2.1.1. Exposure definition

The Working Group placed the greatest emphasis on the studies that reported data separately for unprocessed red meat (i.e. “red meat”) or processed meat, and had a clear definition of what questions or types of meats were included in the meat variables. For definitions, please see Section 1 of this Monograph and (a) and (b) below. Studies that defined total red meat as including processed meat and studies that reported on “red meat” (unclear whether unprocessed or total red meat) were also included in the Working Group discussion, but were given less weight; the latter studies were given the least weight for many cancers (e.g. cancer of the colorectum).

2.1.2. Sample size and the number of exposed cases

The sample size and the number of exposed cases can have an impact on statistical power. As there was a large number of informative studies, those with a sample size of fewer than 100 cases were excluded.

2.1.3. Study design

For cohort studies, prospective cohort studies and case–control or case–cohort analyses of such studies were considered. For cancer sites with a large number of informative studies and with low case fatality, studies based on mortality data were excluded or given less weight. These decisions are noted, where relevant, in the sections for each specific cancer site. For case–control studies, the selection of hospital-based versus population-based cases and controls was considered. Greater emphasis was given during the evaluation to studies that used population-based controls, as they were more representative of the underlying population. For hospital-based controls, studies that clearly listed the diseases of the controls were given greater emphasis, as the inclusion of controls with conditions related to risk factors for the disease under study may lead to bias. In particular, if the people selected as controls had conditions that could potentially lead to modifications in their diet, they would be less representative of the underlying population, thus leading to biased estimates.

2.1.4. Exposure assessment tools

Greater emphasis was given to studies that used validated dietary instruments and in-person interviews compared with non-validated dietary instruments and mailed, self-administered questionnaires, respectively. The Working Group assessed whether the questionnaires were validated in the population under study, whether the red or processed meat questions captured most subtypes of red or processed meats consumed in that population, and whether there was detailed assessment of portion size (e.g. use of pictures and models, in addition to frequency of consumption).

2.1.5. Adjustment for potential confounding factors

Studies that appropriately adjusted for confounding factors were given greater weight. Studies with insufficient adjustment were either noted and given less weight, or excluded from the review, depending on the number of studies available for a particular cancer site. For each cancer site, potential confounders for associations with meat intake are listed.

In general, total energy/caloric intake, physical activity, and body mass index (BMI) were considered important confounders; however, several other factors were considered for specific cancer sites (e.g. alcohol for cancer of the colorectum and breast, tobacco smoking for cancer of the lung and colorectum, etc.).

Total caloric intake is a putative risk factor for several cancers, and given that red meat and processed meat are significant contributors to total caloric intake, appropriate consideration of this confounder was important. Similarly, given the established or putative role of other dietary and lifestyle factors that may be correlated with meat intake, the consideration of these factors as possible confounders was important, depending on the cancer site (e.g. dietary fibre, BMI, and physical activity). In particular, it has been shown that individuals who consume high levels of processed meat often tend to eat less fruits and vegetables, to drink more alcoholic beverages, to smoke more tobacco, to consume more calories and more fat, and to be more obese and less active than those who do not consume processed meat (Fung et al., 2003; Dixon et al., 2004; Kesse et al., 2006; Nkondjock & Ghadirian 2005).

References

• Dixon LB, Balder HF, Virtanen MJ, Rashidkhani B, Männistö S, Krogh V, et al. Dietary patterns associated with colon and rectal cancer: results from the Dietary Patterns and Cancer (DIETSCAN) Project. Am J Clin Nutr. 2004;80(4):1003–11. [PubMed: 15447912]
• Fung T, Hu FB, Fuchs C, Giovannucci E, Hunter DJ, Stampfer MJ, et al. Major dietary patterns and the risk of colorectal cancer in women. Arch Intern Med. 2003;163(3):309–14. [PubMed: 12578511] [CrossRef]
• Kesse E, Clavel-Chapelon F, Boutron-Ruault MC. Dietary patterns and risk of colorectal tumors: a cohort of French women of the National Education System (E3N). Am J Epidemiol. 2006;164(11):1085–93. [PMC free article: PMC2175071] [PubMed: 16990408] [CrossRef]
• Nkondjock A, Ghadirian P. Associated nutritional risk of breast and colon cancers: a population-based case-control study in Montreal, Canada. Cancer Lett. 2005;223(1):85–91. [PubMed: 15890240] [CrossRef]

2.2.1. Cohort studies

This section includes prospective cohort studies and case–control studies nested within prospective studies on the association between red or processed meat intake and risk of cancer of the colorectum. The most recent publication of a cohort study, or the publication with the highest number of cases in the analysis, was included in the review. The results of superseded studies were not detailed.

This evaluation excluded prospective studies with colorectal cancer mortality, rather than incidence, as the end-point, and study results on the association between meat intake and colorectal cancer risk when the definition of meat intake included poultry and/or fish. Studies on dietary patterns and studies with fewer than 100 cases in the analyses were also not included.

The results of the included studies are presented according to the type of meat investigated: red meat (i.e. unprocessed red meat), processed meat, and red meat and processed meat combined. When studies reported on two or more of these types of meat, only the data for red meat and processed meat considered separately were treated in detail. A few studies that reported results only for particular aspects of meat consumption, such as doneness or type of meat, are described in this section, but these studies are not included in the tables. Studies on gene–exposure interactions are described in the section of the corresponding meat type, as are studies on the association between cooking methods or meat doneness levels and colorectal cancer.

As studies with greater precision can be considered more informative, particularly when the strength of the association appears to be weak to moderate, the descriptions of the studies are ordered for each section by the number of cases in the analysis, and tables are ordered chronologically. Other study quality criteria are indicated in the text when relevant. The study results most pertinent to the evaluation are included in the tables. Other findings of interest are briefly described in the text.

(a) Red meat

Fourteen cohort studies and two cohort consortia provided informative data on the association between red meat and risk of colorectal cancer (see Table 2.2.1). A few studies investigated specific types of red meat only. The results of these studies are described at the end of this section.

Table 2.2.1

Cohort studies on consumption of red meat or red meat and processed meat combined and cancer of the colorectum.

The New York University Women’s Health Study (NYUWHS) enrolled women aged 34–65 years at mammographic screening clinics from 1985 to 1991, and followed them up until 1994 through a combination of direct contact and record linkage to cancer registries. A 70–food item, modified Block questionnaire was used to assess diet. Colorectal cancer risk was not significantly associated with red meat intake. The relative risk (RR) for the highest compared with the lowest quartile was 1.23 (95% confidence interval, CI, 0.68–2.22) (Kato et al., 1997). [The Working Group noted that the amount of red meat intake was not reported in the publication, and the study was small (100 cases in the analysis).]

In a nested case–control study using data from the Monitoring Project on Cardiovascular Disease Risk Factors study in the Netherlands (Tiemersma et al., 2002), 102 incident colorectal cancer cases were identified during 8.5 years of follow-up, and a random sample of 537 controls were matched for sex and age. The odds ratio (OR) for consumption of red meat ≥ 5 times/week compared with ≤ 3 times/week was 1.6 (95% CI, 0.9–2.9). In an analysis stratified by sex, a positive association was observed in men (OR, 2.7; 95% CI, 1.1–6.7; P_trend = 0.06), but not in women (OR, 1.2; 95% CI, 0.5–2.8; P_trend = 0.64). The same comparison was statistically significant in men and women combined after the exclusion of participants who were younger than age 50 years at the end of the follow-up (RR, 2.0; 95% CI, 1.1–3.8; highest vs lowest intake). The relationship between red meat and colorectal cancer was not modified by NAT1, NAT2, and GSTM1 genotypes. [The Working Group noted that a limited number of cancer cases were included in the study, and the assessment of meat intake was not comprehensive. A major source of meat intake – a mix of minced pork and beef – in the Dutch population was missed by the questionnaire. However, the authors indicated that meat consumption was estimated by the questionnaire, with acceptable reproducibility and validity when compared with a dietary history method (data were not given in the paper).]

A cohort study in Takayama, Japan, included 30 221 subjects aged 35 years or older who completed a general questionnaire and a 169–food item, validated food frequency questionnaire (FFQ) at baseline in 1992. Until 2000, 111 cases of colon cancer in men and 102 cases in women were identified through the medical records of two hospitals in Takayama, accounting for about 90% of the colon cancer cases registered in the city cancer registry (Oba et al., 2006). Red meat intake was unrelated to colon cancer risk. Multivariate-adjusted relative risks for the highest compared with the lowest tertile of intake were 1.03 (95% CI, 0.64–1.66; P_trend = 0.86) in men and 0.79 (95% CI, 0.49–1.28; P_trend = 0.20) in women. Rectal cancer cases were not included in the analysis. [The Working Group noted that a limited number of cancer cases were included in the study, and meat intake was low compared with meat intake in North American and European cohorts.]

In a 6-year follow-up of a cohort of 32 051 non-Hispanic, White members of the Adventist Health Study (AHS) in California, USA (1976–1982), 157 colon cancer cases were identified (Singh & Fraser, 1998). The participants completed at baseline a semiquantitative, 55–food item dietary questionnaire, in which six questions were on meat intake. Participants who consumed beef or pork ≥ 1 time/week were at increased risk of colon cancer compared with those who did not consume beef or pork (RR, 1.90; 95% CI, 1.16–3.11; P_trend = 0.02). White meat intake was also positively associated with colon cancer risk. [The Working Group noted that out of the 157 colon cancer cases identified, 42 cases were vegetarians and 40 cases were occasional meat eaters. The association with red meat remained significant in the analysis stratified by intake of white meat, and the analyses were adjusted for tobacco smoking and physical activity. Given the nature of the study population, and that residual confounding could not be ruled out, other lifestyle differences for low meat eaters and vegetarians could at least partially explain the association observed with both red and white meats. The exclusion of current or past smokers, and alcohol consumers did not substantially alter the association with red meat.]

In the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, a randomized, double-blind, placebo-controlled trial on the prevention of incidence of lung cancer in Finnish male smokers, 185 colorectal cancer cases were identified during 8 years of follow-up (Pietinen et al., 1999). Usual diet at baseline was assessed using a self-administered questionnaire with 276 items, and total red meat was defined as beef, lamb, and pork and processed meat. Colorectal cancer was not associated with intake of beef, pork, and lamb (i.e. red meat), specifically; the relative risk for the highest compared with the lowest quartile was 0.8 (95% CI, 0.5–1.2; P_trend = 0.74) (Pietinen et al., 1999). Intake of fried meats (determined by adding up the frequency of intake of all dishes where the meat was prepared by frying) was not related to colorectal cancer risk (RR, 0.9; 95% CI, 0.6–1.3; for 204 vs 60 times/year). [The Working Group noted that fried meats may have included fried white meats. No other cooking methods were reported. A main limitation of this study was the low number of cases.]

In the Iowa Women’s Health Study (IWHS), a study in postmenopausal women, 212 incident colon cancer cases were identified during 5 years of follow-up. Diet was assessed using a validated, 127–food item semiquantitative food frequency questionnaire (SQFFQ). Total red meat was defined as beef, lamb, or pork, and processed meat. Consumption of total red meat as defined was not associated with colon cancer, nor was consumption of beef, lamb, or pork as a main dish (RR, 1.21; 95% CI, 0.75–1.96; P_trend = 0.16; for > 3 vs < 1 serving/week) (Bostick et al., 1994). This lack of association was observed in women with or without a family history of colon cancer in first-degree relatives (Sellers et al., 1998).

Andersen et al. (2009) conducted a case–cohort study nested in the Danish Diet, Cancer and Health cohort study (372 cases, 765 controls), and reported a null association between intake of red meat and colorectal cancer risk. [Estimates were not adjusted for total energy intake, raising concerns about uncontrolled confounding.In addition,the Working Group noted that the study had a short follow-up (5 years), and cases identified in the first years of follow-up were not excluded from the analyses.]

In a case–cohort study in the Danish Diet, Cancer and Health cohort, including 379 colorectal cancer cases and 769 subcohort members, colorectal cancer was not significantly associated, although it was slightly increased, with intake of red meat (RR, 1.03; 95% CI, 0.97–1.09, per 25 g/day) or fried red meat (RR, 1.09; 95% CI, 0.96–1.23, per 25 g/day). A higher risk was observed in people who reported a preference for brown–dark pan-fried meat (any type of meat) compared with light–light brown meat (RR, 1.36; 95% CI, 1.04–1.77). This risk did not differ significantly between NAT1 or NAT2 genotype carriers (P_interaction > 0.4) (Sørensen et al., 2008). [The Working Group noted that about 18% of the participants in this cohort were also included in the Danish component of the European Prospective Investigation into Cancer and Nutrition (EPIC).]

In another nested case–control study in the same cohort, a statistically significant increase (RR, 3.70; 95% CI, 1.70–8.04) in colorectal cancer risk per 100 g/day of red meat intake was observed among carriers of the homozygous variant XPC Lys939Gln, and no association among carriers of the wildtype allele was observed (Hansen et al., 2007). None of the other polymorphisms investigated (XPA A23G, XPD Lys751Gln, and XPD Asp312Asn) were related to colorectal cancer risk. [The Working Group noted that results regarding the association between XPC Lys939Gln and red meat intake on colorectal cancer risk might have been a chance finding, as multiple comparisons were made.]

The Shanghai Women’s Health Study (SWHS) included 73 224 women aged 40–70 years at recruitment who completed an FFQ by interview at the baseline assessment beginning in 1997. Follow-up was through active surveys and periodic linkage to the Shanghai Cancer Registry. After a mean follow-up of 7.4 years, 394 incident cases of colorectal cancer (236 colon, 158 rectum) were identified (Lee et al., 2009). The risk of colorectal cancer was not related to the amount of red meat intake. The relative risks for the highest compared with the lowest quintile (> 67 g/day and < 24 g/day, respectively) were 0.8 (95% CI, 0.6–1.1; P_trend = 0.53) for colorectal cancer, 0.9 (95% CI, 0.6–1.5; P_trend = 0.31) for colon cancer, and 0.6 (95% CI, 0.3–1.1; P_trend = 0.79) for rectal cancer. When intakes of 90 g/day and 100 g/day were instead used as cut-points in a further analysis, the relative risk estimates for colorectal cancer were 1.29 (95% CI, 0.88–1.89) and 1.67 (95% CI, 1.11–2.52), respectively. [The Working Group noted that the association may not have been detected in the previous analyses due to an overall low level of meat consumption.] In an analysis of cooking methods, the risk of colon cancer was significantly associated with preparing food by smoking (RR, 1.4; 95% CI, 1.1–1.9; for ever vs never), but not with other cooking methods. [The Working Group noted that the definition of red meat was not given, but appeared to be unprocessed pork, beef, and lamb. Cooking methods were for all animal foods. The range of meat intake was low in the study.]

In the Melbourne Collaborative Cohort Study, the relative risk of colorectal cancer for consuming red meat more than 6.5 times/week compared with < 3 times/week was 1.4 (95% CI, 1.0–1.9; P_trend = 0.2; 451 cases). Red meat was defined as veal, beef, lamb, pork, and rabbit or other game. The association was mainly driven by a positive association with rectal cancer (RR for the same comparison, 2.3; 95% CI, 1.2–4.2; P_trend = 0.07; 169 cases). The relative risk for colon cancer was 1.1 (95% CI, 0.7–1.6; P_trend = 0.9; 283 cases) (English et al., 2004). In analyses with continuous variables for meat consumption, the relative risks for an increase of 1 time/week were 1.0 (95% CI, 0.94–1.07) for the colon and 1.08 (95% CI, 0.99–1.16) for the rectum.

In the Swedish Mammography Cohort (SMC), 733 incident cases of colorectal cancer were identified after completion of a 67-item, self-administered dietary questionnaire at baseline in 1987–1990. Consumption of unprocessed beef and pork was associated with almost a twofold risk of distal colon cancer for ≥ 4 servings/week, whereas there was no apparent association with risk of proximal colon or rectal cancers (Larsson et al., 2005a). The relative risks for consumption of beef and pork ≥ 4 times/week compared with < 2 times/week were 1.22 (95% CI, 0.98–1.53) for colorectal cancer, 1.10 (95% CI, 0.74–1.64) for proximal colon cancer (234 cases), 1.99 (95% CI, 1.26–3.14; P_trend = 0.01) for distal colon cancer (155 cases), and 1.08 (95% CI, 0.72–1.62) for rectal cancer (230 cases), respectively. [The Working Group noted that case ascertainment was virtually complete, and the analyses were controlled for main potential confounders.]

Singaporean Chinese aged 45–74 years who resided in government-built housing estates were enrolled in a prospective study in 1993–1998. At baseline, a 165-item quantitative FFQ, developed for and validated in this population, was administered to assess usual diet over the past year. After an average follow-up duration of nearly 10 years, 941 incident colorectal cancer cases were identified through record linkage to the population-based Singapore Cancer Registry (Butler et al., 2008 b). The adjusted hazard ratio (HR) for the highest compared with the lowest quartile of red meat intake was 1.01 (95% CI, 0.82–1.26; P_trend = 0.6). [The Working Group noted that the usual diet was mainly composed of mixed dishes. Red meat appeared to be unprocessed, but the definition was not given in the paper. The cut-off points of the quartiles were not given, and the 95th percentile of red meat intake in non-cases was 76 g/day.]

The EPIC study identified 1329 colorectal cancer cases during a mean follow-up of 4.8 years. Red meat included all fresh, minced, and frozen beef, veal, pork, and lamb. In the EPIC study (Norat et al., 2005), the relative risk for colorectal cancer was 1.17 (95% CI, 0.92–1.49; P_trend = 0.08) for an intake of red meat > 80 g/day compared with < 10 g/day. A significant association (RR, 1.21; 95% CI, 1.02–1.43, per 100 g/day; P_trend = 0.03) was observed when red meat was expressed as a continuous increment. The association with red meat was strengthened, but not significant, after calibration using 24-hour recall data. The calibrated relative risk for colorectal cancer per 100-g increment was 1.49 (95% CI, 0.91–2.43). The associations were similar for cancers of the colon and rectum, and of the proximal and distal colon. Analysis of specific meat types showed significant positive trends for intake of pork (highest vs lowest intake RR, 1.18; 95% CI, 0.95–0.48; P_trend = 0.02) and lamb (HR, 1.22; 95% CI, 0.96−1.55; P_trend = 0.03), but not for intake of beef/veal (HR, 1.03; 95% CI, 0.86−1.24; P_trend = 0.76). When mutually adjusted, only the trend for pork remained significant. [The Working Group noted that the strengths of the study were that participants were from 10 European countries with different dietary habits, and detailed validated dietary questionnaires were used. Dietary data were also calibrated using 24-hour recall in a subset of the population to partially correct the relative risk estimates for dietary measurement error. This study investigated red meat, processed meat, and specific meat types in relation to colorectal cancer risk. Follow-up was virtually complete, and the analyses were adjusted for main potential confounders. A potential limitation of the study was that different dietary questionnaires were used in the centres; however, the associations were strengthened after calibration of the dietary data, and no heterogeneity across centres was detected.]

The Nurses’ Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS) were among the first American cohorts to investigate the association between red and processed meat and colon cancer risk. The NHS included female, married nurses aged 30–55 years, and diet was assessed by a validated, 61-item SQFFQ. Self-reported cases were validated by medical or pathology records. The HPFS included men aged 40–75 years, and diet was assessed by a self-administered FFQ. Both studies had repeated measures of diet during follow-up (NHS, from 1980 to 2010; HPFS, from 1986 to 2010). Early reports from these cohorts, which included a small number of cases, showed significant positive associations between red and processed meat and colon cancer (age- and energy-adjusted) (Willett et al., 1990; Giovannucci et al., 1994). Several papers on the cohorts have since been published (Wei et al., 2004, 2009; Fung et al., 2010; Zhang et al., 2011; Bernstein et al., 2015), generally showing no association between beef, pork, or lamb as a main dish and colorectal cancer risk (Wei et al., 2004; Fung et al., 2010; Bernstein et al., 2015).

In the most recent analysis of the NHS and the HPFS (Bernstein et al., 2015), which included 2731 colorectal cancer cases (1151 proximal colon, 816 distal colon, and 589 rectum), the cumulative average intake of unprocessed red meat was not associated with colorectal cancer risk (RR per 1 serving/day increase, 0.99; 95% CI, 0.87–1.13; P_trend = 0.88). The results were similar when analysed in grams of intake. When analysed by tumour location, red meat consumption was inversely associated with risk of distal colon cancer (RR per 1 serving/day increase, 0.75; 95% CI, 0.68–0.82; P_trend < 0.001); a weak, non-significant positive association was observed with proximal colon cancer (RR, 1.14; 95% CI, 0.92–1.40; P_trend = 0.22)., and no association was observed with rectal cancer (RR, 1.14; 95% CI, 0.86–1.51; P = 0.37). The inverse associations with distal colon cancer were primarily seen after adjustment for specific nutrients, including fibre, folate, and calcium in men and calcium in women. [The Working Group noted that the analyses took into account long-term exposure and several potential risk factors simultaneously. Multiple sensitivity and effect modification analyses were conducted, and the results were robust.]

In a previous nested case–control study of 183 colorectal cancer cases and 443 controls enrolled in the NHS, women with the NAT2 rapid acetylator genotype who consumed > 0.5 servings/day of beef, pork, or lamb as a main dish had an increased risk of colon cancer compared with women who consumed less red meat (OR, 3.01; 95% CI, 1.10–8.18). No association was observed in slow acetylators (multivariate OR, 0.87; 95% CI, 0.35–2.17; P_interaction = 0.07) or in all women (OR, 1.21; 95% CI, 0.85–1.72) (Chan et al., 2005). [The Working Group noted that this study was large. Diet was estimated from repeated questionnaires, and there was a detailed selection of potential confounders.]

The Multiethnic Cohort Study identified 3404 incident cases of colorectal cancer up to 2007 among a sample of African Americans, Japanese Americans, Latinos, native Hawaiians, and Whites aged 45–75 years living in Hawaii and California, USA (Nöthlings et al., 2009; Ollberding et al., 2012). Red meat intake was not associated with colorectal cancer risk. The relative risk for the highest compared with the lowest quintile (34.86 and 4.59 g/1000 kcal, respectively) was 0.98 (95% CI, 0.87–1.10; P_trend = 0.58). For all types of meats considered together, the risk did not vary by doneness preference (cooked until dark brown or well done) or cooking method preference (pan-fried, oven-broiled, or grilled/barbecued); data were not reported by the authors. [The Working Group noted that this was a large study that sampled people from different ethnic groups for better generalizability of results. There was a strong attenuation of the effect estimates after multivariable adjustment.]

In a nested case–control in the United Kingdom Dietary Cohort Consortium, based on seven cohort studies in the United Kingdom (Spencer et al., 2010), diet was assessed using 4-, 5-, or 7-day food diaries. Red meat was defined as including beef, pork, lamb, and meat from burgers, and other non-processed meat items made with these meats. Red meat intake was not related to risk of colorectal cancer (579 cases). The relative risk estimate for an increase in intake of 50 g of red meat was 1.01 (95% CI, 0.84–1.22) for colorectal cancer. Similar relative risks were observed for colon and rectal cancers. [The Working Group noted that meat intake was relatively low in the overall consortium, as many participants were either vegetarians or low meat eaters. The use of food diaries may also have led to overestimation of the number of non-consumers of infrequently consumed food items.]

In a pooled analysis of the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and the Colon Cancer Family Registry (CCFR) (Kantor et al., 2014), which included 9160 cases of colorectal cancer and 9280 controls, the pooled relative risk estimate for colorectal cancer for each serving per day increase in intake of red meat was 1.33 (95% CI, 1.23–1.44) for all studies combined. The purpose of the study was to investigate gene–environment interactions, and the estimates of associations reported were controlled only for age, sex, and study centre. In another paper based on the same pooled study, Figueiredo et al. (2014) reported a relative risk of 1.23 (95% CI, 1.12–1.34) for red meat consumption above versus below the median and a relative risk of 1.15 per quartile of intake. In another publication based on GECCO and the CCFR that included data from case–control studies nested in five cohorts, red meat consumption was related to colorectal cancer risk only from retrospective case–control studies. The pooled odds ratio from four retrospective case–control studies was 1.75 (95% CI, 1.55–1.98). The relationship was not modified by NAT2 enzyme activity (based on polymorphism at rs1495741) (Ananthakrishnan et al., 2015). No interaction involving any gene and red meat was detected in a genome-wide diet–gene interaction analysis in GECCO or in a study on colorectal cancer susceptibility loci (Hutter et al., 2012) [The exact definition of red meat was not given in these studies.]

Five additional cohort studies did not investigate the overall association between colorectal cancer risk and red meat consumption, but did evaluate associations with specific red meat items (data not reported in Table).

In a prospective study conducted by the Norwegian National Health Screening Service (143 cases of colon cancer) among Norwegian men and women aged 20–54 years between 1977 and 1983 (Gaard et al., 1996), consumption of meatballs, meat stews, and fried or roasted meats was unrelated to colon cancer risk. [The Working Group noted that the analyses were only for specific red meat types and adjusted only for age.]

In the Women’s Health Study (WHS), a randomized trial in the USA of low-dose aspirin and vitamin E in the primary prevention of cancer and cardiovascular disease, diet was assessed at study baseline using a 131-item FFQ that was previously validated in the NHS. Two hundred and two incident colorectal cancer cases were identified during 8.7 years of follow-up. The definition of red meat included hot dogs, bacon, and other processed meats. Data for consuming unprocessed red meat were limited to beef or lamb as a main dish and were stratified by cooking method. In comparison with beef or lamb cooked rare or medium–rare, the relative risks were 0.73 (95% CI, 0.47–1.11) for medium doneness, 1.02 (95% CI, 0.68–1.52) for medium well-done meat and 0.94 (95% CI, 0.63–1.41) for well-done meat (P_trend = 0.83) (Lin et al., 2004). Meat doneness was available only for beef or lamb as a main dish. This study also reported a positive association between white meats and colorectal cancer.]

In a case–cohort analysis including 448 colon and 160 rectal cancer cases and a subcohort of 2948 participants in the Netherlands Cohort Study (NLCS), intake of beef, pork, minced meat, or liver was not significantly associated with colon or rectal cancer risk, although a positive association was suggested for beef and colon cancer (RR for highest vs lowest category of beef intake, 1.28; 95% CI, 0.96–1.72; P_trend = 0.06) (Brink et al., 2005). In another analysis (434 colon cancer cases, 154 rectal cancer cases) (Lüchtenborg et al., 2005), beef consumption was associated with an increased risk of colon tumours without a truncating APC somatic mutation. The incidence rate ratio for the highest versus the lowest quartile of intake was 1.58 (95% CI, 1.10–2.25; P_trend = 0.01). [The Working Group noted that the follow-up period was short, and cases diagnosed in the first years of follow-up were excluded.]

A recent full cohort analysis of the Netherlands Cohort Study – Meat Investigation Cohort (NLCS-MIC), with all individuals reporting to be vegetarian or to consume meat only 1 day/week, was conducted with 20.3 years of follow-up (Gilsing et al., 2015). For red meat, defined as fresh meat without chicken, no clear association was observed with colon or rectal cancer.

In a cohort study in Japan, 47 605 residents aged 40–64 years from the Miyagi Prefecture completed a self-administered, 40-item FFQ in 1990. Four hundred and seventy-four colorectal cancer cases were identified after an average follow-up of 11 years through linkage to the Miyagi Prefectural Cancer Registry. Relative risk estimates for the highest compared with the lowest intake were 0.93 (95% CI, 0.67–1.30; P_trend = 0.63) for beef and 1.13 (95% CI, 0.79–1.74; P_trend = 0.31) for pork intake. No associations were observed with risk of cancers of the colon, proximal or distal colon, and rectum (Sato et al., 2006). [The Working Group noted that the number of categories in the questionnaire was low, and there was low variability in meat intake. The median intake in the top category was 7.4 g/week for beef and 26.3 g/week for pork (excluding ham and sausage). Beef and pork combined was not investigated.]

In the Japan Public Health Center-based Prospective Study (JPHC Study), men and women completed a self-administered questionnaire in 1995–1999 at age 45–74 years (Takachi et al., 2011), and 1145 cases of colorectal cancer were identified until the end of 2006. The category of red meat was defined as including processed products and chicken liver. In women, a significant association between beef intake and colon cancer was observed (RR for fifth vs first quintile, 1.62; 95% CI, 1.12–2.34; P_trend = 0.04), and a non-significant association was observed for pork (RR for fifth vs first quintile, 1.42; 95% CI, 0.99–2.04; P_trend = 0.05) (Takachi et al., 2011). No significant association between beef or pork intake and colon or rectal cancer was observed in men. [The Working Group noted that although red and processed meat consumption was lower in this cohort than in cohorts from Western countries, there was a sevenfold difference in the median intakes of the lowest and highest quintiles. Total consumption of red meat was not investigated.]

(b) Processed meat

Associations between colorectal cancer and consumption of processed meat have been examined in 18 informative cohort studies and two pooled analyses (see Table 2.2.2); some of these studies also reported data for red meat.

Table 2.2.2

Cohort studies on consumption of processed meat and cancer of the colorectum.

Intake of processed meat (ham and sausages) was not related to colorectal cancer risk in the NYUWHS (Kato et al., 1997). The relative risk for the highest compared with the lowest quartile was 1.09 (95% CI, 0.59–2.02; P_trend = 0.735; 100 cases). [The Working Group noted that this study had a small sample size. The analyses were adjusted only for energy intake, age, place, and education level.]

Colorectal cancer was not associated with intake of processed meat in the ATBC Study in Finnish male smokers (185 cases) (Pietinen et al., 1999). The relative risk for the highest compared with the lowest quartile (medians, 122 g/day and 26 g/day, respectively) was 1.2 (95% CI, 0.7–1.8; P_trend = 0.78). [The Working Group noted that a main limitation of this study was the low number of cases.]

In the WHS, processed meat intake was inversely, although not significantly, associated with colorectal cancer in the analysis including 202 cases (Lin et al., 2004). The relative risk for the highest compared with the lowest quintile was 0.85 (95% CI, 0.53–1.35; P_trend = 0.25; medians of the quintiles, 0.5 servings/day and 0 servings/day, respectively). Processed meat was defined as hot dogs, bacon, and other processed meats. [The Working Group noted that this study reported an inverse non-significant association between total red meat and colorectal cancer, and positive associations between white meat and colorectal cancer, in contrast with the results of other cohort studies.]

In the IWHS cohort (Bostick et al., 1994), which included 212 cases, the relative risk of colon cancer for consumption of > 3 servings/week of processed meat compared with none was 1.51 (95% CI, 0.72–3.17; P_trend = 0.45). In the same cohort, nitrate-treated meats were not related to colon cancer in women with or without a family history of colon cancer in first-degree relatives (Sellers et al., 1998). [The Working Group noted that this study had a small sample size, follow-up was 5 years, and cases identified in the first years of follow-up were not excluded from the analyses.]

In a community-based prospective study in Takayama, Japan, including 213 cases of colorectal cancer, there was a twofold, significant increased risk of colon cancer only in men who consumed a higher intake of processed meats (Oba et al., 2006). The relative risks for the highest compared with the lowest tertile of intake were 1.98 (95% CI, 1.24–3.16; P_trend < 0.01) in men and 0.85 (95% CI, 0.50–1.43; P_trend = 0.62) in women. Processed meat was defined as ham, sausage, bacon, and yakibuta (Chinese-style roasted pork). The results did not change after the exclusion of cases diagnosed in the first 3 years of follow-up.

Processed meat intake was associated with colorectal cancer in the Melbourne Collaborative Cohort Study (451 cases) (English et al., 2004). The relative risks were 1.5 (95% CI, 1.1–2.0; P_trend = 0.01) for the highest compared with the lowest intake and 1.07 (95% CI, 1.01–1.13) for an increase of 1 serving/week. Processed meat intake was more strongly associated with risk of rectal cancer than with risk of colon cancer in a categorical analysis. The relative risks for the highest compared with the lowest quartile were 1.3 (95% CI, 0.9–1.9) for the colon and 2.0 (95% CI, 1.1–3.4) for the rectum. The hazard ratios for each additional serving per week were similar; the hazard ratios were 1.07 (95% CI, 1.00–1.14) and 1.08 (95% CI, 0.99–1.18) for the colon and rectum, respectively (P = 0.8, test of homogeneity of trends).

In the Breast Cancer Detection Demonstration Project (BCDDP) in the USA (467 cases), women completed a 62-item National Cancer Institute (NCI)/Block FFQ. The Block FFQ defined processed meat as bacon, ham, lunchmeat, hot dogs, and sausage (Flood et al., 2003). The relative risk for the highest compared with the lowest quintile of processed meat intake was 0.97 (95% CI, 0.73–1.28; P_trend = 0.35; medians of the quintiles, 22.2 and 0.02 g/1000 kcal, respectively) after adjustment for age, energy, and total meat consumption. The inclusion of several other variables, including smoking, alcohol drinking, and BMI, did not materially change the estimates and were not kept in the final models. [The Working Group noted that colorectal cancer diagnosis was self-reported in most cases. Pathology reports were obtained for 79% of these cases, and the diagnosis confirmed in 94% of them, suggesting that case identification was not an issue.]

In the Miyagi Cohort Study in Japan, processed meat consumption was not related to risk of colorectal cancer (colorectum, colon, proximal colon, and distal colon and rectum); the analysis included 474 incident colorectal cancer cases (Sato et al., 2006). The relative risk for the highest compared with the lowest quartile was 0.91 (95% CI, 0.61–1.35; P_trend = 0.99). No associations were observed for cancers of the colon, rectum, or proximal and distal colon. [The Working Group noted that the number of categories in the questionnaires was low, and there was low variability in meat intake due to low frequency of consumption of some meat items.]

In the Danish Diet, Cancer and Health study (18% of the cases were included in the Danish component of the EPIC study), the relative risks per 25 g/day increase in intake of processed meats were 1.03 (95% CI, 0.94–1.13; 644 cases) for the colon and 0.93 (95% CI, 0.81–1.07; 345 cases) for the rectum (Egeberg et al., 2013). No significant associations were observed with intakes of sausages, cold cuts, or liver pâté. In addition, associations were not modified by four polymorphisms (XPA A23G, XPC Lys939Gln, XPD Lys751Gln, and XPD Asp312Asn) of enzymes involved in the nucleotide excision repair pathway in a case–control study nested in the cohort (405 colorectal cancer cases, 810 controls) (Hansen et al., 2007). Another analysis of 379 colorectal cancer cases and 769 subcohort members showed no association with consumption of processed meat when stratified by NAT1 or NAT2 genotypes (Sørensen et al., 2008).

In the SMC (Larsson et al., 2005a), processed meat intake was not related to risk of colorectal cancer or colorectal cancer subsites. The relative risk estimates for the highest compared with the lowest quartile of intake were 1.07 (95% CI, 0.85–1.33; P_trend = 0.23) for the colorectum (733 cases), 1.02 (95% CI, 0.69–1.52; P_trend = 0.97) for the proximal colon (234 cases), 1.39 (95% CI, 0.86–2.24; P_trend = 0.20) for the distal colon (155 cases), and 0.90 (95% CI, 0.60–1.34; P_trend = 0.88) for the rectum (230 cases). [The Working Group noted that the dietary questionnaire had 67 food items. Follow-up was long (13.9 years on average), and changes in dietary habits during follow-up were not taken into account. Case ascertainment was virtually complete, and the analyses were controlled for main potential confounders.]

In the Singapore Chinese Health Study (SCHS) (Butler et al., 2008b), the relative risk for the highest compared with the lowest quartile of processed meat intake was 1.16 (95% CI, 0.95–1.41; 941 incident colorectal cancer cases after an average follow-up of 10 years). Types of processed meats were not defined. [The Working Group noted that the cut-points of the quartiles were not given, and processed meat intake was low (the 95th percentile of processed meat intake in non-cases was 10 g/day).]

In the JPHC Study (Takachi et al., 2011) (1145 cases of cancer of the colorectum), processed meat included ham, sausage or wiener sausage, bacon, and luncheon meat. The relative risks of colon cancer for the highest compared with the lowest quintile were 1.27 (95% CI, 0.95–1.71; P_trend = 0.10) in men and 1.19 (95% CI, 0.82–1.74; P_trend = 0.64) in women. Similar results were observed for proximal and distal colon cancers. The relative risk for rectal cancer was 0.70 (95% CI, 0.45–1.09; P_trend = 0.10) in men and 0.98 (95% CI, 0.53–1.79; P_trend = 1.00) in women. [The Working Group noted that the range of processed meat intake was low. The median intake in the top quintile was 16 g/day in men and 15 g/day in women.]

In the European EPIC study (1329 incident colorectal cancer cases), processed meats included mostly pork and beef preserved by methods other than freezing, such as salting (with and without nitrites), smoking, marinating, air-drying, or heating (i.e. ham, bacon, sausages, blood sausages, meat cuts, liver pâté, salami, bologna, tinned meat, luncheon meat, corned beef, and others). The relative risk of colorectal cancer for an intake of > 80 g/day of processed meat compared with < 10 g/day of processed meat was 1.42 (95% CI, 1.09–1.86; P_trend = 0.02) (Norat et al., 2005). The relative risk for an increase in intake of 100 g/day of processed meat was 1.32 (95% CI, 1.07–1.63; P_trend = 0.009). This was strengthened to 1.70 (95% CI, 1.05–2.76; P_trend = 0.03) after calibration using 24-hour recall data from a subset of the study population. The relative risks for the highest versus the lowest quintile were 1.62 (95% CI, 1.04–2.50), 1.48 (95% CI, 0.87−2.53), and 1.19 (95% CI, 0.70–2.01) for rectal, distal, and proximal colon cancer, respectively. No significant differences across cancer sites were observed (P_{heterogeneity} = 0.87). Intake of ham (RR for highest vs lowest intake, 1.12; 95% CI, 0.90−1.37; P_trend = 0.44), bacon (HR, 0.96; 95% CI, 0.79−1.17; P_trend = 0.34), and other types of processed meats (HR, 1.05; 95% CI, 0.84−1.32; P_trend = 0.22) was not significantly related to colorectal cancer risk. [This was a large study in 10 European countries that used extensive dietary questionnaires. Follow-up is virtually complete, and the analyses were adjusted for main potential confounders.] In a substudy of the EPIC-Norfolk study, higher consumption of processed meat was associated with an increased risk of colorectal cancer harbouring a truncating APC mutation and, in particular, rectal tumours with GC→AT transitions compared with colorectal cancer without mutations (OR for increment of 19 g/day, 1.68; 95% CI, 1.03–2.75) (Gay et al., 2012).

A case–cohort analysis of the Netherlands Cohort Study (NLCS) included 1535 incident colorectal cancer cases identified after 9.3 years of follow-up through linkage to the Netherlands Cancer Registry (Balder et al., 2006). The relative risks for processed meats (meat items mostly cured, and sometimes smoked or fermented) and colorectal cancer (RR for highest vs lowest quartile) were 1.18 (95% CI, 0.84–1.64; P_trend = 0.25) in men and 1.05 (95% CI, 0.74–1.48; P_trend = 0.62) in women. No associations were observed for colon or rectal cancer in men or women. In another analysis in the same cohort, consumption of meat products (same definition as for processed meats) was significantly positively associated with risk of colon tumours with a wildtype K-ras gene (RR for highest vs lowest quartile of intake, 1.42; 95% CI, 1.00–2.03; P_trend = 0.03) (Brink et al., 2005) and APC-positive colon cancer (RR for highest vs lowest quartile of intake, 1.61; 95% CI, 0.96–2.71; P_trend = 0.04) (Lüchtenborg et al., 2005), but not with other types of colon or rectal tumours. These analyses included more than 430 colon and 150 rectal cancers occurring during 7.3 years of follow-up, excluding the first 2.3 years, and 2948 subcohort members. An analysis of the MIC embedded within the NLCS, which included individuals reporting to be vegetarian or to consume meat only 1 day/week, was conducted with 20.3 years of follow-up (Gilsing et al., 2015). For processed meat, a statistically significant association with rectal cancer was observed (RR, 1.36 for every 25 g/day of intake; 95% CI, 1.01–1.81; P_trend = 0.008). No significant association was observed with colon cancer, although a positive association with distal colon cancer was suggested.

The Cancer Prevention Study II (CPS-II) Nutrition Survey enrolled men and women in the USA who completed a mailed FFQ in 1992–1993 (1667 incident colorectal cancer cases) (Chao et al., 2005). The relative risk for the highest quintile compared with the lowest quintile of processed meat intake was 1.13 (95% CI, 0.91–1.41; P_trend = 0.02) in women and men combined. A significant trend was observed in men (P_trend = 0.03), but not in women (P_trend = 0.48). No significant associations were observed with proximal or distal colon cancer, and rectal cancer, although the relative risk estimates were higher for distal and rectal tumours. When long-term consumption of processed meat was considered, based on consumption reported in 1982 and at baseline in 1992–1993, participants in the highest tertile of consumption had an increased risk of distal colon cancer (RR, 1.50; 95% CI, 1.04–2.17). A non-significant 14% and 21% increased risk of cancers of the proximal colon, and rectosigmoid junction and rectum were observed. [The Working Group noted that the 1982 questionnaire did not assess the number of servings per day, and could not differentiate people who ate multiple servings from those who ate processed meat only once per day. It was also not possible to estimate total energy intake from the 1982 dietary questionnaire.]

In the NHS and the HPFS (Bernstein et al., 2015), using cumulative dietary intake data, the relative risk of colorectal cancer per 1 serving/day increment of processed meat was 1.15 (95% CI, 1.01–1.32; P_trend = 0.03), and it was 1.08 (95% CI, 0.98–1.18; P_trend = 0.13) when diet, as assessed at baseline, was analysed. Using cumulative dietary intake data, the relative risks were 0.99 (95% CI, 0.79–1.24) for proximal colon cancer (1151 cases), 1.36 (95% CI, 1.09–1.69; P_trend = 0.006) for distal colon cancer (817 cases), and 1.18 (95% CI, 0.89–1.57) for rectal cancer (589 cases). [The analyses were extensively adjusted for potential risk factors. The use of repeated questionnaires should have reduced dietary measurement error. Several sensitivity and stratified analyses showed the robustness of the results.] In an earlier nested case–control in the NHS including 197 cases identified by the year 2000 (Tranah et al., 2006), colorectal cancer risk was not related to consumption of > 1 slice/week of processed meat (OR, 1.06; 95% CI, 0.73–1.55), > 2 pieces/week of bacon (OR, 0.94; 95% CI, 0.56–1.58), or > 1 hot dog/week (OR, 1.06; 95% CI, 0.68–1.65). Compared with infrequent consumption of these items, no association with all types of processed meats combined was observed. There was no significant interaction on a multiplicative scale between the MGMT genotype and intake of processed meat, bacon, and hot dogs in women.

In the Multiethnic Cohort Study, the relative risk of colorectal cancer (n= 3404 cases) for the highest compared with the lowest quintile of processed meat intake was 1.06 (95% CI, 0.94–1.19; P_trend = 0.259) (Ollberding et al., 2012). Relative to the significant association that was observed in models adjusted only for age, ethnicity, and sex (HR, 1.25; 95% CI, 1.12–1.40; P < 0.001), this relative risk was attenuated after further adjustment for family history of colorectal cancer, history of colorectal polyps, BMI, pack-years of cigarette smoking, nonsteroidal anti-inflammatory drug use, alcohol consumption, vigorous physical activity, history of diabetes, hormone replacement therapy use (women only), total calories, and dietary fibre, calcium, folate, and vitamin D. [The main strengths of this study were its large size, the ethnic diversity of the study population, and the population-based sampling frame that was used, which allowed for better generalizability of the study results. As indicated in the section on red meats, the Working Group noted that there was a strong attenuation of the association estimates after multivariable adjustment.]

The National Institutes of Health – American Association of Retired Persons (NIH-AARP) Diet and Health Study was based on a cohort of over 500 000 men and women from eight states in the USA, aged 50–71 years at baseline (1995–1996), who completed a validated, 124-item FFQ. In an analysis of 5107 colorectal cancer cases, identified on average during 8.2 years of follow-up (Cross et al., 2007), processed meat consumption was significantly related to colorectal cancer risk. The relative risk for the fifth compared with the first quintile of intake was 1.20 (95% CI, 1.09–1.32; P_trend < 0.001). The relative risks were similar for colon cancer and rectal cancer. Similar results were observed in another study in the same cohort that explored the mechanisms relating colorectal cancer and meat intake (Cross et al., 2010). The overall relative risk for the association between colorectal cancer and processed meat intake was 1.16 (95% CI, 1.01–1.32; P_trend = 0.017) for the highest compared with the lowest quintile. For colon and rectal cancer separately, the relative risks for the same comparison were 1.11 (95% CI, 0.95–1.29) and 1.30 (95% CI, 1.00–1.68), respectively. Nitrate and nitrite intake from processed meats was estimated using a database containing measured values of nitrate and nitrite from 10 types of processed meats. The relative risk of colorectal cancer for the highest compared with the lowest quintile of intake of nitrate from processed meat was 1.16 (95% CI, 1.02–1.32; P_trend = 0.001; medians of the quintiles, 289.2 µg/1000 kcal per day and 23.9 µg/1000 kcal per day, respectively). The association with nitrite from processed meat did not attain statistical significance (RR for highest vs lowest quintile, 1.11; 95% CI, 0.97–1.25; P_trend = 0.055; medians of the quintiles, 194.1 µg/1000 kcal per day and 11.9 µg/1000 kcal per day, respectively). In a lag analysis excluding the first 2 years of follow-up (1941 colorectal cancer cases), the association between processed meat intake and colorectal cancer remained significant (HR, 1.19, 95% CI, 1.02–1.39, P_trend = 0.013). Participants in the NIH-AARP study also completed a 37-item FFQ about diet 10 years before baseline. Participants in the highest intake category of processed meat 10 years before baseline had a higher risk of cancer of the colon (RR, 1.30; 95% CI, 1.13–1.51; P_trend < 0.01) and rectum (RR, 1.40; 95% CI, 1.09–1.81; P_trend = 0.02) than participants in the lower intake category (Ruder et al., 2011). [The Working Group noted that the questionnaire to assess diet 10 years before baseline was not validated, and did not allow for estimation of total energy intake.]

In the United Kingdom Dietary Cohort Consortium (Spencer et al., 2010), processed meat was assessed as ham, bacon, the meat component of sausages, and other items made with processed meat. For a 50 g/day increase in consumption of processed meat, the odds ratio for colorectal cancer was 0.88 (95% CI, 0.68–1.15). The odds ratios for colon and rectal cancer separately were also non-significantly different from unity.

In a pooled analysis of the GECCO study (Kantor et al., 2014), the pooled relative risk of colorectal cancer for each serving per day increase in intake of processed meats was 1.48 (95% CI, 1.30–1.70) for all studies combined. [The main strength of the study was the large number of cases included in the analysis.] In genome-wide diet–gene interaction analyses in GECCO, which included five retrospective case–control studies and five case–control studies nested in prospective studies, there was a positive interaction between rs4143094 (10p14/near GATA3) and processed meat consumption (OR, 1.17; 95% CI, 1.11–1.23; P = 8.7E–09), which was consistently observed across studies (P_{heterogeneity} = 0.78) (Figueiredo et al., 2014). The risk of colorectal cancer associated with processed meat was increased among individuals with the rs4143094–TG (OR, 1.20; 95% CI, 1.13–1.26) and –TT genotypes (OR, 1.39; 95% CI, 1.22–1.59), and null among those with the –GG genotype (OR, 1.03; 95% CI, 0.98–1.07). In another study in GECCO on gene–environment interactions and colorectal cancer susceptibility loci, no interaction with processed meat was detected (all studies combined) (Hutter et al., 2012).

In the prospective study conducted by the Norwegian National Health Screening Service (Gaard et al., 1996), colon cancer risk was higher in women who consumed fried or poached sausages as their main meal ≥ 5 times/month compared with those who reported a consumption of < 1 time/month (RR, 3.50; 95% CI, 1.02–11.9; P_trend = 0.03). Among men, a similar, but not significant, association was observed (RR, 1.98; 95% CI, 0.70–5.58; P_trend = 0.35). [The Working Group noted that only specific types of processed meats were investigated. The analyses were only adjusted for age. The 50 535 participants were relatively young (age, 20–54 years) at recruitment in 1977–1983, and only 143 cases of colon cancer were identified through linkage to the Norwegian Cancer Registry after 11.4 years of follow-up.]

2.2.2. Case–control studies

Numerous case–control studies have examined the association between red or processed meat intake and risk of colorectal cancers. This section presents studies by how meat was defined in the following order: red meat and processed meat separately, red meat and processed meat combined, and then red meat, unclear whether fresh or processed.

In reviewing and interpreting the available literature, the Working Group considered for each of these categories the criteria summarized in Section 2.1 and the greatest weight was given to studies that met the following criteria:

• Had an unambiguous definition of red and processed meat (studies that reported data for unprocessed red and/or processed meat separately, and/or listed subtypes of meats included in each meat definition) (see criterion 1 in Section 2.1.1);
• Met the definition of a population-based study, or included hospital-based cases using approaches that ensured a representative sample of the underlying population (e.g. community hospitals that serve specific regions in a country) and population-based controls (see criterion 3 in Section 2.1.3);
• Used a previously validated dietary instrument (see criterion 4 in Section 2.1.4); and
• Considered detailed assessment for potential confounders, in particular total energy intake (see criterion 5 in Section 2.1.5).

The Working Group also considered as informative studies that met these criteria but showed limitations in criteria 3, 4, or 5 summarized above. Sample size was considered for informativeness (see criterion 2 in Section 2.1.2). The main limitations identified by the Working Group are noted between brackets in the description of each paper.

The Working Group gave less weight to other studies that showed important limitations in criterion 3, 4, or 5 above, and/or defined “total red meat” without further clarifying whether processed meat was included.

The Working Group excluded the following papers due to the reasons described below. None of the excluded studies are presented in the tables.

Studies with fewer than 100 cases were excluded because of limited statistical power (e.g. Phillips, 1975; Dales et al., 1979; Pickle et al., 1984; Tajima & Tominaga, 1985; Vlajinac et al., 1987; Wohlleb et al., 1990; Nashar & Almurshed, 2008; Guesmi et al., 2010; Ramzi et al., 2014).

Certain dietary patterns (e.g. traditional “Western-type” diet) are often characterized by a higher intake of red and processed meats, but these patterns also capture other foods that tend to be consumed with a diet high in red and processed meats, such as refined grains and a high intake of sugar. Thus, these studies are not specific enough to address the role of red meat and processed meats. Therefore, the Working Group also excluded from this review studies that reported on dietary patterns or dietary diversity, or only examined red meat in combination with other foods (e.g. McCann et al., 1994; Slattery et al., 1997, 2003; Rouillier et al., 2005; Satia et al., 2009; De Stefani et al., 2012b; Pou et al., 2012, 2014; Chen et al., 2015). In addition, the Working Group also excluded studies that reported on “meat” variables without a clear definition of what types of meats were included, making it impossible to rule out the inclusion of poultry and/or fish (e.g. Zaridze et al., 1992; Roberts-Thomson et al., 1996; Ping et al., 1998; Welfare et al., 1999; Zhang et al., 2002; Kim et al., 2003; Yeh et al., 2003, 2005; Kuriki et al., 2006; Little et al., 2006; Wakai et al., 2006; Skjelbred et al., 2007; Sriamporn et al., 2007; Jedrychowski et al., 2008; Arafa et al., 2011; Mahfouz et al., 2014; Pimenta et al., 2014), and studies that stated clearly that they had included poultry in their meat definition (e.g. Hu et al., 1991; Fernandez et al., 1996; Kuriki et al., 2005; Ganesh et al., 2009).

The Working Group also excluded studies that did not provide sufficient information to abstract risk estimates for red and processed meat intake per se or within strata defined by genotype (e.g. Gerhardsson de Verdier et al., 1990; Ghadirian et al., 1997; Keku et al., 2003; Forones et al., 2008; da Silva et al., 2011; Gialamas et al., 2011; Silva et al., 2012; Zhivotovskiy et al., 2012; Angstadt et al., 2013; Helmus et al., 2013). Studies were not described if they only reported on estimated amounts of carcinogens derived from meat, and not on meat variables. Of note, studies that reported on the same study population, published at different times, were generally summarized together, if applicable. The most recent, complete, or informative publication was included.

A few studies reported on selected red meat types (e.g. beef), groups of red meat types (e.g. beef/pork), or total processed meats, and presented estimates for total red meat variables, including processed meats. For these studies, the Working Group only summarized the estimates for red meat types and/or processed meat, but not the estimates for the combination of both, as the Working Group did not find these as informative.

Studies that unambiguously defined red meat as unprocessed only, or as unprocessed and processed combined, or did not provide an unambiguous definition and referred to “total red meat”, are summarized in Table 2.2.3. Studies that unambiguously defined processed meat are summarized in Table 2.2.4.

Table 2.2.3

Case–control studies on consumption of red meat and cancer of the colorectum.

Table 2.2.4

Case–control studies on consumption of processed meat and cancer of the colorectum.

2.2.3. Meta-analyses

High intakes of red meat and processed meats were associated with a moderate, but significant, increase in colorectal cancer risk in several meta-analyses conducted before 2010 (Sandhu et al., 2001; Norat et al., 2002; Larsson et al., 2006; Huxley et al., 2009). The results of more recent meta-analyses of the associations between colorectal cancer and consumption of unprocessed red meat and processed meat, as well as specific meat types, haem iron, and genetic interactions with red and processed meat intake are described here.

In all meta-analyses, similar methods were used to derive summary estimates of dose–response and relative risks for the highest compared with the lowest intake categories. In most analyses, significant associations were observed for all prospective studies combined. However, because the magnitudes of the summary associations were moderate to small, the statistical significance was often lost in subgroup analyses with fewer studies. In addition, some inconsistencies in the results remained unexplained, as the relatively low number of studies in each subgroup did not allow for extensive exploration of all potential sources of heterogeneity.

Chan et al. (2011) summarized the results of prospective studies on red and processed meat and colorectal cancer risk for the World Cancer Research Fund/American Institute of Cancer Research (WCRF/AICR) Continuous Update Project. For red meat, the relative risks for the highest compared with the lowest intake were 1.10 (95% CI, 1.00–1.21; I² = 22%; 12 studies) for colorectal cancer, 1.18 (95% CI, 1.04–1.35; I² = 0%; 10 studies) for colon cancer, and 1.14 (95% CI, 0.83–1.56; I² = 38%; 7 studies) for rectal cancer. Within the colon, the summary risk for increase of cancer was 13% for proximal colon cancer and 57% for distal colon cancer, but the associations were not significant. The relative risk for an increase of 100 g/day of red meat was 1.17 (95% CI, 1.05–1.31; 8 studies) for colorectal cancer, 1.17 (95% CI, 1.02–1.33; 10 studies) for colon cancer, and 1.18 (95% CI, 0.98–1.42; 7 studies) for rectal cancer. For processed meats, the relative risk for the highest compared with the lowest intake was 1.17 (95% CI, 1.09–1.25; I² = 6%; 13 studies) for colorectal cancer, 1.19 (95% CI, 1.11–1.29; I² = 0%; 11 studies) for colon cancer, and 1.19 (95% CI, 1.02–1.39; I² = 20%; 9 studies) for rectal cancer. Within the colon, the summary risk for increase of cancer was 4% for proximal colon cancer and 20% for distal colon cancer, but the associations were not significant (five studies in the analyses). The relative risks for an increase of 50 g/day were 1.18 (95% CI, 1.10–1.28; I² = 12%; 9 studies) for colorectal cancer, 1.24 (95% CI, 1.13–1.35; I² = 0%; 10 studies) for colon cancer, and 1.12 (95% CI, 0.99–1.28; I² = 0%; 8 studies) for rectal cancer.

The most recent, comprehensive meta-analysis of colorectal cancer and meat consumption included data from 27 prospective cohort studies, published in the English language and identified through 2013 (Alexander et al., 2015). Statistical analyses were based on comparisons of the highest intake category with the lowest intake category. Intake levels in these categories varied across studies. Linear dose–response slopes were derived from categorical meta-analyses of two subgroups, based on the units of red meat intake reported by the studies (grams or servings). Random effect models were used. The summary relative risk of colorectal cancer for the highest compared with the lowest intake of red meat and processed meat was 1.11 (95% CI, 1.03–1.19; I² = 33.6%; P = 0.014). Heterogeneity was reduced when the analysis was restricted to studies on (unprocessed) red meat. The summary relative risk for those 17 studies was 1.05 (95% CI, 0.98–1.12; I² = 8.4%; P = 0.328).

In analyses by cancer site, the association was significant with no heterogeneity for the colon (RR, 1.11; 95% CI, 1.04–1.18; 16 studies), and not significant with high heterogeneity for the rectum (RR, 1.17; 95% CI, 0.99–1.39; I² = 51.97%; 13 studies). When the analyses were restricted to studies of (unprocessed) red meat, there was no evidence of heterogeneity across studies (RR, 1.06; 95% CI, 0.97–1.16; 11 studies) for colon cancer and 1.03 (95% CI, 0.88–1.21; 10 studies) for rectal cancer.

Stronger but more heterogeneous associations were observed in studies conducted in North America compared with studies published in other countries. The weakest associations were observed in Asian studies, where meat intake is lower than in North America and Europe.

In the dose–response analysis, the relative risks were 1.02 (95% CI, 1.00–1.14; 10 studies) for 1 serving/day increase, and heterogeneity was moderate to low (I² = 26.5%), and 1.05 (95% CI, 0.97–1.13; 13 studies) for each 70 g/day increase.

Alexander et al. (2015) did not investigate processed meats. However, in an earlier meta-analysis, Alexander et al. (2010) reported the relative risks for the highest compared with the lowest intake of processed meat as 1.16 (95% CI, 1.10–1.23; P_{heterogeneity} = 0.556; 20 studies) for any colorectal cancer, 1.19 (95% CI, 1.10–1.28; 12 studies) for colon cancer, and 1.18 (95% CI, 1.03–1.36; 8 studies) for rectal cancer. The relative risk of any colorectal cancer was 1.10 (95% CI, 1.05–1.15; 9 studies) for an increase of 30 g of processed meat intake and 1.03 (95% CI, 1.01–1.05; 6 studies) for each serving per week intake.

[The Working Group noted that there was no significant evidence of publication bias. The pooled analyses of the GECCO study, which included some cohorts included in the meta-analysis, did not find an association between red and processed meats and colorectal cancer. The Danish Diet, Cancer and Health study (Egeberg et al., 2013), in which red and processed meats were not related to colorectal cancer risk, was published after the preparation of the meta-analysis, and therefore was not included. The Japanese study by Takachi et al. (2011) was included in Alexander et al. (2015), but was published after the end of the search for the meta-analysis by Chan et al. (2011).]

The statistical methods used by Alexander et al. (2015) and Chan et al. (2011) were similar. However, Chan et al. (2011) rescaled times consumed or servings to grams of intake using values reported in the studies, or standard portion sizes of 120 g for red meat and 50 g for processed meat, following the methodology of the WCRF/AICR second expert report. [The Working Group noted that the rescaling may have increased the measurement error of the diet in the rescaled studies, but allowed for the inclusion of all studies in the analyses. Chan et al. (2011) reported that the summary risk estimate in the studies using serving as the intake unit was lower than that in the studies using grams (same finding in Alexander et al. (2010) for processed meats). It is possible that the rescaling of the intake may have attenuated the observed association. Another difference between the meta-analyses is that Chan et al. (2011) grouped the studies according to exposure: red and processed meats, red meats (unprocessed), and processed meats.]

A meta-analysis of six Japanese cohort studies reported no significant associations between total and specific meat types and colorectal cancer risk (Pham et al., 2014). For red meat consumption, the summary relative risk estimates for the highest compared with the lowest intake in the studies were 1.20 (95% CI, 1.00–1.44; 4 cohort studies) for colon cancer and 0.95 (95% CI, 0.71–1.28; 3 studies) for rectal cancer. For processed meats, the summary relative risks for the same comparison were 1.18 (95% CI, 0.92–1.53; 4 studies) for colon cancer and 0.94 (95% CI, 0.72–1.21; 3 studies) for rectal cancer. When the authors combined the results of the cohort studies with those of 13 case–control studies, the summary relative risks for red meat were 1.16 (95% CI, 1.001–1.34) and 1.21 (95% CI, 1.03–1.43) for colorectal and colon cancer, respectively, and those for processed meat consumption were 1.17 (95% CI, 1.02–1.35) and 1.23 (95% CI, 1.03–1.47) for colorectal and colon cancer, respectively.

Another meta-analysis of prospective studies summarized the associations between types of red meats and risk of colorectal cancer (Carr et al., 2016). The meta-analysis included one study from the Netherlands, one from Denmark, two from Japan, and the 10 European cohorts participating in the EPIC study. For the highest compared with the lowest intake of beef, the summary relative risks were 1.11 (95% CI, 1.01–1.22), 1.24 (95% CI, 1.07–1.44), and 0.95 (95% CI, 0.78–1.16) for colorectal, colon, and rectal cancer, respectively. Higher consumption of lamb was also associated with an increased risk of colorectal cancer (RR, 1.24; 95% CI, 1.08–1.44). No association was observed for pork (RR, 1.07; 95% CI, 0.90–1.27).

Qiao & Feng (2013) summarized the results of eight prospective studies on haem iron intake. The summary relative risk of colorectal cancer for the highest versus the lowest intake was 1.14 (95% CI, 1.04–1.24). The observed associations were not significantly modified by cancer site or sex. In the dose–response analyses, the summary relative risk was 1.11 (95% CI, 1.03–1.18) for an increment of haem iron intake of 1 mg/day.

In another meta-analysis, people with the NAT2 fast acetylator phenotype who consumed a high intake of total meat had a statistically non-significant increased risk of colorectal cancer compared with slow acetylators who consumed a low intake of total meat (4 cohorts; P_interaction = 0.07) (Andersen et al., 2013). No interaction with the NAT1 phenotype was observed (cohort studies) on the multiplicative scale.

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2.3.1. Cohort studies

(b) Processed meat

See Table 2.3.2

Table 2.3.2

Cohort studies on consumption of processed meat and cancer of the stomach.

Studies investigating the association between consumption of total processed meat, specific processed meat are presented below. Of the reviewed papers, we excluded papers reporting fewer than 100 cases (e.g. Kneller et al., 1991; Knekt et al., 1999; Khan et al., 2004). Studies focusing on dietary pattern (e.g. Pham et al., 2010), studies from mortality data (e.g. McCullough et al., 2001, Ngoan et al.., 2002; Tokui et al., 2005; Iso et al., 2007), studies that were overlapping or updated (Cross et al., 2007) were excluded. Finally, seven studies were included.

Among 7990 American men of Japanese ancestry in a cohort study in which 150 cases of gastric cancer were observed, Nomura et al. (1990) reported an age-adjusted relative risk of 1.3 (95% CI, 0.9–2.0) for the highest versus the lowest frequency of intake of ham and sausage. [The Working Group noted that only age was adjusted. Smoking status was related to gastric cancer, but was not adjusted for. No subsite analysis was conducted.]

In a cohort of 11 907 randomly selected Japanese residents of Hawaii, USA, with an average follow-up period of 14.8 years, 108 observed cases of gastric cancer (44 women, 64 men) were identified, and no association was observed between processed meat consumption and incidence of gastric cancer (Galanis et al., 1998). The adjusted odds ratios for the highest frequency compared with the lowest frequency of consumption were 1.0 (95% CI, 0.5–1.9; 20 exposed cases) and 1.2 (95% CI, 0.6–2.4; 15 exposed cases) for men and women, respectively. [The Working Group noted that the case number was small, especially for women. An FFQ was used with only 13 items. No subsite analysis was conducted.]

González et al. (2006) examined the association between processed meat consumption and risk of gastric cancer in the EPIC study. The adjusted hazard ratio for the association with processed meat intake (highest vs lowest quintile) was 1.62 (95% CI, 1.08–2.41; P_trend = 0.02), which was more apparent in non-cardia cancer (HR, 1.92; 95% CI, 1.11–3.33; P_trend = 0.01) than in cardia cancer (HR, 1.14; 95% CI, 0.52–2.49; P_trend = 0.91). No difference was seen by histological type. When H. pylori infection was considered in the case–control data set nested in the present study, H. pylori antibody status did not appear to modify the association. [The Working Group noted that it was defined that white meat was not included. The population size was large, and detailed information on subsite, histological type, and H. pylori was available.]

In a population-based cohort of 61 433 Swedish women, Larsson et al. (2006) found a positive association between long-term processed meat consumption (using two surveys 10 years apart) and gastric cancer risk. During 18 years of follow-up, 156 incident cases of gastric cancer were diagnosed. The multivariate-adjusted hazard ratio for the highest versus the lowest serving per week of total processed meat was 1.66 (95% CI, 1.13–2.45; 67 exposed cases). [The Working Group noted that using a survey from two time points enabled the effect of long-term exposure to be seen. The number of cases was small. No subsite analysis was conducted.]

In the NIH-American Association of Retired Persons (NIH-AARP Diet and Health Study cohort of 494 979 individuals, aged 50–71 years, Cross et al. (2011) investigated intake of processed meat and meat cooking by-products with accrued 454 gastric cardia cancers (GCAs) and 501 GNCAs. After adjusting for important confounders, no association was observed between processed meat consumption and GCA and GNCA. For the highest versus the lowest quintile, the hazard ratios were 0.82 (95% CI, 0.59–1.14; P_trend = 0.285) and 1.09 (95% CI, 0.81–1.48; P_trend = 0.329), respectively. Nitrate and nitrite were not associated with gastric cancer. [The Working Group noted that this was a large study with a large number of cases, both for GCA and GNCA.]

In the Netherlands Cohort Study (NLCS), Keszei et al. (2012) reported on the association between intake of processed meat and gastric cancer risk in both men and women, after adjusting for important confounders. The case–cohort study consisted of 120 852 men and women, and after 16.3 years of follow-up, 163 GCAs and 489 GNCAs were observed. The definition of processed meat included all meat items that had undergone some form of preservation, including cold cuts, croquettes, and all types of sausages. For the highest compared with the lowest category, the relative risks of intake of processed meat for GCA and GNCA were 1.49 (95% CI, 0.81–2.75; P_trend = 0.34; 32 exposed cases) and 1.19 (95% CI, 0.78–1.79; P_trend = 0.36; 77 exposed cases), respectively, in men. [The Working Group noted that the number of cases for gastric cancer of the cardia was small. A detailed FFQ with 150 items was used.]

Epplein et al. (2014) investigated the interaction between preserved meat, comprising intake of smoked meat, salted meat, and “Chinese” sausage, and H. pylori infection among 226 GNCA cases and 451 controls nested within the Shanghai Men’s Health Study (SMHS prospective cohort. Overall, after adjusting for important confounders, including age, education, smoking, and total energy, preserved meat intake was not associated with gastric cancer. For the highest compared with the lowest category of intake, the relative risk of preserved meat was 1.01 (95% CI, 0.66–1.55; P_trend = 0.99). An effect modification by H. pylori was not apparent (P_interaction = 0.09). [The Working Group noted that information on H. pylori infection was available. This was a study in a population with over 90% prevalence of CagA-positive H. pylori infection. Socioeconomic status or education was not adjusted for. Processed meat intake was low in the study population.]

2.3.2. Case–control studies

(b) Processed meat

The Working Group reviewed several case–control studies of gastric cancer that reported on the association with consumption of processed meat. Few studies were hospital-based (Lee et al., 1990; Boeing et al., 1991b; De Stefani et al., 1998, 2012; Huang et al., 2004), and the majority were population-based (Risch et al., 1985; La Vecchia et al., 1987; Sanchez-Diez et al., 1992; Ward & López-Carrillo, 1999; Palli et al., 2001; Takezaki et al., 2001; Chen et al., 2002; Nomura et al., 2003; Lissowska et al., 2004; Wu et al., 2007; Navarro Silvera et al., 2008; Pourfarzi et al., 2009; Hu et al., 2011; Ward et al., 2012).

(i) Hospital-based case–control studies

See Table 2.3.4

Table 2.3.4

Case–control studies (hospital-based) on consumption of processed meat and cancer of the stomach.

Several hospital-based case–control studies of gastric cancer were conducted in Taipei, Taiwan, China (Lee et al., 1990), Germany (Boeing et al., 1991a, b), Uruguay (De Stefani et al., 1998, 2012), and Japan (Huang et al., 2004). All but two studies (Huang et al., 2004; De Stefani et al., 1998) reported increased risks of gastric cancer associated with processed meat consumption in multivariable models. The possibility of selection bias (due to the selection of hospital-based controls that may have been admitted for conditions leading to modifications in diet), recall bias, and confounding (due to inadequate adjustment for potential confounding variables) could not be ruled out.

(ii) Population-based case–control studies

See Table 2.3.5

Table 2.3.5

Case–control studies (population-based) on consumption of processed meat and cancer of the stomach.

Several population-based case–control studies of gastric cancer that reported on processed meat consumption were identified from Canada (Risch et al., 1985; Hu et al., 2011), Italy (La Vecchia et al., 1987; Palli et al., 2001), Poland (Boeing et al., 1991a; Lissowska et al., 2004), Spain (Sanchez-Diez et al., 1992), Mexico (Ward & López-Carrillo, 1999), China (Takezaki et al., 2001), the Islamic Republic of Iran (Pourfarzi et al., 2009), and the USA, specifically Nebraska (Chen et al., 2002; Ward et al., 1997, 2012), Hawaii (Nomura et al., 2003), Los Angeles (Wu et al., 2007), Connecticut, New Jersey, and western Washington state (Navarro Silvera et al., 2008).

Nearly all the studies reported odds ratios above one, although chance, bias, and confounding could not be ruled out as possible explanations for the observed excesses due to study limitations, including inadequate adjustment for potential confounders (e.g. tobacco smoking, total energy intake), recall bias, and information bias (e.g. large amount of information obtained from proxy respondents).

However, no association between processed meat and gastric cancer was reported in a population-based case–control study from 1988 to 1994 in Nebraska, USA (Ward et al., 2012): the multivariate odds ratio for the highest versus the lowest quartile of processed meat consumption was 0.97 (95% CI, 0.51–1.85; P_trend = 0.87; 46 exposed cases). Although, in a previous study, Ward et al. (1997) reported a positive association between processed meat and gastric cancer based on servings per day (P_trend = 0.06). The 2012 publication conducted a more accurate analysis, estimating grams per day and considering adequate confounding factors. [The Working Group noted that the response rate was high. No subsite analysis was conducted.]

2.3.3. Meta-analyses

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2.4.1. Cohort studies

Cohort studies on cancer of the pancreas have been conducted in North America, Europe, and Asia. Considering the high mortality rate for cancer of the pancreas, both studies of incidence and mortality were included in the review. Studies investigating the association between consumption of red meat or specific red meats, such as beef, pork, or other meats, are reviewed first, followed by studies on consumption of processed meat or specific processed meat items, such as ham or bacon. Findings for red meat and processed meat combined are presented only when a study did not present data for either type of meat separately.

For studies reporting on more than one type of meat, the descriptive details are given in the section the first time the study is cited, while only the key results are provided for subsequent citations. The Working Group’s comments, if any, on the study’s strengths and limitations are also presented only the first time a study is cited, unless different issues were noted in each analysis. Studies that did not adjust for important potential confounders for pancreatic cancer, including age, smoking, BMI, and energy intake, are noted.

After reviewing all of the available studies, the Working Group excluded the following groups of publications from further consideration: studies reporting fewer than 100 cases (e.g. Zheng et al., 1993), due to their limited statistical power; studies reporting risk estimates that were not specific for red meat intake (e.g. Yun et al., 2008; Berjia et al., 2014; Hirayama, 1990); and reports on study populations that were included in or updated by subsequent reports (e.g. Khan et al., 2004; Cross et al., 2007; Iso et al., 2007).

(a) Red meat

See Table 2.4.1

Table 2.4.1

Cohort studies on consumption of red meat and cancer of the pancreas.

In the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study cohort in Finland (Stolzenberg-Solomon et al., 2002), 27 111 male smokers aged 50–69 years were followed from 1985 to 1997, and 163 developed pancreatic cancer. The median value of red meat intake was 128.7 g/day for non-cases. The adjusted hazard ratio for the highest quintile versus the lowest quintile of consumption was 0.95 (95% CI, 0.58–1.56; P_trend = 0.71). Beef and pork also did not show any association. [The Working Group noted that the definition of red meat was not reported. Subjects were male smokers with largely atypical diets, so generalizability of the results was limited.]

In the Nurses’ Health Study (NHS), 178 pancreatic cancer cases were observed over 18 years of follow-up in 88 802 women (Michaud et al., 2003). Diet was assessed by questionnaire four times during follow-up. The definition of red meat included processed meat, so those results are not reported here. For the highest versus the lowest quintile of consumption of beef, pork, or lamb as a main dish, the multivariate hazard ratio was 0.75 (95% CI, 0.41–1.40). Updating the dietary exposures reportedly produced similar results, but data were not shown. [The Working Group noted that the sample size was small.]

Nöthlings et al. (2005) observed positive associations between red meat, beef, and pork consumption and pancreatic cancer incidence in 190 545 men from the Multiethnic Cohort Study in Hawaii and California, USA. During 7 years of follow-up, 482 incident pancreatic cancers occurred. For the highest compared with the lowest quintiles, after adjusting for important confounders, the multivariate relative risks for intakes of red meat, beef, and pork were 1.45 (95% CI, 1.19–1.76; P_trend < 0.01), 1.21 (95% CI, 0.99–1.47; P_trend = 0.03), and 1.53 (95% CI, 1.25–1.87; P_trend < 0.01), respectively. [The Working Group noted that the sample size was large, and the cohort included considerable dietary heterogeneity due to the multi-ethnic background. There was no adjustment for BMI.]

In a population-based cohort of 61 433 Swedish women recruited for mammography screening, Larsson et al. (2006) reported a positive association between long-term red meat consumption, measured by two surveys 10 years apart, and pancreatic cancer risk. During follow-up from 1987 to 2004, 172 incident cases of pancreatic cancer were observed. After adjusting for important confounders, the multivariate hazard ratio for the highest versus the lowest number of servings per week of red meat was 1.73 (95% CI, 0.99–2.98). A dose–response relationship was observed (P_trend = 0.01). [The Working Group noted that using surveys from two time points enabled the effect of long-term exposure to be seen. The cohort was restricted to women. The sample size was small.]

In the Japan Collaborative Cohort (JACC) Study, Lin et al. (2006) evaluated the relationship between dietary factors, including meat, and risk of pancreatic cancer death; 46 465 men and 64 327 women aged 40–79 years were followed up, and 300 deaths from pancreatic cancer were recognized. After adjustment, the multivariate relative risks for the highest compared with the lowest category of intake of beef were 2.3 (95% CI, 0.83–6.39; P_trend = 0.33; 4 observed deaths) for men and 0.98 (95% CI, 0.14–7.11; P_trend = 0.74; 1 observed death) for women. The corresponding results for pork were 1.63 (95% CI, 0.62–4.26; P_trend = 0.34; 5 observed deaths) for men and 1.71 (95% CI, 0.71–4.09; P_trend = 0.35; 6 observed deaths) for women. [The Working Group noted that, while the total number of deaths was not small, the number of observed deaths among the highest category of intake was small. BMI and total energy were not adjusted.]

In a case–cohort analysis of the Netherlands Cohort Study (NLCS), Heinen et al. (2009) observed no association between intake of red meat or individual red meat items and pancreatic cancer risk. The study consisted of 120 852 men and women, and 350 pancreatic cancer cases, identified during 13 years of follow-up. Meat consumption was assessed using a validated FFQ with 150 items. For the highest compared with the lowest quintile, after adjusting for important confounders, the multivariate relative risks for intakes of red meat, beef, pork, and minced meat were 0.75 (95% CI, 0.52–1.09; P_trend = 0.23), 1.20 (95% CI, 0.84–1.72; P_trend = 0.61), 0.75 (95% CI, 0.52–1.08; P_trend = 0.27), and 0.78 (95% CI, 0.54–1.10; P_trend = 0.16), respectively. The corresponding value for intake of liver, categorized into two groups, was 1.05 (95% CI, 0.83–1.33). [The Working Group noted that red meat was clearly defined as not including processed meat. BMI was not adjusted.]

In the Iowa Women’s Health Study (IWHS), Inoue-Choi et al. (2011) assessed multiple aspects of dietary intake among 34 642 postmenopausal women. A total of 256 pancreatic cancer cases during the period from 1986 to 2007 were included in the analysis. No statistically significant associations were observed between intake of red meat and pancreatic cancer (HR, 0.97; 95% CI, 0.65–1.44; for the highest vs lowest consumption category; P_trend = 0.79). [The Working Group noted that the definition of red meat was not reported. The follow-up was nearly complete. BMI and energy were not adjusted.]

Among the 62 581 subjects randomized to screening in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial in the USA (Anderson et al., 2012), 248 cases of exocrine pancreatic cancer were identified during follow-up from 1993 to 2007. The multivariate hazard ratios for the highest versus the lowest quintile of intake of red meat by doneness preference were 0.84 (95% CI, 0.55–1.29; P_trend = 0.36) for rare to medium well done and 1.60 (95% CI, 1.01–2.54; P_trend = 0.04) for well to very well done. When quintiles 1–4 were combined, the corresponding values for the highest quintile of “red barbecued meat” [definition not reported] were 0.79 (95% CI, 0.55–1.13; 39 exposed cases) for rare to medium well done and 1.35 (95% CI, 1.00–1.83; 56 exposed cases) for well to very well done. Pancreatic cancer was significantly associated with consumption of fried (HR, 1.74; 95% CI, 1.05–2.90) and grilled or barbecued pork chops (HR, 1.80; 95% CI, 1.04–3.13), but not with any other cooking method or preference of doneness for pork chops, hamburger, or steak. [The Working Group noted that BMI was not adjusted. The definitions of red meat and barbecued meat were not reported.]

Rohrmann et al. (2013) examined the association between meat consumption and risk of pancreatic cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. A total of 477 202 EPIC participants from 10 European countries recruited between 1992 and 2000 were included in the analysis. Eight hundred and sixty-five non-endocrine pancreatic cancer cases were observed during follow-up to 2008. After adjusting for important confounders, no significant association between consumption of red meat and pancreatic cancer was observed; the multivariate relative risk for the fourth compared with the first quantile of intake was 1.07 (95% CI, 0.83–1.38). [The Working Group took note of the large international study encompassing diverse diets.]

2.4.2. Case–control studies

Case–control studies on cancer of the pancreas have been conducted in North America, Europe, and Asia. Considering the high mortality rate for cancer of the pancreas, both studies of incidence and mortality data were included in the review. The studies were considered based on the quality of reporting of the type of meat, study design issues (e.g. population- vs hospital-based design), sample size, and exposure assessment, including validation of dietary questionnaires and inclusion of relevant confounders. Studies that did not adjust for important potential confounders (see Section 2.4.1) are noted.

As for cohort studies, case–control studies that investigated the association with consumption of total red meat or specific red meats are presented first, followed by studies that investigated the association with consumption of processed meat. Study details and Working Group comments are provided only the first time a study is cited, unless important differences were noted.

After reviewing all of the available studies, studies with fewer than 100 cases (e.g. Kadlubar et al., 2009; Luckett et al., 2012), papers reporting only dietary patterns (e.g. Bosetti et al., 2013; Chan et al., 2013) or preserved processed items including eggs (e.g. Ji et al., 1995), and overlapping studies of the same population (e.g. Hu et al., 2011) were excluded from further consideration. Studies that did not report pertinent odds ratios (e.g. Li et al., 2007) were excluded when only crude odds ratios could be calculated from the data presented.

(a) Red meat

See Table 2.4.3

Table 2.4.3

Case–control studies on consumption of red meat and cancer of the pancreas.

Lyon et al. (1993) reported the results of a population-based case–control study of cancer of the exocrine pancreas conducted from 1984 to 1987 in Utah, USA; 149 cases of pancreatic cancer were identified from the Utah Cancer Registry, and 363 controls were identified by random digit dialling or health insurance records of those older than 65 years. Dietary intake data were collected from a 32-item FFQ administered to proxy respondents for cases and controls. Red meat was defined as beef and pork. The multivariate odds ratios for the highest versus the lowest level of red meat consumption were 1.41 (95% CI, 0.72–2.75; P_trend = 0.30) in men and 1.44 (95% CI, 0.65–3.20; P_trend = 0.45) in women. [The Working Group noted that the study was small, and BMI and energy were not adjusted.]

Ji et al. (1995) reported findings for red meat consumption in a population-based case–control study conducted from 1990 to 1993 in Shanghai, China. Pancreatic cancer cases (n = 451) were identified by a rapid reporting system. Controls (n = 1552) were selected Shanghai residents, frequency-matched to cases by sex and age. Interviews with next of kin were conducted for 38% of cases and 10% of controls. Usual meat intake over the previous 5 years was ascertained from an 86-item questionnaire. The multivariate odds ratios for the highest versus the lowest quartile of red meat consumption were 0.73 (95% CI, 0.47–1.12; P_trend = 0.24) in men and 1.24 (95% CI, 0.73–2.13; P_trend = 0.86) in women. [The Working Group noted that processed meat was not included. This study was large, but a substantial number of case and control interviews were performed with next of kin. BMI and energy were not adjusted. No validation data for FFQ were reported.]

In a population-based case–control study, conducted from 1995 to 1999 in California, USA, Chan et al. (2007), reported the results of red meat consumption. Dietary intake of red meat was collected from a validated, 131-item SQFFQ. Cases were 532 pancreatic cancer patients from the Northern California Cancer Center. Controls were 1701 area residents identified by random digit dialling, and frequency-matched to cases by sex and age. Compared with a frequency of < 1 time /month, the multivariate odds ratios for ≥ 2 times /week frequency of beef or lamb intake as a main dish and pork intake as a main dish were 2.2 (95% CI, 1.0–4.5; 14 exposed cases) and 0.6 (95% CI, 0.3–1.1; P_trend = 0.2; 11 exposed cases), respectively. Results for total red meats, including processed red meats, were also reported. [The Working Group noted that the study design was sound.]

Hu et al. (2008) reported the results of a population-based case–control study of pancreatic cancer conducted from 1994 to 1997 in eight Canadian provinces. Dietary intake of red meat was collected from a mailed, validated questionnaire with 69 items. Cases were 628 individuals identified from provincial cancer registries. Controls were 5039 individuals selected from a random sample within the provinces. The multivariate odds ratio for the highest versus the lowest quartile of frequency of red meat consumption was 1.1 (95% CI, 0.9–1.5; P_trend = 0.31). [The Working Group noted that the sample size was large, and a validated FFQ was used.]

In a population-based case–control study, Anderson et al. (2009) reported the results of red meat consumption from 2003 to 2007 in Canada. Dietary intake of red meat was collected from a mailed FFQ. Cases were 422 pancreatic cancer patients identified by the Ontario Cancer Registry. Controls were 312 subjects recruited through random digit dialling. The age-adjusted odds ratio for > 3 servings/week versus ≤ 1 serving/week of red meat consumption was 1.49 (95% CI, 0.98–2.28). Adjusting for other factors, such as smoking and education, did not alter the results. [The Working Group noted that the exact definition of red meat was not reported. This study was large, but the questionnaire was not validated. BMI and energy were not adjusted.]

Tavani et al. (2000), using data from a hospital-based case–control study of several cancers in northern Italy in 1983–1996, reported results for red meat consumption and pancreatic cancer. Cases were 362 hospital patients younger than 75 years with confirmed pancreatic cancer. Controls were 7990 patients younger than 75 years admitted to the same network of hospitals as the cancer cases for acute non-cancer conditions. Dietary intake of red meat over the previous 2 years was collected by FFQ, which defined red meat as beef, veal, or pork, excluding processed items. The multivariate odds ratio for the highest (≥ 7 times/week) versus the lowest (≤ 3 times/week) level of red meat consumption was 1.6 (95% CI, 1.2–2.1). [The participation of cases and controls was similar and almost complete. The questionnaire was not tested for validity, but reproducibility was reported to be satisfactory. BMI and energy were not adjusted.] Similar findings were reported in an earlier paper based on the same study (Soler et al., 1998), which also provided data for liver consumption (OR, 1.43; 95% CI, 1.01–1.99). [The Working Group noted that the study population appeared to overlap with those studied by Soler et al. (1998), Tavani et al. (2000), Polesel et al. (2010), and Di Maso et al. (2013).]

Polesel et al. (2010) reported the results of a hospital-based case–control study of pancreatic cancer conducted from 1991 to 2008 in northern Italy. [The study population appeared to overlap with that studied by Tavani et al. (2000).] Cases were 326 men and women with incident pancreatic cancer. Controls were 652 hospital patients admitted for acute conditions. Dietary intake of red meat was collected from a validated questionnaire with 78 items. Cooking methods were assessed for all meats combined. After adjusting for important potential confounders, the multivariate odds ratio for the highest versus the lowest quintile of red meat consumption was 1.99 (95% CI, 1.18–3.36). Data were also reported for pork and processed meat combined (multivariate OR, 1.25; 95% CI, 0.85–1.84; P_trend = 0.27). [The definition of red meat was not reported. and data were not reported for pork and processed meat separately. The Working Group judged the data on cooking methods to be uninformative, as they were reported only for all meats combined. The response rate was high for both cases and controls.]

Di Maso et al. (2013) also reported results of a hospital-based case–control study that partially overlapped with that of Tavani et al. (2000). Red meat was defined as including beef, veal, pork, horse meat, and meat sauces. The multivariate odds ratio for pancreatic cancer was 1.51 (95% CI, 1.25–1.82) per 50 g/day increment. Associations with red meat cooked in different ways were also examined, with no significant heterogeneity identified between meats cooked by roasting/grilling, boiling/stewing, and frying/pan-frying. [The Working Group noted that the results of later, overlapping studies were similar to those reported by Tavani et al. (2000), and the Tavani et al. study had a large number of cases and controls, and the definition of red meat was clearly described and did not include processed meat.]

2.4.3. Meta-analyses

Associations between pancreatic cancer and consumption of red meat and processed meat were estimated in two meta-analyses published in 2012: Larsson & Wolk (2012), focused on prospective studies, and Paluszkiewicz et al. (2012), considered both cohort and case–control studies.

Larsson & Wolk (2012), in a meta-analysis based on 11 prospective studies with 6643 cases identified through PubMed and Embase searches through November 2011, reported on red and processed meat consumption. An increase in red meat consumption of 120 g/day was associated with a meta-relative risk of 1.13 (95% CI, 0.93–1.39; P_{heterogeneity} < 0.001; 11 studies). For processed meat, the relative risk for a 50 g/day increase in consumption was 1.19 (95% CI, 1.04–1.36; P_{heterogeneity} = 0.46; 7 studies). [The Working Group noted that there were no studies missing. Studies considering specific items of red or processed meat were also included. No evidence of publication bias was found. ]

Paluszkiewicz et al. (2012) included cohort studies and case–control studies identified through MEDLINE, PubMed, Cochrane Library, Embase, CANCERLIT, Scopus, and Google Scholar through 2010. Six cohort studies and four case–control studies provided data for red meat. For the highest versus the lowest category of red meat intake, a statistically significant increased risk was observed for case–control studies (OR, 1.48; 95% CI, 1.25–1.76; P_{heterogeneity} = 0.7716), but not for cohort studies (RR, 1.14; 95% CI, 0.94–1.38; P_{heterogeneity} = 0.004). Analyses for processed meat were not reported. [The Working Group noted that several electronic databases were searched for relevant studies. Study quality was assessed, but how quality scores were used in the analysis was not reported. No analyses of sensitivity or publication bias were reported.]

Two large prospective studies were published since these meta-analyses, both showing no association overall between red or processed meat consumption and pancreatic cancer risk (Rohrmann et al., 2013; Jiao et al., 2015). However, results in Jiao et al. (2015) were positive for red meat before adjusting for AGEP consumption.

References

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2.5.1. Cohort studies

See Table 2.5.1 (red meat) and Table 2.5.2 (processed meat, web only; available at: http://publications.iarc.fr/564)

Table 2.5.1

Cohort studies on consumption of red meat and cancer of the prostate.

The quality of the studies was evaluated based on sample size, quality of reporting of the type of meat, consideration of relevant confounders, study design issues (e.g. population- vs hospital-based design, response rates), and exposure assessment, including validation of dietary questionnaires. The Working Group considered total energy intake, BMI, and race as important potential confounders. Cancer of the prostate poses a special problem compared with other sites because there is a broad range of clinical behaviours, and the classification is not uniform across studies (e.g. grade, stage, Gleason score, or other definitions of clinical aggressiveness). In addition, the widespread use of prostate-specific antigen (PSA) testing, which may be associated with dietary habits, further complicates the interpretation of epidemiological findings.

More than 20 cohort studies have reported on the intake of red meat or processed meat and the incidence of or mortality (when incident cases were also considered) from prostate cancer, spanning from 1984 to 2011. The Americas, Asia, and Europe were represented, with studies from Japan, Norway, the Netherlands, the United Kingdom, and the USA.

The most informative cohorts were published by Schuurman et al. (1999), Michaud et al. (2001), Cross et al. (2005) (PLCO randomized trial), Rodriguez et al. (2006), Park et al. (2007), Allen et al. (2008), Koutros et al. (2008), Agalliu et al. (2011), and Major et al. (2011), and several of these studies were included in a pooled analysis of 15 prospective cohort studies (Wu et al., 2016).

Studies with fewer than 100 exposed cases are not described further in the text or tables (e.g. Gann et al., 1994; Giovannucci et al., 1993; Loh et al., 2010; Phillips & Snowdon, 1983; Richman et al., 2011; Rohrmann et al., 2007; Sander et al., 2011; Snowdon et al., 1984; Veierød et al., 1997; Wu et al., 2006).

2.5.2. Case–control studies

See Table 2.5.3 (red meat) and Table 2.5.4 (processed meat, web only; available at: http://publications.iarc.fr/564)

Table 2.5.3

Case–control studies on consumption of red meat and cancer of the prostate.

More than 20 case–control studies were considered, six with a population-based design. The Working Group considered first the population-based studies that tended to be more informative, given the uncertainty in the choice of hospital controls, who were affected by diseases that could have possibly had an impact on dietary habits. Studies with fewer than 100 cases were excluded (see details below).

References

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2.6.1. Cohort studies

More details of the cohort studies can be found in Table 2.6.1 and Table 2.6.2 (web only; available at: http://publications.iarc.fr/564).

Intake of red and processed meat was evaluated in relation to cancer of the breast in cohort studies conducted in the USA, Canada, the Netherlands, the United Kingdom, Sweden, Denmark, and France, as well as in the EPIC study, which included multiple European countries, and in a cohort consortium of eight studies in North America and Europe. Important potential confounders for breast cancer included age, alcohol intake, reproductive factors (such as age at menarche, parity, age at first birth, use of oral contraceptives, age at menopause), use of postmenopausal hormones among postmenopausal women, family history of breast cancer, obesity, and energy intake. Studies that did not adjust for these covariates are noted. Recent publications with more reliable exposure assessment, more adequate adjustment for potential confounders, and longer follow-up time were included in the evaluation.

Studies were considered uninformative and not included in the evaluation if they assessed meat intake without specifying the types of meats included (e.g. Mills et al., 1988; van den Brandt et al., 1990; Vatten et al., 1990; Knekt et al., 1994; Gaard et al., 1995). In addition, studies that evaluated breast cancer in relation to dietary patterns, rather than the consumption of red or processed meat (e.g. Männistö et al., 2005; Cottet et al., 2009; Butler et al., 2010; Couto et al., 2013), or had a low number of cases (Byrne et al., 1996) were excluded from further review.

Mills et al., (1989) evaluated individual red meat items, “beef index”, and breast cancer in a low-risk cohort of 20 341 Californian, Seventh-Day Adventist women aged 25–99 years. The beef index was the sum of intake from individual red meat items, including beef hamburger, beef steak, and other beef/veal. During a mean follow-up of 6 years (1976–1982), 215 primary breast cancer cases were histologically verified. The relative risk for the top (≥ 1 time/week) versus the bottom (never) category of the beef index was 1.05 (95% CI, 0.75–1.47). Intake of red meat (i.e. beef hamburger, beef steak, and other beef/veal) was not associated with breast cancer. [Alcohol and caloric intake were not adjusted for in statistical analyses. This study was part of the Pooling Project of Prospective Studies by Missmer et al., (2002). A smaller number of cases were included in the pooling project (160 cases).]

Toniolo et al. (1994) conducted a nested case–control study of 180 breast cancer cases and 829 controls from the first 6 years of follow-up (median follow-up time, 22.2 months) in the New York University Women’s Health Study (NYUWHS) cohort. The study originally included 14 291 women aged 35–65 years enrolled between 1985 and 1991. Diet was assessed with a 71–food item, validated Block FFQ. The relative risk for the top versus the bottom quintile of meat intake was 1.87 (95% CI, 1.09–3.21; P_trend = 0.01). [The Working Group noted the relatively small sample size. In addition, the study did not specify red meat. Meat included beef, veal, lamb, or pork preparations or processed luncheon meats (ham, cold cuts, turkey rolls), that is, unprocessed and processed red meat and processed white meat. Alcohol intake was not adjusted for. This study was part of the Pooling Project of Prospective Studies by Missmer et al. (2002). A larger number of cases were included in the pooling project (385 cases).]

The Iowa Women’s Health Study (IWHS) cohort included 41 836 postmenopausal (age, 55–69 years) women. Five nested case–control studies of the cohort were included (Zheng et al., 1998; Zheng et al., 1999; Deitz et al., 2000; Zheng et al., 2001; Zheng et al., 2002). These studies are described in more detail below.

Zheng et al. (1998) conducted a nested case–control study of 273 cases and 657 controls nested within the IWHS. All eligible subjects were asked to complete a self-administered FFQ on meat intake habits during the reference year. The questionnaire included questions on usual intake and preparation of 15 meats. A doneness score was also calculated to describe the eating preferences of the participants based on their responses to colour photographs. The study found a positive dose–response relationship between doneness of red and processed meat and breast cancer risk. The odds ratios for very well-done meat versus rare or medium-done meat were 1.54 (95% CI, 0.96–2.47) for hamburger, 2.21 (95% CI, 1.30–3.77) for beef steak, and 1.64 (95% CI, 0.92–2.93) for bacon. Women who consumed these three meats consistently very well done had an odds ratio of 4.62 (95% CI, 1.36–15.70; P_trend = 0.001) compared with women who consumed the meats rare or medium done. In addition, compared with women in the lowest tertile of intake of these three types of meats with a doneness level of rare/medium, those who were in the top tertile of intake with a doneness level of consistently very well done had an odds ratio of 3.01 (95% CI, 1.47–6.17). [The Working Group noted that there was a statistically significant positive association between intake of red meat and risk of breast cancer (P_trend = 0.02), with a 78% elevated risk observed for the highest versus the lowest tertile of intake group; however, red meat included processed meat. Reproductive factors and alcohol intake were not adjusted for in statistical analyses. This study was part of the Pooling Project of Prospective Studies by Missmer et al. (2002). A much larger number of cases were included in the pooling project (1130 cases).]

Deitz et al. (2000) used a subset of the nested case–control study data from the IWHS (174 cases, 387 controls) with DNA samples, and evaluated doneness score and red meat [which included processed meat] intake and breast cancer by NAT2 polymorphism. Polymorphisms in the NAT2 gene may result in a rapid, intermediate, and slow acetylation phenotype. The study found that a higher intake of red meat was suggestively positively associated with breast cancer among women with the NAT2 rapid/intermediate type (OR, 1.7; 95% CI, 0.9–3.4; for the highest vs lowest tertile of intake), but not associated with breast cancer among those with the NAT2 slow type (OR, 0.9; 95% CI, 0.5–1.7; for the same comparison). However, the P value for interaction by NAT2 genotype was not significant (P = 0.91). For the association between doneness score and breast cancer, there was a borderline significant interaction by NAT2 genotype (P = 0.06). Compared with women who reported consuming hamburger, beef steak, and bacon rare/medium (doneness score, 3/4), those who reported consuming these meats very well done (doneness score, 9) had odds ratios of 3.9 (95% CI, 0.8–18.9; P_trend = 0.22) for the NAT2 slow genotype and 7.6 (95% CI, 1.1–50.4; P_trend = 0.003) for the NAT2 rapid/intermediate type. [The Working Group noted that the sample size was much more limited than the original study by Zheng et al. (1999) because a large number of the subjects had buccal cell samples instead of blood samples, and NAT2 amplification was successful only in 9% (79/878) of buccal cell DNA samples. Sample size was too small to evaluate the interaction with genetic polymorphisms. Only age was adjusted for. Red meat included processed meat.]

A similar study using a subset of the nested case–control study data from the IWHS was conducted to evaluate the association between doneness of red meat and breast cancer risk stratified by SULT1A1 polymorphism (Zheng et al., 2001). The study included 156 cases and 332 controls, with blood samples. The association between doneness of red meat [which included processed meat] and breast cancer appeared to differ by the polymorphism, although the P value for interaction was not significant (P = 0.40). Compared with participants consuming rare/medium-done red meat, those who consistently consumed well-done red meat had relative risks of 3.6 (95% CI, 1.4–9.3; P_trend = 0.01) for the SULT1A1 Arg/Arg genotype, 1.8 (95% CI, 0.9–3.8; P_trend = 0.10) for the Arg/His genotype, and 1.0 (95% CI, 0.3–3.7; P_trend = 0.98) for the His/His genotype. [The Working Group noted that the sample size was too small to evaluate the interaction with genetic polymorphisms, and most of the categories had fewer than 20 cases. Age, waist:hip ratio, and number of live births were adjusted for. Red meat included processed meat.]

Zheng et al. (2002) also evaluated a similar interaction between meat doneness level and breast cancer risk by GSTM1 and GSTT1 polymorphisms in a nested case–control study in the IWHS (202 cases, 481 controls; with blood samples and genotyping for GSTM1). The association between doneness of red meat and breast cancer did not vary by GSTT1 genotype. However, there was a significant interaction by GSTM1 genotype (P_interaction = 0.04). Compared with women who consumed rare/medium-done meat and had the GSTM1 genotype, those who consistently consumed well- or very well-done meat and had the GSTM1 null genotype had a relative risk of 2.5 (95% CI, 1.3–4.5). [The Working Group noted that the sample size was too small to evaluate the interaction with genetic polymorphisms. Age, waist: hip ratio, number of live births, and family history were adjusted for. Red meat included processed meat.]

Voorrips et al. (2002) evaluated red meat and processed meat intake and breast cancer in the Netherlands Cohort Study on Diet and Cancer (NLCS), among a cohort of 62 573 women aged 55–69 years. Diet was assessed with a validated FFQ with 150 food items. Red meat, which was presented as “fresh meat”, included beef and pork, and did not include processed meat. Subjects were classified into quintiles or categories of consumption (g/day), based on the distribution in the control group of 1598 women. During a mean follow-up of 6 years, 941 breast cancer cases were documented. The relative risk for the top (median, 145 g/day) versus the bottom (median, 45 g/day) quintile of red meat intake was 0.98 (95% CI, 0.73–1.33) for breast cancer. The relative risk for the top (median, 13 g/day) versus the bottom (median, 0 g/day) category of processed meat intake was 0.93 (95% CI, 0.67–1.29) for breast cancer. Intake of beef and pork was also not associated with breast cancer. [The Working Group noted that assessment and adjustment of information on postmenopausal hormone use was not mentioned. This study was part of the Pooling Project of Prospective Studies by Missmer et al. (2002). Almost the same number of cases was included in the pooling project (937 cases).]

Missmer et al. (2002) conducted a pooled analysis of eight prospective cohort studies (Adventist Health Study (AHS); Canadian National Breast Screening Study (CNBSS); IWHS; NLCS; New York State Cohort, (NYSC); New-York University Women’s Health Study (NYUWHS); Nurses’ Health Study (NHS); and Sweden Mammography Cohort (SMC)) from North America and western Europe, which used validated FFQs. A total of 7379 breast cancer cases diagnosed during up to 15 years of follow-up were included. Pooled multivariate-adjusted relative risks for an increase of 100 g/day in red meat intake were 0.98 (95% CI, 0.93–1.04) in all women, 0.97 (95% CI, 0.79–1.20) in premenopausal women, and 0.97 (95% CI, 0.91–1.03) in postmenopausal women. None of the red meat items, including ground beef, organ products or processed meats, bacon products, sausage products, and hot dogs, were associated with breast cancer risk. [The Working Group noted that red meat included both fresh and processed red meat, blood pudding, liver, and kidney.]

Holmes et al. (2003) evaluated red meat and processed meat intake and breast cancer among 88 647 women included in the NHS. Diet was assessed using a 61–food item FFQ at baseline and a 116–food item FFQ since 1984. Both FFQs were validated. FFQs were sent to the women multiple times during follow-up. Red meats included hamburger, beef/pork/lamb as a main dish, beef/pork/lamb in sandwiches or mixed dishes, hot dogs, bacon, and other processed meats. Between 1980 and 1998, 4107 cases of invasive breast cancer were identified. There was no association between intake of red meat or processed meat and breast cancer. The relative risk for the top (≥ 1.32 servings/day) versus the bottom (≤ 0.55 servings/day) quintile of red meat intake was 0.94 (95% CI, 0.84–1.05). The relative risk for the top (≥ 0.46 servings/day) versus the bottom (≤ 0.10 servings/day) quintile of processed meat intake was 0.94 (95% CI, 0.85–1.05). The associations were similar by menopausal status. [The study was limited by the definition of red meat, which included processed meat. Fung et al. (2005) evaluated the same cohort, with a shorter follow-up period (1984–2000) and a smaller number of cases (3026 cases), and was not considered. Similarly, Wu et al. (2010) evaluated the consumption of mutagens from meats cooked at a high temperature in an NHS subcohort, with a shorter follow-up period (1996–2006) and fewer cases (2317 cases), and was not considered. The NHS was part of the Pooling Project of Prospective Studies by Missmer et al. 2002. A smaller number of cases were included in the pooling project (2661 cases).]

van der Hel et al. (2004) evaluated red meat and processed meat intake in relation to breast cancer in a nested case–control study of 229 cases (average age, 48 years) and 264 controls, with blood samples, nested within a Dutch prospective study. Controls were frequency-matched by age, town, and menopausal status. Meat consumption was recorded at baseline with the use of a validated, self-administered FFQ. Red meat intake in grams per day was calculated by adding up intakes of beef and pork. There was no association between red meat or processed meat intake and breast cancer risk. Compared with women who had a red meat intake of < 30 g/day, women who were in the high-intake category of ≥ 45 g/day had an odds ratio of 1.32 (95% CI, 0.84–2.08). Compared with women with a processed meat intake of < 20 g/day, those who were in the high-intake category of ≥ 35 g/day had an odds ratio of 1.08 (95% CI, 0.60–1.70). When polymorphisms related to metabolism of HAAs, including NAT1, NAT2, GSTM1, GSTT1, were evaluated, there was a positive association with GSTM1 null genotype. When the association with red meat intake was stratified by GSTM1 polymorphism, no interaction was observed. [The Working Group noted that the sample size was too limited to evaluate the interaction with genetic polymorphisms. Family history of breast cancer and postmenopausal hormone use were not adjusted for in the multivariate analysis.]

Kabat et al., (2007) evaluated red meat and haem iron intake and breast cancer in the CNBSS, a randomized controlled trial of screening for breast cancer involving women aged 40–59 years. Diet was assessed with a validated FFQ with 86 food items. During a mean follow-up of 16.4 years, 2491 breast cancer cases (1171 premenopausal cases, 993 postmenopausal cases) were included. The relative risk for the top (≥ 40.30 g/day) versus the bottom (< 14.25 g/day) quintile of red meat intake was 0.98 (95% CI, 0.86–1.12) for breast cancer. The relative risk for the top (> 2.95 mg/day) versus the bottom (< 1.58 mg/day) quintile of haem iron intake was 1.03 (95% CI, 0.90–1.18) for breast cancer. The results were similar by menopausal status. [The Working Group noted that red meat was not defined. Although this study was part of the Pooling Project of Prospective Studies by Missmer et al. (2002), which evaluated red meat intake, only 419 breast cancer cases, with a shorter follow-up period (5 years), were included in the pooling project.]

Taylor et al. (2007) evaluated red meat and processed meat intake and breast cancer in the United Kingdom Women’s Cohort Study (UKWCS) in 678 cases (283 premenopausal cases, 395 postmenopausal cases). Diet was assessed between 1995 and 1998 using a 217-item, postal FFQ developed from that of the EPIC study. Red meat consisted of beef, pork, lamb, and other red meats included in mixed dishes, such as meat lasagne, moussaka, ravioli, and filled pasta with sauce. Processed meat consisted of bacon, ham, corned beef, spam, luncheon meats, sausages, pies, pasties, sausage rolls, liver pâté, salami, and meat pizza. Higher intakes of both red meat and processed meat were associated with an elevated risk of breast cancer. Compared with non-consumers, those who were in the high-intake category had a hazard ratio of 1.41 (95% CI, 1.11–1.81) for red meat (> 57 g/day) and 1.39 (95% CI, 1.09–1.78) for processed meat (> 20 g/day). When the association was evaluated by menopausal status, the hazard ratios for the highest versus the lowest quartile of intake were 1.32 (95% CI, 0.93–1.88; 61 cases) among premenopausal women and 1.56 (95% CI, 1.09–2.23; 106 cases) among postmenopausal women for red meat. [The Working Group noted that family history of breast cancer and alcohol intake were not adjusted for.]

Egeberg et al. (2008) conducted a nested case–control study among 24 697 postmenopausal women included in the Diet, Cancer and Health cohort study (1993–2000) in Denmark. The study included 378 breast cancer cases and 378 matched controls. Meat consumption was estimated from a 192-item, validated FFQ, completed at baseline, covering the participants’ habitual diet during the preceding 12 months. Intake of red meat in grams per day was calculated by adding up intakes of beef, veal, pork, lamb, and offal. [Intake of processed meat included processed fish, and was not reviewed.] Compared with women whose red meat intake was < 50 g/day, those who consumed > 80 g/day had a relative risk of 1.65 (95% CI, 1.09–2.50; P_trend = 0.03). The associations were also stratified by NAT1 and NAT2 polymorphisms. There was no significant interaction by NAT1 polymorphism, but there was a significant interaction by NAT2 polymorphism for red meat intake (P_interaction = 0.04). The relative risks per 25 g/day increase in red meat intake were 1.37 (95% CI, 1.07–1.76) for the NAT2 intermediate/fast acetylator phenotype and 1.00 (95% CI, 0.85–1.18) for the NAT2 slow acetylator phenotype. [The Working Group noted that sample size was limited in some of the stratified analyses by NAT polymorphisms. Caloric intake and family history of breast cancer were not adjusted for in the multivariate analysis.]

Kabat et al. (2009) evaluated the association between red meat intake and meat preparation in relation to breast cancer among postmenopausal women only in the NIH-AARP study. Diet was assessed with the NCI Diet History Questionnaire (DHQ), a self-administered, validated FFQ with 124 food items. [Red meat included many types of processed meats, and data are not reported here.] Processed meat included bacon, red meat sausage, poultry sausage, luncheon meats (red and white meat), cold cuts (red and white meat), ham, regular hot dogs, and low-fat hot dogs made from poultry. During a follow-up of 8 years, 3818 breast cancer cases were documented. Processed meat was not associated with breast cancer risk. The relative risk for the top (> 12.5 g/1000 kcal) versus the bottom (≤ 2.2 g/1000 kcal) quintile of processed meat intake was 1.0 (95% CI, 0.90–1.12) for breast cancer. Cooking methods (grilled or barbecued meat, pan-fried meat, oven-broiled meat, sautéed meat, baked meat, or microwaved meat) and meat doneness levels (rare/medium-done cooked meat or well/very well-done cooked meat) were not associated with breast cancer risk. [The Working Group noted that an earlier publication of the NIH-AARP cohort that had a shorter follow-up and inferior adjustment for potential confounders of breast cancer (Cross et al., 2007) was not considered. Evaluation of cooking methods and doneness levels included poultry.]

Larsson et al. (2009) evaluated red meat intake and breast cancer in the SMC, which was established in 1987–1990 in central Sweden. Diet was assessed with a 67– and 96–food item FFQ at baseline and in 1997, respectively. During a mean follow-up of 17.4 years, 2952 breast cancer cases were ascertained. For overall breast cancer, the relative risks for the top (≥ 98 g/day) versus the bottom (< 46 g/day) quintile of intake were 0.98 (95% CI, 0.86–1.12) for red meat, 1.08 (95% CI, 0.96–1.22) for processed meat, 1.10 (95% CI, 0.90–1.34) for estrogen receptor (ER)+/progesterone receptor (PR)+ tumours, 0.86 (95% CI, 0.60–1.23) for ER+/PR– tumours, and 1.12 (95% CI, 0.70–1.79) for ER–/PR– tumours. [The Working Group noted that red meat included all fresh and minced pork, beef, and veal. Processed meats included ham, bacon, sausages, salami, processed meat cuts, liver pâté, and blood sausages. This study was part of the Pooling Project of Prospective Studies by Missmer et al. (2002). However, a much smaller number of cases were included in the pooling project (1320 cases).]

Ferrucci et al., (2009) evaluated red meat and processed meat intake and cooking methods and doneness levels, and breast cancer risk in the Prostate, Lung, Colorectal and Ovarian (PLCO) trial, a multicentre, randomized controlled trial in women aged 55–74 years who were recruited in 1993–2001. Diet was assessed with by the NCI Diet history Questionnaire (DHQ), a self-administered, validated FFQ with 124 food items. During a mean follow-up of 5.5 years, 1205 breast cancer cases were documented. [Red meat included processed meat, and data are not reported here.] Processed meat included bacon, cold cuts, hams, hot dogs, and sausage. The hazard ratio for the top (> 11.6 g/1000 kcal; median, 16.9 g/1000 kcal) versus the bottom (≤ 2.4 g/1000 kcal; median, 1.4 g/1000 kcal) quintile of processed meat intake was 1.12 (95% CI, 0.92–1.36; P_trend = 0.22). Intake of steak, hamburger, sausage, bacon, and pork chops was not associated with breast cancer. The hazard ratios for the top versus the bottom quintile were 1.03 (95% CI, 0.84–1.27) for pan-fried meat, 1.10 (95% CI, 0.90–1.34) for grilled meat, 1.09 (95% CI, 0.90–1.32) for well/very well-done meat, and 1.20 (95% CI, 0.99–1.45) for grilled/pan-fried well/very well-done meat. [The Working Group noted that red meat included processed meat.]

Pala et al. (2009) evaluated the association between red meat and processed meat and breast cancer in the EPIC study. Information on diet was collected from 319 826 women aged 20–70 years in 1992–2003. Diet was assessed by using country-specific (Italy and Sweden centre-specific) validated FFQs designed to capture habitual consumption of food over the preceding year. Red meat consisted of fresh, minced, and frozen beef, veal, pork, and lamb. Processed meats were mostly pork and beef preserved by methods other than freezing, such as salting, smoking, marinating, air-drying, or heating, and included ham, bacon, sausages, blood sausages, liver pâté, salami, mortadella, tinned meat, and others. A total of 7119 invasive breast cancer cases were documented during a median of 8.8 years of follow-up. A higher intake of processed meat, but not red meat, was associated with a modest elevated risk of breast cancer. The hazard ratio for the highest (median, 84.6 g/day) compared with the lowest (median, 1.4 g/day) quintile of red meat consumption was 1.06 (95% CI, 0.98–1.14; P_trend = 0.19). The hazard ratio for the highest (median, 56.5 g/day) compared with the lowest (median, 1.7 g/day) quintile of processed meat consumption was 1.10 (95% CI, 1.00–1.20; P_trend = 0.07). The positive association was limited to postmenopausal breast cancer (3673 postmenopausal cases vs 1699 premenopausal cases). The corresponding hazard ratios were 1.13 (95% CI, 1.00–1.28; P_trend = 0.06) for postmenopausal women and 0.99 (95% CI, 0.82–1.19; P_trend = 0.72) for premenopausal women. [The Working Group noted that family history of breast cancer was not adjusted for.]

Loh et al. (2010) evaluated the association between red and processed meat intake and breast cancer stratified by MGMT Ile143Val polymorphism in the EPIC-Norfolk study in 276 cases and 1498 controls. There was no significant interaction with the polymorphism. [The Working Group noted that the sample size was too small to evaluate the interaction with genetic polymorphisms.]

Lee et al. (2013) conducted a nested case–control study within the NHS to evaluate the interaction between red meat intake and NAT2 acetylator genotype and cytochrome P450 1A2−164 A/C (CYP1A2) polymorphism. The study included 579 cases and 981 matched controls. There was no interaction between NAT2 acetylator genotype or CYP1A2 polymorphism and red meat intake in relation to breast cancer. [The Working Group noted that the study was limited by the definition of red meat, which included processed meat. Holmes et al. (2003) evaluated red meat intake in the same cohort.]

Genkinger et al. (2013) evaluated breast cancer among African American women from the Black Women’s Health Study (BWHS). The study included a total of 1268 cases, among 52 062 women, identified during 12 years of follow-up. Diet during the past year was estimated from a 68-item, modified Block FFQ completed at baseline in 1995. In 2001, a modified version of the 1995 FFQ, which asked about 85 food items, was administered to collect updated dietary information. The 1995 FFQ ascertained the intake of 13 meat items; the 2001 FFQ asked about 15 meat items. Intakes of red meat or processed meat were not associated with breast cancer. Compared with women with a red meat intake of < 100 g/week, those who consumed ≥ 400 g/week had a relative risk of 1.02 (95% CI, 0.83–1.24; P_trend = 0.83). Compared with women with a processed meat intake of < 100 g/week, those who consumed ≥ 200 g/week had a relative risk of 0.99 (95% CI, 0.82–1.20; P_trend = 0.96). The associations were similar by menopausal status. [The Working Group noted that information on the definitions of red meat and processed meat, and validation of the FFQs was not provided.]

The study by Pouchieu et al. (2014) was based on the SU.VI.MAX, a randomized, double-blind, placebo-controlled trial of a combination of low-dose antioxidants (ascorbic acid, vitamin E, β-carotene, selenium, and zinc), conducted from 1994 to 2002. The study included 190 cases, among 4684 women aged 35–60 years at baseline, identified during a median of 11.3 years of follow-up (1994–2007). Participants completed a dietary record every 2 months, in which they declared all foods and beverages consumed during periods of 24 hours. These dietary records were randomly distributed between week and weekend days, and over seasons to take into account intra-individual variability. Dietary records from the first 2 years of follow-up were used in the study. Portion sizes were assessed using a validated picture booklet, and the amounts consumed from composite dishes were estimated using French recipes validated by food and nutrition professionals. Red meat consisted of fresh, minced, and frozen beef, veal, pork, and lamb. Processed meats were mostly pork and beef preserved by methods other than freezing, such as salting, smoking, marinating, air-drying, or heating, and included ham, bacon, sausages, blood sausages, liver pâté, salami, mortadella, tinned meat, and others. There was no association between baseline intake of either red meat or processed meat and breast cancer in the whole population. The relative risks for the top versus the bottom quartile of intake were 1.19 (95% CI, 0.79–1.80; P_trend = 0.3) for red meat (< 24.9 vs > 63.7 g/day) and 1.45 (95% CI, 0.92–2.27; P_trend = 0.03) for processed meat (< 16.4 vs > 43.5 g/day). However, processed meat intake was positively associated with breast cancer risk in the placebo group, but not in the treatment group. The relative risks for the highest compared with the lowest quartile of processed meat consumption were 2.46 (95% CI, 1.28–4.72; P_trend = 0.001) in the placebo group and 0.86 (95% CI, 0.45–1.63; P_trend = 0.7) in the antioxidant-supplemented group (P_interaction = 0.06). [The Working Group took note of the relatively small number of cases. No information was provided on the number of cases in each red meat intake category. Adjustment of lipid intake would be an overadjustment. Some reproductive factors were not adjusted for.]

Farvid et al. (2014) also evaluated early-adulthood total red meat intake and breast cancer in the NHS II. The study included 2830 cases, among 88 803 premenopausal women aged 26–45 years, identified during 20 years of follow-up. Diet was assessed by validated FFQ, with approximately 130 food items. The study found that a higher total red meat (i.e red meat and processed read meat) intake was associated with an elevated risk of breast cancer. The relative risk for the top (median, 1.50 servings/day) versus the bottom (median, 0.14 servings/day) quintile of intake was 1.22 (95% CI, 1.06–1.40; P_trend = 0.01). The association was similar by menopausal status, but not statistically significant. [The Working Group noted that the study was limited by the definition of red meat, which included processed meat. Earlier studies of the cohort by Cho et al. (2003) and Cho et al. (2006) were not evaluated.]

Farvid et al. (2015) also evaluated the association between adolescent total red meat intake and breast cancer risk in the NHS II. A subcohort of 44 231 women aged 33–52 years, who filled in a special 124-item FFQ about diet during high school, were followed up for 13 years, and 1132 breast cancer cases were documented. Total red meat intake included unprocessed red meat (hamburger, beef, lamb, pork, and meatloaf) and processed red meat items (hot dog, bacon, and other processed meats such as sausage, salami, and bologna). There was a positive association between adolescent total red meat intake and premenopausal breast cancer. The relative risk for the top (median, 2.43 servings/day) versus the bottom (median, 0.7 servings/day) quintile of total red meat intake was 1.43 (95% CI, 1.05–1.94; P_trend = 0.007). The positive association was similar, but significant only for processed meat (RR, 1.29; 95% CI, 0.98–1.70; P_trend = 0.02) when intakes of red meat and processed meat were evaluated separately. The association with premenopausal breast cancer was stronger among those with ER+/PR+ breast cancer than among those with ER–/PR– breast cancer; the relative risks per 1 serving/day of total red meat were 1.23 (95% CI, 1.06–1.44) for ER+/PR+ breast cancer and 1.18 (95% CI, 0.87–1.60) for ER–/PR– breast cancer. Haem iron intake was not associated with breast cancer risk. [The Working Group noted that the relative risks for breast cancer by quintile of processed meat and red meat intake in premenopausal, postmenopausal, and all women were reported in tables. A limitation was that the adolescent dietary intake was reported when women were 33–52 years of age. An earlier study by Linos et al. (2008) was not evaluated.]

2.6.2. Case–control studies

Case–control studies on the association between breast cancer and consumption of red meat (see Table 2.6.3, web only) or processed meat (see Table 2.6.4, web only) have been conducted in North America, Latin America, Europe, North Africa, and Asia (these tables are available online at: http://publications.iarc.fr/564). These studies are organized according to the definition of red meat or processed meat, and within these categories, by publication year and study design. Important potential confounders for breast cancer include age, alcohol intake, reproductive factors, use of postmenopausal hormones among postmenopausal women, family history of breast cancer, obesity, and energy intake. Studies that did not adjust for these covariates are noted. In addition, studies with low participation rates (< 50%) in cases or controls, or with large differences in the participation rates of cases and controls are noted because this may have led to selection bias.

Studies that met several exclusion criteria were considered to be uninformative for this evaluation and were not considered further. Studies that evaluated meat intake without providing data specifically for red meat or processed meat were excluded (e.g. Hirayama, 1978; Kinlen, 1982; Talamini et al., 1984; Kato et al., 1992; Malik et al., 1993; Holmberg et al., 1994; Trichopoulou et al., 1995; Núñez et al., 1996; Potischman et al., 1998; Han et al., 2004; Lee et al., 2004; Ko et al., 2013; Bessaoud et al., 2008; Dos Santos Silva et al., 2002; La Vecchia et al., 1987). Similarly, studies that evaluated breast cancer in relation to dietary patterns instead of evaluating red or processed meat were excluded (e.g. Cui et al., 2007; Wu et al., 2009; Cade et al., 2010; Cho et al., 2010; Ronco et al., 2010; Buck et al., 2011; Zhang et al., 2011; Bessaoud et al., 2012; Jordan et al., 2013; Mourouti et al., 2014; Pou et al., 2014). Other reasons for exclusion were small sample size (about < 100 breast cancer cases) (e.g. Phillips, 1975; Kikuchi et al., 1990; Ingram et al., 1991; Morales Suárez-Varela et al., 1998; Delfino et al., 2000; Lima et al., 2008; Di Pietro et al., 2007; Landa et al., 1994), and the availability of updated or more complete data from the same population (Lee et al., 1991; Levi et al., 1993; Ronco et al., 1996; Favero et al., 1998).

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2.7.1. Cohort studies

See Table 2.7.1 and Table 2.7.2 (web only; available at: http://publications.iarc.fr/564)

Six cohort studies were considered informative with respect to the association between cancer of the lung and meat intake. Unlike for other cancer sites, such as the colorectum, there were fewer studies available for the review of cancer of the lung. Therefore, the Working Group included most studies of lung cancer and red or processed meat, with exceptions as noted. The Working Group included one study investigating mortality; given the short survival of lung cancer patients, mortality is a reasonable surrogate for incidence. Balder et al. (2005) was excluded because it referred to a mixed category of “pork, processed meat, and potatoes”. The study by Knekt et al. (1994) was excluded because it only reported results for fried meat (did not specify if red or white).

Breslow et al. (2000) studied 20 195 individuals with dietary data from the 1987 National Health Interview Survey, who were then linked to the National Death Index. Baseline diet was assessed with a 59-item FFQ. Food groups, including total meat/poultry/fish, red meats, and processed meats, were analysed after adjustment for age, sex, BMI, smoking, and other variables, but not total energy. There were 158 deaths from lung cancer. Red meat intake was associated with lung cancer mortality. The relative risk was 1.6 (95% CI, 1.0–2.6; P_trend = 0.014) for the highest (6.6 servings/week) versus the lowest (0–2.3 servings/week) quartile. No association was found with processed meat (P_trend = 0.721). [The Working Group noted that this was a small study based on mortality, with a limited FFQ and no adjustment for total energy.]

Tasevska et al. (2009) studied 278 380 men and 189 596 women from the National Institutes of Health-AARP Diet and Health (NHI-AARP) study. Diet was assessed with a 124-item FFQ. Meat-cooking modalities were investigated, and the CHARRED database was used to estimate the intake of HAAs, benzo[a]pyrene (BaP), and haem iron. A high intake of red meat was associated with an increased risk of lung cancer in both men (HR, 1.22; 95% CI, 1.09–1.38; P_trend = 0.005) and women (HR, 1.13; 95% CI, 0.97–1.32; P_trend = 0.05) for the highest compared with the lowest category of intake. A high intake of processed meat increased the risk only in men (HR, 1.23; 95% CI, 1.10–1.37; P_trend = 0.003). In an analysis stratified by smoking status, never-smoking men and women had increased risks with red meat consumption that were not statistically significant. The hazard ratios for the 90th versus the 10th percentile were 1.19 (95% CI, 0.69–2.06; P_trend = 0.52) in men and 1.21 (95% CI, 0.76–1.94; P = 0.44) in women for red meat. The relative risk for the highest versus the lowest tertile of intake of well/very well-done meat was 1.20 (95% CI, 1.07–1.35; P_trend = 0.002), and for intake of MeIQx, it was 1.20 (95% CI, 1.04–1.38; P_trend = 0.04) in men. Haem iron intake for the highest compared with the lowest quintile was associated with an increased risk of lung carcinoma in both men (HR, 1.25; 95% CI, 1.07–1.45; P_trend = 0.02) and women (HR, 1.18; 95% CI, 0.99–1.42; P_trend = 0.002).

Linseisen et al. (2011) used the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, with 1822 incident lung cancers, exposure assessment based on a validated FFQ and 24-hour recall, and statistical analyses including adjustment for several smoking variables. With a continuous model, they found a statistically non-significant increase in risk of lung cancer. The relative risks were 1.06 (95% CI, 0.89–1.27) per 50 g increment of red meat and 1.13 (95% CI, 0.95–1.34) for the same amount of processed meat. Some subcohorts included health-conscious or vegetarian subjects [very large size].

Tasevska et al. (2011) used the Prostate, Lung, Colorectal and Ovarian (PLCO) cohort in which lung cancer screening was offered. There were 454 lung cancer cases in men and 328 in women. No information was given on response rates and losses to follow-up. No association was found with red meat or processed meat intake in men in multivariable modelling. Women showed slightly elevated relative risks with increasing quintiles of red meat intake (from ≤ 14.6 to > 42.5 g/1000 kcal): 1.33 (95% CI, 0.91–1.94), 1.60 (95% CI, 1.10–2.33), 1.24 (95% CI, 0.84–1.85), 1.30 (95% CI, 0.87–1.95), with no dose–response (P_trend = 0.65; adjusted for total energy intake and several other confounders, including smoking). [The Working Group noted that the study included both screened and non-screened arms, and the authors reported that associations were similar. There was accurate adjustment for smoking variables.]

Gnagnarella et al. (2013) invited asymptomatic volunteers aged 50 years or older who were current smokers or recent quitters, and had smoked at least 20 pack-years, to undergo annual screening with computed tomography. They assessed participants’ diet at baseline using a self-administered FFQ that included 188 food items and beverages. During a mean screening period of 5.7 years, 178 of 4336 participants were diagnosed with lung cancer. In the multivariable analysis, red meat consumption was associated with an increased risk of lung cancer [HR for quartile 4 vs quartile 1, 1.73; 95% CI, 1.15–2.61; P_trend = 0.003]. [The Working Group noted that this was a relatively small study of heavy smokers.]

Butler et al. (2013) published a study based on data from a prospective cohort study among Chinese in Singapore that included 1004 lung cancer cases. A 165-item FFQ was used. The relative risk for fried meat was 1.13 (95% CI, 0.98–1.31) for the second tertile and 1.09 (95% CI, 0.94–1.27) for the third tertile of intake, but it was not specified whether fried meat was red or white. The corresponding relative risks for adenocarcinomas were 1.31 (95% CI, 1.03–1.68) and 1.36 (95% CI, 1.06–1.74). Risk estimates for fried pork consumption separately showed no clear association. [The Working Group concluded that a limitation was that the fried meat definition included both white and red meat. The strengths were that the study used a validated FFQ, had a large sample size, and adequately controlled for smoking, with 70% of the cohort being non-smokers.]

2.7.2. Case–control studies

See Table 2.7.3 and Table 2.7.4 (web only; available at: http://publications.iarc.fr/564)

The Working Group identified 21 case–control studies on the association between lung cancer and red and processed meat consumption from the USA, Uruguay, Europe, China, and China, Hong Kong Special Administrative Region, India, Canada, Singapore, Pakistan, and Brazil. When there were multiple publications from the same study, only the most recent one was included. Most of these studies were not originally designed to assess meat consumption, and most of the available papers reported positive associations. The potential for reporting bias (i.e. reporting only statistically significant associations among the many associations that were investigated), therefore, needed to be considered in the evaluation of these findings.

The Working Group subsequently excluded eight case–control studies (most hospital-based) because the type of meat (red or white) was not specified (Suzuki et al., 1994; Phukan et al., 2014), the methods of control selection were unclear (Kubík et al., 2001; Shen et al., 2008; Chiu et al., 2010), the response rates were not given (Dosil-Díaz et al., 2007), or the information on adjustment for confounders was inadequate (Ganesh et al., 2011; Luqman et al., 2014). Brennan et al. (2000) was included, in spite of the lack of distinction between white and red meat, because it was one of the few studies to report estimates for non-smokers only.

Goodman et al. (1992) conducted a population-based study in Hawaii, USA, among 326 cases of histologically confirmed lung cancer and 865 controls. Exposure assessment was good, with an FFQ with 130 items. Results were inconsistent, with an increased risk for sausages, luncheon meat, and bacon in men (weaker and not statistically significant in women) and lack of association for red meat. A strong interaction was found with smoking, with odds ratios rising up to 11.8 (95% CI, 2.3–61.6) for smokers with > 70 pack-years of cigarettes consuming more than the median intake of sausages (men only for squamous cell carcinoma). There was also a statistically significant association with estimated nitrosamine intake. [The Working Group noted that the method of selection of controls changed during the conduction of the study. Strong odds ratios were based on the subgroup analysis.]

The study by Swanson et al. (1992) from China was based on a case–control design nested within an occupational population (a mining company) and a population-based study in a city. The response rate was very high. The accuracy of cancer ascertainment was uncertain, although the authors stated that it was based on pathological examinations. No association with meat intake (almost exclusively pork) was found. [The Working Group noted that there was a very small number of non-smoking cases.]

Sankaranarayanan et al. (1994) conducted a hospital-based study in India, based on 387 cases. Controls were relatives of patients or bystanders. Forty-five items were included in the dietary questionnaire. Strong but statistically unstable associations were reported for beef, with no dose–response. [The Working Group noted that the number of meat eaters in this study was small.]

Sinha et al. (1998) reported on a population-based study from the USA that included 593 cases and 628 controls, drawn from the drivers’ licences or health care financing rosters. [The selection of controls was unclear, particularly oversampling of smokers.] A 110-item Health Habits and History Questionnaire (HHHQ) with 15 items related to red meat was used to assess exposure. Information on cooking methods and doneness levels was also obtained. Only women were included. There were statistically significant increases in risk with 10 g/day increments in the consumption of all red meat, well-done red meat, and fried red meat. When comparing the 90th and 10th percentiles, lung cancer risk increased for all red meat (OR, 1.8; 95% CI, 1.2–2.7), for well-done red meat (OR, 1.5; 95% CI, 1.1–2.1), and for fried red meat (OR, 1.5; 95% CI, 1.1–2.0).

Brennan et al. (2000) conducted a multicentre, hospital-based case–control study in non-smokers (defined as having smoked < 400 cigarettes in a lifetime) in Europe with a large samples size (506 cases, 1045 controls); diseases in controls were not specified. There was no association with meat intake, except in small cell carcinomas. Odds ratios were 1.2 (95% CI, 0.3–4.5) and 1.6 (95% CI, 1.1–2.2) in increasing tertiles ( weekly/several times and weekly/daily vs never, respectively). [The Working Group noted that the study was informative because it provided data on non-smokers. However, no distinction between white and red meat was made, and no adjustment for second-hand smoke was made.]

Alavanja et al. (2001) conducted a population-based study in the USA, with 360 cases identified through the Surveillance, Epidemiology, and End Results (SEER) Program and 574 controls sampled from drivers’ licences and Medicare rosters (females only). A 70-item FFQ (NCI Block questionnaire) was used. Red meat was defined as hamburger, beef burritos, beef stew, pot pie, meatloaf, beef (fat unspecified), pork (fat unspecified), ham, lunchmeats, bacon, liver, sausage, or hot dogs. [The response rate, particularly in controls, was low.] The researchers found an association with increasing levels of red meat intake. Odds ratios were 1.7 (95% CI, 0.9–3.3) for 3.5–5.5 times/week, 2.0 (95% CI, 1.4–4.0) for 5.6–7.6 times/week, 2.5 (95% CI, 1.2–5.2) for 7.7–9.8 times/week, and 3.3 (95% CI, 1.7–7.6) for > 9.8 times/week (P_trend = 0.005). In addition, effect modification by histological type and smoking was considered. The odds ratios for red meat consumption were similar among adenocarcinoma cases (OR, 3.0; 95% CI, 1.1–7.9) and non-adenocarcinoma cases (OR, 3.2; 95% CI, 1.3–8.3), and among lifetime non-smokers and ex-smokers (OR, 2.8; 95% CI, 1.4–5.4) and current smokers (OR, 4.9; 95% CI, 1.1–22.3). [Red meat included processed meat.]

Hu et al. (2002) published the results of a population-based study in Canada in which controls were drawn from an insurance plan or random digit dialling. Only women who never smoked were included. A 70-item FFQ based on the NCI Block questionnaire was used. Overall, 161 cases and 483 controls were included, with a 1:3 case–control ratio. Modest associations were found with red meat (OR, 0.8 for second quartile, 2–3 servings/week; OR, 1.4. for third quartile, 3.1–5 servings/week; OR, 1.4 for fourth quartile, > 5 servings/week; none statistically significant). An increase in risk for processed red meat and bacon was not statistically significant, except for smoked meat (third tertile vs first tertile OR, 2.1; 95% CI, 1.1–4.0). Never-smokers were examined separately with the following results: for red meat, in increasing quartiles of servings/week, OR were 0.8 (95% CI, 0.4–1.5), 1.4 (95% CI, 0.7–2.6), and 1.4 (95% CI, 0.7–2.8), and for smoked meat, in increasing tertiles, 1.3 (95% CI, 0.8–2.3) and 2.1 (95% CI, 1.1–4.0). [The Working Group noted that the study size was small.]

Zatloukal et al. (2003) published the results of a study in the Czech Republic using spouses, relatives, and friends of hospital patients as controls. They found an association between lung cancer and increasing tertiles of intake of red meat, but only for histologies other than adenocarcinoma. The odds ratios were 1.54 (95% CI, 0.89–2.67) for weekly consumption and 1.81 (95% CI, 1.04–3.8) for daily consumption (P_trend = 0.04) [subgroup analysis noted].

Kubík et al. (2004) published the results of a hospital-based study in the Czech Republic among non-smoking women only (130 cases; 1022 controls were spouses, friends, or relatives of hospital patients). [Only nine food items were included in the dietary questionnaire.] They found an association with red meat (≥ 1 time/day to ≥ 1 time/week vs ≤ 1 time/week to > 1 time/month ; OR, 2.2; 95% CI, 1.07–4.51).

Lam et al. (2009) published a well-designed population-based study in Italy, with high response rates (87% cases, 72% controls) and large numbers (1903 cases, 2073 controls). Exposure assessment included a 58-item FFQ, with estimation of exposure to mutagens and detailed information on cooking practices. The researchers found increased odds ratios with increasing tertiles of red meat intake, 1.3 (95% CI, 1.1–1.6) and 1.8 (95% CI, 1.5–2.2). The odds ratios with increasing tertiles of processed meat intake were 1.3 (95% CI, 1.1–1.5) and 1.7 (95% CI, 1.4–2.1). The odds ratios for estimated intake of the mutagen PhIP were 1.1 (95% CI, 0.9–1.4) and 1.5 (95% CI, 1.2–1.8). Never-smokers were examined separately. For red meat, the odds ratios with increasing tertiles were 1.1 (95% CI, 0.7–2.0) for the second tertile and 2.4 (95% CI, 1.4–4.0) for the third tertile for red meat (P_trend = 0.001), and 1.5 (95% CI, 0.9–2.6) and 2.5 (95% CI, 1.5–4.2) for processed meat (P = 0.001). [The Working Group noted that adjustment for smoking was accurate and detailed.]

Concerning hospital-based studies, Aune et al. (2009) from Uruguay reported associations with the highest compared with the lowest quartile of intake of red meat (OR, 2.17; 95% CI, 1.52–3.10) and processed meat (OR, 1.7; 95% CI, 1.28–2.25). They also looked at beef and lamb separately, and associations were similar. Twin papers from Uruguay were published by De Stefani et al. (2009) and Deneo-Pellegrini et al. (2015). The first differed because exposure assessment was broader with estimation of exposure to mutagens, and the second was restricted to squamous cell carcinoma in men. In addition to finding results that were very similar to Aune et al. (2009), De Stefani et al. (2009) reported results for exposure to PhIP, assessed through a database compiled from the literature (Jakszyn et al., 2004). In increasing tertiles of exposure, the odds ratios for PhIP were 1.12 (95% CI, 0.80–1.56), 1.48 (95% CI, 1.05–2.07), and 2.16 (95% CI, 1.48–3.15). Deneo-Pellegrini et al. (2015) reported on squamous cell lung cancer, and the odds ratios were 1.82 (95% CI, 1.13–2.91) and 1.09 (95% CI, 0.73–1.64) for the highest versus the lowest tertiles of intake of red meat and processed meat, respectively.

Lim et al. (2011) published the results of a hospital-based study in Singapore (399 cases, 815 controls) with high response rates (81% cases, 85% controls), but only 18 meat-related items were included in the FFQ. There was no significant association with total meat, pork, or processed meat intake. However, there was a significant association with high-bacon consumption (OR, 1.51; 95% CI, 1.06–2.16).

2.7.3. Meta-analyses

Two meta-analyses of the association between lung cancer and consumption of red or processed meat were identified. Yang et al. (2012) included 23 case–control studies and 11 cohort studies identified via MEDLINE, Embase, and the Web of Science through 2011. The meta-relative risk for the highest compared with the lowest category of intake was significantly greater than unity for red meat (RR, 1.34; 95% CI, 1.18–1.52), but not for processed meat intake (RR, 1.06; 95% CI, 0.90–1.25). The association with red meat was observed in never-smokers (RR, 1.66; 95% CI, 1.31–2.11), and was robust in sensitivity analyses that took into account the study type and quality. In general, results for processed meat were weak or inconsistent. All estimates (including those for red meat) showed high heterogeneity, with highly significant P values (P < 0.001) and high I² levels. There was no evidence of publication bias.

The second meta-analysis was an extension of the previous one, and aimed to explore the dose–response relationships in more detail (Xue et al., 2014). Dose–response data were available from 11 studies for red meat and 11 studies for processed meat. The meta-relative risks were 1.35 (95% CI, 1.25–1.46) for red meat (per 120 g increment) and 1.20 (95% CI, 1.11–1.29) for processed meat (per 50 g increment). In general, estimates varied considerably by study design. In cohort studies, the relative risks for red meat and processed meat were 1.21 (95% CI, 1.14–1.28; P_{heterogeneity} = 0.7) and 1.09 (95% CI, 0.99–1.19; P_{heterogeneity} = 0.1), respectively, with higher estimates in case–control studies. In case–control studies and other subgroup analyses by region and sex, P values for heterogeneity were highly significant.

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2.8.1. Cohort studies

2.8.2. Case–control studies

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• Zhu HC, Yang X, Xu LP, Zhao LJ, Tao GZ, Zhang C, et al. Meat consumption is associated with esophageal cancer risk in a meat- and cancer-histological-type dependent manner. Dig Dis Sci. 2014;59(3):664–73. [PubMed: 24395380] [CrossRef]

2.9.1. Non-Hodgkin lymphoma

For studies on non-Hodgkin lymphoma, apart from the criteria previously mentioned for all cancers, the studies were also evaluated carefully in regard to the main confounders, including age, sex, and energy intake. Some studies additionally adjusted for occupational exposures (if available) or excluded participants with HIV infection, namely in case–control studies. The Working Group noted when studies did not meet the criteria.

2.9.2. Cancer of the liver (hepatocellular carcinoma)

2.9.3. Cancers of the gallbladder and biliary tract

2.9.4. Cancer of the testis

2.9.5. Cancer of the kidney

2.9.6. Cancer of the bladder

2.9.7. Cancer of the ovary

2.9.8. Cancer of the endometrium

2.9.9. Leukaemia

2.9.10. Cancer of the brain

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