Masterclass Report Diet and Cancer: From Prevention to Survival 1-3 October 2014 Wageningen, the Netherlands

Masterclass Report Diet and Cancer: From Prevention to Survival 1-3 October 2014 Wageningen, the Netherlands 1. Introduction & background to the Masterclass On 1 3 October 2014, international experts and PhD students assembled in the Netherlands to disseminate research findings and discuss how to conduct more robust research on diet and cancer prevention, prognosis and survival. Following the first Masterclass on diet and cancer in 2007 that celebrated the publication of our Second Expert Report, this Masterclass sealed the end of our six-year research collaboration with Wageningen University on the colorectal cancer project. The organisers 1 were proud to welcome the two keynote speakers Professor Wendy Demark-Wahnefried from the University of Alabama at Birmingham and Professor John Potter from the Fred Hutchinson Cancer Research Center, both Masters in the field of diet and cancer. 2. Key objectives The overarching objectives of the Masterclass were to:! Share epidemiological evidence and reveal biological mechanisms that underpin the associations between diet, body composition and physical activity in cancer etiology and prognosis.! Discuss any research challenges and how to stimulate more robust research in the future.! Identify gaps in the current evidence and propose future research directions. 3. An evening learning from our masters 1 October 2014 Professor Wendy Demark-Wahnefried and Professor John Potter opened the event, inspiring delegates by engaging in discussions and drawing on their experiences on how best to deal with practical and personal challenges as researchers. Key topics discussed were as follows:! Choosing a mentor it is important for career development to seek the skills and knowledge that the mentee lacks, but hopes to acquire. A mentor should stimulate the ability to generate novel research questions.! Finding a research focus historically researchers were encouraged to focus on one research area. Recently it has become increasingly important and acceptable to cover a wider scope of research areas, especially since funding is limited and competitive.! Applying for research funding perseverance and enthusiasm are key attributes for achieving funding if it is believed a research question is important and will generate a successful study. If a proposal is rejected, it is important to revise as advised and resubmit to another funding organisation. 1 World Cancer Research Fund International would like to thank the Masterclass organisers for kindly providing comments on this report 1

! Strive to find a balance between professional and personal life try to utilise passion for your chosen research area to complete tasks and manage workload. 4. Primary cancer prevention 2 October 2014 Diet and cancer prevention: epidemiology The first day of the scientific programme addressed the importance of diet, body composition and physical activity on primary cancer prevention, exploring the epidemiological evidence, through to mechanisms that underpin the epidemiological associations. The morning commenced with a joint talk on our Continuous Update Project by Dr Panagiota Mitrou from World Cancer Research Fund International and Dr Teresa Norat from Imperial College London. They explained that the project aims to systematically review the epidemiological evidence on diet, nutrition, physical activity and cancer risk, which is ultimately used as a basis to form cancer our prevention recommendations. Dr Norat noted that BMI is the most frequently investigated exposure across different cancer sites, and most strongly associated with cancer risk. Next to follow was Professor John Potter, who asked delegates to look beyond the traditional genetic theories of carcinogenesis, and hence the hallmarks of cancer when assessing the association between diet and cancer. He suggested that dietary exposures might be morphogenic the ability to directly disrupt the cell microenvironment resulting in aberrant cell morphology, the most prominent feature of cancer cells. Further, Professor Potter went on to ask delegates to question how non-genetic theories of carcinogenesis could better characterise the link between diet and cancer, questioning to which carcinogen is obesity exposing us that results in the strong association to an increased cancer risk? In response to Professor Potter s question, the next theme focused on energy balance an exposure implicated in obesity and cancer risk. Professor Matty Weijenberg from Maastricht University presented findings from the World Cancer Research Fund awarded grant assessing how energy restriction in early life impacts cancer risk in life. Interestingly, the project found that exposure to energy restriction in early life was associated with reduced risk of developing colorectal cancer in participants of the Netherlands Cohort Study. The mechanisms are poorly understood, however energy restriction has been associated with lower DNA methylation of promoter regions of tumour suppressor and DNA repair genes, suggesting that epigenetic changes that occur in early life are important for determining later cancer risk. Dr Fränzel van Duijnhoven from Wageningen University continued by explaining that characterising diet-gene interactions is crucial in understanding cancer risk, as well as the observed population variation in diet-cancer associations. She explained that Single Nucleotide Polymorphisms in genes involved in nutrient metabolism might play a role in cancer susceptibility. Noting that the occurrence of these Single Nucleotide Polymorphisms vary across different populations, Dr van Duijnhoven indicated that sub-group specific cancer prevention recommendations on lifestyle are needed. Concluding the morning s focus on epidemiological evidence, and to further explore the role of genetic differences in diet-cancer associations, Professor Ellen Kampman from Wageningen University delivered an overview of the GEOLynch study a cohort of persons with Lynch Syndrome continued as part of the colorectal cancer project. Professor Kampman explained that in this high-risk group, the association between BMI and colorectal cancer is stronger than that of the general population. This recent evidence highlights the role of the environment in persons with Lynch Syndrome and the subsequent susceptibility to colorectal cancer risk. We are currently funding a grant that aims to assess the impact of health promotion materials on increasing awareness of, and adherence to our cancer prevention recommendations in this high-risk group. 2

Diet and cancer prevention: biology A clear take home message from the morning s session was that to further understand the link between diet and cancer, the mechanisms underpinning the links need to be better characterised. To explore this, Dr Mazda Jenab from the International Agency for Research on Cancer opened the afternoon session and addressed the implications of measuring biomarkers of dietary intake in molecular epidemiological studies to assess diet and disease relationships. Noting that this approach eliminates random and/or systematic errors that occur in observational dietary assessment, it is important to characterise which biomarkers are best correlated with dietary intake. For example, heterogeneity of Vitamin C content in fruit and vegetables might explain why Vitamin C status does not correlate well with total fruit and vegetable intake. He explained that metabolomics offers an approach to assessing multiple dietary exposures simultaneously, which might better predict the association with cancer and other co-morbidities such as cardiovascular disease, than assessing single biomarkers of dietary intake. Professor Cornelia Ulrich from the Huntsman Cancer Institute in Utah continued the topic of omics, presenting epigenomic evidence from the Women s Health Initiative a cohort of postmenopausal women assessing the role of folate on cancer risk. DNA methylation patterns were dependent on the timing of folate intake (pre, peri or post folate fortification) mechanisms of DNA methylation might be dependent on the form (dietary vs. fortification) of folate intake. She further noted that Epigenome Wide Association Studies (EWAS) are important in identifying the most relevant epigenetic markers of cancer risk. It was clear that identifying the best biomarkers of cancer risk is central to understanding the biology of diet and cancer. Dr Dieuwertje Kok from Wageningen University proposed that omics tools are a biological toolbox for characterising mechanisms underlying the effects of diet on cancer development. Dr Kok focused on the Infinium 450k Array; a tool for assessing genomewide DNA methylation to identify nutrient sensitive regions of DNA important in cancer development. She explained that this technique has been used to identify folate sensitive regions that could be important for determining later cancer risk. Continuing the emphasis on mechanistic work, Dr Panagiota Mitrou presented work commissioned as part of our Continuous Update Project to develop a novel methodology for systematically reviewing the mechanistic evidence on the link between diet, nutrition, physical activity and cancer. She explained that this work conducted by a research team at the University of Bristol will further strengthen the epidemiological evidence and conclusions drawn on the links between diet, nutrition, physical activity and cancer formed from our Continuous Update Project. The afternoon closed with presentations delivered by delegates, giving a snapshot of their recent work. It was rewarding to be presented with findings of a World Cancer Research Fund grant on wholegrains and colorectal cancer by Dr Cecilie Kyro from the Danish Cancer Society Research Center, who completed her PhD working on this project. She explained that the research showed an inverse association between wholegrain intake and colorectal cancer, however it was unclear which bioactive compounds were responsible for this relationship. Furthermore, the inverse association between fibre intake and colorectal cancer is stronger for cereal fibre than for fruit and vegetable fibre. 3

5. Day two 3 October 2014 Diet and cancer survivors Moving from cancer prevention to cancer survivors, the morning focused on tertiary cancer prevention, informing delegates on the evidence on diet and cancer survival from cohort studies and randomised controlled trials. Dr Teresa Norat opened the session presenting findings from our breast cancer survivors report published in October 2014 as part of the Continuous Update Project the first published systematic literature review of diet, nutrition, physical activity and body composition and cancer survivorship. You can view the findings and conclusions here. Delegates were keen to discuss the report findings, and more widely the evidence on cancer survivors. Although the evidence is too limited to generate breast cancer survivor specific recommendations on diet, nutrition, physical activity and weight, a plant-based diet low in saturated fat indicates longer survival. In addition, breast cancer survivors should aim to follow our cancer prevention recommendations. Dr Norat noted that breast cancer survivors alter their dietary pattern upon diagnosis, including increased dietary supplement intake, however one-year post diagnosis the dietary pattern returns to baseline. Further, dietary patterns during treatment are often not a lifestyle choice but a result of treatment side effects and reduced quality of life. Highlighting some of the implications in conducting research in this high-risk group, it was clear that research in cancer survivors is heterogeneous and therefore difficult to draw firm conclusions. Delegates agreed that this is a high priority research area, and Dr Norat suggested that systematic literature review protocol for breast survivors could be used as a basis for future studies assessing other cancer sites. Reinforcing Dr Norat s earlier thoughts, Professor Wendy Demark-Wahnefried stressed the need for tertiary cancer prevention recommendations, noting that there are many challenges in implementing lifestyle intervention trials in cancer survivors, which implicates development of specific recommendations for this specific group of individuals. Although intervention studies in cancer survivors often have high participant dropout rates due to complications in the disease, there is promising preliminary data emerging from the Harvest for health gardening intervention feasibility study. Results show that a home-based intervention might increase study participation, as well as adherence to the intervention in this case, physical activity in cancer survivors. Next, we were excited to hear findings of the COLON study a cohort initiated as part of the colorectal cancer project from Moniek van Zutphen from Wageningen University. As part of the COLON study, an ongoing prospective cohort study from diagnosis until 5 years after diagnosis among 1,000 colorectal cancer survivors in the Netherlands, the researchers are assessing the association between physical functioning and physical activity post surgery. Preliminary results show that physical functioning within 6 months post-surgery does not return to baseline level in over 50% colorectal cancer patients. This work will be important for informing the feasibility of physical activity in cancer survivors. Body composition and weight management in patients In the afternoon, the theme moved from the research setting to the clinical setting, focusing on body composition in cancer patients. Introducing the theme, Dr Jvalini Dwarkasing from 4

Wageningen University explained that sarcopenia and weight loss is commonly observed in cancer patients undergoing treatment. She went on to present evidence from animal models indicating that hypothalamic resistance to appetite stimulating hormones could be responsible for appetite suppression, and hence anorexia observed during cancer treatment. Further, the role of serotonin (appetite suppressant) and neuropeptide-y (appetite stimulant) is unclear in this mechanism. Moving from animal to human studies, Dr Renate Winkels from Wageningen University proceeded to explain that there is a paradox associated with the optimal body weight in cancer survivors. Certain studies suggest that a lower BMI is associated with longer cancer survival, while in other studies higher BMI is associated with longer survival. The mechanisms explaining this are unclear, but methodological issues regarding timing and/or method of body weight assessment across studies could confound results. Dr Winkels explained that there needs to be a shift in focus from BMI to body composition to better understand the mechanisms. Research is ongoing in the COLON study to assess the association between body composition and colorectal cancer recurrence and survival, using CT scans regularly made to stage the disease to assess body composition. Preliminary evidence suggests that BMI is not well correlated to muscle mass in cancer survivors, and hence BMI may not necessarily be an indicator of sarcopenia or sarcopenic obesity. In a new project, in which Maastricht University, the Comprehensive Cancer Centre, South of the Netherlands and Wageningen University are collaborating on a study funded by World Cancer Research Fund, the association between body composition and colorectal cancer recurrence and survival will be studied further. Closing the afternoon session, Dr Meeke Hoedjes from VU University reviewed interventions for managing weight loss in cancer survivors, explaining that long-term weight loss is difficult to sustain in this highly vulnerable group. The optimal strategy for achieving weight-loss is unclear, a combination of behavioural change techniques should be considered when determining the most effective weight loss strategy. 6. Challenges and future research directions Throughout the event delegates discussed how on-going or future studies could be better designed to generate more robust results, and shared their thoughts on future research directions in the area of diet and cancer. Key challenges and future research directions noted below: Primary cancer prevention! Cancer prevention recommendations must be based on the most up-to-date robust scientific evidence. Epidemiologists and biologists should combine data and share expertise to better understand the association between diet and cancer. Further, it is important to consider study heterogeneity to strengthen judgement of exposure and cancer associations.! Nutrient-nutrient interactions are important in understanding the association between dietary patterns and cancer risk. Future work on dietary patterns is important for informing cancer prevention recommendations.! A cancer prevention recommendation specifically on wholegrain would be beneficial to the public. Identifying the bioactive components in wholegrain most strongly associated with reduced cancer risk would help inform this recommendation.! The association between fruit and vegetable intake and cancer risk is less clear than for other exposures. A greater understanding of how variation in nutrient composition in fruit and vegetable impacts cancer risk might shed light on this association. 5

! The association between folate and cancer risk is crucial to informing public health policy on folate fortification and supplementation. Further exploration of how timing, dose and form of folate intake effects epigenetic patterning and its association with cancer risk is needed.! A life-course approach to assessing diet-cancer associations is critical. For example, it is important to assess the association between energy balance in early life and cancer risk.! Monitoring the generational effects of genetic imprinting on cancer risk in cohort studies is important. Trans-generational data on epigenetic imprinting, for example histone acetylation, will help better characterise epigenetic markers of cancer risk.! More studies are needed to confirm the importance of lifestyle factors in Lynch Syndrome. Therefore, World Cancer Research Fund is funding an international study to combine data from international Lynch Syndrome cohorts, increasing the power to study interactions as well as several less frequently occurring types of cancer in this familial cancer syndrome.! An exposome approach to assess the totality of environmental exposures is important in understanding mechanisms of cancer development.! The application of findings from animal studies in translational medicine must consider heterogeneity of human disease. A better understanding of how to extrapolate findings from animal models to human cancer to reveal underlying mechanisms is needed.! Increasingly, researchers are highlighting the importance of systematic reviews of mechanistic studies (human/animal/cell lines). However, there is no existing systematic method similar to that followed for epidemiological studies for the Continuous Update Project. Such methodology will ensure Continuous Update Project is at forefront of cutting edge science on mechanisms and will be mainstream approach to review such studies worldwide. Find out about our mechanisms work here. Tertiary cancer prevention! Cancer survivors are at increased risk of co-morbidities other than cancer, including metabolic syndrome, diabetes and cardiovascular disease. It is important to consider these comorbidities when developing tertiary cancer prevention recommendations.! Participant recruitment is challenging in cancer survivor studies, with survivors responding better to treatment and/or that have a quicker recovery more likely to participate resulting in population bias. It is beneficial to develop a recruitment protocol based on preliminary data from pilot studies to ensure there is sufficient study power, as well as to ensure the sample is representable.! Tools to assess quality of life across studies in cancer survivors are varied resulting in study heterogeneity. Future studies should consider standardising methodology for assessing quality of life.! Dietary patterns can be transient in cancer patients, therefore assessment methods used to study cancer patients should be sensitive to the effect treatment can have on dietary intake.! Motivation for changing lifestyle behaviours in cancer survivors is important to maximise adherence to an intervention. Tools and guidelines for implementing an intervention should consider how the patient expects the behaviour change to influence their outcome. 6

! Better monitoring of the impact of nutritional intervention during cancer treatment on cancer prognosis and survival is needed. Understanding how the timing of intervention (during or post treatment) impacts cancer prognosis and survival would be beneficial.! The message on body weight in cancer survivors is unclear; a better understanding of how body composition during and post treatment is associated with prognosis and survival will help inform recommendations on body weight. Identifying the best biomarkers of body composition and cancer outcome i.e. BMI, muscle mass, strength or physical functioning will be important for developing this recommendation! Better understanding of mechanisms that underpin the anorexic phenotype observed in cancer patients during treatment will be beneficial.! The accumulating weight loss intervention data is complex due to high study heterogeneity (cancer site, cancer stage and intervention tool). Development of a systematic review protocol on weight loss interventions in cancer survivors is missing in the current literature, and would help determine the optimal strategy for achieving long-term weight loss. 7. Conclusions It is clear that accumulating epidemiological and biological evidence is crucial for drawing conclusions on the association between diet, body composition, and physical activity and cancer risk and survival. Characterising the underlying mechanisms that explain these associations will be important in understanding variation in cancer risk in response to diet, nutrition, physical activity and body weight observed across different sub-groups, including cancer survivors. In addition, this Masterclass demonstrated the value of sharing expertise to identify how best to design studies and interpret findings, and ultimately prevent cancer development and recurrence. You can view the World Cancer Research Fund International related presentations delivered at the Masterclass on our conferences page. 7