Adherence to the 2018 World Cancer Research Fund (WCRF)/American Institute for Cancer Research (AICR) Cancer Prevention Recommendations and risk of 14 lifestyle-related cancers in the UK Biobank prospective cohort study | BMC Medicine

This is the first study to investigate associations between cancer risk in a UK cohort and adherence to the 2018 WCRF/AICR Cancer Prevention Recommendations assessed using a fully operationalised version of the standardised scoring system [4]. Further, it is the first to investigate associations between 2018 WCRF/AICR Score and the risk of all lifestyle-related cancers individually. To date, internationally, associations between adherence to the latest, 2018 version of the WCRF/AICR Cancer Prevention Recommendations (derived using various scoring systems including the 2018 WCRF/AICR Score) and cancer risk have been restricted to studies of prostate, breast, colorectal, lung, pancreatic, and uterine cancers and chronic lymphocytic leukaemia. Thus, we are the first to investigate associations between the 2018 WCRF/AICR Score and risks of kidney, bladder, ovarian, head and neck, oesophageal, stomach, liver and gallbladder cancers individually. Findings from studies that have investigated associations between the earlier 2007 version of the Cancer Prevention Recommendations and the incidence of multiple cancer sites have been summarised by Solans et al. [3].

All cancers combined

We found a significant inverse association between total adherence score and risk of all cancers combined equivalent to a 7% reduction in risk per 1-point increment in score when adjusting for age, sex, deprivation, ethnicity, and smoking status. Further, compared with those in the lowest score tertile (0–3.5 points), participants in the middle (3.75–4.25 points) and highest (4.5–7 points) score tertiles had an 8% and 16% lower risk of developing all cancers combined, respectively.

To our knowledge, only one other study [11] has investigated associations between adherence to the 2018 Cancer Prevention Recommendations and the risk of combined cancers overall using the 2018 WCRF/AICR Score. In the Swedish Mammograph Cohort and Cohort of Swedish Men which included 12,693 incident cancer cases over a 15-year follow-up, Kaluza and colleagues reported a 3% reduction in cancer risk per 1-point increment in score [11], which is considerably less than the 7% reduction observed in the present study. In addition, these authors reported a 12% lower cancer risk in participants in the highest score category (> 4 points) compared with those in the lowest category (0–2 points) [11]. This emphasises the need to examine these associations in different populations worldwide.

Breast cancer

We observed a 10% reduction in the risk of breast cancer per 1-unit increment in adherence score. The lowest risk of breast cancer was observed in participants with a total score between 5.75 and 7 points, corresponding to a HR between 0.54 and 0.60. Further, women in the highest score tertile (≥ 4.5 points) had an 18% lower risk of developing breast cancer compared with those scoring ≤ 3.5 points. To our knowledge, only three other studies have fully applied the standardised scoring system to assess associations between adherence to the 2018 Cancer Prevention Recommendations and breast cancer risk [5, 10, 19]. In the US NIH-AARP Diet and Health Study, which included post-menopausal women only, Korn and colleagues reported a reduction in risk per 1-point increase in score of 7–19%, depending on smoking status [10]. In a Spanish study of 10,930 women (including 119 incident breast cancers) with a median follow-up of 12 years, a non-significant trend for a lower risk of breast cancer in women with higher adherence scores was reported [5]. However, there was a 73% lower risk of post-menopausal breast cancer in women with maximum compliance (scoring > 5 points) compared with those with minimal compliance (scoring ≤ 3 points) [5]. In the South African Breast Cancer case–control study, Jacobs and colleagues reported a 46% lower risk of breast cancer in women with greater adherence (> 4.5 versus < 3.25 points) in post-menopausal, but not pre-menopausal, women [19]. Note that the latter study operationalised the eighth, optional component of the 2018 WCRF/AICR score regarding breastfeeding.

Two studies have used UK Biobank data to examine lifestyle and breast cancer risk but without assessing adherence to the Cancer Prevention Recommendations using the 2018 WCRF/AICR Score. One study explored associations between a modified ‘Healthy Lifestyle Index’ score, which included components of the scoring system, and breast cancer risk in 146,326 women [20]. Specifically, the score included physical activity, BMI, waist circumference, smoking, and the intake of fruits and vegetables, cereals and grains, and red and processed meat. Women in the highest healthy lifestyle score tertile had 22% and 31% lower risks of pre-menopausal and post-menopausal breast cancer, respectively. A further study calculated a ‘lifestyle score’, ranging from 0 to 6 points, and found an 8% reduction in risk of invasive breast cancer per 1-point increment in score [21]. However, these authors used dietary data collected using the baseline touchscreen questionnaire only, which does not allow for the assessment of the intake of UPFs, estimated ‘partial fibre’ intake only, and used a question on sugar avoidance as a proxy to assess adherence to the recommendation to ‘limit sugary drinks’ [21].

Colorectal cancer

We observed a 10% reduction in colorectal cancer risk per 1-point increment in score. Furthermore, participants in the middle and highest score tertiles had a 21% lower risk of developing colorectal cancer compared with those in the lowest score tertile. To our knowledge, only one other study, conducted in the USA, has assessed relationships between the risk of colorectal cancer and adherence to the Cancer Prevention Recommendations by fully operationalising the 2018 WCRF/AICR Score [10]. In participants who had never smoked, Korn and colleagues reported a 13% and 10% reduction in risk of colorectal cancer per 1-point increment in score in males and females, respectively [10]. Significant associations of a similar magnitude were also observed in former, but not current, smokers [10]. In the present study, following stratification according to baseline smoking status, associations between score and colorectal cancer risk were only statistically significant in UK Biobank participants who reported never smoking.

Four studies have investigated adherence to the 2018 WCRF/AICR Cancer Prevention Recommendations and colorectal cancer risk by devising their own scoring systems [6, 22,23,24]. Using data from the Spanish PREvencion con DIeta MEDiterranea (PREDIMED) cohort, Barrubes et al. assessed associations between adherence to the Cancer Prevention Recommendations in 7216 older men and women at increased cardiovascular risk [6]. This analysis used an alternative scoring system with different cut-offs from those proposed by Shams-White and colleagues [4]; for example, the researchers did not operationalise the waist circumference sub-component but instead assessed weight gain throughout adulthood using tertiles as cut-offs [6]. During a median follow-up time of 6 years, during which 97 colorectal cancer cases were identified, there was a 21% reduction in colorectal cancer risk per 1-point increment in adherence score. In the Nurses’ Health Study and the Health Professionals Follow-Up Study, Petimar and colleagues reported a 36% and 14% lower risk of colorectal cancer in men and women, respectively, in the highest versus the lowest adherence score quintile [22]. Similarly, in the other two studies which were conducted in the USA [23] and Morocco [24], greater adherence to the Cancer Prevention Recommendations was associated with lower colorectal cancer risk [24, 25]. The consistency of the patterns of relationships between adherence and colorectal cancer risk in different populations indicates the importance of public health messages about a healthy lifestyle—rather than individual aspects of lifestyle—for prevention of this cancer.

Risk of other cancers

To our knowledge, we are the first to report lower risks of kidney, oesophageal, ovarian, liver, and gallbladder cancers with greater adherence to the 2018 WCRF/AICR Cancer Prevention Recommendations. In the EPIC Study, Romaguera et al. reported 42% lower risk of oesophageal cancer, 29% lower risk of kidney cancer, and 15% lower risk of liver cancer in participants in the fourth and fifth highest categories (≥ 4 points) of a score used to assess adherence to the previous (2007) version of the WCRF/AICR Cancer Prevention Recommendations compared with those in the lowest score category (0–2 and 0–3 points for men and women, respectively) [25]. The WCRF/AICR have concluded that there is strong evidence for increased risk of oesophageal adenocarcinoma and of kidney, gallbladder, liver, and ovarian cancers with greater body fatness and for increased risk of liver cancer and of oesophageal squamous cell carcinoma with higher alcohol intake [2]. The evidence for the influence of additional lifestyle factors on these cancers is limited—for example, the WCRF/AICR report limited evidence for a protective effect of physical activity against liver and oesophageal cancers [2]. Because of the potential for cancer prevention, these findings warrant further investigation and confirmation in other populations.

Since mortality from pancreatic cancer is high and there is little possibility of secondary or tertiary prevention, studies which identify the role of potentially modifiable risk factors are important in terms of primary prevention. In a prospective cohort study in the USA, Zhang et al. observed a 33% lower pancreatic cancer risk in participants scoring ≥ 5 points on the adherence score compared with those scoring < 4 points, and a 14% reduction in pancreatic cancer risk per 1-point increment in score [9]. These findings are similar to those observed in our study (13% reduction in pancreatic cancer risk per 1-point increment in score). However, after adjusting for smoking status the association was only borderline significant (p = 0.056) in our study. Importantly, when we performed a sensitivity analysis using the date of the last completed valid 24-h dietary assessment as the time of study entry, we observed a 19% lower risk in pancreatic cancer per 1-point increment in score. The American study was of a similar size to the present study (95,962 participants) but included more pancreatic cancer cases (337 versus 213). Furthermore, although they assessed adherence using the 2018 WCRF/AICR Score, the authors included the optional eight component regarding breastfeeding (score range 0–8 points versus 0–7 points in the present study). The importance of breastfeeding in influencing pancreatic cancer risk is uncertain. The Norwegian Women and Cancer study reported an inverse linear relationship between cumulative breastfeeding duration and pancreatic cancer incidence [26], although no significant associations were found in a study in Japan [27].

The Spanish population-based case–control CAPLIFE study, which also fully operationalised the 2018 WCRF/AICR Score, reported a 19% reduction in risk of prostate cancer per 1-point increase in score, but there were no significant associations when investigating associations according to score tertiles [7]. We did not find associations between adherence score and prostate cancer incidence in the present study, despite including 1818 prostate cancer cases. Similarly, in the NIH-AARP Diet and Health Study which included 920 prostate cancer cases, adherence scores were not significantly associated with prostate cancer risk regardless of smoking status [10]. The evidence for associations between lifestyle and prostate cancer is limited, with evidence only for body fatness and risk of advanced prostate cancer.

Lastly, we were somewhat surprised by the increased risk of head and neck cancers with greater adherence score, although this was limited to analyses on the score as a continuous variable, after adjusting for smoking status. The explanation for this is not immediately obvious. It may be due to the fact that there are multiple (sub)sites within head and neck cancers which vary in their aetiology; in particular, cancers at some subsites are driven largely by exposure to human papillomavirus while others are heavily influenced by tobacco and alcohol exposure. Further analyses examining adherence and risk of cancers at different head and neck (sub)sites are warranted. Only one study has reported a reduced risk of oral cavity and pharyngeal cancers and laryngeal cancer with greater adherence to the previous (2007) version of the Cancer Prevention Recommendations using data from two Italian case–control studies [28].

Strengths and limitations

We are one of the few studies to fully operationalise the 2018 WCRF/AICR Score to assess adherence to the 2018 WCRF/AICR Cancer Prevention Recommendations [4, 29], allowing for comparability across studies, and we are the first to do so for a UK-based prospective cohort study. Moreover, as encouraged by the score creators, we applied national cut-offs to assess adherence to the recommendation to limit alcohol consumption. In addition, we ran sensitivity analyses using a score derived with the original cut-offs to assess adherence to the alcohol recommendation, based on US guidelines. More generally, we conducted a series of sensitivity analyses around the multivariable models; the results of these largely followed a similar pattern as to the primary analyses, suggesting our findings are robust.

A limitation of our study is that the UK Biobank cohort is not fully representative of the general population in the UK; participants were older, more often female and less socioeconomically deprived, and had ‘healthier’ lifestyles (less likely to have obesity and to smoke, and consumed less alcohol) [30]. Although mean adherence score for participants in the UK Biobank may be higher than that for the general population, our findings on comparisons of different levels of adherence should be generalisable. Further, the characteristics of the UK Biobank participants with sufficient data to allow us to derive a total score, included in the present study, are broadly similar to the rest of the UK Biobank participants, including the proportions of males and females and smoking status [31]. Nonetheless, we adjusted for these as potential confounding factors in our analyses. We carefully assessed the covariates to be included in our statistical models, by testing potential confounders to be added to the statistical models individually, as also described by van Zutphen and colleagues [32]. Nonetheless, we ran an additional model which included potential confounders such as education, multimorbidity, and for female cancers, female-related factors such as contraceptive use, and found that our results were largely unchanged with the exception of associations between the score and risk of oesophageal, ovarian, and liver cancers which were somewhat attenuated and no longer reached statistical significance. As with any such study, our analyses may be subject to residual or unmeasured confounders. We did not include cancer screening as a potential confounder as this variable is likely to be of questionable quality and to have different meanings for different cancers at different times. For example, the screening programmes started at different times (colorectal cancer screening in England began for people aged 60–69 in 2006), and analysis of the first 2.6 million invitations to participate in England shows that uptake was only 54% and that there were considerable inequalities in uptake in ethnically diverse areas and a striking gradient by socioeconomic status [33]. Moreover, whether self-report of having been screened is likely to have a direct influence on adherence is unclear. Lastly, a limitation of the data on smoking status is that this was self-reported at baseline and does not provide information on smoking intensity or the timing of when former smokers quit.

We applied robust methodology to operationalise the 2018 WCRF/AICR Score and to define the participants to be included in our study, including only participants who had completed at least two 24-h dietary assessments. However, this meant that we significantly reduced the cohort size. One of the consequences of this was that, for some cancers, we do not have a large number of cases, limiting our statistical power and resulting in wide CIs. Nonetheless, we are the first to investigate associations between adherence score and the risk of less common cancers including ovarian, stomach, and liver cancers. Further, we conducted a landmark analysis to minimise the effect of reverse causation by excluding cancer cases in the first 2 years of follow-up. However, the results should be interpreted with caution as, although we investigated associations with multiple cancers and have conducted a range of sensitivity analyses, we did not choose a priori to adjust for multiple testing [34].

The dietary and physical activity data used to operationalise the 2018 WCRF/AICR Score were collected using self-reported questionnaires, which may be prone to misreporting. However, estimates of energy and nutrient intake obtained from the Oxford WebQ online 24-h dietary questionnaire that was used to collect dietary data in UK Biobank correlated well with objective biomarkers for protein, potassium, and total sugar intake and total energy expenditure estimated by accelerometry [35]. Likewise, self-report physical activity data showed similar relationships with morbidity and mortality outcomes in UK Biobank to those observed using objective measures of physical activity [36]. Estimating habitual dietary intake is challenging and there is no ‘gold standard’ methodology. We have adopted an approach that is used widely in epidemiological studies to estimate habitual dietary intake using means of the completed 24-h dietary assessments, and included only participants who completed at least two Oxford WebQs—the latter criterion was applied because a single 24-h dietary assessment is less likely to represent long-term (habitual) dietary intake. In the UK Biobank, Carter and colleagues have concluded that taking the mean of at least two 24-h dietary assessments may be similar to FFQs for capturing longer-term dietary intakes [37], and Bradbury and colleagues have reported that dietary intake stayed relatively stable during 4 years of follow-up [38]. Further, the Oxford WebQ used for the 24-h dietary assessments has been recently validated and is considered to perform well in estimating dietary intake [35, 39]. In addition, when we performed a sensitivity analysis setting the date of the last completed valid 24-h dietary assessment as the time of study entry (to address potential concerns around immortal time bias), associations between the score, both as a continuous variable and as score tertiles, and cancer incidence were similar in terms of pattern, magnitude effect estimates, and statistical significance; in addition, a significant inverse association between total score and risk of pancreatic cancer was observed. It should be noted that UK Biobank participants who completed at least one 24-h dietary assessment were more likely to be women, older, of white ethnic background, less deprived, and more educated compared with non-responders, and those who completed multiple assessments were also more likely to be White, older, and more highly educated compared with those who only complete one [40].