Diet, Nutrition, Physical Activity and Cancer: a Global Perpective

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1 Diet, Nutrition, Physical Activity and Cancer: a Global Perspective A summary of the Third Expert Report

2 Cover illustration: Estimated incidence (per 100,000 persons per year) of all cancers (excluding non-melanoma skin cancer) in men and women, worldwide, in 2012 ≥ 244.2 174.3–244.2 1 37. 6 –174 . 3 101.6–137.6 < 101.6 No data/not applicable Data source: GLOBOCAN 2012 Map production: International Agency for Research on Cancer (http://gco.iarc.fr/today) World Health Organization

3 Special thanks are due to Martin Wiseman and Rachel Thompson , for their assiduous and indispensable contribution to this report and to the Continuous Update Project as a whole, and to Kate Allen for her exceptional leadership of the project and the team behind it.

4 How to cite the 2018 Third Expert Report: World Cancer Research Fund/American Institute for Cancer Research. Diet, Nutrition, Physical Activity and Cancer: a Global Perspective. Continuous Update Project Expert Report 2018. Available at dietandcancerreport.org © 2018 World Cancer Research Fund International All rights reserved Readers may make use of the text and graphics in this Report for teaching and personal purposes, provided they give credit to World Cancer Research Fund and American Institute for Cancer Research. ISBN (print): 978-1-912259-46-5 ISBN (pdf): 978-1-912259-47-2

5 Diet, Nutrition, Physical Activity and Cancer: a Global Perspective A summary of the Third Expert Report

6 Preface The World Cancer Research Fund (WCRF) and the American Institute for Cancer Research (AICR) can be credited with great foresight and perspicacity in setting an ambition over 25 years ago to better define the relationship between diet, nutrition and physical activity, and cancer. Against a seemingly impossible challenge, their perseverance to progressively untangle a complex series of inter- relationships has been extraordinary. Among a number of players seeking to better understand the factors that account for chronic non-communicable diseases, WCRF and AICR have identified a special need within a unique space. This report marks the most recent contribution in this remarkable journey and sets the stage for a further agenda that likely will see substantial impact on the prevention of cancer, which is set to become the most common affliction across the globe. The First Expert Report, published in 1997, was informed by a body of evidence that was based very much upon anecdotal and ecological experience. It was generally considered that this evidence was not strong and for many not sufficiently persuasive to command wide agreement. It did however help identify a need and set the task of collating and interpreting a literature that at best could be considered contentious. The difficulties were clear in that untangling any relationship was a far from simple task, given the multiple cancer sites and many varied exposures that of themselves were poorly characterised. The evidence tended to be fragmentary and difficult to interpret with confidence, given the long period of time over which the exposure had to operate before the evident appearance of a disease. Drawing a secure relationship between the two was inherently testing. This early experience was drawn on directly in preparation for the second report in 2007. For this, major emphasis was placed upon the need to organise the evidence using a structured approach and for this evidence to be systematically interrogated, thereby giving greater security to the conclusions and recommendations. Further, the participation internationally of a wide scientific community knowledgeable in the range of considerations of relevance ensured that the different perspectives and emphases could be embraced to resolve major differences of opinion. Thus, the interpretation was more secure than had been achieved previously and commanded wide respect. The 2007 Second Expert Report set a landmark and standard. Most importantly it clarified the value of a structured process for the collection and review of the available evidence thereby facilitating our ability to arrive at secure judgements with confidence. Further, it defined with greater clarity the nature and extent of what was known with confidence, and what was not known but of seeming importance. Of itself, this helped to direct attention to focus on the nature of the research that needed to be done. This has acted as a stimulus to many others who by organising their work and research within a common framework enable direct comparison, add value to each other and ensure that the whole is greater than the sum of the parts. a Global Perspective 4 Diet, Nutrition, Physical Activity and Cancer:

7 The creation of and support for the Continuous Update Project (CUP) during the last ten years marks a further remarkable commitment to a reliable process for the capturing of all relevant new evidence and enabling its up-to-date interrogation in ‘real time’. Because the CUP has embedded the value of a structured and systematic approach, it has continued to enable scientists from disparate backgrounds to share knowledge and reach agreed interpretation. The increased number of cohort studies and the better quality of evidence has informed the reflections of the CUP. The recommendations made today are very securely based. This has considerable value in presenting to policymakers and the wider public a consistent message of what can be done with confidence to prevent cancer. It also raises the challenge of how to better understand what people who have already experienced cancer might do to improve their life. There has been a progressive need to identify the factors that account for variability in risk and the response to treatment. Out of this concern for people living with cancer has emerged the considerable opportunities for deeper understanding offered by studies with a focus on secondary prevention and a clearer understanding of the underlying biological mechanisms. The relatively simple statements that emerge as recommendations represent a massive commitment of effort from many people within a highly skilled organisation. I would specifically like to show appreciation to those who have given their time readily to act as peer reviewers or have participated in the Expert Panel. The way the judgements have been made, through a shared interactive process in which depth of experience has been used to assess nuanced considerations, has been exceptional. The Panel’s task was made possible only because of the outstanding quality of the material that they were given to consider. This was completely dependent upon the quality of the CUP team at Imperial College London, and the management of this by the scientific Secretariat at WCRF and AICR. The ongoing infrastructural support from WCRF and AICR, which allowed the space and time for careful, considered reflection in a conducive environment, is a valued and remarkable commitment from a charity. Together this community of people have given their time and shared effort to arrive at a series of recommendations which we believe to be extremely robust and of relevance across the globe. We anticipate that the recommendations will inform policy, advice and practice. Further, they help set the stage for the next generation of enquiry in which a deeper understanding of mechanisms, and experience from better structured approaches to nutrition care in people with cancer, will enable ever greater ability to prevent and treat the disorder. Thereby, this will justify the trust placed in science from the many who in one way or another have supported the work of WCRF and AICR. All who have enabled and participated in this process deserve our sincere and heartfelt thanks. The work has been carried out with the good grace, strong commitment, and endless good humour and persistence necessary for completing a difficult and complex task. The reward for this effort is in the knowledge that the current recommendations, if followed, will ensure less risk of cancer and better health for many. Alan Jackson CUP Panel Chair 2018 5 A summary of the Third Expert Report

8 Contents 4 Preface Introduction 7 1. Diet, nutrition, physical activity and the cancer process 15 2. Judging the evidence 31 3. The evidence for cancer risk: a summary matrix 37 4. Survivors of breast and other cancers 39 5. Recommendations and public health and policy implications 43 6. Changes since the 2007 Second Expert Report 79 7. 83 Future research directions Conclusions 87 Acknowledgements 89 Abbreviations 95 Glossary 96 References 108 Our Cancer Prevention Recommendations 113 Key References to the different parts of the full Third Expert Report, available online at dietandcancerreport.org , are highlighted in purple . References to other sections in this Summary are highlighted in bold . a Global Perspective 6 Diet, Nutrition, Physical Activity and Cancer:

9 Introduction The Third Expert Report, including this Summary, will help people who are keen The Third Expert Report to know how to prevent cancer and improve survival after a diagnosis. It may be The Third Expert Report, Diet, Nutrition, Physical particularly useful to: , from Activity and Cancer: a Global Perspective World Cancer Research Fund and American archers Rese Institute for Cancer Research (see Box 1 ) brings ...when studying specific cancers together the very latest research, findings and and for guiding plans for future Cancer Prevention Recommendations from the studies. Continuous Update Project (CUP) – see Box 2 . Medical and health professionals . ..by providing reliable, up-to-date The Third Expert Report builds on the recommendations on preventing groundbreaking achievements of the First and and surviving cancer to share with Second Expert Reports, published in 1997 and patients. 2007 respectively. Like its predecessors, the Third Expert Report provides a comprehensive Policymakers analysis, using the most meticulous of methods, ...when setting public health goals and implementing policies of the worldwide body of evidence on preventing that prioritise cancer prevention and surviving cancer through diet, nutrition and and help people to follow the physical activity, and presents the latest global Recommendations. Cancer Prevention Recommendations. Civil society organisations, including cancer organisations ..when benchmarking progress and . holding governments to account. The media ...by providing authoritative and trusted information on cancer prevention and a source of comment. People looking to reduce their risk of cancer or live well after a diagnosis ...the Recommendations together constitute a blueprint for reducing cancer risk through changing dietary patterns, reducing alcohol consumption, increasing physical activity, and achieving and maintaining a healthy body weight – including after a diagnosis of cancer. 2018 7 A summary of the Third Expert Report

10 The entire contents of the Third Expert Report, Newly published studies will continue to be added including this Summary, are freely available to the CUP evidence database and reviewed as online at dietandcancerreport.org . For an outline part of the ongoing CUP. In between the Expert of the contents, including how this Summary Reports, regular reports of the evidence and the and the online full report relate to each other, CUP Expert Panel’s conclusions are published. Table 1 (pages 10 to 11). This please see The Cancer Prevention Recommendations are Summary has been produced to provide reviewed and updated at regular intervals, based . an overview of the full online report on the latest evidence. Box 1: World Cancer Research Fund and American Institute for Cancer Research (WCRF/AICR) What we do We investigate the causes of cancer and help people to understand what they can do to prevent it as well as improve survival and quality of life after a cancer diagnosis. How we do this We fund scientific research into We give people practical, easy-to- understand advice about how to the links between cancer and lifestyle, particularly diet, nutrition reduce their risk of cancer. and physical activity. We promote collaboration between the nutrition and cancer research We analyse all the research in this area from around the world to ensure communities, and work with our messages are current and based governments and decision-makers on the most accurate evidence. to influence policy. a Global Perspective 8 Diet, Nutrition, Physical Activity and Cancer:

11 Box 2: The Continuous Update Project (CUP) The Continuous Update Project (CUP) is a rigorous, systematic and ongoing programme to gather, present, analyse and judge the global research on how diet, nutrition and physical activity affect cancer risk and survival, and to make Cancer Prevention Recommendations. Among experts worldwide, the CUP is a trusted, authoritative scientific resource which underpins current dietary guidelines and helps inform policy on cancer prevention and survival. Scientific research from around the world is continually added to the CUP’s unique database, which is held and systematically reviewed by a team of scientists at Imperial College London. This invaluable database is available to researchers on request. An independent multi-disciplinary panel of experts, the CUP Panel, carries out ongoing evaluations of Section 5: this evidence and uses its findings to update the Cancer Prevention Recommendations (see in this Summary). Recommendations and public health and policy implications Through this process, the CUP ensures that everyone, including scientists, policymakers, health professionals and members of the public, has access to the most up-to-date information on how to reduce the risk of developing cancer. The CUP also helps to identify priority areas for future research. The CUP is led and managed by World Cancer Research Fund International in partnership with the American Institute for Cancer Research, on behalf of World Cancer Research Fund UK, Wereld Kanker Onderzoek Fonds and World Cancer Research Fund HK. For more information on the robust approach taken in the CUP, see Section 2: Judging the evidence in this Summary. Continuous Update Project The process we use to analyse worldwide research Prepare protocols Draw conclusions Use Panel conclusions One central Conduct systematic from the and Cancer Prevention database reviews, analyse External review evidence Recommendations for cancer of protocols meta-data and to make public health Review Cancer prevention and reports update central recommendations and Prevention research database set research priorities Recommendations Prepare reports Scientists at Imperial College London CUP Panel Peer reviewers World Cancer Research collate the worldwide evidence (cancer experts from Fund Network around the world) with support from WCRF/ AICR Secretariat THIRD SECOND EXPERT EXPERT 2018 2007 CONTINUOUS UPDATE PROJECT REPORT REPORT 2018 9 A summary of the Third Expert Report

12 Table 1: Contents of the Third Expert Report and this Summary Abbreviated information from The full Third Expert Report, Diet, Nutrition, Physical Activity and Cancer: different parts of the Third a Global Perspective , is available online at dietandcancerreport.org Expert Report is available in this Summary as listed below: It comprises the components listed below: This publication is the Summary A summary of the Third Expert Report of the Third Expert Report. The Overview of the whole report, with a particular focus on the Cancer Summary is available online at Prevention Recommendations and on public health and policy implications. dietandcancerreport.org and can See right column. also be ordered in print. Cancer trends Not included in this Summary. Cancer statistics (available online only). The cancer process Section 1: Diet, nutrition, Summarises the wealth of evidence on how diet, nutrition and physical physical activity and the activity can influence the biological processes that underpin the cancer process development and progression of cancer. Judging the evidence Outlines the rationale and methodology of the CUP, describing the rigorous Section 2: Judging the evidence scientific processes involved in gathering, presenting, assessing and judging evidence. Exposures sections Collating evidence and judgements by exposure Each of the 10 exposure sections covers definitions and background information, issues relating to interpretation of the evidence, the evidence itself (from epidemiological studies featured in CUP systematic literature reviews and from research into biological mechanisms) and judgements on the evidence. Wholegrains, vegetables and fruit and the risk of cancer • The evidence for Section 3: Meat, fish and dairy products and the risk of cancer • cancer risk: a summary matrix Preservation and processing of foods and the risk of cancer • Non-alcoholic drinks and the risk of cancer • Alcoholic drinks and the risk of cancer • Other dietary exposures and the risk of cancer • Physical activity and the risk of cancer • Body fatness and weight gain and the risk of cancer • Height and birthweight and the risk of cancer • Lactation and the risk of cancer • a Global Perspective 10 Diet, Nutrition, Physical Activity and Cancer:

13 Abbreviated information from The full Third Expert Report, Diet, Nutrition, Physical Activity and Cancer: different parts of the Third , is available online at dietandcancerreport.org a Global Perspective Expert Report is available in this Summary as listed below: It comprises the components listed below: CUP cancer reports and systematic literature reviews (SLRs) Collating evidence and judgements by cancer CUP cancer reports, which summarise the CUP systematic literature reviews, focus on a particular cancer site, covering trends in incidence and survival, pathogenesis, other established causes, methodology, issues relating to interpretation of the evidence, the evidence itself (from epidemiological studies featured in CUP systematic literature reviews and from research into biological mechanisms) and judgements on the evidence. Diet, nutrition, physical activity and: Section 3: The evidence for breast cancer cancers of the mouth, • • cancer risk: a summary matrix pharynx and larynx ovarian cancer • 1 nasopharyngeal cancer • endometrial cancer • 2 oesophageal cancer • cervical cancer • lung cancer • prostate cancer • stomach cancer • kidney cancer • pancreatic cancer • bladder cancer • 1 gallbladder cancer • skin cancer • liver cancer • breast cancer survivors • colorectal cancer • Diet, nutrition and physical activity: Energy balance and 1 The evidence for Section 3: body fatness cancer risk: a summary matrix Presents information, evidence and judgements on exposures that increase or decrease the risk of weight gain, overweight and obesity. Survivors of breast and other cancers Presents information on current knowledge of the importance of diet, Survivors of breast Section 4: nutrition and physical activity for cancer survivors, with a particular and other cancers emphasis on breast cancer. Also includes current advice and research priorities. Recommendations and public health and policy implications Presents the latest Cancer Prevention Recommendations, with information Recommendations Section 5: on the reasons behind each Recommendation. Also includes other findings and public health and policy of the CUP relating to regional and special circumstances, as well as public implications health and policy implications, along with a new policy framework. Changes since the 2007 Second Expert Report Changes since the Section 6: Important shifts in emphasis since the 2007 Second Expert Report 2007 Second Expert Report (webpage only). Section 7: Future research directions Future research Outlines areas where further research is needed. directions 1 Systematic literature review available now; report not yet published. 2 Systematic literature review available now; no report being published. 2018 11 A summary of the Third Expert Report

14 The Recommendations for Regional and special circumstances Cancer Prevention Some findings of the CUP are not suitable The Recommendations for Cancer Prevention for inclusion in the global Recommendations featured in the Recommendations and public even though evidence is judged to be strong. health and policy implications¹ part of the Third For example, the evidence may relate to foods Expert Report and in Section 5 of this Summary or drinks that are relevant only in discrete are based on the findings of the CUP – a rigorous geographical locations. These findings are systematic review of the evidence relating diet, Section 5.2: Regional and special presented in nutrition and physical activity to the incidence . Where appropriate, locally circumstances of cancer, and outcomes after a diagnosis, as applicable actions are recommended. well as an expert review of biological pathways (mechanisms) that could plausibly explain links Acknowledging the ‘causes of the between exposures and cancer. causes’ of disease The Recommendations take the form of a The goal of the Recommendations is to help series of general statements that constitute people make healthy choices in their daily a comprehensive package of behaviours lives to reduce the risk of cancer and other that, when taken together, promote a healthy non-communicable diseases (NCDs) and to pattern of diet and physical activity to reduce be beneficial for cancer survivors. cancer risk, to be used by individuals, health professionals, communities and policymakers, However, simply informing people of lifestyle as well as the media. factors that cause, or protect against, cancer and making recommendations about healthy A significant body of evidence (from large behaviours are by themselves insufficient to population studies) has accumulated since bring about substantial, sustained changes the 2007 Second Expert Report showing that in behaviour. following a dietary pattern close to the 2007 WCRF Cancer Prevention Recommendations Although people’s choices are influenced by reduces the risk of new cancer cases, dying their knowledge, attitudes and beliefs, these are from cancer and dying from all causes poor predictors of behaviour. Much behaviour [1–3]. These findings demonstrate that the is not the result of active choice but is instead Recommendations work in real-life settings. a passive reflection of social norms and wider upstream factors (the ‘causes of the causes’ of disease). These may be social or economic, or relate to the physical or other environment, and may operate at local, national or global levels. 1 The Recommendations and public health and policy implications part of the Third Expert Report is available online at wcrf.org/cancer-prevention-recommendations a Global Perspective 12 Diet, Nutrition, Physical Activity and Cancer:

15 expensive, treatment of cancer is not always The importance of public health policy successful and many treatment options are unavailable in low- and middle-income countries. Governments have a prime responsibility, in protecting the health of their citizens, to create The economic costs of cancer, as well as the environments that are conducive to health. financial burden of treating other NCDs, pose a significant challenge to patients, families, The effectiveness of efforts to change diet communities and governments around the world, and physical activity depends substantially especially in low- and middle-income countries on policies that influence the upstream factors facing multiple burdens of disease [11]. and social norms that are the main determinants of people’s behaviour. The prevention of cancer depends on creating an environment Many cases of cancer can be prevented that encourages lifelong healthy eating and a physically active lifestyle. Public health Cancer can affect anyone, but some people are policies that prioritise prevention, in the form at higher risk than others. Although some risk of laws, regulations and guidelines, are critical factors, such as inherited mutations, are fixed, Section 5.3. Public health and policy (see a range of modifiable lifestyle and environmental in this Summary). implications factors can have a strong influence on cancer risk, meaning many cases of cancer are preventable. Between 30 and 50 per cent of all The rising burden of cancer – a global issue cancer cases are estimated to be preventable through healthy lifestyles and avoiding exposure Cancer causes one in eight deaths worldwide [4] to occupational carcinogens, environmental and has overtaken cardiovascular disease (CVD) pollution and certain long-term infections [12]. as the leading cause of death in many parts of the world [5, 6]. The global cancer burden is Avoiding tobacco in any form, together with expected to increase to 21.7 million new cases appropriate diet, nutrition and physical activity, and 13 million deaths by 2030, mainly owing and maintaining a healthy weight, have the to an ageing population [4]. Incidence rates of potential over time to reduce much of the cancer vary widely by country, with total cancer global burden of cancer. However, with current rates highest in high-income countries [7]. trends towards decreased physical activity and increased body fatness, the global burden of More people are living with and surviving cancer cancer can be expected to continue to rise than ever before, at least in part because of until these issues are addressed, especially earlier detection and the increasing success given projections of an ageing global population. rates of treatment for several cancers [8]. If current trends continue, overweight and obesity Globally, in 2012, an estimated 32.6 million are likely to overtake smoking as the number people were living with cancer [9]. one risk factor for cancer. The overall economic cost of cancer is For information on how cancer develops, and the astonishing: globally, the total cost of cancer influence of diet, nutrition and physical activity, in 2030, including direct medical costs, non- see Section 1: Diet, nutrition, physical activity medical costs and income losses, is projected in this Summary. and the cancer process to be US$458 billion [10]. As well as being 2018 13 A summary of the Third Expert Report

16 Prioritising prevention Wider benefits of cancer prevention: non-communicable diseases and the The case for prioritising the prevention of cancer environment is strong: cancer can take a heavy personal Trends in cancer rates are part of a broader toll on those affected, and the global burden global phenomenon of increases in NCDs, of cancer is high and rising, yet many cases of including cancer, diabetes and chronic respiratory cancer are preventable. What is more, preventing disease and, at least in low- and middle- cancer has additional benefits both for other income countries, CVDs. Different NCDs share common NCDs and even for the environment. common underlying risk factors including diet, Prevention of additional cancers and other overweight and obesity, physical inactivity, alcohol NCDs remains important after a diagnosis of consumption, tobacco use and certain long-term cancer, hence the Recommendation for cancer ). Helicobacter pylori infections (for example, survivors – people who have been diagnosed Therefore, approaches to preventing cancer with cancer, including those who have recovered can provide benefits across a range of NCDs. Section 4: Survivors the disease. (See from Moreover, it is increasingly recognised that of breast and other cancers and Section 5.1: policy actions conducive to health are consonant Recommendations for Cancer Prevention in with those needed to create a sustainable this Summar y.) ecological environment. By providing a comprehensive analysis of the worldwide body of evidence on preventing and surviving cancer through diet, nutrition and physical activity, and presenting the latest global Cancer Prevention Recommendations, the Third Expert Report (including this Summary) ensures that governments, civil society and individuals are equipped with the knowledge needed to prioritise cancer prevention and reduce the number of deaths from preventable cancers. a Global Perspective 14 Diet, Nutrition, Physical Activity and Cancer:

17 Diet, nutrition, physical activity 1 and the cancer process 1.1 16 What is cancer and how does it develop? 24 1.2 Body fatness and the hallmarks of cancer 1.3 27 Dietary exposures and the hallmarks of cancer 1.4 Physical activity and height and the hallmarks of cancer 28 1.5 Summary 29 For further information, see the more detailed The cancer process part of the Third Expert Report available online at wcrf.org/cancer-process

18 1.1.1 Cancer develops from rogue cells, 1.1 What is cancer and how does with genetic changes, that acquire capabilities it develop? known as the ‘hallmarks of cancer’ This section summarises the wealth of evidence There are several hundred types of cancer, arising on how diet, nutrition and physical activity (see from different tissues. Even tumours arising from ) can influence the biological processes Box 3 the same tissue are increasingly recognised that underpin the development and progression as comprising several different subtypes. What of cancer. Some of the more technical terms characterises cancer is a shared constellation that are not explained here are included in of abnormal cell behaviours, such as rapid cell the . Glossary division and invasion of surrounding tissue, which are linked to changes in DNA. To help explain what cancer is, how it develops, and how nutrition and physical Cancer develops when the normal processes activity influence this, some key concepts that control cell behaviour fail and a rogue cell . Sections 1.1.1 to 1.1.6 are outlined in becomes the progenitor of a group of cells that share its abnormal behaviours or capabilities. This generally results from accumulation of genetic damage in cells over time (see ). Box 4 The cancer cell is a critical part of a tumour but only one of several important types of cell that Box 5 ). create the tumour microenvironment (see Box 3: Diet, nutrition, physical activity and body fatness Nutrition is the set of integrated processes by which cells, tissues, organs and indeed a whole organism acquire the energy and nutrients needed to function normally and have a normal structure. Nutrition is important throughout life, allowing an organism to grow, develop and function according to the template defined by the genetic code in the organism’s DNA. Ultimately, all the energy and nutrients needed for the life-sustaining biochemical reactions that take place in an organism – for metabolism – come from the diet. Some, known as essential nutrients, must be consumed ready-made; the body can synthesise others from various components of the diet. The diet also contains many substances that are not nutrients (not necessary for metabolism) but can nevertheless influence metabolic processes. These include common chemicals such as phytochemicals, dietary fibre and caffeine, as well as some harmful substances such as arsenic. Physical activity is any movement using skeletal muscle. It is more than just exercise; it also includes everyday activities such as standing, walking, domestic work and even fidgeting. Appropriate physical activity creates a metabolic environment in the body that reduces susceptibility to some cancers. The amount and type of physical activity can influence the body’s overall metabolic state, as well as total requirements for energy, which in turn can impact on the amount of food (and nutrients) that can be consumed without storing excess energy as fat. Excess energy intake that is not balanced by physical activity leads to positive energy balance and ultimately weight gain and higher body fatness. When we talk about nutrition in this report this includes body composition which encompasses body fatness. a Global Perspective 16 Diet, Nutrition, Physical Activity and Cancer:

19 Box 4: Genetic damage and cancer The rogue capabilities of cancer cells generally result from the accumulation of genetic damage – to cells’ DNA – over time. This damage tends to involve multiple mutations and epigenetic changes. Mutations are permanent changes to the DNA sequence, which are inherited by daughter cells when cells divide. Epigenetic changes affect the structure of DNA in other ways (for example, extra methyl groups may be added). These changes, while reversible, can still be passed on when cells divide. Mutations can have potentially beneficial effects, which underpins the possibility of evolution by natural selection. Some are neutral. Others, like those linked to cancer, are harmful. A mutation may lead to the production of a protein that functions abnormally, or not at all, or to changes in the amount of protein that is produced – including the complete failure of a gene to produce a protein. Normal cells use epigenetic modifications to regulate gene expression – to control which genes are turned on and off. Patterns of gene expression are crucial to determining the structure of all cells, and how they behave. Control over the pattern of gene expression enables the capabilities of cells to change over time during early development and allows cells to specialise. Although all healthy cells within an organism carry the same genetic code in their DNA, specialised cells have a unique appearance and set of capabilities because they have a particular set of functioning genes, controlled by epigenetic influences. Both the genetic and epigenetic changes that cancer cells accumulate can alter gene expression (see ) in ways that enable the cells to acquire the capabilities known as the hallmarks of cancer. below Please note: this figure updated from what may appear in some printed versions From: Cell 144, Hanahan D and Weinberg RA, Hallmarks of cancer: the next generation, 646–74, Copyright (2011), with permission from Elsevier. 2018 17 A summary of the Third Expert Report

20 Box 5: Cells of the tumour microenvironment Most solid tumours contain a range of distinct cell types and subtypes that collectively enable tumour growth and progression [13]. The abundance, spatial organisation and functional characteristics of these multiple cell types, and the make-up of the extracellular matrix, change during progression to create a succession of different tumour microenvironments. Thus, the core of the primary tumour microenvironment differs from microenvironments seen in tumours that are invading normal tissue and in metastatic tumours that are colonising distant tissues. The premalignant stages in tumorigenesis (not shown in the figure) also have distinctive microenvironments. The normal cells that surround the primary and metastatic tumour sites probably also affect the character of the various tumour microenvironments. Text [adapted] and illustration reprinted from: Cell 144, Hanahan D and Weinberg RA, Hallmarks of cancer: the next generation, 646–74, Copyright (2011), with permission from Elsevier. a Global Perspective 18 Diet, Nutrition, Physical Activity and Cancer:

21 Although a bewildering variety of possible Sometimes one or more of the genetic factors that contributes to the development of cancer is genetic changes can combine to cause cancer, the range of abnormal capabilities that cancer inherited. Such familial cancers are uncommon cells share is much narrower. These capabilities (playing a role in 5 to 10 per cent of all cancers) [14], but it is important to identify them so are known as the ‘hallmarks of cancer’ (see that personalised preventive strategies can Figures 1 and 2 ). be offered to carriers and their families. Figure 1: Hallmarks of cancer and two enabling characteristics Enabling characteristics Cell 144, Hanahan D and Weinberg RA, Hallmarks of cancer: the next generation, 646–74, Copyright (2011), with permission from Elsevier. Adapted from: Despite the multitude of pathways through which genetic damage can lead to the development of cancer, almost all solid tumours can be characterised by a relatively small number of phenotypic functional abnormalities. These eight hallmarks of cancer are facilitated by two enabling characteristics, genome instability and mutation, and tumour-promoting inflammation. 2018 19 A summary of the Third Expert Report

22 Figure 2: Stages of cancer development and the hallmarks of cancer 2015; From: Block KI, Gyllenhaal C, Lowe L, et al . Designing a broad-spectrum integrative approach for cancer prevention and treatment. Semin Cancer Biol 35 Suppl: S276-s304. Licenced under CC BY 4.0. The hallmarks of cancer represented on the right are functional abnormalities characteristic of cancer cells, which can be related to the pathophysiological stages of cancer development, represented on the left. 1.1.2 The rogue capabilities of cancer involve As an organism develops from a fertilised egg dysregulated activities of normal cells during embryonic and fetal life, its cells display a range of behaviours that are appropriate to The rogue capabilities of cancer cells, which can each stage of development, but which tend be harmful to an organism, are not all unique to lie dormant at other times. These include to cancer. They are actually beneficial to some capabilities that are typical of cancer cells, such normal cells at certain times. a Global Perspective 20 Diet, Nutrition, Physical Activity and Cancer:

23 as rapid cell division and invasion of surrounding 1.1.3 Almost all cells are vulnerable to the genetic damage that causes cancer tissues. Inappropriate and untimely activation of such capabilities in cells of an adult organism Almost all cells in an organism are vulnerable can mean those cells behave in the way that to damage to their DNA (see ). Figure 3 defines cancer. This can happen if the genetic changes that accumulate in cancer cells affect For example, mutations can happen during which genes are turned on or off (see Box 4 ). cell division. Throughout life, an organism’s cells are constantly growing and dividing via One way of thinking about cancer, therefore, a highly regulated process called the cell cycle. is that it is the inappropriate and abnormal This allows tissues to grow and stay healthy. resurrection of capabilities needed by cells Before a cell divides, it must replicate its DNA during normal development after fertilisation. Figure 3: Diet, nutrition and physical activity, other environmental exposures and host factors interact to affect the cancer process Invasive cancer Preneoplasia Normal epithelium CANCER PROCESS Genetics, Epigenetics, Food contaminants, Microbiome, Age, Viruses, Gender, UV radiation, Host Environmental Metabolic state, Environmental Factors Factors carcinogens, Inflammatory state and immune function, Other environmental factors Other host factors Diet/Lifestyle Factors Nutrients, Energy intake, Phytochemicals, Other food components, Alcohol, Physical activity, Smoking, Other lifestyle factors The process by which normal cells transform into invasive cancer cells and progress to clinically significant disease typically spans many years. The cancer process is the result of a complex interaction involving diet, nutrition and physical activity, and other lifestyle and environmental factors, with host factors that are related both to inheritance and to prior experience, possibly through epigenetic change. Such host factors influence susceptibility to cancer development, in particular related to the passage of time. This allows both opportunity to accumulate genetic damage, as well as impairment of function, for example, DNA repair processes with ageing. The interaction between the host metabolic state and dietary, nutritional, physical activity and other environmental exposures over the whole life course is critical to protection from or susceptibility to cancer development. 2018 21 A summary of the Third Expert Report

24 (and therefore its genetic code), so that each carcinogenesis [15]. Humans have evolved of its two daughter cells has identical DNA to various physiological mechanisms that protect the parent cell. DNA replication is a complex against the adverse effects of some of these process and is vulnerable to the introduction carcinogens. For example, a family of enzymes of errors in the DNA sequence. termed ‘phase I and phase II metabolising enzymes ’ are involved in a process that DNA can be damaged at other times too. ultimately quenches, or neutralises, reactive Cells are constantly exposed to factors that agents that can damage DNA so they can can damage DNA, either agents from the be excreted in bile or urine [ 16]. environment outside the body (exogenous), such not Repairing DNA damage so it is • as radiation or chemicals in cigarette smoke, Cells have transmitted to daughter cells – or agents generated by processes that occur a number of processes that can detect and within the body (endogenous), such as free repair particular types of DNA damage. For radicals or other by-products of metabolism. example, normal progression through the cell A substance or agent that is capable of causing cycle is monitored at checkpoints that sense cancer is known as a carcinogen, although not errors in DNA replication. Activation of these all carcinogens damage DNA directly. checkpoints stops the cell cycle, allowing cells to repair any defects and prevent their Ageing allows increasing opportunity for cells transmission to daughter cells [17]. to accumulate DNA damage. Ageing is also often accompanied by reduced capacity in many Ensuring cells with damaged DNA do not • metabolic and physiological functions, including survive – If DNA repair is unsuccessful protection against DNA damage. and normal cell function is compromised, damaged cells undergo a process called 1.1.4 Cells can protect themselves apoptosis, which means the cells effectively against acquiring DNA damage and the self-destruct [18]. This protects the tissues hallmarks of cancer from accumulating cells with damaged DNA. Cells have evolved a range of mechanisms to prevent the accumulation of DNA damage, which 1.1.5 The protective mechanisms of cells protects them against acquiring the hallmarks sometimes fail, increasing the chances that of cancer. These mechanisms include: cancer will develop The mechanisms that protect cells against Eliminating or detoxifying external agents • accumulating DNA damage and the hallmarks of Cells can be that can cause DNA damage – cancer are not perfect and may be compromised exposed to a multitude of substances and by several factors that can increase the risk of agents both natural and anthropogenic that cancer, such as: have the potential to damage DNA, disrupt normal cell function and contribute to Inherited genetic defects – A small • proportion of cancers (<10 per cent) are linked to specific mutations inherited from an individual’s parents (germ-line mutations) [14] and therefore present in every cell in the body that has a nucleus. The inheritance of a cancer-linked germ line mutation does not a Global Perspective 22 Diet, Nutrition, Physical Activity and Cancer:

25 mean that a person will definitely go on to normal homeostasis and reduce resilience to develop cancer, but it does confer a higher external challenges. This may manifest in many risk of developing cancer compared with the ways, for instance as susceptibility to infections, general population. to cardiometabolic disease or to cancer. High levels of exposure to external Diet, nutrition and physical activity may influence • The physiological mechanisms carcinogens – cancer risk in a range of different ways. Some that protect humans against carcinogens may foods and drinks may be vectors for specific be overwhelmed by high levels of exposure substances that act as carcinogens at particular and may not work as well to protect against sites. By contrast, obesity and sedentary ways unaccustomed types of carcinogens that have of life may not act through single discrete appeared more recently, such as industrial pathways – instead, they may alter the systemic pollution. metabolic milieu of the body in ways that give rise to cellular microenvironments that are Endogenous factors that compromise • conducive to cancer development at a number DNA integrity – Excessive production of of sites. reactive oxygen and nitrogen species (ROS/ RNS) by neutrophils and macrophages, such There is accumulating evidence on how diet, as occurs with chronic inflammation, can nutrition and physical activity can have an damage nuclear and mitochondrial DNA [19]. impact on the biological processes that Concomitant ROS/RNS damage to key proteins underpin the development and progression of such as DNA polymerases and multiple DNA cancer – and influence whether cells acquire repair enzymes regulating DNA integrity also the phenotypic changes in cellular structure and contribute to cancer susceptibility. function that are characterised as the hallmarks ). For example: Figure 4 of cancer (see Reduced effectiveness of endogenous • Inappropriate nutrition at the whole- • Defects in DNA protective systems – body level is reflected in a disordered surveillance and repair mechanisms as well nutritional microenvironment at the cellular as antioxidant defence systems can lead and molecular levels. This can create to genomic instability [20], meaning cells an environment that is conducive to the accumulate deleterious DNA mutations more accumulation of DNA damage and therefore rapidly, giving them a predisposition to cancer to cancer development. and its progression. This genetic instability Obesity is associated with inflammatory • provides a way for a previously healthy cell to mediators, and metabolic and endocrine accumulate sufficient mutations to become abnormalities, that promote cell growth and malignant [21]. exert anti-apoptotic effects, meaning cancer cells do not self-destruct even following 1.1.6 Inappropriate nutrition and levels of severe DNA damage. physical activity are conducive to cancer development Nutritional factors may influence mechanisms • involved in DNA repair. Diet, nutrition and physical activity are essential aspects of human existence. Imbalanced and Dietary compounds may influence pathways • inappropriate levels of these factors can disturb by which carcinogens are metabolised. 2018 23 A summary of the Third Expert Report

26 Diet may influence epigenetic changes metabolic milieu of the body – as reflected • in cells. in anthropometric measures such as body fatness – as being a critical determinant Drinking alcohol can increase the production • of cancer susceptibility (see Section 6.2: of metabolites that are genotoxic and Assessing and interpreting evidence: fine- carcinogenic [22]. in this Summary). tuning the approach Reduced functional capacity, which occurs • with inappropriate nutrition (and with ageing), Maintaining a healthy weight throughout life is reduces resilience to endogenous or external one of the most important ways to protect against stresses. cancer. It also protects against a number of other common non-communicable diseases (NCDs); Physical activity has been shown to promote • see the ‘Be a healthy weight’ Recommendation healthy immune and hormonal systems. in Section 5.1 and in the more detailed Recommendations and public health and policy The growing body of evidence on such biological 2 part of the Third Expert Report. implications processes adds weight to evidence on the effects of diet, nutrition and physical activity on cancer risk measured at the level of the whole 1.2.1 Sustained proliferative signalling body or indeed in whole populations in clinical Many of the metabolic and endocrine or epidemiological studies. abnormalities associated with obesity, such as elevated levels of fasting insulin and oestradiol, as well as inflammatory mediators 1.2 Body fatness and the hallmarks associated with obesity, exert proliferative of cancer effects. Therefore, in the obese state, there is a general up-regulation of cell growth. This section focuses on links between body fatness and some of the hallmarks of cancer Unlike most healthy cells, cancer cells gradually ). While there are links between Figure 4 (see evolve to become less dependent upon the hallmarks and other exposures studied in hormones and growth factors for continued the Continuous Update Project (CUP) too, body growth and replication. Cancer cells may acquire fatness has been chosen as the example here this ability by, for example, producing growth- because the evidence that greater body fatness promoting signals themselves or by permanently is a cause of many cancers is particularly activating the growth and survival pathways strong, and has grown stronger over the last that normally respond to growth factors, via decade (see also the Exposures: Body fatness mutations that lock in these signals. and weight gain¹ part of the Third Expert Report). What is more, rates of overweight and obesity, 1.2.2 Resisting cell death in children as well as in adults, have been rising in most countries [23]. Normal cells ‘self-destruct’ under certain conditions, a process known as apoptosis. The accumulating results of the CUP increasingly This happens, for example, when a cell’s DNA point to the importance of the systemic is damaged beyond repair. In contrast, cancer 1 The Exposures: Body fatness and weight gain part of the Third Expert Report is available online at wcrf.org/body-fatness 2 The more detailed Recommendations and public health and policy implications part of the Third Expert Report is available online at wcrf.org/cancer-prevention-recommendations a Global Perspective 24 Diet, Nutrition, Physical Activity and Cancer:

27 Figure 4: Obesity and the hallmarks of cancer Insulin/PI3K/mTOR Oestrogen/MAPK/ERK Adipose stromal cell influence peritumoral vascularisation and inflammation Altered mitochondrial function, increased nutrient uptake in obesity-associated tumours, altered glucose metabolism Adipose tissue-associated inflammation, leptin, STAT Cell 144, Hanahan D and Weinberg RA, Hallmarks of cancer: the next generation, 646–74, Copyright (2011), with permission from Elsevier. Adapted from: Several of the cancer hallmarks, and both enabling characteristics, can be affected by factors relating to diet, nutrition and physical activity. Obesity illustrates the wide range of cellular and molecular processes that may be affected to promote cancer development and progression. Abbreviations: ERK, extracellular signal-regulated kinases; MAPK, mitogen-activated protein kinase; mTOR, mechanistic/ mammalian target of rapamycin; PI3K, phosphoinositide 3-kinase; STAT, signal transducer and activator of transcription. 2018 25 A summary of the Third Expert Report

28 cells can downregulate apoptosis and survive 1.2.5 Genome instability and mutation even after severe DNA damage. Genomic instability is an increased tendency of the genome to acquire mutations because of Many of the metabolic and endocrine dysfunction in the process of maintaining the abnormalities associated with obesity, such genome. It can be thought of as an underlying as elevated levels of fasting insulin and enabling characteristic, which expedites cells’ oestradiol, as well as inflammatory mediators acquisition of the other hallmarks of cancer [13]. associated with obesity, exert anti-apoptotic effects. Therefore, in the obese state, there Human studies have linked the obese phenotype is a suppression of apoptosis. with genomic instability in colorectal and endometrial cancer in women [26, 27]. Visceral 1.2.3 Activating invasion and metastasis obesity is also associated with genomic and instability events, both in vivo in in vitro Cancer cells can infiltrate the local tumour oesophageal adenocarcinoma [28]. microenvironment (invasion) and spread (metastasise) to distant organs via the bloodstream or lymphatic system. 1.2.6 Tumour-promoting inflammation Tumour-promoting inflammation can also Certain tissues are particularly prone to acting be thought of as an underlying enabling as colonisation sites for metastatic tissue, characteristic, which can inadvertently contribute such as the liver, bones, brain and lungs. This to cells’ acquisition of multiple other hallmark suggests that the specific microenvironment in capabilities [13]. these tissues is more favourable for the support of tumours than that of other tissues [24]. Body Chronic inflammation has long been recognised fatness is an important determinant of the as a feature of cancer. Several inflammatory tissue microenvironment. Obesity is also linked conditions are established precursors for with metabolic reprogramming in cancer cells so specific cancers, including gastritis for gastric that they are more likely to metastasise [25]. cancer, inflammatory bowel disease for colon cancer and pancreatitis for pancreatic cancer. 1.2.4 Inducing angiogenesis Inflammation is also well-established in the pathogenesis of ovarian cancer. Angiogenesis is the term for the growth and establishment of a vascular network. As a tumour Chronic inflammation has been implicated develops, relying on the local vascular supply in the link between nutrition and cancer in alone causes local hypoxia. This activates genes many epidemiological and preclinical studies. that lead to the expression of growth factors, In particular, obesity is now recognised as a such as vascular endothelial growth factor chronic inflammatory state that predisposes to (VEGF), thereby stimulating the development cancer. Complex interactions between cellular, of cancer-associated vascular networks, which molecular and metabolic factors underlie the are needed to support tumour growth. nutrition-inflammation-cancer triad. For example, obesity is associated with elevated secretion Adipose stromal cells may influence tumour of several pro-inflammatory cytokines and with vascularisation with associated increases in C-reactive protein (an inflammation marker that the proliferative activity of tumour cells. is elevated with obesity, is related to cancer risk and reduces with weight loss) [29, 30]. a Global Perspective 26 Diet, Nutrition, Physical Activity and Cancer:

29 1.3.2 Red and processed meat 1.3 Dietary exposures and the hallmarks of cancer Examples of biological mechanisms thought to underlie the association of red and processed There is evidence that other exposures, in meat with an increased risk of cancer include: addition to body fatness, increase or decrease Cooking meats at high temperatures results • the risk of cancer at multiple cancer sites in the formation of heterocyclic amines Section 3: The evidence for cancer risk (see (HCAs) and polycyclic aromatic hydrocarbons Section 6.2: Assessing and interpreting and (PAHs), which have mutagenic potential in this evidence: fine-tuning the approach through the formation of DNA adducts and Summary). This section provides examples of have been linked to cancer development in how dietary exposures might influence cancer experimental studies. susceptibility. These examples, and others, . Figure 5 and Table 2 are summarised in Haem iron intake has been associated with an • increased risk of colorectal tumours harbouring transitions from guanosine to adenine in the 1.3.1 Vegetables and fruit APC and KRAS genes, which suggests that Vegetables and fruit form a diverse and complex alkylating DNA-damaging mechanisms are food group. Their consumption provides the host involved [32]. with many micronutrients, as well as thousands The high salt content of processed meat may • of phytochemicals, which are not nutrients result in damage to the stomach mucosal but may have bioactivity in humans (see also lining, leading to inflammation, atrophy and Section 3 in the Exposures: Wholegrains, colonisation. Helicobacter pylori part of the Third Expert vegetables and fruit¹ Report). Phytochemicals that have demonstrated See also the mechanisms for red and processed anti-cancer effects in cell and rodent studies meat in Appendix 2 of the Exposures: Meat, fish include dietary fibre, carotenoids, dithiolthiones, 2 and Exposures: Preservation and dairy products isothiocyanates, flavonoids and phenols. 3 parts of the Third and processing of foods Expert Report. Vegetables and fruit are also a rich source of various nutrients that can impact cancer risk, such as vitamins C and E, selenium and folate. 1.3.3 Alcoholic drinks A substantial body of experimental data links The diverse mechanisms by which alcohol many of these compounds with anti-tumorigenic consumption leads to cancer include: effects in various cells in both animal and in Acetaldehyde, a toxic metabolite of ethanol • vitro models [31]. oxidation, can be carcinogenic to some cell types (e.g. colonocytes) [33], due to conversion See also the mechanisms for vegetables of ethanol to acetaldehyde by colonic bacteria. and fruit in Appendix 2 of the Exposures: 1 part of the Wholegrains, vegetables and fruit Higher ethanol consumption can induce • Third Expert Report. oxidative stress through increased production of reactive oxygen species, which are genotoxic and carcinogenic [22]. 1 The Exposures: Wholegrains, vegetables and fruit part of the Third Expert Report is available online at wcrf.org/wholegrains-veg-fruit 2 The Exposures: Meat, fish and dairy products part of the Third Expert Report is available online at wcrf.org/meat-fish-dairy 3 Exposures: Preservation and processing of foods part of the Third Expert Report is available online at wcrf.org/preservation-processing The 2018 27 A summary of the Third Expert Report

30 Alcohol may also act as a solvent for cellular Physical activity has been shown to have • • penetration of dietary or environmental immunomodulatory effects, enhancing innate (e.g. tobacco) carcinogen, or interfere with and acquired immunity, and promoting tumour , 41]. surveillance [38 retinoid and one-carbon metabolism and DNA repair mechanisms [34]. Studies have also shown that aerobic • Alcohol has been linked to changes in hormone exercise can decrease oxidative stress and • metabolism and, for example, is associated reasing s, dec enhance DNA repair mechanism with increased levels of oestradiol [35, 36]. carcinogenesis [41]. See also alcohol mechanisms in Appendix 2 See also physical activity mechanisms in 2 1 part of the of the Exposures: Alcoholic drinks Appendix 2 of the Exposures: Physical activity part of the Third Expert Report. Third Expert Report. 1.4.2 Height 1.4 Physical activity and height and the Mechanisms hypothesised to underlie the hallmarks of cancer association of greater adult attained height with increased cancer risk include the following: There is strong evidence that physical activity and height both affect the risk of cancer at Talle r people generally have higher circulating • Section 3: The evidence for multiple sites (see levels of IGF-I during adolescence and in this Summary). The information cancer risk elevated signalling through the insulin-IGF below gives examples of the biological axis [42, 43], which lead to activation of mechanisms that may be involved. the phosphatidyl-3-kinase-mTOR and MAPK pathways, causing cellular proliferation, 1.4.1 Physical activity suppressed apoptosis and angiogenesis. Physical activity has a beneficial effect on cancer Taller people may have more stem cells and • risk, likely through multiple mechanisms such as thus there is greater opportunity for mutations reductions in circulating oestrogen levels, insulin leading to cancer development [44]. resistance and inflammation – all of which have Site-specific mechanisms may also be at • been linked to cancer development at various play. For example, for colorectal cancer taller anatomical sites when increased. Physical adults have longer intestines with a greater activity also reduces body fatness, in particular number of cells at risk; therefore, there visceral fat, and therefore may have an additional may be greater potential for exposure to indirect impact (see ). Evidence on Figure 5 mutagenic or cancer-promoting agents. mechanisms includes the following: See also height mechanisms in Appendix 2 Physical acti vity improves insulin sensitivity • 3 part of the Exposures: Height and birthweight and reduces fasting insulin levels, which of the Third Expert Report. may decrease the risk of breast cancer [37, 38]. It may also reduce circulating oestrogen levels) [39, 40]. 1 The Exposures: Alcoholic drinks part of the Third Expert Report is available online at wcrf.org/alcoholic-drinks 2 The Exposures: Physical activity part of the Third Expert Report is available online at wcrf.org/physical-activity 3 Exposures: Height and birthweight part of the Third Expert Report is available online at wcrf.org/height-birthweight The a Global Perspective 28 Diet, Nutrition, Physical Activity and Cancer:

31 in turn may lead to one or more of the phenotypic 1.5 Summary changes that characterise cancer (hallmarks). Evidence is growing on how diet, nutrition, Further information on plausible biological physical activity and height can influence mechanisms is available in the more detailed the biological processes that underpin the 2 1 , CUP cancer reports and Exposure sections development and progression of cancer. 3 part of the Third Expert The cancer process Report, which are all available online. Some of the general biological mechanisms that may influence cancer risk by linking Evidence on plausible biological mechanisms specific exposures to discrete hallmarks of forms a vital part of the overall body of evidence cancer are summarised in Figure 5 and Table 2 . that is taken into account in the CUP when making The columns in the table show the potential judgements on whether an exposure causes or physiologic or metabolic impact of each exposure Section 2: protects against cancer; see at the systemic level, and the molecular or Judging the evidence of this Summary. cellular pathways that may be affected, which Figure 5: Nutrition, physical activity and the hallmarks of cancer Obesity, hyperinsulinemia Obesity, altered Obesity macrophage function Physical activity, Obesity, reduced telomere length apoptosis Folate Obesity, deficiency, uracil inflammation misincorporation Nutritional Adipose stromal microenvironment cells at metastatic sites Cell 144, Hanahan D and Weinberg RA, Hallmarks of cancer: the next generation, 646–74, Copyright (2011), with permission from Elsevier. Adapted from: A wide range of factors related to diet, nutrition and physical activity can influence the processes represented by the hallmarks of cancer. 1 The Exposure sections of the Third Expert Report are available online at wcrf.org/exposures 2 CUP cancer reports of the Third Expert Report are available online at wcr f.org /cancers 3 The more detailed The cancer process part of the Third Expert Report is available online at wcrf.org/cancer-process 2018 29 A summary of the Third Expert Report

32 Table 2: Potential impact of diet, nutrition, physical activity and height in increasing susceptibility to cancer Cell function Hallmarks possibly affected Exposure Systemic impact mTOR/PI3K/AKT, Reduced apoptosis; increased proliferation, Hyperinsulinemia MAPK genome instability Increased proliferation in ER+ tissues; MAPK/ERK/PI3K Increased oestradiol genome instability Greater body fatness Reduced apoptosis, increased cell division, STAT3/NF- k B altered macrophage function, etc.; genome instability Inflammation E.g. WNT, P53 E.g. cellular energetics, etc. DNA uracil Genome instability Folate deficiency misincorporation Low dietary fibre Low butyrate Reduced apoptosis; increased proliferation Lower fruit and intake vegetable intake Low levels of Oxidative stress, Increased inflammation, genomic instability, carotenoids, vitamin inflammation reduced apoptosis; increased proliferation A, C, E DNA adduct Reduced apoptosis; increased proliferation; formation -> Elevated exposure to genomic instability mutations in p53, nitrites; endogenous Greater intake of red KRAS, etc. N-nitroso compound and processed meat formation Oxidative stress, Increased inflammation, genomic instability inflammation mTOR/PI3K/AKT, Greater intake of Reduced apoptosis; increased proliferation Higher IGF-I MAPK dairy foods Oxidative stress, Increased inflammation, genomic instability Elevated acetaldehyde lipid peroxidation Increased oestradiol MAPK/ERK/PI3K Increased proliferation in ER+ tissues Greater alcohol Reduced apoptosis, increased cell division, intake STAT3/NF- Inflammation B k altered macrophage function, etc. Folate deficiency; DNA uracil Genome instability interference with misincorporation 1-carbon metabolism Increased apoptosis; reduced proliferation, mTOR/PI3K/AKT, Reduction in insulin MAPK less genome instability Reduction in Reduced proliferation in ER+ tissues; oestradiol and MAPK/ERK/PI3K reduced genome instability testosterone Greater physical activity Increased apoptosis, increased cell STAT3/NF- B division, altered macrophage function etc; k Reduced inflammation reduced genome instability (long term); improved immune function E.g. WNT, P53 E.g. cellular energetics, etc. mTOR/PI3K/AKT, Greater height Reduced apoptosis; increased proliferation Higher IGF-I MAPK Abbreviations: AKT, also known as protein kinase B; DNA, deoxyribonucleic acid; ER+, oestrogen receptor positive; ERK, extracellular signal-regulated kinases; IGF-I, insulin-like growth factor 1; KRAS, please see glossary; MAPK, mitogen- activated protein kinase; mTOR, mechanistic/mammalian target of rapamycin; NF-kB, nuclear factor kappa-light-chain- enhancer of activated B cells; P53, tumour protein p53; PI3K, phosphoinositide 3-kinase; STAT3, signal transducer and activator of transcription 3; WNT, Wingless-related integration site. a Global Perspective 30 Diet, Nutrition, Physical Activity and Cancer:

33 Judging the evidence 2 32 2.1 The aim 32 The approach – in summary 2.2 Gathering and presenting the evidence 33 2.3 36 2.4 Discussing and judging the evidence For further information, see the more detailed Judging the evidence part of the Third Expert Report available online at wcrf.org/judging-evidence

34 The aim 2.1 2.2 The approach – in summary This Third Expert Report brings together all of A team at Imperial College London conducts • systematic literature reviews (SLRs) – gathering the findings of the Continuous Update Project and presenting the best-available, current, (CUP) – an ongoing programme to analyse global scientific evidence from around the world. research on how diet, nutrition and physical activity affect the risk of developing cancer and There are 18 SLRs (17 on different % influence survival after a diagnosis. Thus, the cancers and one on breast cancer report provides a comprehensive analysis, using survivors), as well as a review of evidence the most meticulous of methods, of the worldwide on energy balance and body fatness (the body of evidence. determinants of weight gain, overweight and obesity conducted by WCRF/AICR). The aim when judging evidence is to identify, The SLRs are peer reviewed by external % with sufficient confidence to support a peer reviewers. recommendation, what causes cancer, what protects against cancer and what is unlikely The International Agency for Research on • to have an effect. This work also reveals where Cancer (IARC) provides expert reviews of the evidence is inadequate and further research main hypotheses-related mechanisms to is needed. support the epidemiological evidence. Judgements are used to update the Cancer The focus is on possible ways in which % Section 5.1: Prevention Recommendations (see the lifestyle factors studied in the CUP Recommendations for Cancer Prevention in may cause or protect from cancer at levels this Summary) to give people the best possible of exposure that are typical in humans. advice on cancer prevention, helping them to make healthy choices in their daily lives. The CUP Panel evaluates and interprets • the evidence, making judgements on the Much of the human evidence on diet, nutrition strength of the evidence and, where possible, and physical activity is observational, though it the likelihood that the exposures studied is reinforced by findings of extensive laboratory increase, decrease or have no effect on the investigations. There is no perfect way to risk of cancer. establish whether observed associations between these exposures and cancer are The Panel makes recommendations for the • definitely causal. However, the CUP Panel public based on its judgements. believes the rigorous, integrated and systematic The WCRF/AICR Secretariat, responsible for approach enables them to make sound • day-to-day management of the CUP, supports judgements and reliable recommendations. the work of the Panel. Methods used are explained and displayed The CUP Panel comprises internationally transparently (as summarised here and renowned, independent experts in a variety described in more detail in the full online version of disciplines from around the world. As well ), so they can be readily of Judging the evidence¹ as their role in judging evidence and making accessed and challenged as science develops. 1 The more detailed Judging the evidence part of the Third Expert Report is available online at wcrf.org/judging-evidence a Global Perspective 32 Diet, Nutrition, Physical Activity and Cancer:

35 recommendations, the members of the Panel (cohort) of healthy people are assessed, and also provide expertise and advice on maintaining the group is followed over a period of time ). a rigorous, independent process (see Box 2 to identify relevant outcomes (cancer, in the case of a healthy cohort or death in the case of a survivors cohort). Comparisons are 2.3 Gathering and presenting the evidence then made between people with the relevant outcome and those without it. 2.3.1 Systematic literature reviews Cohort studies are the most common studies SLRs are conducted according to a common reviewed in the CUP. The main advantages methodology, first used for the 2007 Second of these studies are that measurements can Expert Report, which defines how to search for be taken before a diagnosis of cancer, follow- evidence, select which evidence to use, and up may last decades and multiple types assess, analyse and display the evidence. of cancer can be examined in one cohort. The approach is objective, reproducible, openly However, because of their observational documented and subject to peer review at nature, it is impossible to fully exclude or critical stages. adjust for confounding factors, which can make interpretation of the causality of 2.3.1.1 Evidence considered in systematic associations difficult. literature reviews The SLRs are updates of those completed for When there are no, or few, RCTs or cohort the 2007 Second Expert Report. studies, evidence from case-control studies is also taken into account: When possible, SLRs focus on evidence from case-control studies , people diagnosed In randomised controlled trials and cohort studies. • with a specific type of cancer (‘cases’) are A randomised (RCT) is an clinical trial • compared with otherwise similar people experiment in which participants are randomly who have not been diagnosed with cancer assigned to groups that receive, or do not (‘controls’). The control group is a sample receive, an experimental intervention (often of the population from which the cases called intervention and control groups). RCTs arose and provides an estimate of how the are considered the gold standard when exposures being studied are distributed in testing the efficacy of drugs and other medical that population. treatments, especially when ‘double-blind’, meaning neither participants nor investigators Case-control studies are not routinely know which group each participant has been reviewed for the CUP because such studies assigned to. However, few RCTs investigate related to diet and physical activity may be the effect of diet, nutrition and physical activity particularly prone to recall and other biases. on the risk of cancer incidence because of feasibility and limitations, for example, trial Cohort and case-control studies are examples duration and resources. , which describes and of epidemiological research seeks to explain the incidence and distribution studies (usually simply In prospective cohort • of health and disease within human populations called cohort studies), the diet, body fatness and does not involve deliberate intervention. and/or physical activity levels of a large group 2018 33 A summary of the Third Expert Report

36 In epidemiological studies, ‘exposures’ are the lowest levels of exposure provides factors that may or may not influence the risk information on direction of effect (whether of disease, such as people’s diet, nutritional cancer risk is increased, decreased or state, circumstances or behaviour. The unchanged at higher levels of exposure than exposures studied include foods and drinks, lower levels). and their constituents and contaminants, dietary Dose –response meta-analyses: • patterns, supplements, physical activity, body These analyses reveal how the effect fatness, weight gain, height and birthweight. on cancer risk changes with the level of The CUP analyses of epidemiological data reveal exposure, showing both the direction of effect associations between these exposures and the Box 6 and the shape of the association (see ). risk of cancer, which may or may not be causal. Considerable weight is placed on linear dose– response meta-analyses, partly because the Other types of studies that may be considered demonstration of a biological gradient adds in the CUP include descriptive studies, migrant weight to evidence that a relationship may studies and ecological studies. For further be causal. Non-linear dose–response meta- information, see the more detailed Judging analyses are useful for detecting thresholds the evidence¹ part of the Third Expert Report and non-linear associations. available online. 2.3.2 Determinants of weight gain, overweight 2.3.1.2 How evidence is assessed and presented and obesity in systematic literature reviews As 12 of the 17 cancers reviewed by the CUP Owing to widespread interest in the study of are linked to greater body fatness, a review on diet, nutrition, physical activity and cancer, a the determinants of weight gain, overweight and large number of studies have been published, obesity has been undertaken (see the Energy which allows meta-analyses to be carried out. 2 part of the Third balance and body fatness Meta-analyses combine the results of several Expert Report). The review aimed to look at how studies that address similar questions, which diet, nutrition and physical activity affect weight give them a greater statistical power than the gain, and the chance of being overweight or individual studies to detect associations between obese. Owing to the large amount of published exposures and the risk of cancer. Increased evidence, this was conducted as a review of statistical power also allows subgroup analyses, published reviews. which help to characterise the association. For example, to evaluate if an association differs 2.3.3 Experimental evidence on biological by sex, age, body fatness, smoking status, mechanisms geographical location or cancer subtype. Judgements that an exposure causes or Where possible, the following types of meta- protects against cancer require evidence on analyses are conducted and the findings plausible ways in which that might happen at presented visually using plots: levels of exposure that are typical in humans. Hypotheses may be based on evidence from Highest versus lowest meta-analyses: • human or animal studies, with a preference Comparing cancer risk for the highest and for human studies. 1 The more detailed Judging the evidence part of the Third Expert Report is available online at wcrf.org/judging-evidence 2 The more detailed Energy balance and body fatness part of the Third Expert Report is available online at wcrf.org/energy-balance-body-fatness a Global Perspective 34 Diet, Nutrition, Physical Activity and Cancer:

37 Box 6: Interpretation of the evidence heterogeneity Interpretation of epidemiological evidence is Is there high , a large variation in • complex. A wide range of general considerations the results of the studies, which would lead to must be taken into account, including the less confidence in the overall summary estimate? following: Is the overall evidence limited to a particular • geographic area and can results be How relevant are the patterns and ranges of • extrapolated at a global scale? examined in the existing studies to intake populations globally? Do studies take into account the possibilities • of , confounding effect modification and What about ? Do the studies classification • ? reporting bias classify food and drink consumption, and physical activity, in ways that correspond A confounding factor is a variable that is % to patterns globally? associated with the exposure being studied, and is also a risk factor for the disease of the level measurements How accurate are • (in the case of the CUP, cancer), but is not of exposure in the study population, such on the causal pathway from the exposure as levels of intake of a food or its dietary to the disease. It is essential to adjust for constituents? confounding factors to try to minimise consistent between studies? terminology Is • distortion of results, as they can account For some exposures, such as ‘processed meat’, for part or all of an observed association there are no generally agreed definitions. between an exposure and a disease. How reliable and complete is the data on • Effect modification occurs when the % cancer outcomes – on incidence and mortality, magnitude of the effect of an exposure and subtypes? changes depending on the level of another variable (the effect modifier); it means study design appropriate? The hierarchy Is the • that the effect of an exposure on risk of evidence places RCTs at the top, followed varies depending on a third factor. by cohort studies, then case control studies, with ecological studies and case reports at the Reporting bias can introduce systematic % bottom, but there are merits in considering errors because of deviation of observed a number of different study designs. results from their true value in a particular direction. For example, in studies that between shape of the association What is the • rely on self-reporting, people tend to the exposure and the cancer? For example, is over-report consumption of foods and it linear, with a uniform increase (or decrease) drinks they believe to be healthy and in risk for rising levels of exposure? Is there under-report foods and drinks they believe a threshold above which an association is to be unhealthy. found or a plateau where no further increase or decrease in risk is observed? Or does More specific information on issues relating to the direction of association (whether risk Interpretation of the evidence is provided in the 1 is increased or decreased) change with the of the Third Expert Report Exposure sections level of exposure? available online. 1 The Exposure sections of the Third Expert Report are available online at wcrf.org/exposures 2018 35 A summary of the Third Expert Report

38 Summaries of plausible biological mechanisms ideas, are used in the CUP when assessing – covering the primary hypotheses that currently evidence, drawing conclusions and making prevail – are presented in the Exposure sections. recommendations (see the WCRF/AICR grading 1 These summaries are not currently based on criteria in Section 8 of the Judging the evidence part of the Third Expert Report). an exhaustive search of the literature, but work to develop a more systematic process for The WCRF/AICR criteria require a range of reviewing evidence from experimental studies factors to be considered. These include the is continuing. quality of the studies – for example, whether the possibility of confounding, measurement errors 2.4 Discussing and judging the evidence and selection bias has been minimised. They also include the number of different study types 2.4.1 Uncertainty in epidemiology and cohorts, whether there is any unexplained Even though the best available evidence has heterogeneity between results from different been used, that evidence does not normally studies or populations, whether there is a dose– prove, beyond all doubt, whether the exposures response relationship, and whether there is – diet, nutrition and physical activity – cause, evidence of plausible biological mechanisms or protect against, cancer. The exposures at typical levels of exposure. themselves are complex and difficult to manipulate The clearly defined grading criteria provide a in experimental studies. Furthermore, even if a systematic way to judge how strong any evidence person’s way of living does cause cancer, it may of causality is. They enable evidence to be take years or decades for that cancer to develop. categorised as being ‘strong’ (‘convincing’, Although RCTs have the power to test cause ‘probable’ or ‘substantial effect on risk unlikely’) and effect vigorously, controlled manipulation of or ‘limited’ (‘limited – suggestive’ or ‘limited – no diet and physical activity in RCTs over the long conclusion’). Only evidence judged to be strong is period of time required to study these exposures usually used as the basis for Recommendations is not possible. Much of the data on cancer risk (see Section 5: Recommendations and public therefore comes from epidemiological studies, in this Summary). health and policy implications and there is normally a degree of uncertainty Judgements are displayed in the summary surrounding whether observed associations presents Section 3 matrices. The matrix in in these studies are causal. Best judgement all of the Panel’s judgements from the CUP. is therefore needed when interpreting and The matrix in Section 5.1.5 presents the assessing results. strong evidence (judgements of ‘probable’ or ‘convincing’) which underpin the 2018 Cancer 2.4.2 Best judgement and grading criteria Prevention Recommendations. Matrices for In 1965, Sir Austin Bradford Hill suggested nine judgements relating to specific cancer sites can characteristics of observational evidence, since 2 . Matrices for be found in the CUP cancer reports used widely, that could be used when judging judgements relating to specific exposure groups, how likely it is that associations observed in for example, alcoholic drinks, can be found in the epidemiological studies are causal [45]. Modified 3 . Exposure sections grading criteria, which build on Bradford Hill’s 1 The more detailed Judging the evidence part of the Third Expert Report is available online at wcrf.org/judging-evidence 2 The CUP cancer reports of the Third Expert Report are available online at wcr f.org /cancers 3 Exposure sections The of the Third Expert Report are available online at wcrf.org/exposures a Global Perspective 36 Diet, Nutrition, Physical Activity and Cancer:

39 The evidence for cancer risk: 3 a summary matrix The Panel’s judgements are summarised in this matrix. The evidence is presented by cancer types (in rows) and by exposure (in columns). For breast and oesophageal cancer, two subtypes are presented due to the difference in the nature of the relationship between diet, nutrition physical activity and cancer. The bottom row relates to the outcome of risk of weight gain, overweight and obesity. CUP cancer Further information can be found in the Energy balance and the Exposure sections , reports part of the Third Expert Report and body fatness available online at dietandcancerreport.org

40 and fruit juice concentrate. This includes, among others, sodas, sports drinks, energy drinks, sweetened waters, cordials, barley water, and coffee- and tea-based beverages with sugars or syrups and vegetables, with modest amounts of meat and dairy, some fish and wine, and rich in unrefined olive oil. Traditionally it is also associated with high levels of physical activity. Currently most There are recognised scores for quantifying adherence to a ‘Mediterranean type’ dietary pattern but it is unclear exactly what such a diet comprises. It generally describes a diet rich in fruits limiting intake of red and processed meat; limiting intake of alcoholic drinks; and a higher intake of wholegrains, vegetables and fruit. recommendations or patterns. They are characterised by factors such as healthy weight management; engagement in physical activity; limiting intake of foods and drinks that promote weight gain; Judgements relate to healthy dietary patterns as marked by greater healthy dietary indices. These indices produce an integrated score to assess adherence to healthy eating or lifestyle Basal cell carcinoma and malignant melanoma. and overall the evidence is more persuasive of a protective effect: greater consumption of non-starchy vegetables or fruit probably protects against a number of aerodigestive cancers. which showed a significant increased risk at intakes of 100 grams or less per day when compared with an intake of 200 grams per day. to draw a conclusion for intakes above 30 grams of ethanol per day. The conclusion for alcoholic drinks and kidney cancer was based on alcohol intakes up to approximately 30 grams of ethanol per day (about two drinks a day). There was insufficient evidence Stomach cardia cancer only. No threshold level of alcohol intake was identified in the evidence for alcoholic drinks and breast cancer (pre and postmenopause). The evidence for non-starchy vegetables and fruit and bladder cancer relates to combined consumption of vegetables and fruit. The evidence for foods containing carotenoids and lung cancer is derived from studies on dietary intake and serum levels. based on intakes below 30 grams of ethanol per day. The conclusion for alcoholic drinks and colorectal cancer was based on alcohol intakes above approximately 30 grams of ethanol per day (about two drinks a day). No conclusion was possible The Panel’s conclusion for foods containing carotenoids and breast cancer relates to the evidence for breast cancer overall (menopausal status not specified). The evidence is derived from studies on dietary intake and serum or plasma levels, and includes both foods that naturally contain carotenoids and foods that have had carotenoids added. drinks a day). No conclusions were possible for these cancers based on intakes below 45 grams of ethanol per day. The conclusions for alcoholic drinks and cancers of the liver, stomach and pancreas were based on evidence for alcohol intakes above approximately 45 grams of ethanol per day (about three The evidence for foods containing beta-carotene and lung cancer is derived from studies on dietary intake and serum levels. The evidence for beta-carotene and prostate cancer is derived from studies on dietary intake and serum or plasma levels, as well as studies on supplement use (20, 30 and 50 milligrams Alcoholic drinks include beers, wines, spirits, fermented milks, mead and cider. The consumption of alcoholic drinks is graded by IARC as carcinogenic to humans (Group 1). per day). The evidence for foods containing vitamin C and lung cancer in people who smoke tobacco is derived from studies on dietary intake. added. This does not include versions of these drinks which are ‘sugar free’ or sweetened only with artificial sweeteners. countries around the Mediterranean do not consume such a diet. Sugar sweetened drinks are defined here as liquids that are sweetened by adding free sugars, such as sucrose, high fructose corn syrup and sugars naturally present in honey, syrups, fruit juices The Panel’s conclusion is for foods containing vitamin C and colon cancer. No conclusion was drawn for foods containing vitamin C and rectal cancer. Basal cell carcinoma (men and women) / malignant melanoma (women). The evidence for foods containing isoflavones and lung cancer in people who have never smoked tobacco is derived from studies on dietary intake. The effect of coffee on the risk of endometrial cancer is observed with both caffeinated and decaffeinated coffee so cannot be attributed to caffeine. Working Group declared that drinking very hot beverages, including mate, above 65 degrees is probably carcinogenic to humans (Group 2A). Mate, an aqueous infusion prepared from dried leaves of the plant Ilex paraguariensis, is traditionally drunk scalding hot through a metal straw in parts of South America. In 2016, an IARC mining and industrial practices. Countries particularly affected by higher levels of arsenic in drinking water include Bangladesh, China and India. is also classed separately as a human carcinogen (Group 1). Water can become contaminated by arsenic as a result of natural deposits present in the earth, volcanic activity, or agricultural, The International Agency for Research on Cancer (IARC) has judged arsenic and inorganic arsenic compounds to be carcinogenic to humans (Group 1). Drinking water contaminated with arsenic these factors. Aggregated exposure which contains evidence from the following exposures: non-starchy vegetables (greater intake), non-starchy vegetables (low intake), fruit (greater intake), fruit (low intake) for foods preserved by salting and stomach cancer comes from salt-preserved foods including vegetables and fish. The term ‘foods preserved by salting’ refers mainly to high-salt foods and salt-preserved foods, including pickled vegetables and salted or dried fish, as traditionally prepared in East Asia. Evidence and citrus fruit. The Panel notes that while the evidence for links between individual cancers and non-starchy vegetables or fruit is limited, the pattern of association is consistent and in the same direction, The evidence for dairy products and prostate cancer includes total dairy, milk, cheese and yogurt intakes. Such diets are characterised by high intakes of free sugars, meat and dietary fat, which are probably the factors responsible for the effects on weight. The overall conclusion includes all ‘Aerodigestive cancers’ include: mouth, pharynx and larynx, nasopharynx, oesophagus (squamous cell carcinoma and adenocarcinoma), lung, stomach and colorectal. The evidence for dairy products and premenopausal breast cancer includes total dairy and milk intakes. The term ‘red meat’ in the CUP refers to beef, veal, pork, lamb, mutton, horse and goat. The term ‘processed meat’ in the CUP refers to meats transformed through salting, curing, fermentation, smoking or other processes to enhance flavour or improve preservation. The evidence for dairy products and colorectal cancer includes total dairy, milk and cheese and dietary calcium intakes. Non-cardia stomach cancer only. The term ‘haem iron’ refers to iron attached to a haemoprotein, which is found only in foods of animal origin. Foods that contain haem iron include red and processed meat, fish and poultry. case-control studies, there is only one cohort study. in the northern part of China, is allowed to ferment, and so is eaten in a decomposed state. This conclusion does not apply to fish preserved (or salted) by other means. Evidence is primarily from Cantonese-style salted fish is part of the traditional diet consumed by people living in the Pearl River Delta region in Southern China. This style of fish, which is prepared with less salt than is used The evidence for aflatoxins and liver cancer relates to foods that may be contaminated with aflatoxins and includes cereals (grains) as well as pulses (legumes), seeds, nuts and some vegetables An increased risk of stomach cancer was not apparent when the data for fruit were analysed assuming a linear response but became apparent when conducting a non-linear analysis which Although the dose-response meta-analysis for colorectal cancer showed a statistically significant decreased risk with increased consumption of non-starchy vegetables, a non-linear relationship The evidence for foods containing dietary fibre and colorectal cancer includes both foods that naturally contain fibre and foods that have had fibre added. wholegrains (or their products) which contain all three constituents. in oestrogen receptor-negative (ER-negative or ER-) breast cancer only. People who smoke or used to smoke tobacco. was apparent which showed a significant increased risk at intakes of 100 grams or less per day when compared with an intake of 200 grams per day. showed a significant increased risk at intakes below 45 grams per day when compared with an intake of about 100 grams per day. The Panel’s conclusion for non-starchy vegetables (greater intake) and breast cancer relates to evidence for breast cancer overall (menopausal status not specified). The observed association was Refined grains refers to the grains themselves, or products of such grains, that have been mechanically processed to remove one or more of the bran, germ or endosperm. This is in contrast to Although the dose-response meta-analysis for colorectal cancer showed a statistically significant decreased risk with increased consumption of fruit, a non-linear relationship was apparent and fruit. The studies reported on elevated levels of biomarkers of aflatoxin exposure. 15 24 36 17 14 31 30 13 37 19 29 12 38 18 11 28 21 10 34 39 22 33 9 40 27 41 25 23 42 16 26 43 35 32 20 3 7 4 5 8 6 2 1 Footnotes Having been breastfed 80 Lactation 78 79 79 Greater birthweight 74 76 77 Adult attained height 73, 74 75 Adult weight gain 72 Body fatness in young adulthood SLR, systematic literature review. 71 71 Adult body fatness 62 66 66 67 69 64 62 62 62 63 62 65 70 68 Screen time 61 Abbreviation: Sedentary behaviours dietandcancerreport.org 60 59 Walking Vigorous physical activity 57 57 Physical activity 54 56 55 55 58 57 57 © 2018 World Cancer Research Fund International. All rights reserved Multivitamin supplements 53 Calcium supplements 52 Beta-carotene 51 supplements High-dose beta-carotene 49 50 concentrations Low plasma selenium concentrations Low plasma alpha-tocopherol serum, supplements) Vitamin D (food containing, 48 Foods containing retinol 47 acids Foods containing saturated fatty fructose Foods & drinks containing 46 Glycaemic load 45 ‘Fast foods’ 44 ‘Western type’ diet 43 pattern ‘Mediterranean type’ dietary 42 Healthy dietary patterns 41 Alcoholic drinks 35 37 36 39 40 36 36 38 38 Sugar sweetened drinks 34 Tea Coffee 33 32 Mate 31 Arsenic in drinking water 30 Foods preserved by salting 29 Diets high in calcium Dairy products 26 28 27 (charbroiled) meat and fish Grilled (broiled) or barbecued Cantonese-style salted fish 25 Fish Height and birthweight Physical activity Lactation/having been breastfed Other dietary exposures Body fatness and weight gain Foods containing haem iron 24 Processed meat 22 23 Red meat 21 (aggregated) Exposure Group Key Non-starchy vegetables or fruit 18 19 Foods containing isoflavones 17 Foods containing vitamin C 15 16 Foods containing beta-carotene 13 14 Foods containing carotenoids Wholegrains, vegetables and fruit Preservation and processing of foods Non-alcoholic drinks Alcoholic drinks Meat, fish and dairy products 11 12 12 Non-starchy vegetables & fruit 10 Citrus fruit 9 Fruit (low intake) 8 7 Fruit (greater intake) 4 Preserved non-starchy vegetables (low intake) Non-starchy vegetables 6 (greater intake) Non-starchy vegetables Summary of conclusions 5 4 5 Aflatoxins 3 Convincing increases risk Probable increases risk Limited – suggestive increases risk Substantial effect on risk unlikely Foods containing dietary fibre 2 Refined grains 1 Wholegrains Conclusions Key 20 81, 82 2018 Convincing decreases risk Limited – suggestive decreases risk Probable decreases risk LUNG 2017 SKIN 2017 (SLR) BREAST PREMENOPAUSE 2017 NASOPHARYNX 2017 (SLR) CERVIX 2017 (SLR) PROSTATE 2014 BLADDER 2015 BREAST POSTMENOPAUSE 2017 STOMACH 2016 OR OBESITY 2018 RISK OF WEIGHT GAIN, OVERWEIGHT OVARY 2014 ENDOMETRIUM 2013 OESOPHAGUS AERODIGESTIVE CANCERS (ADENOCARCINOMA) 2016 PANCREAS 2012 GALLBLADDER 2015 LIVER 2015 MOUTH, PHARYNX, LARYNX 2018 OESOPHAGUS (SQUAMOUS CELL COLORECTUM 2017 CARCINOMA) 2016 KIDNEY 2015 (AGGREGATED) 2016–2018 For the full-size version of this summary matrix see the fold-out section inside the back cover of this wcrf.org/interactivematrix Summary. See also the online interactive version of this matrix at 38 a Global Perspective Diet, Nutrition, Physical Activity and Cancer:

41 Survivors of breast and 4 other cancers Defining cancer survivors 40 4.1 4.2 Findings from the CUP and other sources 40 4.3 Nature of the evidence 41 41 Research gaps on cancer survivors 4.4 42 vivors Recommendations for cancer sur 4.5 For further information, see the more detailed Survivors of breast and other cancers part of the Third Expert Report available online at wcrf.org/cancer-survivors

42 Each stage of survivorship has its own particular 4.1 Defining cancer survivors characteristics, and the impact of interventions or exposures, including diet, nutrition and physical In recent decades, progress in the early detection activity, varies according to this. and treatment of cancer has led to a dramatic increase in the number of cancer survivors: in 2012, 32.6 million people worldwide were living 4.2 Findings from the CUP and with a diagnosis of cancer [4]. It is therefore other sources increasingly important that evidence on how diet, nutrition and physical activity influences The evidence from the CUP (see matrix below) outcomes in cancer survivors is analysed as and other sources is persuasive that nutritional part of the Continuous Update Project (CUP). factors such as body fatness, as well as physical activity, reliably predict important outcomes for The term ‘cancer survivor’ covers people in people with breast and other cancers. a wide variety of circumstances beginning at diagnosis, through cancer treatment to the end of However, the evidence that changing these life. Using a single term to cover cancer survivors factors after diagnosis will alter the clinical at all of these stages cannot do justice to the course of cancer is limited, particularly by the diverse nature of cancer and its survivorship. quality of published studies and by the DIET, NUTRITION, PHYSICAL ACTIVITY AND BREAST CANCER SURVIVAL – ALL-CAUSE MORTALITY DECREASES RISK INCREASES RISK Exposure Timeframe Exposure Timeframe Convincing STRONG EVIDENCE Probable Before diagnosis Before diagnosis Physical ≥12 months <12 months activity Body fatness after diagnosis after diagnosis ≥12 months LIMITED Limited – Before diagnosis Foods after diagnosis suggestive containing EVIDENCE ≥12 months fibre Total fat Before diagnosis after diagnosis Foods ≥12 months Saturated Before diagnosis after diagnosis containing soy fatty acids Substantial STRONG effect on EVIDENCE risk unlikely STRONG : Evidence strong enough to support a judgement of a convincing or probable causal relationship and generally justify making recommendations Evidence that is too limited to justify making specific recommendations : LIMITED a Global Perspective 40 Diet, Nutrition, Physical Activity and Cancer:

43 challenge of understanding how weight loss and agents. Given the complexity of cancer weight gain during the dynamic cancer process ent strategies care and the unique treatm affect outcome (for a full review of the evidence for specific types or subtypes of cancer, as see the Survivors of breast and other cancers¹ well as the shortcomings of observational part of the Third Expert Report available online). data, especially in the survivor setting, it is important that such evidence is derived from 4.3 Nature of the evidence randomised controlled trials (RCTs), which in turn should be based on human observational A major challenge when reviewing the evidence data and relevant preclinical models. for diet, nutrition, physical activity and cancer For people who have completed therapy, • survivorship is the scale and heterogeneity of there are few RCTs informing on optimal the field. Part of this heterogeneity stems from dietary and physical activity strategies. Many the different phases of survivorship and the specific cancer treatments have effects on relative priorities of associated endpoints during a range of long-term health outcomes, such each phase. Characterisation both of exposure as cardiac function, bone health, metabolic (diet, physical activity, body fatness) and of syndrome and cognition. outcome (such as progression-free survival, Future studies should focus on dietary and • disease-specific mortality, co-existing conditions, lifestyle interventions that are specifically quality of life or side effects) is complex and designed to address pre-defined outcomes. imprecise at present. Accurate capture of detailed treatment information is critical to Future studies must take account of • enable adjustment for potential confounders. issues that may be unique to specifi c cancers, as well as the type of treatment As a consequence, the current evidence on and stage of disease. breast cancer survivors, as reviewed by the CUP, Greater understanding of the underlying • has a number of limitations, including a lack of biological mechanisms linking diet, nutrition evidence from randomised controlled trials. In and physical activity to outcomes in cancer addition, the quality of most published studies survivors is important. is limited because they do not account for relevant factors such as cancer subtypes, type Understanding the different roles that diet, and intensity of treatment, and other illnesses. nutrition and physical activity may play at These limitations are also likely to apply to the each phase of survivorship, and for each type evidence for survivors of other cancers. (and potentially subtype) of cancer, along with the biological mechanisms at play, is 4.4 Research gaps on cancer survivors a priority (see Section 7.5 in this Summary). There are several questions about how diet, nutrition and physical activity affect outcomes in cancer survivors: More needs to be known about how these • exposures influence responses to or potential adverse effects of therapeutic 1 The more detailed Survivors of breast and other cancers part of the Third Expert Report is available online at wcrf.org/cancer-survivors 2018 41 A summary of the Third Expert Report

44 4.5 Recommendations for cancer survivors The available evidence on the effect of diet, nutrition and physical activity on the risk of all-cause mortality in cancer survivors is limited, and the amount and quality of research in this area is insufficient to make firm conclusions. However, the Panel judges that following the Cancer Prevention Recommendations is unlikely to be harmful to cancer survivors who have finished treatment. Therefore, cancer survivors are encouraged, if appropriate to their circumstances and unless otherwise advised by a health professional, to follow the general advice for cancer prevention. For some cancers, especially those diagnosed at early stages (for example, prostate and breast cancer), cardiovascular disease (CVD) will be a more common cause of death than cancer. As the risk of diseases other than cancer are also modified by diet, nutrition and physical activity, following the Cancer Prevention Recommendations is also expected to help reduce the risk of other non-communicable diseases (NCDs). Other organisations also provide guidance on nutrition and physical activity for cancer survivors; this information can be found in the more detailed Survivors of breast and other cancers¹ available online. 1 The more detailed Survivors of breast and other cancers part of the Third Expert Report is available online at wcrf.org/cancer-survivors a Global Perspective 42 Diet, Nutrition, Physical Activity and Cancer:

45 Recommendations and public 5 health and policy implications 5.1 Recommendations for Cancer Prevention 44 Be a healthy weight 48 50 Be physically active Eat a diet rich in wholegrains, vegetables, fruit and beans 53 Limit consumption of ‘fast foods’ and other processed 56 foods high in fat, starches or sugars 58 Limit consumption of red and processed meat Limit consumption of sugar sweetened drinks 60 Limit alcohol consumption 62 Do not use supplements for cancer prevention 64 66 For mothers: breastfeed your baby, if you can After a cancer diagnosis: follow our Recommendations, if you can 68 5.2 Regional and special circumstances 70 Public health and policy implications 73 5.3 For further information, see the more detailed Recommendations and public health and policy part of the Third Expert Report available implications online at wcrf.org/cancer-prevention-recommendations

46 (see the Exposure sections¹ , CUP cancer 5.1 Recommendations for and CUP systematic literature reviews³ reports² Cancer Prevention of the Third Expert Report available online). The Cancer Prevention Recommendations, The risk of other diseases, as well as cancer, presented in this section are one of the is also modified by diet, nutrition and physical most important outputs of the Continuous activity. This includes diseases related to Update Project (CUP). The Cancer Prevention nutritional deficiencies, cardiovascular diseases Recommendations are intended to reduce (CVDs) and other non-communicable diseases the incidence of cancer by helping people to (NCDs). When making the Cancer Prevention maintain a healthy weight and adopt healthy Recommendations, other recommendations patterns of eating, drinking and physical activity on the prevention of these diseases made throughout life, and by informing policy action. by authoritative international and national The Recommendations take the form of a series organisations from around the world were of general statements to be used by individuals, therefore also taken into account (see Appendix families, health professionals, communities and 1 in the more detailed Recommendations and policymakers, as well as the media. 4 part of public health and policy implications the Third Expert Report available online). A whole-of-government, whole-of-society approach is necessary to create environments for people and communities that are 5.1.2 An overall lifestyle conducive to following the Cancer Prevention There are individual Recommendations on weight Recommendations. For more information, and physical activity and on particular aspects of Section 5.3: Public health and policy see diet and nutrition. The Recommendations focus implications in this Summary. on foods and drinks, rather than on nutrients or other bioactive constituents, for a variety In addition to the Cancer Prevention of reasons. Recommendations presented here, the importance of not smoking, and of avoiding It is important to emphasise that the other exposure to tobacco, excess sun and Recommendations are intended to work together long-term infections that can cause cancer, and be adopted as a lifestyle package. Individual is emphasised. recommendations are likely to be less effective if followed in isolation. Each has relevance for 5.1.1 Making the Cancer the others, and there are interactions between Prevention Recommendations the exposures they address. Together, the The Panel uses its judgements on the findings Recommendations promote an overall way of life of the CUP to make the Cancer Prevention – a healthy pattern of diet and physical activity Recommendations. Evidence and judgements – that is conducive to the prevention of cancer, from the CUP are summarised in the exposure other NCDs and obesity. and cancer parts of the Third Expert Report 1 The Exposure sections of the Third Expert Report are available online at wcrf.org/exposures 2 The CUP cancer reports of the Third Expert Report are available online at wcr f.org /cancers 3 The CUP systematic literature reviews of the Third Expert Report are available online at wcrf.org/toolkit 4 The more detailed Recommendations and public health and policy implications part of the Third Expert Report is available online at wcrf.org/cancer-prevention-recommendations a Global Perspective 44 Diet, Nutrition, Physical Activity and Cancer:

47 A growing body of evidence shows that the more When quantifying the Goals, evidence from people adhere to the 2007 Recommendations, the CUP was taken into account, as well as the greater the reductions in the risk of specific recommendations in other reports (on other cancers, of cancer as a whole and of death NCDs, for example) on levels of body fatness from any cause [1–3]. Therefore, confidence in and physical activity, and of intake of foods the protective effect from following all of the and drinks. To minimise confusion, existing Recommendations is greater than that for any quantified guidance has sometimes been individual Recommendation. selected from these other reports if consistent with the evidence on cancer prevention. A diet based on the Recommendations is likely to be ‘nutrient dense’ – containing foods and 5.1.4 Relevant worldwide beverages with a relatively high concentration The Recommendations have been designed of vitamins and minerals and other dietary to be culturally relevant throughout the world. constituents such as dietary fibre, without Most of the available evidence comes from excessive salt, saturated or trans fats, added high-income countries, yet cancer is a problem sugars or refined starches – thereby promoting worldwide. The Recommendations are therefore good nutritional health and protecting against designed to be achievable in and appropriate to nutrient deficiency and NCDs. the very different circumstances and cultures that exist throughout the world. 5.1.3 Realistic and achievable goals People interested in reducing their risk of Some evidence from the CUP is strong enough cancer, health professionals who advise on to support recommendations but is not suitable preventing cancer and people involved in the for inclusion in a set of global recommendations development of public health policy need for a variety of reasons. These examples specific, relevant advice that they can act on. Section 5.2: Regional and are discussed in People need to know how much of what foods and in the full version of special circumstances and drinks, what levels of body fatness and how Recommendations and public health and policy much physical activity are most likely to protect available online. implications¹ against cancer. For these reasons, Goals are provided with each Recommendation. The Goals provide specific advice, quantified whenever possible, on how to meet the Recommendations. Goals are designed to result in real health gains while being achievable for most people. However, even without fully achieving a stated Goal, a change toward the Goal is worthwhile – any change is likely to provide at least some benefit. 1 The more detailed Recommendations and public health and policy implications part of the Third Expert Report is available online at wcrf.org/cancer-prevention-recommendations A summary of the Third Expert Report 2018 45

48 5.1.5 Diet, nutrition, physical activity and Evidence that greater body fatness is a cause cancer – an overview of the Panel’s judgements of many cancers is particularly strong; hence the following Recommendation is presented first: The matrix presented here summarises all the strong evidence judgements on links between Be a healthy weight • diet, nutrition and physical activity, and the risk The following two Recommendations promote of cancer or weight gain, overweight or obesity. positive changes that can be made to reduce The rows correspond to the cancer types (with both the risk of cancer and the risk of weight cancer as the outcome) and to energy balance gain, overweight and obesity (which themselves and body fatness (with weight gain, overweight are associated with an increased risk of cancer): and obesity as the outcome). The columns Be physically active • correspond to the exposures. Colours show the Eat a diet rich in wholegrains, vegetables, • strength of the evidence (whether ‘convincing’, fruit and beans ‘probable’ or ‘substantial effect on risk unlikely’) and the direction of the effect (whether there is The next four Recommendations focus on what an increase, a decrease or no effect on the risk to limit to reduce the risk of cancer, or of weight of cancer), as explained in the key. gain, overweight and obesity, and are listed in order by foods and drinks: Judgements of ‘convincing’ and ‘probable’ are normally strong enough to support a Limit consumption of ‘fast foods’ and • Recommendation, while judgements of ‘limited other processed foods high in fat, starches – suggestive’ generally are not. Each conclusion or sugars on the likely causal relationship between an Limit consumption of red and • exposure and outcome forms a part of the processed meat overall body of evidence that is considered Limit consumption of sugar • during the process of making Cancer Prevention sweetened drinks Recommendations. Any single conclusion does not represent a Recommendation in Limit alcohol consumption • its own right. The 2018 Cancer Prevention Recommendations are based on a synthesis The next Recommendation relates to of all these separate conclusions, as well as supplements: other relevant evidence. Do not use supplements for cancer prevention • 5.1.6 Introducing the Recommendations ecia Two sp commendations aimed at l Re specific groups of people follow: There are 10 Cancer Prevention Recommendations. Each Recommendation is intended to be one in ed your baby, For mothers: breastfe • a comprehensive package of behaviours that, if you can when taken together, promote a healthy pattern After a cancer diagnosis: follow our • of diet and physical activity conducive to the Recommendations, if you can prevention of cancer, other NCDs and obesity. a Global Perspective 46 Diet, Nutrition, Physical Activity and Cancer:

49 SUMMARY OF STRONG EVIDENCE ON DIET, NUTRITION, PHYSICAL ACTIVITY AND THE PREVENTION OF CANCER 2 To reference this matrix please use the following citation: World Cancer Research Fund International/American Institute 19 for Cancer Research. Continuous Update Project: Diet, Nutrition, Physical Activity and the 15 21 15 Prevention of Cancer. Summary 16 of Strong Evidence. Available at: wcrf.org/cupmatrix accessed on DD-MM-YYYY 22 Abbreviation: SLR, systematic literature review. Dairy products Foods preserved by salting Arsenic in drinking water Mate Coffee Sugar sweetened drinks Alcoholic drinks ‘Mediterranean type’ dietary pattern ‘Western type’ diet ‘Fast foods’ Wholegrains High-dose beta-carotene supplements Beta-carotene Calcium supplements Physical activity (moderate and vigorous) Vigorous physical activity Walking Screen time (children) Foods containing dietary fibre Screen time (adults) Aflatoxins Adult body fatness Foods containing beta-carotene Body fatness in young adulthood Non-starchy vegetables or fruit (aggregated) Adult weight gain Adult attained height Glycaemic load Greater birthweight Lactation Red meat Having been breastfed Processed meat Cantonese-style salted fish 2018 MOUTH, PHARYNX, LARYNX NASOPHARYNX 2017 (SLR) OESOPHAGUS (ADENOCARCINOMA) 2016 OESOPHAGUS (SQUAMOUS CELL 2016 CARCINOMA) 10 2017 LUNG 5 17 STOMACH 2016 PANCREAS 2012 GALLBLADDER 2015 5 LIVER 2015 4 6 12 13 2017 COLORECTUM 7 BREAST PREMENOPAUSE 2017 7 2017 BREAST POSTMENOPAUSE 2014 OVARY ENDOMETRIUM 2013 18 11 2014 PROSTATE 8 KIDNEY 2015 2015 BLADDER 20 2017 (SLR) SKIN 3 AERODIGESTIVE CANCERS 1 2016 (AGGREGATED) –2018 14 9 RISK OF WEIGHT GAIN, OVERWEIGHT 23,24 OR OBESITY 2018 Convincing decreases risk Probable decreases risk Probable increases risk Convincing increases risk Substantial effect on risk unlikey 1 Includes mouth, pharynx and larynx, nasopharynx, oesophagus (squamous cell carcinoma and Colon cancer only. 13 1 Includes mouth, pharynx and larynx, nasopharynx, oesophagus (squamous cell carcinoma and adenocarcinoma), lung, stomach and colorectal cancers. adenocarcinoma), lung, stomach and colorectal cancers. Aerobic physical activity only. 14 2 Aggregated exposure which contains evidence for non-starchy vegetables, fruit and citrus fruit. Aggregated exposure which contains evidence for non-starchy vegetables, fruit and citrus fruit. 2 15 Screen time is a marker of sedentary behaviour. 3 The Panel notes that while the evidence for links between individual cancers and non-starchy vegetables or fruits is limited, the pattern of association is consistent and in the same direction, and overall the evidence The Panel notes that while the evidence for links between individual cancers and non-starchy vegetables 3 16 Body fatness is marked by body mass index (BMI) and where possible waist circumference and waist-hip ratio. is more persuasive of a protective effect. or fruits is limited, the pattern of association is consistent and in the same direction, and overall the 17 Stomach cardia cancer only. Includes evidence on total dairy, milk, cheese and dietary calcium intakes. 4 evidence is more persuasive of a protective effect. Advanced prostate cancer only. 18 5 Stomach and liver: Based on intakes above approximately 45 grams of ethanol per day (about 3 drinks). Includes evidence on total dairy, milk, cheese and dietary calcium intakes. 4 19 Young women aged about 18 to 30 years; body fatness is marked by BMI. 6 Based on intakes above approximately 30 grams of ethanol per day (about 2 drinks per day). Stomach and liver: Based on intakes above approximately 45 grams of ethanol per day (about 3 drinks). 5 20 Malignant melanoma only. Based on intakes above approximately 30 grams of ethanol per day (about 2 drinks per day). 6 Adult attained height is unlikely to directly influence the risk of cancer. It is a marker for genetic, 21 7 No threshold level of intake was identified. 7 No threshold level of intake was identified. environmental, hormonal and nutritional factors affecting growth during the period from preconception Based on intakes up to 30 grams of ethanol per day (about 2 drinks per day). There is insufficient evidence for intake greater than 30 grams per day. 8 Based on intakes up to 30 grams of ethanol per day (about 2 drinks per day). There is insufficient 8 to completion of growth in length. 9 Such diets are characterised by high intakes of free sugars, meat and dietary fat; the overall conclusion includes all these factors. evidence for intake greater than 30 grams per day. Evidence relates to effects on the mother who is breastfeeding and not to effects on the child who 22 10 Evidence is from studies of high-dose supplements in smokers. 9 Such diets are characterised by high intakes of free sugars, meat and dietary fat; the overall conclusion is being breastfed. Relates to overall breast cancer (unspecified). 11 Includes both foods naturally containing the constituent and foods which have the constituent added and includes studies using supplements. includes all these factors. 23 The factors identified as increasing or decreasing risk of weight gain, overweight or obesity do so by Evidence derived from studies of supplements at dose >200 milligrams per day. 12 10 Evidence is from studies of high-dose supplements in smokers. promoting positive energy balance (increased risk) or appropriate energy balance (decreased risk), 13 Colon cancer only. 11 Includes both foods naturally containing the constituent and foods which have the constituent added through a complex interplay of physiological, psychological and social influences. 14 Aerobic physical activity only. and includes studies using supplements. 24 Evidence comes mostly from studies of adults but, unless there is evidence to the contrary, also apply 12 Evidence derived from studies of supplements at dose >200 milligrams per day. to children (aged 5 years and over). 15 Screen time is a marker of sedentary behaviour. 16 Body fatness is marked by body mass index (BMI) and where possible waist circumference and waist-hip ratio. 17 Stomach cardia cancer only. wcrf.org 2018 May Advanced prostate cancer only. 18 Young women aged about 18 to 30 years; body fatness is marked by BMI. 19 20 Malignant melanoma only. Adult attained height is unlikely to directly influence the risk of cancer. It is a marker for genetic, environmental, hormonal and nutritional factors affecting growth during the period from preconception 21 to completion of growth in length. 22 Evidence relates to effects on the mother who is breastfeeding and not to effects on the child who is being breastfed. Relates to overall breast cancer (unspecified). The factors identified as increasing or decreasing risk of weight gain, overweight or obesity do so by promoting positive energy balance (increased risk) or appropriate energy balance (decreased risk), through 23 a complex interplay of physiological, psychological and social influences. Evidence comes mostly from studies of adults but, unless there is evidence to the contrary, also apply to children (aged 5 years and over). 24 2018 47 A summary of the Third Expert Report

50 RECOMMENDATION Be a healthy weight 1 Keep your weight within the healthy range and avoid weight gain in adult life Ensure that body weight during childhood and adolescence projects towards the GOAL lower end of the healthy adult BMI range GOAL Keep your weight as low as you can within the healthy range throughout life 2 GOAL Avoid weight gain (measured as body weight or waist circumference) throughout adulthood 2 1 [46]. Different reference ranges have been proposed The healthy (or, as defined by WHO, ‘normal’) range of BMI for adults is 18.5–24.9 kg/m for Asian populations [46]. Where these ranges differ from the WHO definition, they are to be used as the guide. Further research is required to establish appropriate thresholds in other ethnic groups. The healthy range for BMI during childhood varies with age [47]. 2 WHO recommends keeping waist circumference below 94 cm (37 inches) in men and 80 cm (31.5 inches) in women (based on data from 2 [48]. For Asian populations, cut-offs for waist circumferences European people). These values are roughly equivalent to a BMI of around 25 kg/m of 90 cm (35.4 inches) for men and 80 cm (31.5 inches) for women have been proposed [48]. Further research is required to establish appropriate waist circumference values for other ethnic groups. Avoid weight gain (measured as GOAL Overweight and obesity, generally assessed body weight or waist circumference) by various anthropometric measures throughout adulthood including body mass index (BMI) and waist circumference, are now more prevalent than As there may be adverse effects specifically ever. In 2016, an estimated 1.97 billion adults from gaining weight during adulthood, it is best and over 338 million children and adolescents to maintain weight within the healthy range were categorised as overweight or obese throughout adult life. globally [23]. The increase in the proportion of adults categorised as obese has been This overall Recommendation is best achieved observed both in low- and middle-income by maintaining energy balance throughout life by countries and in high-income countries. following four of the other Recommendations: being physically active • Goals eating a diet rich in wholegrains, vegetables, • Ensure that body weight during childhood fruit and beans GOAL and adolescence projects towards the consumption of ‘fast foods’ and limiting • lower end of the healthy adult BMI range other processed foods high in fat, starches Keep your weight as low as you can within or sugars GOAL the healthy range throughout life limiting c onsumption of sugar • sweetened drinks. These two related Goals emphasise the importance of preventing excess weight gain, overweight and obesity, beginning in childhood. a Global Perspective 48 Diet, Nutrition, Physical Activity and Cancer:

51 Public health and policy implications Justification This recommendation was made for A comprehensive package of policies is needed to enable people to achieve and maintain several reasons: a healthy weight, including policies that from the CUP strong evidence There is • influence the food environment, food system, ): 5.1.5 and Sections 3 (see matrices in built environment and behaviour change Greater body fatness is a cause of many % communication across the life course. These cancers. This evidence has become policies can also help contribute to a sustainable stronger over the last decade. ecological environment. Policymakers are encouraged to frame specific goals and For some cancers the increase in risk % actions according to their national context. is seen with increasing body fatness even within the so-called ‘healthy’ range. Nevertheless, most benefit is to be gained For further information on the by avoiding overweight and obesity. evidence, analyses and judgements that led to this Recommendation, The International Agency for Research on • see the following parts of the Third Cancer (IARC) reviewed evidence for three Expert Report available online: additional cancers and concluded that greater Recommendations and public health body fatness is a cause of thyroid cancer, and policy implications multiple myeloma and meningioma [49]. (wcrf.org/cancer-prevention-recommendations) Exposures: Body fatness and weight gain Overweight and obesity in childhood and • (wcrf.org/body-fatness) early life are liable to be carried through Energy balance and body fatness to adulthood. (wcrf.org/energy-balance-body-fatness) CUP cancer reports (wcrf.org/cancers) Implications for other diseases CUP systematic literature reviews It is well established that greater body fatness (wcrf.org/toolkit) has a causal role in the development of several other disorders and diseases, such as type 2 diabetes, dyslipidaemia, hypertension, stroke and coronary heart disease, as well as digestive and musculoskeletal disorders [50–54]. People with obesity often develop several of these disorders or diseases, leading to multiple comorbidities (see Appendix 1 in the more Recommendations and public health detailed and policy implications¹ part of the Third Expert Report available online). 1 The more detailed Recommendations and public health and policy implications part of the Third Expert Report is available online at wcrf.org/cancer-prevention-recommendations 2018 49 A summary of the Third Expert Report

52 RECOMMENDATION Be physically active Be physically active as part of everyday life – walk more and sit less 1 GOAL , and follow or exceed national guidelines Be at least moderately physically active GOAL Limit sedentary habits 1 Moderate physical activity increases heart rate to about 60 to 75 per cent of its maximum. In most parts of the world, levels of physical For cancer prevention, it is likely that the greater activity are insufficient for optimal health [64]. the amount of physical activity, the greater the Sedentary ways of life have become common in benefit. To have a significant impact on weight high-income countries since the second half control, higher levels of activity are required of the 20th century and have subsequently also (45–60 minutes of moderate-intensity physical become widespread in most populations around activity per day) [56]. the world [65]. Children and young people aged 5 to 17 are advised to accumulate at least 60 minutes of Goals moderate- to vigorous-intensity physical activity Be at least moderately physically active, daily. Being physically active for longer than 60 GOAL and follow or exceed national guidelines minutes provides additional health benefits [57]. Establish a daily habit of being physically active Activities that are moderate in intensity throughout life, including when older. People include walking, cycling, household chores, whose work is sedentary need to take special gardening and certain occupations, as care to build some physical activity into well as recreational activities such as everyday life. swimming and dancing. Vigorous activities include running, fast swimming, fast WHO advises adults to be active daily, taking cycling, aerobics and some team sports. part throughout each week in at least 150 minutes of moderate-intensity, aerobic physical activity or at least 75 minutes of vigorous, aerobic physical activity (or a combination) [55]. This represents a minimum amount of physical activity for cardiometabolic health. a Global Perspective 50 Diet, Nutrition, Physical Activity and Cancer:

53 Justification This recommendation was made for several reasons: There is from the CUP strong evidence • Sections 3 (see matrices in ): 5.1.5 and Physical activity helps protect against % several cancers. Physical activity, including walking, helps % protect against weight gain, overweight and obesity. Greater screen time is a cause of weight % gain, overweight and obesity. Greater body fatness is a cause of % many cancers. A lack of physical activity and sedentary • lifestyles are both globally widespread. In most parts of the world, levels of % GOAL Limit sedentary habits physical activity are insufficient for optimal health [64]. Both adults and children are advised to minimise Sedentary ways of life have become % the amount of time spent being sedentary for common in high-income countries since extended periods. the second half of the 20th century For adults, many occupations involve prolonged and have subsequently also become periods of sitting. widespread in most populations around the world [65]. For both adults and children, watching screens (including when working) on devices such as Implications for other diseases televisions, computers, smartphones and video Regular physical activity of at least moderate games is a form of sedentary behaviour. In intensity decreases the risk of all-cause some countries, children commonly spend more mortality [66], coronary heart disease [67], than three hours a day on such devices, during high blood pressure [68], stroke [69], type which they are also often exposed to heavy 2 diabetes [67], metabolic syndrome [70] marketing of highly processed foods and drinks and depression [71]. high in fat, refined starches or sugars [58, 59]. Screen time may also be associated with Regular weight-bearing and muscle- consumption of energy dense snacks and strengthening exercise has documented health drinks [60–63]. benefits, including promoting bone health and reducing blood pressure [72]. 2018 51 A summary of the Third Expert Report

54 Greater body fatness is a common risk For further information on the factor for many other diseases and disorders, evidence, analyses and judgements including cardiovascular disease (CVD) and type that led to this Recommendation, 2 diabetes (see the Recommendation ‘be a see the following parts of the Third Expert Report available online: healthy weight’). Recommendations and public For further information on the implications for health and policy implications other diseases see Appendix 1 in the more (wcrf.org/cancer-prevention-recommendations) detailed Recommendations and public health Exposures: Physical activity and policy implications¹ part of the Third Expert (wcrf.org/physical-activity) Report available online. Energy balance and body fatness (wcrf.org/energy-balance-body-fatness) Public health and policy implications CUP cancer reports (wcrf.org/cancers) A comprehensive package of policies is needed CUP systematic literature reviews to promote and support physical activity, including (wcrf.org/toolkit) policies that influence the food environment, food system, built environment and behaviour change communication across the life course. These policies can also help contribute to a sustainable ecological environment. Policymakers are encouraged to frame specific goals and actions according to their national context. 1 The more detailed Recommendations and public health and policy implications part of the Third Expert Report is available online at wcrf.org/cancer-prevention-recommendations a Global Perspective 52 Diet, Nutrition, Physical Activity and Cancer:

55 RECOMMENDATION Eat a diet rich in wholegrains, vegetables, fruit and beans Make wholegrains, vegetables, fruit, and pulses (legumes) such as beans and lentils a major part of your usual daily diet 1 GOAL Consume a diet that provides at least 30 grams per day of fibre from food sources GOAL Include in most meals foods containing wholegrains, non-starchy vegetables, fruit and pulses (legumes) such as beans and lentils GOAL Eat a diet high in all types of plant foods including at least five portions or servings (at least 400 grams or 15 ounces in total) of a variety of non-starchy vegetables and fruit every day GOAL If you eat starchy roots and tubers as staple foods, eat non-starchy vegetables, fruit and pulses (legumes) regularly too if possible 1 Measured by the AOAC method. Relatively unprocessed foods of plant Goals origin are rich in nutrients and dietary fibre. Consume a diet that provides at GOAL Higher consumption of these foods instead least 30 grams per day of fibre of processed foods high in fat, refined from food sources 1 would provide a diet starches and sugars Include in most meals foods containing that is higher in essential nutrients and GOAL wholegrains, non-starchy vegetables, more effective for regulating energy intake fruit and pulses (legumes) such as beans relative to energy expenditure. This could and lentils protect against weight gain, overweight and obesity and therefore protect against obesity- Eat a diet high in all types of plant GOAL related cancers. Wholegrains, non-starchy foods including at least five portions vegetables, fruit and beans are a consistent or servings (at least 400 grams or feature of diets associated with lower risk 15 ounces in total) of a variety of non- of cancer and other non-communicable starchy vegetables and fruit every day diseases (NCDs), as well as obesity [73]. 1 Processed foods high in refined starches include products made from white flour such as bread, pasta and pizza; and processed foods that are high in fat, starches or sugars include cakes, pastries, biscuits (cookies), other bakery foods and confectionery (candy). 2018 53 A summary of the Third Expert Report

56 The goal for fibre intake can be met by eating Wholegrains, non-starchy vegetables, fruit a range of foods of plant origin, including and pulses (legumes) all contain substantial wholegrains and non-starchy vegetables and amounts of fibre and a variety of micronutrients, fruit of different colours (for example, red, green, and are low or relatively low in energy density. yellow, white, purple and orange). For cancer prevention, it is best if these, and not foods of animal origin, are the basis for a usual Examples of wholegrains include brown rice, daily diet. wheats, oats, barley and rye. Justification Examples of non-starchy vegetables include several This recommendation was made for green leafy vegetables, broccoli, okra, aubergine reasons: (eggplant) and bok choy, but not, for instance, potatoes, yams or cassava. There is strong evidence from the CUP • ): 5.1.5 and Sections 3 (see matrices in For the purposes of this Recommendation, Consuming wholegrains helps protect % non-starchy roots and tubers such as carrots, against colorectal cancer. artichokes, celeriac (celery root), swede Consuming dietary fibre helps protect (rutabaga) and turnips are considered to % against colorectal cancer and weight gain, be non-starchy vegetables. overweight and obesity. One portion of non-starchy vegetables or Greater body fatness is a cause of % fruit is approximately 80 grams or 3 ounces. many cancers. If consuming the recommended amount of vegetables and fruit, consumption would be Although the evidence for links between % at least 400 grams or 15 ounces per day. individual cancers and consumption of non-starchy vegetables or fruit is limited, If you eat starchy roots and tubers GOAL the pattern of association and the as staple foods, eat non-starchy direction of effect are both consistent. vegetables, fruit and pulses (legumes) Overall the evidence is more persuasive regularly too if possible of a protective effect and that greater consumption of non-starchy vegetables In many parts of the world, traditional food and or fruit helps protects against a systems are based on roots or tubers such as number of aerodigestive cancers and cassava, sweet potatoes, yams and taro. Where some other cancers. appropriate, it is advisable to protect traditional food systems – in addition to their cultural some evidence from the CUP There is • value, and their suitability to local climate and (see matrix in ) to suggest: Section 3 terrain, they are often nutritionally superior to the diets that tend to displace them. However, Consuming fruit and vegetables might % monotonous traditional diets, especially those decrease the likelihood of many cancers. that contain only small amounts of non-starchy Consuming fruit and vegetables might % vegetables, fruit and pulses (legumes), are likely decrease the likelihood of weight gain, to be low in essential micronutrients and thereby overweight and obesity. increase susceptibility to some cancers. a Global Perspective 54 Diet, Nutrition, Physical Activity and Cancer:

57 People who eat no or low levels of % Public health and policy implications vegetables and fruit, who increase their A comprehensive package of policies is needed consumption, may benefit most from to promote and support physical activity, including following this Recommendation policies that influence the food environment, food system and behaviour change communication Wholegrains, non-starchy vegetables, fruit • across the life course. These policies can also and beans are a consistent feature of diets help contribute to a sustainable ecological associated with lower risk of cancer and environment. Policymakers are encouraged other NCDs, as well as obesity [73]. to frame specific goals and actions according to their national context. Relatively unprocessed foods of plant origin • are rich in nutrients and dietary fibre. Higher consumption of these foods instead of For further information on the processed foods high in fat, refined starches evidence, analyses and judgements and sugars would mean the diet is higher in that led to this Recommendation, see the following parts of the essential nutrients and more effective for Third Expert Report available online: regulating energy intake relative to energy expenditure. Recommendations and public health and policy implications (wcrf.org/cancer-prevention-recommendations) Implications for other diseases Exposures: Body fatness and weight gain The Goals and Recommendation on wholegrains, (wcrf.org/body-fatness) vegetables, fruit and beans are based on Exposures: Wholegrains, vegetables and fruit evidence on cancer, but are supported by (wcrf.org/wholegrains-veg-fruit) evidence on cardiovascular disease and type Energy balance and body fatness 2 diabetes [67, 74, 75]. Many other, broadly (wcrf.org/energy-balance-body-fatness) similar recommendations have been issued by CUP cancer reports (wcrf.org/cancers) a range of authoritative international and national organisations (see Appendix 1 in the CUP systematic literature reviews more detailed Recommendations and public (wcrf.org/toolkit) health and policy implications¹ part of the Third Expert Report available online). Greater body fatness is a common risk factor for many other diseases and disorders, including cardiovascular diseases (CVDs) and type 2 diabetes (see the Recommendation ‘Be a healthy weight’ and Appendix 1 in Recommendations and public health and 1 ). policy implications 1 The more detailed Recommendations and public health and policy implications part of the Third Expert Report is available online at wcrf.org/cancer-prevention-recommendations 2018 55 A summary of the Third Expert Report

58 RECOMMENDATION Limit consumption of ‘fast foods’ and other processed foods high in fat, starches or sugars Limiting these foods helps control calorie intake and maintain a healthy weight GOAL Limit consumption of processed foods high in fat, starches or sugars – including 1 ‘fast foods’ ; many pre-prepared dishes, snacks, bakery foods and desserts; and confectionery (candy) 1 ‘Fast foods’ are readily available convenience foods that tend to be energy dense and are often consumed frequently and in large portions. Overweight and obesity are at the highest Justification levels ever seen globally. Processed foods high This recommendation was made for in fat, starches or sugars embody a cluster of several reasons: characteristics that encourage excess energy strong evidence There is from the CUP • consumption, for example, by being highly and (see matrices in 5.1.5 ): Sections 3 palatable, high in energy, affordable, easy Consuming ‘fast foods’ (readily available % to access and convenient to store. convenience foods that tend to be energy dense and are often consumed frequently Goal and in large portions) is a cause of weight Limit consumption of processed foods gain, overweight and obesity. GOAL high in fat, starches or sugars – including Consuming a ‘Western type’ diet % ‘fast foods’; many pre-prepared dishes, (characterised by a high amount of free snacks, bakery foods and desserts; and sugars, meat and fat) is a cause of weight confectionery (candy) gain, overweight and obesity. This Recommendation does not imply that all Glycaemic load (the increase in blood % foods high in fat need to be avoided. Some, glucose (and insulin) after consumption of such as certain oils of plant origin, nuts and food) is a cause of endometrial cancer. seeds, are important sources of nutrients. Greater body fatness is a cause of % Their consumption has not been linked with many cancers. weight gain and by their nature they tend to be consumed in smaller portions. a Global Perspective 56 Diet, Nutrition, Physical Activity and Cancer:

59 The increasing availability, affordability • Public health and policy implications and acceptability of ‘fast foods’ and other A comprehensive package of policies is processed foods high in fat, starches or needed to limit the availability, affordability and sugars (which are highly palatable, high acceptability of ‘fast foods’ and other processed in energy and convenient to store) is foods, including policies that restrict marketing contributing to rising rates of overweight of such foods, especially to children. Policies are and obesity worldwide [76]. needed that influence the food environment, food system and behaviour change communication across the life course. These policies can also Implications for other diseases help contribute to a sustainable ecological Limited intake of processed foods high in fat, environment. Policymakers are encouraged starches or sugars is recommended by many to frame specific goals and actions according other organisations to reduce the risk of several to their national context. non-communicable diseases (NCDs) [77]. Limiting intake of ‘fast foods’ and other For further information on the processed foods high in fat, starches or sugars evidence, analyses and judgements reduces the risk of weight gain, overweight and that led to this Recommendation, obesity. Greater body fatness is a common risk see the following parts of the factor for many other diseases and disorders, Third Expert Report available online: including cardiovascular diseases (CVDs) and Recommendations and public type 2 diabetes (see the Recommendation health and policy implications ‘Be a healthy weight’ and Appendix 1 in the (wcrf.org/cancer-prevention-recommendations) more detailed Recommendations and public Exposures: Body fatness and weight gain health and policy implications¹ part of the Third (wcrf.org/body-fatness) Expert Report available online). Energy balance and body fatness (wcrf.org/energy-balance-body-fatness) CUP cancer reports (wcrf.org/cancers) CUP systematic literature reviews (wcrf.org/toolkit) 1 The more detailed Recommendations and public health and policy implications part of the Third Expert Report is available online at wcrf.org/cancer-prevention-recommendations 2018 57 A summary of the Third Expert Report

60 RECOMMENDATION Limit consumption of red and processed meat 1 Eat no more than moderate amounts of red meat , such as beef, pork and lamb. Eat little, if any, 2 processed meat GOAL If you eat red meat, limit consumption to no more than about three portions per week. Three portions is equivalent to about 350 to 500 grams (about 12 to 18 ounces) 3 cooked weight of red meat. Consume very little, if any, processed meat 1 The term ‘red meat’ refers to all types of mammalian muscle meat, such as beef, veal, pork, lamb, mutton, horse and goat. 2 The term ‘processed meat’ refers to meat that has been transformed through salting, curing, fermentation, smoking or other processes to enhance flavour or improve preservation. 3 500 grams of cooked red meat is roughly equivalent to 700–750 grams of raw meat, but the exact conversion depends on the cut of meat, the proportions of lean meat and fat, and the method and degree of cooking. The Recommendation is not to completely avoid An integrated approach to the evidence shows that diets that reduce the risk of cancer and eating meat; meat can be a valuable source other non-communicable diseases (NCDs) of nutrients, in particular protein, iron, zinc contain no more than modest amounts of red and vitamin B12. However, it is not necessary meat and little or no processed meat. to consume red meat in order to maintain adequate nutritional status [78]. People who choose to eat meat-free diets can obtain Goal adequate amounts of these nutrients through If you eat red meat, limit consumption careful food selection. Protein can be obtained GOAL to no more than about three portions from a mixture of wholegrains (cereals) and per week. Three portions is equivalent pulses (legumes), such as beans and lentils. to about 350 to 500 grams (about 12 Iron is present in many plant foods, though to 18 ounces) cooked weight of red meat. it is less bioavailable than that in meat. Consume very little, if any, processed meat Poultry and fish are valuable substitutes for red meat. Eggs and dairy are also valuable sources of protein and micronutrients for people who do eat other foods of animal origin. High consumers of red meat and processed meat who reduce their intakes are expected to gain the greatest benefit from following this Recommendation. a Global Perspective 58 Diet, Nutrition, Physical Activity and Cancer:

61 Opportunities to use refrigeration to preserve Eating patterns that include a low intake of fresh meat remain limited in some countries, meat, processed meat and processed poultry where processed meat might be an important are associated with reduced risk of CVD in source of protein and iron. adults [77] and possibly of type 2 diabetes [77]. Meat is an important source of iron but Justification restricting the amount of red meat consumed This recommendation was made for per person per week to a maximum of 350 several reasons: to 500 grams would have little effect on the proportion of adults with iron intakes below from the CUP There is strong evidence • recommended levels in people eating a mixed ): 5.1.5 and Sections 3 (see matrices in diet [82]. If unbalanced, vegetarian diets may Consuming red meat and consuming % increase the risk of iron deficiency. processed meat are causes of colorectal cancer. Public health and policy implications Red meat is a good source of protein, • A comprehensive package of policies is needed iron and other micronutrients (although to support people to consume diversified diets consumption of red meat is not necessary to including limited red meat and little, if any, maintain adequate nutritional status) [78]. processed meat, including policies that influence the food environment, food system and behaviour The amount of red meat specified in the % change communication across the life course. Recommendation was chosen to provide a Globally, food systems that are directed towards balance between the advantages of eating foods of plant rather than animal origin are more red meat (as a source of essential macro- likely to contribute to a sustainable ecological and micronutrients) and the disadvantages environment. Policymakers are encouraged (an increased risk of colorectal cancer and to frame specific goals and actions according other NCDs). to their national context. Processed meat is generally energy • dense, can contain high levels of salt, and some of the methods used to create it For further information on the evidence, analyses and judgements generate carcinogens. that led to this Recommendation, The data on processed meat show % see the following parts of the Third Expert Report available online: that there is no level of intake that can confidently be associated with a lack of Recommendations and public risk of colorectal cancer. health and policy implications (wcrf.org/cancer-prevention-recommendations) Exposures: Meat, fish and dairy products Implications for other diseases (wcrf.org/meat-fish-dairy) Greater consumption of red and processed (wcrf.org/cancers) CUP cancer reports meat is associated with increased risk of death from cardiovascular disease (CVD) [78] and risk CUP systematic literature reviews of stroke [79] and type 2 diabetes [80]. (wcrf.org/tooklit) 2018 59 A summary of the Third Expert Report

62 RECOMMENDATION Limit consumption of sugar sweetened drinks Drink mostly water and unsweetened drinks 1 GOAL Do not consume sugar sweetened drinks 1 Sugar sweetened drinks are defined here as liquids that are sweetened by adding free sugars, such as sucrose, high fructose corn syrup and sugars naturally present in honey, syrups, fruit juices and fruit juice concentrate. This includes, among others, sodas, sports drinks, energy drinks, sweetened waters, cordials, barley water, and coffee- and tea-based beverages with sugars or syrups added. This does not include versions of these drinks which are ‘sugar free’ or sweetened only with artificial sweeteners. There is no strong evidence in humans to Consumption of sugar sweetened drinks is suggest that artificially sweetened drinks with increasing in many countries worldwide and is minimal energy content, such as diet sodas, contributing to the global increase in obesity, are a cause of cancer. which increases the risk of many cancers. Goal Justification This recommendation was made for GOAL Do not consume sugar sweetened drinks several reasons: To maintain adequate hydration, it is best from the CUP strong evidence There is • to drink water or unsweetened drinks, such (see matrices in and 5.1.5 ): Sections 3 ) or coffee without as tea ( Camellia sinensis Consuming sugar sweetened drinks (which % added sugar. provide energy but may not reduce appetite) is a cause of weight gain, overweight Coffee and tea both contain caffeine. For and obesity in both children and adults, healthy adults, the maximum safe daily intake especially when consumed frequently or in of caffeine recommended by the European Food large portions. This effect is compounded Safety Authority [83] is 400 milligrams per day at low levels of physical activity. (approximately four cups of brewed coffee). Sugar sweetened drinks do so by promoting The limit is lower in pregnancy. % excess energy intake relative to energy Do not consume fruit juices in large quantities, expenditure. as even with no added sugar they are likely to Greater body fatness is a cause of % promote weight gain in a similar way to sugar many cancers. sweetened drinks. Most national guidelines now recommend limiting intake of fruit juice. a Global Perspective 60 Diet, Nutrition, Physical Activity and Cancer:

63 Consumption of sugar sweetened drinks has • Public health and policy implications rapidly increased in many parts of the world, A comprehensive package of policies is especially in low- and middle-income countries, needed to limit the availability, affordability and contributing to rising rates of overweight acceptability of sugar sweetened drinks, including and obesity [84]. Although sales of sugar marketing restrictions and taxes on sugar sweetened drinks have decreased in many sweetened drinks, and securing access to clean high-income countries over the same period, water (this is of particular relevance to school total consumption has remained high [84]. settings). Policies are needed that influence the food environment, food system and behaviour change communication across the life course. Implications for other diseases These policies can also help contribute to a Greater body fatness is a common risk factor sustainable ecological environment. Policymakers for many other diseases and disorders, are encouraged to frame specific goals and including cardiovascular disease (CVD) and actions according to their national context. type 2 diabetes (see the Recommendation ‘Be a healthy weight’ and Appendix 1 in the more detailed Recommendations and public For further information on the health and policy implications¹ part of the evidence, analyses and judgements Third Expert Report available online). that led to this Recommendation, see the following parts of the Some evidence suggests regular consumption Third Expert Report available online: of sugar sweetened drinks increases the risk Recommendations and public of type 2 diabetes independently of effects on health and policy implications adiposity [85]. (wcrf.org/cancer-prevention-recommendations) Exposures: Body fatness and weight gain Consumption of sugar sweetened drinks is a (wcrf.org/body-fatness) cause of dental caries and impaired oral health, Energy balance and body fatness particularly in children [86]. (wcrf.org/energy-balance-body-fatness) CUP cancer reports (wcrf.org/cancers) CUP systematic literature reviews (wcrf.org/tooklit) 1 The more detailed Recommendations and public health and policy implications part of the Third Expert Report is available online at wcrf.org/cancer-prevention-recommendations 2018 61 A summary of the Third Expert Report

64 RECOMMENDATION Limit alcohol consumption For cancer prevention, it’s best not to drink alcohol GOAL For cancer prevention, it’s best not to drink alcohol Consuming alcoholic drinks is a cause of many Justification cancers. There is no threshold for the level of This recommendation was made for consumption below which there is no increase several reasons: in the risk of at least some cancers. strong evidence There is from the CUP • and Sections 3 (see matrices in ): 5.1.5 Goal Drinking alcohol is a cause of % For cancer prevention, it’s best not to many cancers. GOAL drink alcohol Drinking alcohol helps protect against % kidney cancer (at least up to 30 grams If you do consume alcoholic drinks, do not or two drinks per day), but this is far exceed your national guidelines. Children should outweighed by the increased risk for not consume alcoholic drinks. Do not consume other cancers. alcoholic drinks if you are pregnant. Evidence from the CUP also shows: • Even small amounts of alcoholic drinks can % increase the risk of some cancers – there is no level of consumption below which there is no increase in the risk of at least some cancers. Alcoholic drinks of all types have a % similar impact on cancer risk. This Recommendation therefore covers all types of alcoholic drinks. a Global Perspective 62 Diet, Nutrition, Physical Activity and Cancer:

65 Implications for other diseases Public health and policy implications A comprehensive package of policies is needed Studies suggest some people who consume small amounts of alcohol may have lower risks to reduce alcohol consumption at a population of coronary heart disease (CHD) and early death level, including policies that influence the than non-drinkers, but only at low levels of availability, affordability and marketing of alcoholic drinks. Policymakers are encouraged consumption (about one unit a day) [87]. to frame specific goals and actions according Heavy alcohol use is overwhelmingly to their national context. detrimentally related to many cardiovascular diseases (CVDs), including hypertensive disease, haemorrhagic stroke and atrial fibrillation [88]. For further information on the Alcohol consumption is associated with various evidence, analyses and judgements that led to this Recommendation, kinds of liver disease – with fatty liver, alcoholic see the following parts of the hepatitis and cirrhosis being the most common Third Expert Report available online: – and with an increased risk of pancreatitis Recommendations and public [88] (see Appendix 1 in the more detailed health and policy implications Recommendations and public health and policy (wcrf.org/cancer-prevention-recommendations) implications¹ part of the Third Expert Report Exposures: Alcoholic drinks available online). (wcrf.org/alcoholic-drinks) Despite the uncertainties about the effects of (wcrf.org/cancers) CUP cancer reports moderate alcohol consumption on non-cancer CUP systematic literature reviews outcomes, drinking alcohol is not recommended (wcrf.org/toolkit) for any health benefit. 1 The more detailed Recommendations and public health and policy implications part of the Third Expert Report is available online at wcrf.org/cancer-prevention-recommendations 2018 63 A summary of the Third Expert Report

66 RECOMMENDATION Do not use supplements for cancer prevention Aim to meet nutritional needs through diet alone 1 GOAL High-dose dietary supplements are not recommended for cancer prevention – aim to meet nutritional needs through diet alone 1 A dietary supplement is a product intended for ingestion that contains a ‘dietary ingredient’ intended to achieve levels of consumption of micronutrients or other food components beyond what is usually achievable through diet alone. Justification For most people consumption of the right food and drink is more likely to protect against cancer This recommendation was made for than consumption of dietary supplements. several reasons: from the CUP strong evidence There is • Goal (see matrices in 5.1.5 and ): Sections 3 High-dose dietary supplements are not GOAL Taking high-dose beta-carotene % recommended for cancer prevention – supplements is a cause of lung cancer aim to meet nutritional needs through in current and former smokers. diet alone Trials of other high-dose supplements % This Recommendation applies to all doses have not consistently demonstrated the and formulations of supplements, unless protective effects of micronutrients on supplements have been advised by qualified cancer risk suggested by observational health professional, who can assess studies. Although taking calcium individual requirements as well as potential supplements helps protect against risks and benefits. colorectal cancer, some trials for other cancer sites have shown potential for In some situations – for example, in preparation unexpected adverse effects. for pregnancy or in dietary inadequacy – Disparity between the beneficial effects % supplements may be advisable to prevent of micronutrients from foods observed nutrient or calorie deficiencies. In general in long-term dietary data and the lack though, for otherwise healthy people with secure of beneficial effects observed in short- access to a regular supply of a variety of foods term supplements trial data can lead to and drinks, nutrient-dense diets can provide uncertainty as to the effect of dietary adequate intake of nutrients. supplements on cancer risk. For most people, it is possible to obtain % adequate nutrition from a healthy diet that includes the right foods and drinks. a Global Perspective 64 Diet, Nutrition, Physical Activity and Cancer:

67 The best approach is to protect or improve Implications for other diseases local food systems so that they are nutritionally Supplementation may be needed to achieve adequate and promote healthy diets. This adequate intake of nutrients in populations or also applies in high-income countries, where people with nutrient insufficiency. For example, impoverished communities and families, people with dietary anaemia may need iron or vulnerable people including those living alone, folic acid supplementation [89]. To promote the elderly, and the chronically ill or infirm, may bone health, adequate calcium intakes and also be consuming nutritionally inadequate adequate supply of vitamin D are required; diets. Again, in such cases of immediate supplementation is sometimes necessary need, supplementation is necessary. [72] (see Appendix 1 in the more detailed Recommendations and public health and policy Policymakers are advised to maximise the implications¹ part of the Third Expert Report proportion of the population achieving nutritional available online). adequacy without dietary supplements by implementing policies that create a healthy food Public health and policy implications environment and food system. Policymakers are encouraged to frame specific goals and actions In many parts of the world, nutritional according to their national context. inadequacy is endemic and may increase the risk of non-communicable diseases (NCDs) [90]. In crisis situations it is necessary to supply For further information on the supplements of nutrients to such populations evidence, analyses and judgements or to fortify food to ensure at least minimum that led to this Recommendation, adequacy of nutritional status. see the following parts of the Third Expert Report available online: Recommendations and public health and policy implications (wcrf.org/cancer-prevention-recommendations) Exposures: Other dietary exposures (wcrf.org/other-dietary-exposures) CUP cancer reports (wcrf.org/cancers) CUP systematic literature reviews (wcrf.org/toolkit) 1 The more detailed Recommendations and public health and policy implications part of the Third Expert Report is available online at wcrf.org/cancer-prevention-recommendations 2018 65 A summary of the Third Expert Report

68 RECOMMENDATION For mothers: breastfeed your baby, if you can Breastfeeding is good for both mother and baby GOAL This recommendation aligns with the advice of the World Health Organization, which 1 recommends infants are exclusively breastfed for 6 months, and then up to 2 years of age or beyond alongside appropriate complementary foods 1 ‘Exclusive breastfeeding’ is defined as giving a baby only breastmilk (including breastmilk that has been expressed or is from a wet nurse) and nothing else – no other liquids or solid foods, not even water [93]. It does, however, allow the infant to receive oral rehydration solution, drops or syrups consisting of vitamins, minerals, supplements or medicines [93]. Justification Data from the World Health Organization (WHO) show that the percentage of infants This recommendation was made for who are exclusively breastfed for the first several reasons: 6 months of life is highest in low-income from the CUP strong evidence There is • countries (47 per cent) and lowest in upper- Sections 3 (see matrices in 5.1.5 and ): middle-income countries (29 per cent) [91]. The Breastfeeding helps protect the mother % global average prevalence is 36 per cent [92]. against breast cancer. Having been breastfed helps protect % Goal children against excess weight gain, This recommendation aligns with the GOAL overweight and obesity. advice of the World Health Organization, Greater body fatness is a cause of % which recommends infants are exclusively many cancers. breastfed for 6 months, and then up to 2 years of age or beyond alongside Excess body fatness during childhood tends • appropriate complementary foods to track into adult life (see the more detailed The benefits for both mother and baby are part of the Energy balance and body fatness¹ greater the longer the cumulative duration of Third Expert Report available online). breastfeeding. Excess body fatness during childhood is • Breastfeeding is recommended with caution or associated with an earlier menarche in is not advised in some situations, for example, girls, which in turn increases the risk of for mothers with HIV/AIDS; see WHO guidance several cancers. for further information [94]. 1 The more detailed Energy balance and body fatness part of the Third Expert Report is available online at wcrf.org/energy-balance-body-fatness a Global Perspective 66 Diet, Nutrition, Physical Activity and Cancer:

69 Breastfeeding protects the development of • Public health and policy implications the immature immune system and protects A comprehensive package of policies is needed against infections in infancy and other to promote, protect and support breastfeeding, childhood diseases. including making all hospitals supportive of breastfeeding, providing counselling in healthcare Breastfeeding is vital where water supplies • settings, implementing maternity protection are not safe. in the workplace, and regulating marketing of breastmilk substitutes. Policymakers are Breastfeeding is important for the development • encouraged to frame specific goals and actions of the bond between mother and child. according to their national context. In most countries, only a minority of • mothers exclusively breastfeed their babies For further information on the until 4 months, and an even smaller number evidence, analyses and judgements until 6 months. Increasing the rate of that led to this Recommendation, exclusive breastfeeding is one of WHO’s see the following parts of the Third Expert Report available online: Global Nutrition Targets 2025 [95]. Recommendations and public health and policy implications Implications for other diseases (wcrf.org/cancer-prevention-recommendations) The incidence of infections, as well as mortality Exposures: Lactation (wcrf.org/lactation) rates, during infancy are lower in children Energy balance and body fatness who are breastfed [96]. Benefits continue (wcrf.org/energy-balance-body-fatness) into childhood and adulthood, with lower risks of other diseases, such as asthma [97]. CUP cancer reports (wcrf.org/cancers) There is some evidence to suggest risk of CUP systematic literature reviews type 2 diabetes is reduced in adulthood [97]. (wcrf.org/toolkit) Mothers who breastfeed have a lower risk of type 2 diabetes [97]. Greater body fatness is a common risk factor for many other diseases and disorders, including cardiovascular diseases (CVDs) and type 2 diabetes. For further information on the implications for other diseases see Appendix 1 in the more Recommendations and public health detailed and policy implications¹ part of the Third Expert Report available online. 1 The more detailed Recommendations and public health and policy implications part of the Third Expert Report is available online at wcrf.org/cancer-prevention-recommendations 2018 67 A summary of the Third Expert Report

70 RECOMMENDATION After a cancer diagnosis: follow our Recommendations, if you can Check with your health professional what is right for you 1 GOAL should receive nutritional care and guidance on physical activity All cancer survivors from trained professionals GOAL Unless otherwise advised, and if you can, all cancer survivors are advised to follow the Cancer Prevention Recommendations as far as possible after the acute stage of treatment 1 Cancer survivors are people who have been diagnosed with cancer, including those who have recovered from the disease. The circumstances of cancer survivors vary requirements; as are people after treatment greatly. There is increased recognition of the whose ability to consume or metabolise food potential importance of diet, nutrition, physical has been altered by treatment; and people in the activity and body fatness in cancer survival. later stages of cancer whose immediate need is People who have been diagnosed with cancer to arrest or slow down weight loss. The advice should consult an appropriately trained health of an appropriately trained health professional professional as soon as possible, who can take is essential in all of these situations. each person’s circumstances into account. The evidence does not support the use of supplements as a means of improving survival. Goals However, supplements may be specifically All cancer survivors should receive advised by an appropriately trained professional GOAL nutritional care and guidance on physical for other reasons. activity from trained professionals Unless otherwise advised, and if you can, GOAL There is increased recognition of the potential all cancer survivors are advised to follow the Cancer Prevention Recommendations importance of diet, nutrition, physical activity and as far as possible after the acute stage of body fatness in cancer survival. Circumstances treatment of cancer survivors vary greatly and people who have been diagnosed with cancer should be given There is growing evidence that physical the opportunity, as soon as possible, to consult activity and other measures that control an appropriately trained health professional who weight (both features of the Cancer Prevention can take each person’s circumstances into account. Recommendations) may help to improve survival and health-related quality of life after a breast People who are undergoing treatment for cancer diagnosis. cancer are likely to have special nutritional a Global Perspective 68 Diet, Nutrition, Physical Activity and Cancer:

71 Implications for other diseases Justification This recommendation was made for Evidence shows that following a dietary several reasons: pattern close to the Cancer Prevention Recommendations is likely to help prevent For breast cancer survivors, there is • other NCDs [1–3] as well as to help persuasive evidence that nutritional factors management and control of co-existing NCDs, (in particular body fatness) and physical which can complicate treatment and reduce activity reliably predict important outcomes survival (see Appendix 1 in the more detailed from breast cancer. However, the evidence Recommendations and public health and policy that changing these factors would alter the implications¹ part of the Third Expert Report clinical course of breast cancer is limited, available online). particularly by the quality of published studies. Although research on the effects of diet, • Public health and policy implications nutrition and physical activity and the risk of A comprehensive whole-of-government, whole- cancer is growing, only evidence on the effects of-society approach is necessary to create of these lifestyle factors on survival and future environments for cancer survivors that are risk of breast cancer has been reviewed. This conducive to following the Cancer Prevention is currently the best evidence available. Recommendations, and future, more specific evidence-based recommendations. The current understanding of the biology • of cancer and its interactions with diet, nutrition and physical activity supports this For further information on the Recommendation. evidence, analyses and judgements that led to this Recommendation, More people are surviving cancer than see the following parts of the • Third Expert Report available online: ever before, at least partly because of earlier detection and increasing success Recommendations and public health and policy implications of treatment for many cancers. As a result, (wcrf.org/cancer-prevention-recommendations) cancer survivors are living long enough to develop new primary cancers or other non- Survivors of breast and other cancers (wcrf.org/cancer-survivors) communicable diseases (NCDs). Following the Cancer Prevention Recommendations CUP breast cancer survivors report 2014 may improve survival and reduce the risk (wcrf.org/breast-cancer-survivors-report) both of cancer and of other NCDs. Energy balance and body fatness (wcrf.org/energy-balance-body-fatness) (wcrf.org/cancers) CUP cancer reports CUP systematic literature reviews (wcrf.org/toolkit) 1 The more detailed Recommendations and public health and policy implications part of the Third Expert Report is available online at wcrf.org/cancer-prevention-recommendations 2018 69 A summary of the Third Expert Report

72 focused on the need to provide adequate 5.2 Regional and special circumstances nutrition to prevent stunting (which remains an important issue for some parts of the world). This section summarises findings of the CUP that were not suitable for inclusion in the global In adulthood there is no way to modify • Recommendations even though the evidence these factors. is judged to be strong (either ‘probable’ or ‘convincing’). Where appropriate, locally A better understanding of the developmental • applicable actions are recommended. factors that underpin the association between wth and cancer risk is needed. greater gro For further information, see the more detailed Recommendations and For further information, see the Exposures: public health and policy implications part of the Third Expert Report Height and birthweight¹ part of the Third Expert available online at Report available online. wcrf.org/cancer-prevention-recommendations Arsenic in drinking water 5.2.1 Issues of public health significance Arsenic may contaminate water supplies as The following exposures are judged to be causally a result of agricultural, mining and industrial linked to cancer but are public health issues that practices. It can also occur naturally. people cannot necessarily influence themselves. The Panel’s judgement: Height and birthweight that consuming There is strong evidence • arsenic in drinking water is a cause of several cancers. The Panel’s judgements: that developmental There is strong evidence • factors leading to greater growth in length The International Agency for Research on Cancer in childhood (marked by adult attained (IARC) has judged arsenic and inorganic arsenic height) are a cause of many cancers. compounds to be carcinogenic to humans [98]. that factors There is strong evidence • Drinking water contaminated with arsenic is also that lead to greater birthweight, or classed separately as a human carcinogen [98]. its consequences, are a cause of premenopausal breast cancer. The joint Food and Agriculture Organization of the United Nations/WHO Expert Committee on Food Additives has set a provisional tolerable Height and birthweight are not subject to a weekly intake of 0.015 milligrams of arsenic per Recommendation for several reasons: kilogram of body weight [99]. To date, growth standard s have not taken into • For further information, see the Exposures: 2 account the lifelong risk of NCDs, including part of the Third Expert Non-alcoholic drinks cancer, as policies and programmes have Report available online. 1 Exposures: Height and birthweight part of the Third Expert Report is available online at wcrf.org/height-birthweight The 2 Exposures: Non-alcholic drinks part of the Third Expert Report is available online at wcrf.org/non-alcoholic-drinks The a Global Perspective 70 Diet, Nutrition, Physical Activity and Cancer:

73 regional authorities, other policymakers, health Actions: professionals and for people. Do not use any source of water that may • be contaminated with arsenic. Mate Authorities should ensure that safe • Mate, an aqueous infusion prepared from water supplies are available when such , is Ilex paraguariensis dried leaves of the plant contamination occurs. traditionally consumed scalding hot following repeated addition of almost boiling water to Aflatoxins the infusion. Some foods may become contaminated with aflatoxins, which are produced by some moulds The Panel’s judgement: when foods are stored for too long at warm temperatures in a humid environment. Foods There is strong evidence that consuming • that may be affected include cereals, spices, mate, as drunk in the traditional style in peanuts, pistachios, Brazil nuts, chillies, black South America, is a cause of oesophageal squamous cell carcinoma. pepper, dried fruit and figs. The Panel’s judgement: For further information, see the Exposures: 2 part of the Third Expert Non-alcoholic drinks that higher There is strong evidence • Report available online. consumption of aflatoxin-contaminated foods is a cause of liver cancer. Actions: The Panel recognises that consumption • For further information, see the Exposures: of mate is a traditional practice in parts 1 part of the Wholegrains, vegetables and fruit of South America. However, for cancer Third Expert Report available online. prevention, do not consume mate as drunk scalding hot in the traditional style. Actions: Do not eat mouldy cereals (grains) or pulses • Foods preserved by salting (legumes). Preserved foods may be eaten more by people Authorities should ensure that facilities for • who do not have access to refrigeration. the safe storage of foods are made available in areas at risk of aflatoxin contamination. The Panel’s judgement: 5.2.2 Issues relevant only in specific parts There is strong evidence , mostly from • of the world Asia, that consuming foods preserved If foods and drinks are consumed only in by salting (including salt-preserved particular regions of the world, general actions vegetables, fish and salt-preserved foods are recommended for use by relevant local or in general) is a cause of stomach cancer. 1 part of the Third Expert Report is available online at wcrf.org/wholegrains-veg-fruit The Exposures: Wholegrains, vegetables and fruit 2 Exposures: Non-alcholic drinks part of the Third Expert Report is available online at wcrf.org/non-alcoholic-drinks The 2018 71 A summary of the Third Expert Report

74 For further information, see the Exposures: Coffee Preservation and processing of foods¹ part Coffee is one of the main hot drinks consumed of the Third Expert Report available online. worldwide. It contains several bioactive constituents. Actions: The Panel’s judgement: Do not consume salt-preserved, salted or • salty foods. that consuming There is strong evidence • coffee helps protect against some cancers. Preserve foods without using salt. • Cantonese-style salted fish More research is needed to improve Cantonese-style salted fish, which is part of understanding of how the volume and regularity the traditional diet consumed by people living of consumption, type of coffee, and style of in the Pearl River Delta region in Southern preparation and serving (many people add milk China, is allowed to ferment and is eaten in and sugar), as well as the underlying potential a decomposed state. mechanisms, affect the risk of cancer. For further information, see the Exposures: The Panel’s judgement: Non-alcoholic drinks³ part of the Third Expert There is strong evidence that consuming Report available online. • Cantonese-style salted fish is a cause of nasopharyngeal cancer. ‘Mediterranean type’ dietary pattern Many studies have included a measure of adherence to the so-called ‘Mediterranean type’ For further information, see the Exposures: dietary pattern, but it is unclear exactly what such Meat, fish and dairy products² part of the Third a diet comprises. It generally describes a diet rich Expert Report available online. in fruit, vegetables and unrefined olive oil, with modest amounts of meat and dairy, and some Actions: fish and wine. This dietary pattern is traditionally Do not consume Cantonese-style salted fish. • associated with high levels of physical activity. Do not feed fish prepared in this way • to children. Currently the populations of most countries around the Mediterranean do not consume such a diet. A dietary and lifestyle pattern conforming 5.2.3 Issues of inadequate information to these principles represents one example of For some exposures, although the Panel judged an approach to meeting the Recommendations. there to be strong evidence of an effect on cancer risk, some aspects of that evidence, For further information, see the Energy balance such as the influence of dose, were inadequate 4 part of the Third Expert and body fatness to permit a meaningful recommendation. Report available online. 1 The Exposures: Preservation and processing of foods part of the Third Expert Report is available online at wcrf.org/preservation-processing 2 The Exposures: Meat, fish and dairy products part of the Third Expert Report is available online at wcrf.org/meat-fish-dairy 3 The Exposures: Non-alcoholic drinks part of the Third Expert Report is available online at wcrf.org/non-alcoholic-drinks 4 The Energy balance and body fatness part of the Third Expert Report is available online at wcrf.org/energy-balance-body-fatness a Global Perspective 72 Diet, Nutrition, Physical Activity and Cancer:

75 5.2.4 Issues of divergent evidence 5.3 Public health and policy implications For some exposures, although there was strong 5.3.1 Cancer Prevention Recommendations evidence of increase or decrease in the risk of cancer, there was evidence of an opposite effect The Cancer Prevention Recommendations on another cancer or other disease, meaning together constitute a blueprint for reducing cancer a general recommendation is inappropriate. risk through changing dietary patterns, reducing alcohol consumption, increasing physical activity Dairy products and calcium and achieving and maintaining a healthy body The evidence on dairy products and diets high 2 Together these exposures represent weight. in calcium is mixed. the major modifiable risk factors for cancer after tobacco smoking and other forms of tobacco use [100]; for non-smokers, they are the most The Panel’s judgement: important means of helping prevent cancer [101]. that There is strong evidence • consumption of dairy products, and The Recommendations provide guidance for consumption of calcium supplements, both people on how to reduce their risk by modifying help to protect against colorectal cancer. their choices, and from a policy perspective can physical , be divided into four main areas: diet and , breastfeeding , activity alcohol consumption However, there is also limited but suggestive recognising that these exposures also influence evidence that consumption of dairy products might body weight. increase the risk of prostate cancer. The evidence of potential for harm means no recommendation For further information, see the more has been made for dairy products. detailed Recommendations and public health and policy implications For further information, see the Exposures: part of the Third Expert Report 1 available online at part of the Meat, fish and dairy products wcrf.org/cancer-prevention-recommendations Third Expert Report available online. 5.3.2 Need for policy action Although well-informed choices are important in influencing personal risks of cancer and other diseases, many factors, such as the availability of different foods and the accessibility of physical environments for active ways of life, are outside people’s direct personal control. In order to effect change at a population level, it is essential to consider the environment within which people make their choices [102]. 1 The Exposures: Meat, fish and dairy products part of the Third Expert Report is available online at wcrf.org/meat-fish-dairy 2 The Panel emphasises the importance of not smoking, avoiding other exposure to tobacco, avoiding excess exposure of the skin to ultraviolet radiation (for example, sunlight) and preventing long-term infections that can cause cancer. 2018 73 A summary of the Third Expert Report

76 Environmental, economic and social factors are all throughout the United Nations’ 2030 Agenda important upstream determinants of the behaviours for Sustainable Development [107]. and choices that influence the risk of cancer and Supporting people and communities to follow other NCDs. These factors – which determine the Cancer Prevention Recommendations levels of physical activity, for example, and contributes to the global sustainable patterns of production and consumption of foods development agenda by promoting dietary and drinks (and thus body composition) – overlap patterns based on foods of plant origin, and and operate on global, national and local levels. helping to reduce premature mortality from These factors are experienced at a personal cancer and other NCDs. With the world’s level through their effects on the availability, population projected to reach 8.6 billion affordability, awareness and acceptability of by 2030 and 9.8 billion in 2050, finding a healthy foods, drinks and lifestyles – as well as way to feed the world sustainably is critical 1 – relative to unhealthy foods and breastfeeding [108]. Transport policies and systems drinks, alcohol and physical inactivity [103]. that prioritise walking, cycling and public They also contribute to health inequalities. transport provide opportunities for combined benefits: reducing fossil fuel consumption The same preventive strategies that target and traffic congestion, improving air quality upstream determinants of cancer risk can and increasing the health benefits associated often provide benefits across other diet-related with being physically active [109]. NCDs, owing to common underlying risk factors, making a strong case for a coordinated policy Vulnerable populations are often hit hardest approach. It is crucial that governments by the burden of NCDs and impact of climate prioritise disease prevention. change; therefore policy responses that promote equity are needed. WHO’s Global Action Plan for the Prevention and Control of NCDs 2013–2020 [104] was created 5.3.4 Using a policy framework to to strengthen national efforts to address the support action burden of NCDs. It includes a menu of policy A whole-of-government, whole-of-society approach options (updated in 2017 [105]) and nine is needed to create environments for people voluntary global targets, including a 25 per cent and communities that are conducive to following relative reduction in premature mortality from the Cancer Prevention Recommendations (and NCDs by 2025, but progress towards those improving overall health outcomes). targets has been insufficient [106]. In order to develop an appropriate and 5.3.3 Sustainability and health coordinated response, a framework-type Sustainable development is also important approach, as illustrated by the NOURISHING when considering lifestyle factors that framework described below, is useful. Policy influence the risk of cancer and other frameworks can help policymakers to: NCDs. NCDs pose a major challenge to conceptualise, organise and package policies • sustainable development; they are integrated to address risk factors 1 Policies are needed to promote, protect and support breastfeeding; however, it is recognised that not all mothers are able to breastfeed. a Global Perspective 74 Diet, Nutrition, Physical Activity and Cancer:

77 plan, develop, implement and evaluate policies • Box 8: How different groups use identify available policy levers and policy • NOURISHING options that can be used to create health- enhancing environments Policymakers: develop a comprehensive policy approach, • Enable and inform policy • which can be adapted to reflect national development and strategic direction contexts to achieve system-wide change. Identify what action is needed • 5.3.4.1 The NOURISHING framework Select and tailor policy options • for different populations A well-developed example of a framework-type Assess whether an approach approach is WCRF International’s NOURISHING • is comprehensive food policy framework (see Figure 6 ). Developed in 2013, the framework formalises a comprehensive Civil society organisations: package of policies to promote healthy diets Monitor what governments • and reduce overweight, obesity and diet-related are doing NCDs, including cancer [110]. Together with an Benchmark progress accompanying database of implemented policies • from around the world (see Box 7 ), it is a tool Hold governments to account • designed to help policymakers, civil society Assist governments • ). Box 8 organisations and researchers (see Researchers: The NOURISHING framework outlines 10 policy Identify the evidence available • areas in which governments need to take action for different policies food environment across three domains: , food Identify research gaps • and behaviour change communication system Monitor and evaluate policies • Figure 6 ). Each letter in NOURISHING (see represents a different policy area. A comprehensive approach to policy – taking 5.3.4.2 Broader application of the action across all 10 policy areas – is vital. NOURISHING framework Given the success of the NOURISHING Box 7: The NOURISHING policy database framework, as evidenced by its wide uptake by policymakers, researchers and civil society The NOURISHING database provides an organisations, WCRF International has used it extensive, regularly updated compendium to inform the development of a new structured of policy actions implemented in countries policy framework that addresses physical activity, around the world. A structured methodology alcohol consumption and breastfeeding, in addition is followed when compiling and updating the to diet. Common policy levers – broadly, policy database [111], which includes a process measures that influence availability, affordability, to verify the details and implementation of awareness and acceptability – can be used policy actions with in-country or regional policy to promote healthy diets, physical activity and experts. wcrf.org/NOURISHING breastfeeding, and reduce alcohol consumption. 2018 75 A summary of the Third Expert Report

78 To address the four factors of diet, physical For examples of policy options, and information activity, alcohol consumption and breastfeeding, on how they fit within the broadened framework, the new WCRF International framework has see Appendix 2 in the more detailed broadened NOURISHING’s three overarching Recommendations and public health and health-enhancing policy domains to policy implications¹ part of the Third Expert environments , systems change and behaviour Report available online. and modified and change communication expanded NOURISHING’s 10 policy areas to 11, to include healthy urban design (see ). Figure 7 Figure 6: The NOURISHING framework The WCRF International NOURISHING framework formalises a comprehensive package of policies to promote healthy diets and reduce overweight, obesity and diet-related non-communicable diseases. 1 The more detailed Recommendations and public health and policy implications part of the Third Expert Report is available online at wcrf.org/cancer-prevention-recommendations a Global Perspective 76 Diet, Nutrition, Physical Activity and Cancer:

79 Figure 7: A new policy framework to address diet, physical activity, breastfeeding and alcohol consumption A new policy framework that can be used to identify a comprehensive package of actions needed to create environments for people and communities that are conducive to following the Cancer Prevention Recommendations. 5.3.5 Responsibility for health All actors have an opportunity, and often a responsibility, to make decisions with Securing public health requires the organised a view to their impact on public health, efforts of society as a whole. including cancer prevention, but this does not necessarily happen unless mandated There are many ways of characterising how by the highest level of government. society is constructed. One example features four main pillars – multinational and regional The common feature of successful policy is bodies, government, private sector and civil concerted action led by governments (and society – which can each be segmented further through them multinational and regional bodies), into different groups of policymakers and with the support of civil society and professional decision-makers. organisations, all working in the public interest. It is important to strive for policy coherence – These ‘actors’ operate across different settings, where policies work together to achieve agreed including schools and other educational objectives rather than undermining each institutions, workplaces, public institutions, other. Governance structures that support cities, towns and rural communities, media, the engagement of multiple sectors and social media and networks, and homes. stakeholders can help improve policy coherence. 2018 77 A summary of the Third Expert Report

80 However, the development, adoption and sanctions for violations, is essential to implementation of policies to promote public enforcing regulations. health are often strongly opposed by industry and In contrast, evaluation is the systematic other actors (for example, government agencies assessment of a policy’s design, concerned with trade), who may see such implementation and outcomes, used to policies as obstructing their interests. Strategic draw conclusions about a policy’s relevance, advocacy efforts by civil society and professional effectiveness, cost-effectiveness, efficiency, organisations working in the public interest impact and sustainability. It provides a basis can help counter this opposition, as can robust for revising and improving policy over time. safeguards against conflicts of interest (see ). Box 9 ‘Real world’ implementation of policies can have 5.3.6 Monitoring and evaluation of impact unintended positive, negative or neutral impacts. and effectiveness As such, it is necessary to monitor and evaluate It is critically important to develop a framework policies to determine whether they are having for monitoring and evaluating policies, to assess the anticipated impact(s) along the pathway of the impact and effectiveness of implemented effects and, if not, why, so the policy can be policies, prior to the implementation of adjusted accordingly. regulatory measures. Lessons learned when developing and Monitoring is an ongoing process that uses implementing a policy, including factors that the systematic collection of data on specified promoted or obstructed success, can benefit indicators to assess the extent of progress others around the world. However, too few towards the achievement of a policy’s objective. evaluations of implemented policies are being Monitoring compliance, and imposing effective conducted, with most evaluations taking place in high-income countries. Box 9: Protecting policymaking from conflicts of interest It is important to consider how the core interests of different actors might conflict with those of health, and whether the way they conduct their activities helps or hinders the promotion of healthy diets, physical activity and breastfeeding, and the reduction of alcohol consumption. Governments bear responsibility for setting the policy and regulatory framework for promoting health, and for the prevention of cancer and other NCDs. Bodies such as the World Health Organization (WHO) also have responsibility for establishing normative standards in public health; the need to protect WHO from conflicts of interest is well established. Industry does have a role to play, but this should be restricted to the implementation stage of the policymaking process. It is not the role of industry, in particular the food and beverage industry, to be involved in setting policies (aside from when called upon to give specific feedback), owing to the inherent and unavoidable conflict of interest. Key questions to consider when engaging with private sector entities include whether core products and services are damaging to health, whether corporate social responsibility practices are independently audited, and whether clear parameters are set for engagement (which define, for example, responsibilities of different actors). a Global Perspective 78 Diet, Nutrition, Physical Activity and Cancer:

81 Changes since the 2007 6 Second Expert Report 6.1 An important shift in emphasis to a more holistic focus 80 6.2 Assessing and interpreting evidence: fine-tuning the approach 80 6.3 Emerging evidence of note 81 2018 79 A summary of the Third Expert Report

82 Furthermore, studies evaluating the impact 6.1 An important shift in emphasis to of adherence to the Cancer Prevention a more holistic focus Recommendations from 2007 have shown that the more people adhere to those The Recommendations in the Third Expert recommendations, the greater the reductions in Report are similar to those in the 2007 Second the risk of specific cancers, of cancer as a whole Expert Report. However, they incorporate an and of death from any cause [1–3]. important shift in emphasis in the Panel’s interpretation of the evidence. For all these reasons, therefore, the Panel emphasises the importance of recognising that, Through the years the Continuous Update while following each individual Recommendation CUP), and its predecessors the First Project ( is expected to offer cancer protection benefit, and Second Expert Reports [112, 113], the most benefit is to be gained by treating them have identified many specific foods (such as as an integrated pattern of behaviours relating processed meat) and components of foods to diet and physical activity, and other factors, (such as dietary fibre) in the human diet that that can be considered as a single overarching increase or decrease the risk of one or more ). Figure 8 ‘package’ or way of life (see particular cancers. The consistency in the Recommendations since However, it appears increasingly unlikely that 2007 increases confidence in the evidence base specific foods, nutrients or other components of and in the advice given to policymakers, the foods are themselves important singular factors scientific community, health professionals and in causing or protecting against cancer: rather, the public. different patterns of diet and physical activity combine to create a metabolic state that is more, or less, conducive to the acquisition of the 6.2 Assessing and interpreting evidence: genetic and epigenetic alterations that lead to the fine-tuning the approach phenotypical structural and functional alterations in cells described by the hallmarks of cancer There has been an increase in the overall (see Section 1: Diet, nutrition , physical activity amount of evidence since 2007. This has of this Summary). and the cancer process enabled the Panel to fine-tune its approach to assessing and interpreting evidence: In humans, as with all organisms, the normal physiological and metabolic state is subject to Growth in the number of cohort studies and • external and endogenous challenges (stresses). the number of cases in existing cohorts, Nutrition is an important component of the as well as improvement in the quality of body’s capacity to withstand these stresses these studies, has enabled the Panel to and avoid the development of diseases; in the concentrate more on evidence from cohort absence of frank nutritional deficiency, this studies, which are considered the best resilience is not dependent on the singular source of evidence on cancer prevention. effect of specific nutrients. A more holistic focus This growth has also provided greater on the determinants of resilience to external and confidence in the accumulated evidence. endogenous challenge may be more fruitful than Results from pooled analyses of cohort • a continuing search for specific dietary factors studies have been particularly helpful in that may cause or protect against cancer. adding evidence for subgroup analyses. a Global Perspective 80 Diet, Nutrition, Physical Activity and Cancer:

83 Where possible when reviewing evidence on • 6.3 Emerging evidence of note Panel has increasingly diet and nutrition, the considered the effects of dietary patterns. Emerging evidence that is particularly This is important because people do not eat noteworthy includes: foods in isolation but in combination, to form Growth in the amount of high-quality data that • an overall diet or eating pattern, which itself is available has allowed more sophisticated is related to other health-linked behaviours analyses of how effects on cancer risk such as smoking or physical activity. change with the level of exposure – for instance on the shape of dose–response While sophisticated epidemiological or associations. For fruit and vegetables, for statistical techniques may help to minimise example, emerging evidence suggests that the inevitable effect of confounding, those people who consume the least, who confidence in the nature of the truly causal eat very little or none of these foods, are exposure must always be greater for the most at risk of developing certain cancers. aggregated set of dietary factors and other be more important for these It may therefore behaviours than for any single food, nutrient people to increase their consumption levels or other behavioural marker. Therefore, even than for people who already eat more than where there is no direct evidence on dietary one or two portions per day. patterns the Panel has aimed to interpret The influence of height on cancer risk is • evidence on specific foods in relation to becoming more apparent. However, height dietary patterns. itself is unlikely to be the actual cause of cancer. It is most likely a marker for There is more evidence on subtypes of • developmental factors related to growth cancer now, such as oesophageal cancer, and metabolism operating from the and therefore more conclusions on the effect st stages of life to influence cancer earlie of diet, physical activity or body fatness on susceptibility. More research is needed to differential risks of these subtype s. Evidence build understanding of precisely how this on subtypes is still emerging. This is important might happen. because different exposures might influence the risk of different subtypes in different ways. The importance of the life course in general • is emerging more strongly. There is evidence It has been possible to use non-linear • that greater adult height predicts higher risk analyses more to identify thresholds, or of several cancers; and for breast cancer plateaus. For example, there may be a specifically, that greater birthweight is ure below threshold in the level of expos associated with higher risk, while greater which there is no association with the risk body fatness in young adulthood predicts of cancer and above which there is. This lower risk. However, more research is required has proved important, for example, when to help further understand the mechanisms. making Recommendations on the level of consumption of alcoholic drinks. Evidence on cancer survivors is accumulating, • though is still at an early stage, and more Stratified analyses have provided valuable • is needed, particularly from well-conducted ple, wh en considering insights, for exam trials (some of which are under way). the effect of exposures in relation to smoking status. 2018 81 A summary of the Third Expert Report

84 Figure 8: Our Cancer Prevention Recommendations as an overarching ‘package’ While following each individual Recommendation offers cancer protection benefit, most benefit is gained by treating all ten Recommendations as an integrated pattern of behaviours relating to diet, physical activity and other factors that can be considered as a single overarching ‘package’ or way of life. Diet, Nutrition, Physical Activity and Cancer: a Global Perspective 82

85 Future research directions 7 84 7. 1 Biological mechanisms by which diet, nutrition and physical activity affect cancer processes 85 The impact of diet, nutrition and physical activity throughout 7. 2 the life course on cancer risk 85 Better characterisation of diet, nutrition, body composition 7.3 and physical activity exposures 7.4 85 Better characterisation of cancer-related outcomes 7.5 86 Stronger evidence for the impact of diet, nutrition and physical activity on outcomes in cancer survivors 7.6 86 Globally representative research on specific exposures and cancer For further information, see the more detailed Future research directions part of the Third Expert Report wcrf.org/future-research-directions available online at 2018 83 A summary of the Third Expert Report

86 As part of the Continuous Update Project 7.1 Biological mechanisms by which diet, (CUP) process, the Panel has discussed the nutrition and physical activity affect implications of recent findings that emphasise cancer processes the importance of adopting a more holistic focus, by considering how different patterns Though not yet completely understood, the of diet and physical activity combine to create last few years have seen a rapid development a metabolic state that is more, or less, in the characterisation of the complex and conducive to the development of cancer (rather interacting intracellular and intercellular than focusing on singular effects of specific processes that lead to cancer, and the dietary factors such as individual foods, see generally consistent structural and behavioural Section 6.1: An important shift in emphasis characteristics of cancer cells (hallmarks of of this Summary). to a more holistic focus cancer – see ). However, despite Section 1 evidence of various types and from several These discussions have led the Panel to identify sources implicating nutritional factors as key six areas where research is needed: determinants of cancer patterns in populations, relatively little research has been devoted to 1. Biological mechanisms by which methodically exploring the impact of nutrition diet, nutrition and physical activity on these fundamental biological processes. affect cancer processes All biological processes depend on a supply The impact of diet, nutrition and 2. of energy and nutrients that are necessary physical activity throughout the life for normal function, and a nutritional course on cancer risk perspective would aim to characterise, in 3. Better characterisation of diet, a methodical way, the tolerance of these nutrition, body composition and processes to variations in the supply of energy physical activity exposures or nutrients at the cell or tumour level, and 4. Better characterisation of the extent to which whole body exposures outcomes cancer-related (diet, activity, body composition) impact on the tumour nutritional microenvironment. 5. Stronger evidence for the impact of diet, nutrition and physical activity Examining the impact of diet and nutrition in on outcomes in cancer survivors the epithelial tissue niches from which most 6. Globally representative research common tumours arise, and in the emerging on specific exposures and cancer tumour microenvironment, offers opportunities to reveal the critical mechanisms by which These areas are discussed in the following diet and nutrition can both potentiate and sections and are for consideration by the prevent the development of cancer [114–118]. research community and funding organisations The metabolic and phenotypic plasticity generally. More detailed information on all six of cells, including myofibroblasts, immune areas can be found in the full Future research cells and adipocytes, in microenvironmental part of the Third Expert Report directions¹ niches, is integral to the fate of potentially available online. 1 The more detailed Future research directions part of the Third Expert Report is available online at wcrf.org/future-research-directions a Global Perspective 84 Diet, Nutrition, Physical Activity and Cancer:

87 malignant cells [119]. The role of diet and Incorporating the following markers and specific nutrients in maintaining and perturbing measures into study designs could help to establish causal relationships between diet, appropriate metabolism and function in this nutrition, physical activity and disease, and to microenvironmental context is a research priority. avoid bias and measurement error: and/or new markers of dietary intake better • The impact of diet, nutrition and 7.2 or metabolism and physical activity. physical activity throughout the life more objective methods of measuring the • course on cancer risk effect of exposures, such as the use of The risk of several adult cancers varies with Mendelian randomisation. markers of aspects of growth and development better measures of body composition that • in early life – including birthweight and adult ance of not only take into account the import attained height – as well as with body mass index body fatness but also muscle mass. (BMI) during or at the end of childhood growth. Nutritional factors are key determinants of 7.4 Better characterisation of patterns of growth from conception onwards. cancer-related outcomes Limitation of energy or nutrient supply acts as a potential constraint on growth, and if this occurs The diagnosis, characterisation and treatment during particular periods of growth it can lead to of cancer is increasingly complex. Emerging adaptations in the fetus or child that may persist understanding of molecular phenotypes enables into adulthood, with consequences for the definitions of cancers that go beyond simple adult phenotype. Such phenotypical alterations anatomic classifications. Future study designs include susceptibility to cardiometabolic disease must accommodate and standardise the and may also include susceptibility to cancer. assessment of this phenotypic diversity so that disease endpoints are comparable. In addition, However, the precise mechanisms through which the current literature is not always consistent nutritional factors may influence growth and in the description and definition of cancer development, and their relation to later cancer outcomes, including the genomic evolution risk, remain to be determined. of the tumour over time and with treatment. Better characterisation of risk according to 7.3 Better characterisation of diet, cancer subtypes, and studies that address nutrition, body composition and the molecular variability of cancer as well as physical activity exposures other outcomes, whether cancer-specific (for example, cancer incidence, progression and In the CUP, the collation and interpretation of recurrence) or not (for example, other non- the evidence available in the published literature communicable diseases and quality of life), has highlighted inherent limitations of dietary are therefore important. measurements when it comes to precisely and accurately characterising dietary intake, body composition, relevant metabolic processes and other nutritional states, and physical activity. 2018 85 A summary of the Third Expert Report

88 Stronger evidence for the impact of Globally representative research on 7.6 7.5 specific exposures and cancer diet, nutrition and physical activity on outcomes in cancer survivors The majority of epidemiological studies are There is emerging but still limited data on the conducted in high-income countries such as effect of diet, nutrition and physical activity the UK, the USA and Australia. There is limited in cancer survivors, regarding outcomes, or no data from some countries, especially including prognosis and quality of life during low- and middle-income countries. Most of the and after treatment. In addition, the review of evidence has been based on studies conducted the evidence for breast cancer survivors has in populations of European ancestry and some identified various research gaps in terms of the in Asian populations. However, there is a need quality of the studies to address each phase for research comparing associations by ethnicity of survival and across diverse cancer types and by genetic ancestry. Section 4.4: Research and subtypes (see Patterns of cancer incidence and prevalence of this Summary). gaps in cancer survivors vary considerably according to geographical Diet, nutrition and physical activity, and their region. Furthermore, some strong evidence for interplay with genetic, epigenetic and hormonal particular exposures and cancers is relevant factors, may play an important role in influencing only to specific geographic regions, such as the response to and side effects from treatment, relationship between liver cancer and exposure quality of life during and after treatment, and to aflatoxins in parts of Africa and Asia. risk of metastasis and recurrence, as well as Both observations make the case for future overall and cancer-specific mortality. More studies to address the lack of data from low- research is critically needed in this area. and middle-income countries. a Global Perspective 86 Diet, Nutrition, Physical Activity and Cancer:

89 Conclusions The publication of the Third Expert Report, including this Summary, is an important milestone in the life of the Continuous Update Project (CUP). Like its predecessors, the Third Expert Report provides a comprehensive analysis, using the most meticulous methods, of the current state of the evidence on preventing and surviving cancer through diet, nutrition, maintaining a healthy weight and physical activity, and presents the latest Cancer Prevention Recommendations. This landmark achievement has been made possible by the significant efforts of large numbers of people from around the world; many others have a role in helping to maximise the impact of those efforts for the ultimate benefit of all (see Box 10 ). The Cancer Prevention Recommendations provide a tangible way to reduce the incidence of cancer by helping people to maintain a healthy weight and adopt healthy patterns of eating, drinking and physical activity throughout life, and by informing policy action. The Recommendations are for use by individuals, researchers, medical and health professionals, policymakers, civil society organisations and other cancer organisations, as well as the media. A significant body of evidence suggests that following the Recommendations works in real life. Studies evaluating adherence to the Cancer Prevention Recommendations from the last Expert Report, published in 2007, have shown that the more people adhere to the Recommendations, the greater the reductions in the risk of some specific cancers, of cancer as a whole and of death [1–3]. Moreover, these studies have shown that benefits extend beyond cancer to other non-communicable diseases. Box 10: The benefits of working in partnership The landmark publication of the Third Expert Report has been made possible by the collective efforts of many people around the world. Others, not directly involved in the production of this Report but who share the goals of preventing cancer and improving cancer survival, also have a role to play. Disseminating findings, promoting the Recommendations and guiding future research WCRF and AICR are committed to disseminating the findings of this Third Expert Report, promoting the Cancer Prevention Recommendations and using the findings to help inform and guide future research. Support in this effort is encouraged from the wider community of people with an interest in preventing cancer and improving survival, whether they be individuals, researchers, medical and health professionals, policymakers, civil society organisations and other cancer organisations, as well as the media. Together, our voice is louder, our reach is further and the benefits will be greater. 2018 87 A summary of the Third Expert Report

90 The publication of the Third Expert Report is part of an ongoing process. While the Cancer Prevention Recommendations offer broad health benefits right now, the Report has also revealed important gaps and inadequacies in the evidence that can help the research community and funding organisations by guiding plans for future studies. It is worth emphasising the importance of considering how different overall patterns of diet and physical activity combine to create a metabolic state that is more, or less, conducive to the development of cancer (rather than focusing on singular effects of specific dietary factors such as individual foods). The future holds promise of greater understanding of how diet, nutrition and physical activity can influence the risk of cancer and its progression, as well as its role in the care and management of those living with and beyond cancer. The greatest benefit for public health and for cancer survivors will come from collaborative efforts of all stakeholders (see ). Box 10 This Third Expert Report offers the most robust basis for a future where avoidable cancers are minimised, and where the public and cancer survivors, and those caring for them, know how they can best adapt their ways of living to reduce cancer risk and improve outcome and quality of life after diagnosis. Diet, Nutrition, Physical Activity and Cancer: a Global Perspective 88

91 Acknowledgements Panel Members CHAIR – Alan Jackson CBE MD FRCP FRCPath FRCPCH FAfN University of Southampton Southampton, UK DEPUTY CHAIR – PhD RNutr Hilary Powers University of Sheffield Sheffield, UK MD PhD Elisa Bandera Rutgers Cancer Institute of New Jersey New Brunswick, NJ, USA PhD David Forman Steven Clinton MD PhD (2007 to 2009) The Ohio State University University of Leeds Columbus, OH, USA Leeds, UK MD ScD Edward Giovannucci PhD David Hunter Harvard T H Chan School of Public Health (2007 to 2012) Boston, MA, USA Harvard University PhD MPH Stephen Hursting Boston, MA, USA University of North Carolina at Chapel Hill MD PhD Arthur Schatzkin Chapel Hill, NC, USA (2007 to 2011, d. 2011 ) Michael Leitzmann MD DrPH National Cancer Institute Regensburg University Rockville, MD, USA Regensburg, Germany MD PhD Steven Zeisel MD PhD Anne McTiernan (2007 to 2011) Fred Hutchinson Cancer Research Center University of North Carolina at Chapel Hill Seattle, WA, USA Chapel Hill, NC, USA MD PhD Inger Thune Observers Oslo University Hospital and University PhD Marc Gunter of Tromsø International Agency for Research on Cancer Oslo and Tromsø, Norway Lyon, France Ricardo Uauy MD PhD Elio Riboli MD ScM MPH Instituto de Nutrición y Tecnología de los Imperial College London Alimentos London, UK Santiago, Chile 2018 89 A summary of the Third Expert Report

92 Isabelle Romieu MD MPH ScD Elli Polemiti MSc (2013 to 2016) (2015 to 2016) International Agency for Research on Cancer Research Associate Lyon, France MSc Jakub Sobiecki Research Associate Advisors PhD (2012) John Blundell Ana Rita Vieira MSc University of Leeds (2011 to 2016) Leeds, UK Research Associate PhD John Milner Snieguole Vingeliene MSc d. 2013 ) (2012, (2012 to 2017) National Cancer Institute Research Associate Rockville, MD, USA Christophe Stevens (2013 to 2017) Imperial College London Research Team Database Manager Teresa Norat PhD Principal Investigator Rui Viera (2007 to 2011) Leila Abar MSc Data Manager Research Associate Louise Abela Statistical Adviser (2016 to 2017) PhD Darren Greenwood Research Associate Senior Lecturer in Biostatistics University of Leeds Dagfinn Aune PhD Leeds, UK (2010 to 2016) Research Associate Visiting trainees, researchers, scientists Renate Heine-Bröring PhD MSc Margarita Cariolou (2010, PhD training) Research Assistant Wageningen University, The Netherlands PhD Doris Chan PhD Dirce Maria Lobo Marchioni Research Fellow (2012 to 2013, visiting scientist) Rosa Lau MSc University of São Paulo, Brazil (2008 to 2010) MSc Yahya Mahamat Saleh Research Associate (2016, Masters training) MSc Neesha Nanu Bordeaux University, France Research Assistant PhD Sabrina Schlesinger MSc Deborah Navarro-Rosenblatt (2016, postdoctoral researcher) (2011 to 2015) German Diabetes Center Research Associate Düsseldorf, Germany a Global Perspective 90 Diet, Nutrition, Physical Activity and Cancer:

93 Mathilde Touvier PhD PhD Kate Allen (2009, postdoctoral researcher) Executive Director Nutritional Epidemiology Unit (UREN) Science and Public Affairs Bobigny, France WCRF International Emily Almond WCRF Network Executive Research Interpretation Assistant Marilyn Gentry WCRF International President WCRF International Isobel Bandurek MSc RD Science Programme Manager Kelly Browning (Research Interpretation) Executive Vice President WCRF International AICR PhD Nigel Brockton Kate Allen PhD Director of Research Executive Director AICR Science and Public Affairs WCRF International Susannah Brown MSc Senior Science Programme Manager Deirdre McGinley-Gieser (Research Evidence) Senior Vice President for Programs WCRF International and Strategic Planning AICR PhD Stephanie Fay (2015 to 2016) Stephenie Lowe Science Programme Manager Executive Director (Research Interpretation) International Financial Services WCRF International WCRF Network PhD RD Susan Higginbotham Rachael Gormley (2007 to 2017) Executive Director Vice President of Research Network Operations AICR WCRF International Mariano Kälfors Nadia Ameyah CUP Project Manager Director WCRF International Wereld Kanker Onderzoek Fonds MSc RNutr Rachel Marklew Secretariat (2012 to 2015) HEAD – Rachel Thompson PhD RNutr Science Programme Manager Head of Research Interpretation (Communications) WCRF International WCRF International 2018 91 A summary of the Third Expert Report

94 Deirdre McGinley-Gieser PhD Laure Dossus Senior Vice President for Programs Section of Nutrition and Metabolism and Strategic Planning International Agency for Research on Cancer AICR Lyon, France PhD Giota Mitrou PhD Mazda Jenab Director of Research Funding and Section of Nutrition and Metabolism Science External Relations International Agency for Research on Cancer WCRF International Lyon, France Amy Mullee PhD Neil Murphy PhD (2014 to 2015) Section of Nutrition and Metabolism Science Programme Manager International Agency for Research on Cancer (Research Interpretation) Lyon, France WCRF International Cancer Survivors Protocol Development Committee Prescilla Perera Lawrence H. Kushi CHAIR – ScD (2011 to 2012) Kaiser Permanente Science Programme Manager Oakland, CA, USA WCRF International Marie-Christine Boutron-Ruault MD PhD Malvina Rossi (2016) INSERM, E3N-EPIC Group CUP Project Manager Institut Gustave Roussy WCRF International Villejuif, France FRCP FRCPath FAfN Martin Wiseman Bas Bueno-de-Mesquita MD MPH PhD Medical and Scientific Adviser National Institute for Public Health WCRF International Bilthoven, The Netherlands Scientific consultants PhD MBBS FHKAM Josette Chor RNutr Kirsty Beck School of Public Health and Primary Care Chinese University of Hong Kong Louise Coghlin MBiochem Hong Kong PhD Kate Crawford Wendy Demark-Wahnefried PhD RD University of Alabama at Birmingham Elizabeth Jones PhD Comprehensive Cancer Center Birmingham, AL, USA Rachel Marklew MSc RNutr PhD RD Michelle Harvie Mechanisms authors University of Manchester Marc Gunter LEAD – PhD Manchester, UK Section of Nutrition and Metabolism International Agency for Research on Cancer Lyon, France a Global Perspective 92 Diet, Nutrition, Physical Activity and Cancer:

95 PhD Jo Salmon Policy Advisory Subgroup Deakin University WCRF International Policy Advisory Group Geelong, VIC, Australia MD PhD Heather Bryant Canadian Partnership Against Cancer Lucy M. Sullivan Toronto, ON, Canada 1,000 Days Washington DC, USA Anita George MPA McCabe Centre for Law and Cancer Lucy Westerman MPH Melbourne, VIC, Australia NCD Alliance London, UK Sir Trevor Hassell MD Healthy Caribbean Coalition WCRF International Policy and Public Affairs Bridgetown, Barbados Louise Meincke MA FRSA Head of Policy and Public Affairs Hasan Hutchinson PhD Health Canada Bryony Sinclair MPH Ottawa, ON, Canada Senior Policy and Public Affairs Manager Knut-Inge Klepp PhD MPH Fiona Sing MSc Norwegian Institute of Public Health Policy and Public Affairs Officer Oslo, Norway Reviewers PhD MPH RD Shiriki Kumanyika University of Pennsylvania Cancer Prevention Recommendations Philadelphia, PA, USA Annie S. Anderson BSc PhD RD FRCP (Edin) School of Medicine MD Feisul Idzwan Mustapha University of Dundee Ministry of Health Dundee, UK Putrajaya, Malaysia Francesco Branca MD PhD PhD Anna Peeters World Health Organization (WHO) Deakin University Geneva, Switzerland Geelong, VIC, Australia MD DrPH Graham A. Colditz Sandhya Singh Institute for Public Health National Department of Health Washington University in St Louis Pretoria, South Africa Saint Louis, MO, USA Other policy reviewers The cancer process David Jernigan PhD Christian Abnet PhD MPH Johns Hopkins University National Cancer Institute Baltimore, MD, USA Bethesda, MD, USA 2018 93 A summary of the Third Expert Report

96 PhD Ellen Kampman With special thanks also to the Communications and Marketing team at WCRF International. Division of Human Nutrition Wageningen University and Research Centre Wageningen, The Netherlands PhD Dieuwertje E. G. Kok Division of Human Nutrition Wageningen University and Research Centre Wageningen, The Netherlands Matty P. Weijenberg PhD GROW School for Oncology and Developmental Biology Maastricht University Maastricht, The Netherlands Survivors of breast and other cancers Wendy Demark-Wahnefried PhD RD University of Alabama at Birmingham Comprehensive Cancer Center Birmingham, AL, USA PhD Anne M. May Department of Epidemiology UMC Utrecht Julius Center Utrecht, The Netherlands Energy balance and body fatness PhD OBE Susan Jebb Nuffield Department of Primary Care Health Sciences University of Oxford Oxford, UK MD FAfN FRCP FTOS Nicholas Finer University College Hospital London, UK Peer reviewers For the full list of CUP peer reviewers please visit wcrf.org/acknowledgements Cover illustration by Anton Khrupin ([email protected]) © 2018 World Cancer Research Fund International a Global Perspective 94 Diet, Nutrition, Physical Activity and Cancer:

97 Abbreviations AICR American Institute for Cancer Research BMI Body mass index CHD Coronary heart disease CUP Continuous Update Project CVD Cardiovascular disease DNA Deoxyribonucleic acid HCAs Heterocyclic amines IARC International Agency for Research on Cancer IGF-I insulin-like growth factor 1 MAPK mitogen-activated protein kinase mTOR mechanistic/mammalian target of rapamycin NCDs Non-communicable diseases Polycyclic aromatic hydrocarbons PAHs RCT Randomised control trial RNS Reactive nitrogen species ROS Reactive oxygen species SLR Systematic literature review VEGF Vascular endothelial growth factor WCRF World Cancer Research Fund World Health Organization WHO 2018 95 A summary of the Third Expert Report

98 Glossary Acetaldehyde The major metabolic product of ethanol, which is generated by ethanol dehydrogenase and subsequently metabolised to acetate by aldehyde dehydrogenase. Adenine A purine derivative and one of the four possible nitrogenous bases in nucleotides and nucleic acids (DNA and RNA). Base pairs with thymine. Adenocarcinoma Cancer of glandular epithelial cells. Adenomatous polyposis coli (APC) gene A gene that provides instructions for making the APC protein, which plays a critical role in several cellular processes. The protein acts as a tumour suppressor, keeping cells from growing and dividing too fast or in an uncontrolled way. Adipocytes Cells of adipose tissue, where fats (triglycerides) are stored. Adipose tissue Body fat. Tissue comprising mainly cells containing triglyceride (adipocytes). It acts as an energy reserve, provides insulation and protection, and secretes metabolically active hormones. Adiposity The degree of body fatness; can be measured indirectly in a variety of ways including body mass index (see body mass index ) and percentage body fat. Aflatoxins Naturally occurring mycotoxins that are produced by many species of Aspergillus, a fungus, most notably Aspergillus flavus and Aspergillus parasiticus. Aflatoxins are toxic and carcinogenic to animals, including humans. Alcohol An organic compound that contains a hydroxyl group bound to a carbon atom. Releases energy when OH. H metabolised in the body. Commonly ethanol C 6 5 Angiogenesis The process of generating new blood vessels. Anthropogenic Originating in human activity, usually related to environmental pollution and pollution. a Global Perspective 96 Diet, Nutrition, Physical Activity and Cancer:

99 Anthropometric measures Measures of body dimensions. Apoptosis The death of cells that occurs as a normal and controlled part of the cell cycle. Bias In epidemiology, consistent deviation of an observed result from the true value in a particular direction (systematic error) due to factors pertaining to the observer or to the study type or analysis (see selection bias ). Bile A greenish-yellow fluid secreted by the liver and stored in the gallbladder. Bile plays an important role in the intestinal absorption of fats. Bile contains cholesterol, bile salts, and waste products such as bilirubin. Bioactive constituents Compounds that have an effect on a living organism, tissue or cell. In nutrition, bioactive compounds are distinguished from nutrients. Bioactivity The effect of a given agent on a living organism or on living tissue. Biological mechanisms System of causally interacting processes that produce one or more effects. Body composition The composition of the body in terms of the relative proportions of water and adipose and lean tissue. Can also be described as the proportions of fat (lipid) and fat-free mass. May also include the content of micronutrients, such as iron, and the distribution of adipose tissue, for example, central/ peripheral or visceral/subcutaneous. Body mass index (BMI) Body weight expressed in kilograms divided by the square of height expressed in metres (BMI = 2 ). Provides an indirect measure of body fatness. kg /m C-reactive protein A specific protein whose concentration in the blood rises in response to inflammation. Caffeine An alkaloid found in coffee, tea, kola nuts, chocolate, and other foods that acts as a stimulant and a diuretic. Calcium An essential nutrient for many regulatory processes in all living cells, in addition to playing a structural role in the skeleton. Calcium plays a critical role in the complex hormonal and nutritional 2018 97 A summary of the Third Expert Report

100 regulatory network related to vitamin D metabolism, which maintains the serum concentration of calcium within a narrow range while optimising calcium absorption to support host function and skeletal health. Cancer Any disorder of cell growth that results in the invasion and destruction of surrounding healthy tissue by abnormal cells and which may spread to distant sites. Cancer cells arise from normal cells whose nature is permanently changed. Carcinogen Any substance or agent capable of causing cancer. Carcinogenesis The process by which a malignant tumour is formed. Carcinoma Malignant tumour derived from epithelial cells, usually with the ability to spread into the surrounding tissue (invasion) and produce secondary tumours (metastases). Carotenoids A diverse class of compounds providing colour to many plants. Carotenoids are often classified in two groups: as those providing the host with vitamin A, such as beta-carotene, and the non-pro-vitamin A carotenoids, such as lycopene, which provides the familiar red colour of tomatoes. Case-control study An epidemiological study in which the participants are chosen on the basis of their disease or condition (cases) or lack of it (controls), to test whether distant or recent history of an exposure such as tobacco smoking, genetic profile, alcohol consumption or dietary intake is associated with the disease. Cell Structural and functional unit of most living organisms. Can exist independently or as part of a tissue or organ. Cell cycle The highly regulated process by which cells replicate and divide, allowing tissues to grow and remain healthy. Cell proliferation An increase in the number of cells as a result of increased cell division. Checkpoint Point in the cell cycle of eukaryotic cells at which progress can be halted if the appropriate conditions are not met. Chronic Describing a condition or disease that is persistent or long lasting. a Global Perspective 98 Diet, Nutrition, Physical Activity and Cancer:

101 Cirrhosis A condition in which normal liver tissue is replaced by scar tissue (fibrosis), with nodules of liver regenerative tissue. Colon Part of the large intestine extending from the caecum to the rectum. Colonisation sites The first site in a different organ from which the cancer originates that metastatic tissue colonises. Colonocyte An epithelial cell of the colon. Compliance The extent to which people such as study participants follow an allocated treatment programme. Cytokines Cell-signalling molecules that aid cell-to-cell communication in immune responses and stimulate the movement of cells toward sites of inflammation, infection and trauma. Deoxyribonucleic acid (DNA) The double-stranded, helical molecular chain found within the nucleus of each cell, which carries the genetic information. Diet, nutrition and physical activity diet , the food and drink In the CUP, these three exposures are taken to mean the following: people habitually consume, including dietary patterns and individual constituent nutrients as well nutrition , as other constituents, which may or may not have physiological bioactivity in humans; the process by which organisms obtain energy and nutrients (in the form of food and drink) for growth, maintenance and repair, often marked by nutritional biomarkers and body composition (encompassing body fatness); and physical activity , any body movement produced by skeletal muscles that requires energy expenditure. Dietary fibre Constituents of plant cell walls that are not digested in the small intestine. Several methods of analysis are used, which identify different components. The many constituents that are variously included in the definitions have different chemical and physiological features that are not easily defined under a single term. The different analytical methods do not generally characterise the physiological impact of foods or diets. Non-starch polysaccharides are a consistent feature and are fermented by colonic bacteria to produce energy and short chain fatty acids including butyrate. The term ‘dietary fibre’ is increasingly seen as a concept describing a particular aspect of some dietary patterns. Dietary supplement A substance, often in tablet or capsule form, which is consumed in addition to the usual diet. Dietary supplements typically refer to vitamins or minerals, though phytochemicals or other substances may be included. 2018 99 A summary of the Third Expert Report

102 DNA adduct A chemical that binds to DNA. This distorts the DNA structure and disrupts its replication, increasing the likelihood of errors in DNA replication, subsequent mutations and possibly cancer. Dose–response A term derived from pharmacology that describes the degree to which an association or effect changes as the level of an exposure changes, for instance, intake of a drug or food. Effect modification Effect modification (or effect-measure modification) occurs when the effect of an exposure differs according to levels of another variable (the modifier). Enabling characteristic Property a cancer cell exhibits which facilitates the attainment and sustainment of the ‘hallmarks of c a n c e r ’. Endogenous Substances or processes that originate from within an organism, tissue or cell. Energy Energy, measured as calories or joules, is required for all metabolic processes. Fats, carbohydrates, proteins, and alcohol from foods and drinks release energy when they are metabolised in the body. Energy balance The state in which the total energy absorbed from foods and drink equals total energy expended, for example, through basal metabolism and physical activity. Also the degree to which intake exceeds expenditure (positive energy balance) or expenditure exceeds intake (negative energy balance). Enzyme Protein that acts as a catalyst in biochemical reactions. Each enzyme is specific to a particular reaction or group of similar reactions. Many require the association of certain non-protein cofactors in order to function. Epigenetics Relating to the control of gene expression through mechanisms that do not depend on changes in the nucleotide sequence of DNA, for example, through methylation of DNA or acetylation of histone. Essential nutrient A substance that is required for normal metabolism that the body cannot synthesise at all or in sufficient amounts, and thus must be consumed. Ethanol An organic compound in which one of the hydrogen atoms of water has been replaced by an alkyl alcohol group. See . a Global Perspective 100 Diet, Nutrition, Physical Activity and Cancer:

103 Exposure A factor to which an individual may be exposed to varying degrees, such as intake of a food, level or type of physical activity, or aspect of body composition. Extracellular matrix The material that surrounds cells in animal tissues. Contains an aqueous lattice of proteins and other molecules. Familial Relating to or occurring in a family or its members. Fat Storage lipids of animal tissues, mostly triglyceride esters. See adipose tissue . Folate A salt of folic acid. Present in leafy green vegetables, peas and beans, and fortified breads and cereals. Free radicals An atom or molecule or that has one or more unpaired electrons. A prominent feature of radicals is that they have high chemical reactivity, which explains their normal biological activities and how they inflict damage on cells. There are many types of radicals, but those of most importance in biological systems are derived from oxygen and known collectively as reactive oxygen species. Functional capacity The optimal or maximum level at which the body, organ or tissue can function. Gene Unit of heredity composed of DNA. Visualised as a discrete particle, occupying specific position (locus) on a chromosome, that determines a particular characteristic. Gene expression The manifestation of the effects of a gene by the production of the particular protein, polypeptide or type of RNA whose synthesis it controls. The transcription of individual genes can be ‘switched on’ or ‘switched off’ according to the needs and circumstances of the cell at a particular time. Genetic code Means by which genetic information in DNA is translated into the manufacture of specific proteins by the cell. Represented by codons, which take the form of a series of triplets of bases in DNA, from which is transcribed a complementary sequence of codons in messenger RNA. The sequence of these codons determines the sequence of amino acids during protein synthesis. Genomic instability Abnormal rate of genetic change in a cell population which becomes evident as proliferation continues. 2018 101 A summary of the Third Expert Report

104 Genotoxic Referring to chemical agents that damage the genetic information within a cell, causing mutations, which may lead to cancer. Glucose A six-carbon sugar, the main product of photosynthesis, that is a major energy source for metabolic processes. It is broken down by glycolysis during cellular respiration. Growth factors Various chemicals, particularly polypeptides, that have a variety of important roles in the stimulation of cell growth and replication. They bind to cell surface receptors. Guanosine A nucleoside consisting of one guanine molecule linked to a ribose sugar molecule in DNA. Hallmarks of cancer Key phenotypic characteristics in structure and function that represent an essential part of the biology of a cancer cell. Hepatitis Inflammation of the liver, which can occur as the result of a viral infection or autoimmune disease, or because the liver is exposed to harmful substances, such as alcohol. Heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs) Potentially carcinogenic chemicals formed when muscle meat, including beef, pork, fish or poultry, is cooked using high-temperature methods. Heterogeneity A measure of difference between the results of different studies addressing a similar question. 2 test. In meta-analysis, the degree of heterogeneity may be calculated statistically using the I High-income countries As defined by the World Bank, countries with an average annual gross national income per capita of US$12,236 or more in 2016. This term is more precise than and used in preference to ‘economically developed countries’. Homeostasis Regulation of an organism’s internal environment within a controlled range so that physiological processes can proceed at optimum rates. Hormone A substance secreted by specialised cells that affects the structure and/or function of cells or tissues in another part of the body. Hyperinsulinemia High blood concentrations of insulin. a Global Perspective 102 Diet, Nutrition, Physical Activity and Cancer:

105 Immune response The production of antibodies or specialised cells, for instance, in response to foreign proteins or other substances. Immune system Complex network of cells, tissues, and organs that work together to defend against external agents such as microorganisms. In vitro Processes that occur outside the body, in a laboratory apparatus. In vivo Describing biological processes as they are observed to occur within living organisms. Incidence rates The number of new cases of a condition appearing during a specified period of time expressed relative to the size of the population; for example, 60 new cases of breast cancer per 100,000 women per year. Inflammation The immunologic response of tissues to injury or infection. Inflammation is characterised by accumulation of white blood cells that produce several bioactive chemicals (cytokines), causing redness, pain, heat and swelling. Inflammation may be acute (such as in response to infection or injury) or chronic (as part of several conditions, including obesity). Insulin A protein hormone secreted by the pancreas that promotes the uptake and utilisation of glucose, particularly in the liver and muscles. Inadequate secretion of, or tissue response to, insulin leads to diabetes mellitus. Insulin resistance A pathological condition in which cells fail to respond normally to the hormone insulin. KRAS gene Provides instructions for making the K-Ras protein, which is involved in cell signalling pathways, cell growth, cell maturation and cell death. Mutated forms are associated with some cancers. Lactation The production and secretion of milk by the mammary glands. Lipid peroxidation The oxidative degradation of lipids. It is the process in which free radicals ‘steal’ electrons from the lipids in cell membranes, resulting in cell damage. Low-income countries As defined by the World Bank, countries with an average annual gross national income per capita of US$1,005 or less in 2016. This term is more precise than and used in preference to ‘economically developing countries’. 2018 103 A summary of the Third Expert Report

106 Macrophage Large phagocytic cell forming part of the body’s immune system. It can ingest pathogenic microorganisms or cell debris. Malignancy A tumour with the capacity to spread to surrounding tissue or to other sites in the body. Mendelian randomisation A method of using natural variation in genes of known function to mimic a potential causal effect of a modifiable exposure on disease. The design helps to avoid problems from reverse causation and confounding. Metabolism The sum of chemical reactions that occur within living organisms. Metabolites Various compounds that take part in or are formed by chemical, metabolic reactions. Metastasis/metastatic spread The spread of malignant cancer cells to distant locations around the body from the original site. Micronutrient Vitamins and minerals present in foods and required in the diet for normal body function in small quantities conventionally of less than 1 gram per day. Mitogen-activated protein kinase (MAPK) pathway A chain of proteins that transmits chemical signals from outside the cell to the cell’s nucleus to activate transcription factors that control gene expression. Mutation A permanent change in the nucleotide sequence of the genome (an organism’s complete set of DNA). N-nitroso compound A substance that may be present in foods treated with sodium nitrate, particularly processed meat and fish. It may also be formed endogenously, for example, from haem and dietary sources of nitrate and nitrite. N-nitroso compounds are known carcinogens. Neutrophils A type of white blood cell that fights infection by ingesting microorganisms and releasing enzymes that kill microorganisms. Non-communicable diseases (NCDs) Diseases which are not transmissible from person to person. The most common NCDs are cancer, cardiovascular disease, chronic respiratory diseases and diabetes. a Global Perspective 104 Diet, Nutrition, Physical Activity and Cancer:

107 Nucleotide Organic compound consisting of a nitrogen-containing purine or pyrimidine base linked to a sugar (ribose or deoxyribose) and phosphate group. Nutrient A substance present in food and required by the body for maintenance of normal structure and function, and for growth and development. Nutrition Process by which organisms obtain energy and nutrients (in the form of food and drink) for growth, maintenance and repair. Obesity Excess body fat to a degree that increases the risk of various diseases. Conventionally defined as 2 or more. Different cut-off points have been proposed for specific populations. a BMI of 30kg/m Oestradiol The principal female sex hormone produced mainly by the ovaries before menopause and by adipose tissue after. It promotes the onset of secondary sexual characteristics and controls the menstrual cycle. Oestrogen The female sex hormones, produced mainly by the ovaries during reproductive life and also by adipose tissue. Oxidative stress Overproduction of reactive oxygen species that may damage tissues. p53 A protein central to regulation of cell growth. Mutations of the p53 gene are important causes of cancer. Pathogenesis The origin and development of disease. The mechanisms by which causal factors increase the risk of disease. Phase I metabolising enzyme Enzymes in the first phase of detoxification (modification) that introduce reactive and polar groups. Phase II metabolising enzyme Enzymes in the second phase of detoxification (conjugation) that conjugate active substances from phase one to charged species that are more easily excreted, for example, in bile. Phenotype The observable characteristics displayed by an organism; depends on both the genotype (the genetic makeup of a cell) and environmental factors. 2018 105 A summary of the Third Expert Report

108 Physical activity Any movement using skeletal muscles that requires more energy than resting. Phytochemicals Non-nutritive bioactive plant substances that may have biological activity in humans. Policy A course of action taken by a governmental body including, but not restricted to, legislation, regulation, guidelines, decrees, standards, programmes and fiscal measures. Policies have three interconnected and evolving stages: development, implementation and evaluation. Policy development is the process of identifying and establishing a policy to address a particular need or situation. Policy implementation is a series of actions taken to put a policy in place, and policy evaluation is the assessment of how the policy works in practice. Prevalence The total number of individuals who have a characteristic, disease or health condition at a specific time, related to the size of the population, for example, expressed as a percentage of the population. Processed meat Meats transformed through salting, curing, fermentation, smoking or other processes to enhance flavour or improve preservation. Proliferation Increase in the number of cells, for example, in a tissue. Protein Polymer of amino acids linked by peptide bonds in a sequence specified by mRNA with a wide variety of specific functions including acting as enzymes, antibodies, storage proteins and carrier proteins. Randomised controlled trial (RCT) A study in which a comparison is made between one intervention (often a treatment or prevention strategy) and another (control). Sometimes the control group receives an inactive agent (a placebo). Groups are randomised to one intervention or the other, so that any difference in outcome between the two groups can be ascribed with confidence to the intervention. Sometimes, neither investigators nor subjects know to which intervention they have been randomised; this is called ‘double-blinding’. Reactive nitrogen species (RNS) Nitrogen-containing radical species or reactive ions, such as nitric oxide (NO) and peroxynitrite (ONOO-), which are able to damage DNA, such as by inducing DNA strand breaks or base modifications. Reactive oxygen species (ROS) Oxygen-containing radical species or reactive ions that can oxidise DNA (remove electrons), for 2 –). O ) or superoxide radical (0 example, hydroxyl radical (OH–), hydrogen peroxide (H 2 2 Resilience Property of a tissue or of a body to resume its former condition after being stressed or disturbed. a Global Perspective 106 Diet, Nutrition, Physical Activity and Cancer:

109 Retinoid Compounds chemically related to or derived from vitamin A. They may be used for treatment of some cancers. Selection bias Bias arising from the procedures used to select study participants and from factors influencing participation. Statistical power The power of any test of statistical significance, defined as the probability that it will reject a false null hypothesis. Stem cell Cell that is not differentiated but can undergo unlimited division to form other cells, which can either remain stem cells or differentiate to form specialised cells. Stress A state of physiological or psychological strain caused by adverse stimuli that tends to disturb the functioning of an organism. Stromal cells Connective tissue cells of an organ. Systematic literature review (SLR) A means of compiling and assessing published evidence that addresses a scientific question with a predefined protocol and transparent methods. Systemic Describing something that occurs throughout the body, not just locally. Tissue A collection of one or more types of cells of similar structure organised to carry out particular functions. Tumorigenesis The process of tumour development. Tumour A mass of neoplastic and other cells. Visceral obesity Form of obesity due to excessive deposition of fat in the omentum and around the abdominal viscera, rather than subcutaneously (peripheral obesity). Poses a greater risk of diabetes mellitus, hypertension, metabolic syndrome and cardiovascular disease than peripheral obesity. Vitamin One of a number of organic compounds required from food or drinks by living organisms in relatively small amounts to maintain normal structural function. 2018 107 A summary of the Third Expert Report

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114 97. Victora CG, Bahl R, Barros AJD, Breastfeeding in the 21st century: epidemiology, mechanisms, and lifelong et al. Lancet 2016; 387: 475–90. effect. Monographs on the Evaluation of Carcinogenic Risks to 98. International Agency for Research on Cancer (IARC). IARC . 2012. Humans. Volume 100, Part C: Arsenic, metals, fibres and dusts 99. FAO/World Health Organization. Summary of Evaluations Performed by the Joint FAO/WHO Expert Committee on Food Additives . 2006. WHO Framework on Convention on Tobacco Control 100. World Health Organization (WHO). . 2005. Accessed 10/08/2017; available from http://apps.who.int/iris/bitstream/10665/42811/1/9241591013.pdf?ua=1 101. World Cancer Research Fund International/American Institute for Cancer Research. Continuous Update Project: Diet, Nutrition, Physical Activity and the Prevention of Cancer. Summary of Strong Evidence . 2017. Available from wcrf.org/cupmatrix Roberto CA, Swinburn B, Hawkes C, et al. Patchy progress on obesity prevention: emerging examples, entrenched 102. Lancet barriers, and new thinking. 2015; 385: 2400–9. World Cancer Research Fund/American Institute for Cancer Research. Policy and Action for Cancer Prevention. Food, 103. Nutrition and Physical Activity: a Global Perspective . 2009. 104. World Health Organization (WHO). Global Action Plan for the Prevention and Control of Noncommunicable Diseases 2013–2020. Accessed 23/06/2017; available from http://apps.who.int/iris/ bitstream/10665/94384/1/9789241506236_eng.pdf?ua=1 World Health Organization (WHO). 105. Seventieth World Health Assembly, Provisional agenda item 15.1, Preparation for the third high-level meeting of the General Assembly on the prevention and control of non-communicable diseases, to be held in 2018, Annex 1, Draft updated Appendix 3 to the Global Action Plan for the Prevention and Control of Noncommunicable Diseases 2013–2020 . Accessed 10/08/2017; available from http://who.int/ncds/management/ WHO_Appendix_BestBuys.pdf?ua=1 World Health Organization (WHO). Noncommunicable Disease Progress Monitor 2015 . Accessed 04/07/2017; 106. available from http://apps.who.int/iris/bitstream/10665/184688/1/9789241509459_eng.pdf?ua=1 107. United Nations. Transforming Our World: The 2030 Agenda for Sustainable Development . 2015. Accessed 23/06/2017; available from https://sustainabledevelopment.un.org/content/documents/21252030%20 Agenda%20for%20Sustainable%20Development%20web.pdf United Nations. World population projected to reach 9.8 billion in 2050, and 11.2 billion in 2100. 2017. United 108. Nations Department of Economic and Social Affairs. Accessed 20/11/2017; available from https://www.un.org/ development/desa/en/news/population/world-population-prospects-2017.html Xia T, Zhang Y, Crabb S, et al. Cobenefits of replacing car trips with alternative transportation: a review of evidence 109. J Environ Public Health 2013; 2013: 14. and methodological issues. 110. Hawkes C, Jewell J and Allen K. A food policy package for healthy diets and the prevention of obesity and diet related non-communicable diseases: the NOURISHING framework. 2013; 14 Suppl 2: 159–68. Obes Rev 111. NOURISHING: Methods for Compiling and Updating the Database . 2 0 17. World Cancer Research Fund International. Accessed 14/06/2017; available from http://www.wcrf.org/int/policy/nourishing-framework/methodology World Cancer Research Fund/American Institute for Cancer Research. Food, Nutrition, Physical Activity, and the 112. Prevention of Cancer: a Global Perspective . Washington DC: AICR. 1997. 113. World Cancer Research Fund/American Institute for Cancer Research. Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective . Washington DC: AICR. 2007. Available from wcrf.org/about-the-report Kwon OJ and Xin L. Prostate epithelial stem and progenitor cells. 2014; 2: 209–18. 114. Am J Clin Exp Urol Ingthorsson S, Briem E, Bergthorsson JT, 115. Epithelial plasticity during human breast morphogenesis and cancer et al. progression. J Mammary Gland Biol Neoplasia 2016; 21: 139–48. 116. Donne ML, Lechner AJ and Rock JR. Evidence for lung epithelial stem cell niches. BMC Dev Biol 2015; 15: 32. 117. Roberts KJ, Kershner AM and Beachy PA. The stromal niche for epithelial stem cells: a template for regeneration and a brake on malignancy. Cancer Cell 2017; 32: 404–10. 118. Koelwyn GJ, Quail DF, Zhang X, et al. Exercise-dependent regulation of the tumour microenvironment. Nat Rev Cancer 2017; 17: 620–32. 119. DeGregori J. Connecting cancer to its causes requires incorporation of effects on tissue microenvironments. Cancer Res 2017; 77: 6065–8. a Global Perspective 112 Diet, Nutrition, Physical Activity and Cancer:

115 Our Cancer Prevention Recommendations Be a healthy weight Keep your weight within the healthy range and avoid weight gain in adult life Be physically active Be physically active as part of everyday life – walk more and sit less Eat a diet rich in wholegrains, vegetables, fruit and beans Make wholegrains, vegetables, fruit, and pulses (legumes) such as beans and lentils a major part of your usual daily diet Limit consumption of ‘fast foods’ and other processed foods high in fat, starches or sugars Limiting these foods helps control calorie intake and maintain a healthy weight Limit consumption of red and processed meat Eat no more than moderate amounts of red meat, such as beef, pork and lamb. Eat little, if any, processed meat Limit consumption of sugar sweetened drinks Drink mostly water and unsweetened drinks Limit alcohol consumption For cancer prevention, it’s best not to drink alcohol Do not use supplements for cancer prevention Aim to meet nutritional needs through diet alone For mothers: breastfeed your baby, if you can Breastfeeding is good for both mother and baby After a cancer diagnosis: follow our Recommendations, if you can Check with your health professional what is right for you Not smoking and avoiding other exposure to tobacco and excess sun are also important in reducing cancer risk. Following these Recommendations is likely to reduce intakes of salt, saturated and trans fats, which together will help prevent other non-communicable diseases.

116 Managed and produced by: ISBN (print): 978-1-912259-46-5 ISBN (pdf): 978-1-912259-47-2 wcrf.org twitter.com/wcrfint facebook.com/wcrfint WIRF5TERSUM © 2018 World Cancer Research Fund International. All rights reserved wcrf.org/blog

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