | 1.04 (0.75, 1.43) |
| Stage III | 2.09 (1.22, 3.56) | 3.07 (1.65, 5.74) | 3.26 (1.83, 5.83) | 1.27 (0. 90, 1.79) | 1.37 (0.90, 2.09) | 1.48 (1.02, 2.16) |
| Postmenopausal hormone use | ||||||
| Never | 1.23 (0.60, 2.52) | 1.69 (0.77, 3.71) | 3.05 (1.45, 6.41) | 1.04 (0.69, 1.57) | 1.20 (0.75, 1.90) | 1.76 (1.12, 2.77) |
| Ever | 1.17 (0.48, 2.87) | 1.07 (0.40, 2.90) | 1.41 (0.54, 3.65) | 0.85 (0.49, 1.45) | 0.82 (0.45, 1.50) | 0.82 (0.46, 1.45) |
| Years since CRC diagnosis | ||||||
| <5 | 1.41 (0.72, 2.77) | 1.10 (0.55, 2.22) | 1.11 (0.57, 2.14) | 1.12 (0.69, 1.81) | 0.90 (0.53, 1.52) | 0.95 (0.58, 1.54) |
| 5+ | 0.85 (0.45, 1.59) | 1.04 (0.51, 2.09) | 1.77 (0.93, 3.39) | 0.92 (0.69, 1.22) | 0.98 (0.71, 1.36) | 1.22 (0.89, 1.69) |
Postdiagnostic intake at least 6 mo (to avoid potential influence of active treatment) but no more than 4 y after diagnosis of CRC. Cox model stratified by age at diagnosis (<55, 55–59, 60–64, 65–69, 70–74, and 75+ years), cancer stage (I, II, III, and unspecified), and study (NHS and HPFS), with additional adjustments for tumor grade of differentiation (well differentiated, moderately differentiated, poorly differentiated, and unspecified), tumor subsite (proximal colon, distal colon, rectum, and unspecified), year of diagnosis (continuous), time between CRC diagnosis and measurement of dairy food intake assessment (continuous), prediagnostic intake of total dairy (in quartiles), postdiagnostic BMI (<23, 23–24.9, 25–27.4, 27.5–29.9, 30+ kg/m2), postdiagnostic physical activity (<3, 3–8.9, 9–11.9, 12–17.9, 18+ METs, h/wk), postdiagnostic regular use of aspirin (yes or no), postdiagnostic smoking (0, 1–9, 10–19, 20–39, 40+ pack-years), and postdiagnostic alcohol consumption (<5, 5–14.9, 15+ g/d), except when the factor is the variable for stratification. For CRC-specific survival, the P values for interaction were 0.05 for cohort, <0.01 for age, 0.98 for smoking, 0.37 for alcohol, 0.12 for AHEI, 0.37 for BMI, 0.36 for physical activity, 0.67 for regular aspirin use, 0.20 for family history of CRC, 0.69 for cancer subsite, 0.64 for cancer stage, 0.07 for postmenopausal hormone use, and 0.21 for years since CRC diagnosis. For overall survival, the P values for interaction were 0.99 for cohort, 0.05 for age, 0.16 for smoking, 0.30 for alcohol, 0.53 for AHEI, 0.48 for BMI, 0.98 for physical activity, 0.41 for regular aspirin use, 0.48 for family history of CRC, 0.46 for cancer subsite, 0.67 for cancer stage, 0.03 for postmenopausal hormone use, and 0.16 for years since CRC diagnosis. AHEI, Alternative Healthy Eating Index; CRC, colorectal cancer; HPFS, Health Professionals Follow-up Study; METs, metabolic equivalents; NHS, Nurses’ Health Study.
Prediagnostic dairy product intake was not significantly associated with survival among patients with CRC (Supplemental Table 6).
In sensitivity analyses, first, more covariates were added to the model, including postdiagnostic AHEI and intake of vitamin D, folate, total fat, ω-3 fatty acids, ω-6 fatty acids, fiber, red meat, and multivitamins. There was no significant change in the observed associations. Second, when those who died within 3 mo of FFQ return were excluded from the analyses, no obvious change for the conclusions was noted. Third, instead of adjusting for prediagnostic total dairy intake in models, prediagnostic high-fat dairy was adjusted for in examining the association between postdiagnostic high-fat dairy and CRC survival, and prediagnostic low-fat dairy was adjusted for in examining postdiagnostic low-fat intake; this change did not affect the results. Fourth, when postdiagnostic high-fat dairy and low-fat dairy were included in 1 regression model simultaneously, with or without adjusting for prediagnostic total dairy, the associations remained similar (Supplemental Table 7). Fifth, we defined intake of less than 7 servings/week as low level of high-fat or low-fat dairy intake, analyzed the association for high-fat dairy among those low-level intakers of low-fat dairy, and vice versa. We found that the positive associations between high-fat dairy and mortality remained, while the associations for low-fat dairy attenuated (Supplemental Table 8). Sixth, after excluding those patients with unknown stage for cancer diagnosis, including stage IV patients, or excluding those who died within 3 mo of FFQ return, the direction and magnitude of the associations remained similar (data not shown).
Discussion
After following up 1753 US participants with nonmetastatic CRC, this study suggested that higher intake of high-fat dairy was associated with ∼33% increase in overall mortality, whereas higher intake of low-fat dairy was associated with ∼26% risk reduction in overall mortality.
Dairy products have been associated with reduced risk of several cancers, including CRC (26, 27). One meta-analysis based on 19 cohort studies reported reduction in CRC risk among those who had a higher intake of total dairy products, milk, or cheese (16). However, the literature on the association between dairy intake and CRC survival is limited. The American Cancer Society Cancer Prevention Study-II Nutrition Cohort study examined both pre- and postdiagnostic intake and reported inverse associations of postdiagnostic total dairy (HR: 0.75; 95% CI: 0.56, 1.01) and milk (HR: 0.72; 95% CI: 0.55, 0.94) with all-cause mortality and no association between prediagnostic dairy intake and survival (9). In contrast, the European Investigation into Cancer and Nutrition cohort (EPIC) and the Iowa Women's Health Study (IWH) examined only the prediagnostic intake. EPIC reported an overall null association between prediagnostic total dairy intake and survival among patients with CRC, a marginal association between milk (HR: 1.21; 95% CI: 0.99, 1.48, Quartile 4 compared with Quartile 1) and CRC-specific mortality, and no association between yogurt or cheese and survival (14). IWH reported associations of prediagnostic whole milk (HR: 1.20; 95% CI: 1.13, 1.27) and low or nonfat milk (HR: 0.91; 95% CI: 0.86, 0.96) with all-cause mortality (15). We observed similar results in most of the associations, different in a few. Moreover, it was concordant that the association of prediagnostic dairy intake with survival was weaker than that of postdiagnosis intake.
High-fat dairy intake was found to be positively and low-fat dairy inversely associated with CRC-specific and overall mortality in this study. Individual items from the high-fat category (whole milk, American or cheddar cheese, ice cream, and butter) showed a positive association, whereas those from the low-fat category (skim or low-fat milk, cottage or ricotta cheese, and sherbet, frozen yogurt, or nonfat ice cream) showed an inverse association. The aforementioned associations remained essentially unchanged after adjustment for or stratification by important lifestyle factors or confounders, including BMI (28, 29), physical activity (30, 31), alcohol (32) or tobacco use (33, 34), total energy intake (35), or AHEI (36). Obesity and Western dietary pattern are both risk factors of CRC (28, 37), and underlying mechanisms include insulin resistance, low-grade inflammation, changes in gut microbiota, and fat-derived hormonal imbalance (38, 39). Although important nutrients from dairy such as calcium and vitamin D had been observed to be inversely associated with CRC mortality (8, 9, 40), the potential beneficial effect may be reduced by fat or fat-related components. It has been observed that the fasting LDL cholesterol was higher after intake of butter than cheese, and postprandial glucose was higher after cheese than milk, indicating a different effect of fat from different types of dairy products (41). However, it is still controversial whether postdiagnostic fat intake is detrimental to CRC survival, given that generally, neither total nor subtypes of dietary fat were associated with mortality (42). Furthermore, although scientific evidence supports some benefits of dairy products in human health (27, 43–45), dairy products were found to be associated with risk of ovarian cancer (46) and prostate cancer (47), suggesting a cautious recommendation of dairy intake.
Although overall there was no significant association found between total dairy intake and CRC-specific mortality, in subgroup analyses, positive associations were detected among those who were younger, had a lower BMI, had a higher AHEI score, were less physically active, were at cancer stage III, and were females who reported never using postmenopausal hormone. Previous studies observed that sociodemographic characteristics, behaviors, and cancer stage, subtype, and site may modify the associations between exposure and CRC survival (8, 48). It is of further research interest both in populations and in the laboratory to explore whether and why the associations between dairy products and CRC survival vary across certain populations.
The strengths of this study include a large sample size of CRC survivors across the United States, with detailed data on dairy products and important covariates collected. This study also has several limitations. The measurements of dairy product intake and covariates were collected through self-reported questionnaires and thus were inevitably prone to measurement errors, although the FFQs had been validated with reasonable correlations. Second, the participants were primarily white people working as health professionals, and they may differ from the general population with regard to socioeconomic status and lifestyles, including dietary patterns and other behavioral factors, which limits the generalizability of the conclusions. Third, information on treatment after CRC diagnosis was limited. We dealt with this problem by stratification by cancer stage and year of diagnosis, since the treatments for CRC would be under standard protocol based on stage at each time period. Fourth, as an observational study, the association observed between dairy intake and mortality might have been influenced by residual confounding. The socioeconomic status was not fully collected and controlled for study participants. Of note, low-fat dairy tended to be associated with healthful behaviors and high-fat dairy with less healthful behaviors, and we controlled for various behavioral and lifestyle factors available, including smoking, alcohol drinking, and physical activity; adjustment for these multiple factors did not alter the results appreciably. Moreover, we further included marital status, highest degree earned, and husband's degree in analyses for NHS, as well as included marital status in analyses for HPFS and the pooled analyses. The results from regression analyses did not change significantly. Also, as a study conducted among healthy health care workers nested within 2 cohorts instead of specifically among patients with CRC in a clinical setting, complications of CRC were not collected or analyzed as covariates. However, we partly dealt with the potential impact from complications on dairy intake by considering a time lag: dairy information assessed within 6 mo of CRC diagnosis was excluded to avoid short-term disturbance from diagnosis, treatment, or complications.
In conclusion, an overall null association was observed between postdiagnostic dairy product intake and CRC survival. However, higher intake of high-fat dairy, including whole milk and American or cheddar cheese, showed a potential effect on increased mortality, whereas low-fat dairy, including skim or nonfat milk and cottage or ricotta cheese, showed a potential protective effect. Further study is needed, and a moderate intake of high-fat dairy after CRC diagnosis is suggested.
Supplementary Material
Acknowledgments
We thank the participants and staff of the NHS and the HPFS for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, and WY. The authors assume full responsibility for analyses and interpretation of these data.
The authors’ contributions were as follows—XZ: designed research; XL, WY, KW, SO, EG, and XZ: conducted research; XL and WY: analyzed data; XL: wrote the first draft of the paper; SO, WW, NH, ATC, Z-FZ, JAM, EG, and XZ: revised the draft or provided comments or suggestions; XZ: had primary responsibility for final content; and all authors: read and approved the final manuscript.
Author disclosure: The authors report no conflicts of interest.
Notes
The Nurses’ Health Study and Health Professionals Follow-up Study were supported by the National Cancer Institute at the NIH (grants UM1 CA186107, P50 CA127003, P01 CA87969, and U01 CA167552). This work was supported by the NIH (grant numbers R01 CA137178 to A.T.C., K24 DK098311 to A.T.C., K07 CA188126 to X.Z., and R21 CA238651 to X.Z.). A.T.C. is a Stuart and Suzanne Steele MGH Research Scholar. X.Z. is also supported by the American Cancer Society Research Scholar Grant (RSG NEC-130476), Dana-Farber Harvard Cancer Center (DF/HCC) GI SPORE Developmental Research Project Award (P50CA127003), and DF/HCC Cancer Center Support Grant (CCSG, P30CA006516-55). The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. The funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript.
Edward Giovannucci and Xuehong Zhang are co-senior authors.
Supplemental Tables 1–8 and Supplemental Figure 1 are available from the “Supplementary data” link in the online posting of the article and from the same link in the online table of contents at https://academic.oup.com/ajcn/.
Abbreviations used: AHEI, Alternative Healthy Eating Index; CRC, colorectal cancer; EPIC, European Investigation into Cancer and Nutrition cohort; HPFS, Health Professionals Follow-up Study; IWH, Iowa Women's Health Study; NDI, National Death Index; NHS, Nurses’ Health Study.
Contributor Information
Xing Liu, Department of Nutrition, T. H. Chan School of Public Health, Harvard University, Boston, MA, USA; Department of Epidemiology, School of Public Health, Fudan University, Shanghai, P.R. China.
Wanshui Yang, Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Nutrition, School of Public Health, Anhui Medical University, Hefei, Anhui, P.R. China.
Kana Wu, Department of Nutrition, T. H. Chan School of Public Health, Harvard University, Boston, MA, USA.
Shuji Ogino, Department of Nutrition, T. H. Chan School of Public Health, Harvard University, Boston, MA, USA; Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Weibing Wang, Department of Epidemiology, School of Public Health, Fudan University, Shanghai, P.R. China.
Na He, Department of Epidemiology, School of Public Health, Fudan University, Shanghai, P.R. China.
Andrew T Chan, Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Zuo-Feng Zhang, Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA.
Jeffrey A Meyerhardt, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Edward Giovannucci, Department of Nutrition, T. H. Chan School of Public Health, Harvard University, Boston, MA, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, CA, USA.
Xuehong Zhang, Department of Nutrition, T. H. Chan School of Public Health, Harvard University, Boston, MA, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Data Availability
Data described in the manuscript, code book, and analytic code will be made available upon request pending approval from each participating cohort studies.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Data described in the manuscript, code book, and analytic code will be made available upon request pending approval from each participating cohort studies.