World Cancer Research Foundation/American Institute of Cancer Research Continuous Update Project: Keeping the Evidence on Food, Nutrition, Physical Activity, and Cancer Up to Date
Authors: Rachel L. Thompson, PhD, RPHNutr, RD; Susan M. Higginbotham, PhD, RD; Martin J. Wiseman, FRCP, FRCPath
Running Title: WCRF/AICR Continuous Update Project
These abstracts and those in subsequent issues of Nutrition Today will provide readers with an overview of some of the many presentations that were part of the American Institute for Cancer Research (AICR) Annual Research Conference in Washington, DC, November 3-4, 2011. The conference is an annual event organized by the AICR (http://www.aicr.org), a cancer charity that funds research on the relationship of nutrition, physical activity, and weight management to cancer risk; interprets the accumulated scientific literature in the field; and educates people about the choices they can make to reduce their chances of developing cancer. Conference sessions were planned by the program committee: John W. Erdman, Jr, PhD (chair); Robert S. Chapkin, PhD; Steven K. Clinton, MD, PhD; Christine Friedenreich, PhD; Stephen D. Hursting, PhD, MPH; Susan T. Mayne, PhD; John A. Milner, PhD; Cheryl L. Rock, PhD, RD; and June Stevens, MS, PhD. The next AICR conference will be held in Washington, DC, on November 1-2, 2012.
INTRODUCTION
Understanding the causes of cancer depends on synthesizing epidemiologic, clinical, and mechanistic evidence. Using this approach, the 2007 World Cancer Research Foundation/American Institute of Cancer Research (WCRF/AICR) Expert Report1 defined the likely causal contributions of factors related to food, nutrition, and physical activity to cancer risk, based on systematic literature reviews (SLRs) of evidence published up to 2005. The Continuous Update Project (CUP) continues this work and is an ongoing review of nutrition and physical activity and cancer research. The goal of the CUP is to ensure that researchers, policy makers, health professionals, and members of the public have access to recommendations for cancer prevention that are based on the most comprehensive and up-to-date scientific evidence. A team at Imperial College London (ICL) updates the WCRF/AICR CUP database as new diet and cancer studies are published, and systematically reviews the evidence. An independent panel of experts comprising leading scientists in the field of diet, physical activity, obesity, and cancer assesses the findings and draws conclusions based on the body of scientific evidence and where necessary will revise the 2007 WCRF/AICR recommendations.
WCRF/AICR Second Expert Report
The landmark WCRF/AICR Second Expert Report, Food, Nutrition, Physical Activity, and the Prevention of Cancer: A Global Perspective, is the most comprehensive and authoritative report on diet and cancer ever published.1 Seventeen SLRs were conducted by teams of scientists at 9 academic centers across the United States and Europe. An independent international expert panel of 21 renowned scientists reviewed the findings from the SLRs and made judgments based on the available body of evidence, using predetermined criteria. The expert panel considered the totality of evidence for all exposures and cancer sites and issued an integrated set of public health goals and personal recommendations for cancer prevention (Figure 1). The expert panel also identified future strategic research directions seen as especially promising for the research community. These recommendations and strategic research directions form the basis of the education and research programs for the WCRF global network.
CUP Process
The Second Expert Report followed a transparent, collaborative, and rigorous process that involved hundreds of scientists. An advisory group provided guidance and feedback to the SLR teams, a mechanisms working group produced reviews of mechanistic studies and provided insight into plausible mechanistic pathways, and peer reviewers examined SLR protocols and final reports. The expert panel reviewed and interpreted the evidence, developed the recommendations, and approved the content of the final report.
The CUP continues the work of the 2007 Expert Report and follows a similar rigorous process. Having first combined the separate databases for the 17 cancer sites reviewed for the 2007 Expert Report into 1 central database, the ICL team conducts SLRs of links between food, nutrition, physical activity, and specific cancer sites and displays and analyzes the evidence according to peer-reviewed protocols. The CUP will include targeted reviews of mechanistic data using a new protocol currently being developed. Also, because of the growing number of studies now being published on cancer survivorship, a new protocol has been prepared, and a review on food, nutrition, physical activity, and breast cancer survivors is in progress. Outcomes will include quality-of-life measures as well as cancer recurrence and cancer mortality. The protocol will be adapted and used to systematically review studies of other cancer survivors.
The CUP Expert Panel provides an impartial analysis and interpretation of the reports prepared by the ICL team in order to ensure the WCRF/AICR's cancer prevention recommendations from the Second Expert Report are based on the latest available evidence. The panel, chaired by Prof Alan Jackson, includes Second Expert Report Expert Panel members and a Second Expert Report Systematic Review Centre Project Leader, as well as members with expertise in specific areas. The CUP Expert Panel synthesizes the updated evidence from the SLRs and draws conclusions regarding the likely causal relationship between various nutrition and physical activity exposures and each cancer being studied.
The team at ICL is currently using a rolling program to update the CUP database. A complete, continuously updated database is expected by 2015. When the database is completely updated for all cancer sites, it will be possible to query it by exposure across all cancer sites together, which will be a valuable addition to the evidence base. The WCRF and AICR are committed to updating and maintaining this unique resource and intend to make it available for use by the scientific community.
CUP Results
An updated SLR for breast cancer in 2008 added data from 81 new articles published between January 2006 and May 2008 and was consistent with the conclusions of the 2007 Expert Report.2 The CUP Panel concluded that lactation and physical activity decreased, and alcoholic drinks and adult attained height increased risk of premenopausal and postmenopausal breast cancer. Greater body fatness increased the risk of postmenopausal breast cancer and decreased risk of premenopausal breast cancer. Greater abdominal fatness and adult weight gain also increased the risk of postmenopausal breast cancer.3 The panel's conclusions regarding breast cancer are summarized in Figure 2.
An updated SLR for colorectal cancer in 2010 added data from 263 new articles published between 2006 and 2009 and found that evidence for a protective effect from foods containing dietary fiber had strengthened.4 The CUP Panel concluded that this link was convincingly causal, upgraded from probable in 2007. The evidence for convincing or probable causal links between other exposures and colorectal cancer was consistent with the 2007 Expert Report: physical activity, garlic, milk, and calcium were found to be protective, and red meat, processed meat, alcoholic drinks, and greater degrees of body fatness, abdominal fatness, and adult attained height were found to increase risk.5-11 The panel's conclusions regarding colorectal cancer are summarized in Figure 3.
As well as breast and colorectal cancers, the database has been updated for cancers of the pancreas, prostate, ovary, and endometrium. Reports are due later this year for pancreatic, ovarian, and endometrial cancer and in 2016 for prostate cancer. Further reports of updated SLRs will be published on other cancers and on breast cancer survivors. Once the SLRs for all the cancer sites have been updated, the 2007 Expert Report recommendations will be reviewed and, if necessary, revised. This review is expected in 2017. The CUP Expert Panel will consider the effects of all exposures on all cancer sites when reviewing the guidelines and recommendations.
CONCLUSION
Evidence reviewed for the CUP to date is consistent with the conclusions of the 2007 Expert Report. The CUP provides a unique resource synthesizing epidemiologic, clinical, and mechanistic evidence on food, nutrition, physical activity, and cancer and will facilitate related research as well as underpin advice to public and policy makers.
Rachel L. Thompson, PhD, RPHNutr, RD, is deputy head of science at World Cancer Research Fund International, London, England. She is head of the secretariat for the World Cancer Research Foundation/American Institute of Cancer Research Continuous Update Project.
Susan M. Higginbotham, PhD, RD, is director for research at the American Institute for Cancer Research, Research, Washington, DC. She serves on the secretariat for the World Cancer Research Foundation/American Institute of Cancer Research Continuous Update Project.
Martin J. Wiseman, FRCP, FRCPath, is medical and scientific advisor with World Cancer Research Fund International. He is the project director for the World Cancer Research Foundation/American Institute of Cancer Research Continuous Update Project, London, England.
The authors have no conflicts of interest to disclose.
Correspondence: Susan M. Higginbotham, PhD, RD, American Institute for Cancer Research, 1759 R St, NW, Washington, DC 20009 ([email protected]).
References
1. 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.
2. WCRF/AICR. Systematic Literature Review Continuous Update Project Report: the associations between food, nutrition and physical activity and the risk of breast cancer. Imperial College London; 2008. http://www.dietandcancerreport.org/cancer_resource_center/cup_reports.php.
3. WCRF/AICR. Breast Cancer Report Summary 2010. Food, nutrition, physical activity: a global perspective. 2010. http://www.dietandcancerreport.org/cancer_resource_center/cup_summaries.php.
4. WCRF/AICR. Systematic Literature Review Continuous Update Project Report: the associations between food, nutrition and physical activity and the risk of colorectal cancer: Imperial College London; 2010. http://www.dietandcancerreport.org/cancer_resource_center/cup_reports.php.
5. WCRF/AICR. Colorectal Cancer Report Summary 2010. Food, nutrition, physical activity: a global perspective. 2011. http://www.dietandcancerreport.org/cancer_resource_center/cup_summaries.php.
6. Perera P, Thompson RL, Wiseman MJ. Recent evidence for colorectal cancer prevention through healthy food, nutrition and physical activity: implications for recommendations. Curr Nutr Rep. 2012;1:44-54.
7. Touvier M, Chan DS, Lau R, et al. Meta-analyses of vitamin D intake, 25-hydroxyvitamin D status, vitamin D receptor polymorphisms and colorectal cancer risk. Cancer Epidemiol Biomakers Prev. 2011;20:1003-1016.
8. Aune D, Lau R, Chan DS, et al. Nonlinear reduction in risk for colorectal cancer by fruit and vegetable intake based on meta-analysis of prospective studies. Gastroenterology. 2011;141:106-118.
9. Aune D, Lau R, Chan DS, et al. Dairy products and colorectal cancer risk: a systematic review and meta-analysis of cohort studies. Ann Oncol. 2011.
10. Chan DS, Lau R, Aune D, et al. Red and processed meat and colorectal cancer incidence: meta-analysis of prospective studies. PLoS One. 2011;6:e20456.
11. Aune D, Chan DSM, Lau R, et al. Dietary fibre, whole grains, and risk of colorectal cancer: systematic review and dose-response meta-analysis of prospective cohort studies. BMJ. 2011;343:d6617.
Food, Nutrition, Physical Activity, and Cancer: Contributions of Different Types of Research to the Totality of the Evidence
Authors: Susan T. Mayne, PhD; Edward Giovannucci, MD, ScD; JoAnn E. Manson, MD, DrPH; Stephen D. Hursting, PhD, MPH; Steven K. Clinton, MD, PhD
Running Title: Types of Evidence
Abstract
This presentation summarizes the contribution of different types of evidence to our knowledge of food and nutrition in relation to cancer. It was presented as part of the program at the AICR Annual Research Conference in Washington, DC, November 3-4, 2011, an annual event organized by the American Institute for Cancer Research (http://www.aicr.org), a cancer charity that funds research on the relationship of nutrition, physical activity, and weight management to cancer risk; interprets the accumulated scientific literature in the field; and educates people about the choices they can make to reduce their chances of developing cancer.
INTRODUCTION
Agencies such as the American Institute for Cancer Research and the World Cancer Research Fund play an important role in reviewing and interpreting the scientific evidence related to food, nutrition, and physical activity, in relation to cancer,1 with the goal of producing recommendations to prevent cancer and promote global public health. These and other organizations that work at the interface of science and policy must necessarily review and interpret various types of evidence, some of which are not necessarily concordant. Thus, a careful consideration of the strengths and weaknesses of different study designs/types of research is critical before attempting to synthesize information and make recommendations based on the totality of evidence. Also, research on diet and cancer provides excellent examples of the complementary nature and interplay of different study designs in contributing to the totality of evidence.
Investigators trying to obtain evidence about the role of diet and nutrition in relation to cancer risk face some unique complexities and challenges: first, exposure to specific dietary factors (eg, a food or nutrient) is challenging to measure, especially over a long-term basis. Furthermore, diet is complex and multifaceted, and nutrients and foods may interact in complex ways. Attempting to attribute an effect to a single food or nutrient is problematic, because nutrients often track together (eg, folate, vitamin C, fiber, and carotenoids), whereas other nutrients correlate strongly with foods/food groups (eg, calcium and dairy products). Second, metabolism and physiology are complex, and the effect of a nutrient, food, or, more broadly, a dietary pattern should be considered in the context of metabolic pathways. For example, insulin resistance and hyperinsulinemia may be important for carcinogenesis, and specific dietary factors may operate in complex ways. Moreover, the specific dietary factors, as well as interacting genetic factors, that influence insulin resistance may differ across populations. Third, not only is the exposure (diet) complex, but so is the outcome of interest-cancers are heterogeneous in etiology, even within a single anatomic site (eg, colon). Fourth, the entire process of carcinogenesis may require decades to complete. Because of the long latency period for cancer, the challenges of understanding the role of diet may be even greater than for chronic diseases such as cardiovascular disease, type 2 diabetes, or other health conditions that are modifiable over shorter time intervals. As a result, dietary factors that have an impact on events early in carcinogenesis may be especially difficult to identify because of the long time lag between dietary exposures and the cancer end point. The varying study designs discussed in the following sections can address, at least in part, some of these complexities, but no one study design can simultaneously address all of them.
Key Point
* Attempting to attribute an effect to a single food or nutrient is problematic, because nutrients often track together (eg, folate, vitamin C, fiber, and carotenoids), whereas other nutrients correlate strongly with foods/food groups (eg, calcium and dairy products).
Observation Studies
Observational studies have provided a large portion of the evidence base on food, nutrition, and cancer and include international correlational studies,2 migrant studies,3 studies of secular trends within populations, and case-control and prospective studies. The early literature on food, nutrition, and cancer was based heavily on case-control studies-with the maturing of several cohorts around the world, there is now a much greater representation of findings from prospective cohort studies, which offer protection against recall bias and many forms of selection bias, compared with case-control studies. Repeated exposure assessments and integration of biomarker and genetic assessments have improved the value of prospective cohort studies for food, nutrition, and cancer. Observational data may contribute the ability to examine long time lags (eg, intake over decades), large sample sizes that may allow subtyping of cancers, and a diversity of settings/populations to examine associations.
The main challenge of observational studies is conceptualizing the relevant aspects of diet to measure, with approaches ranging from assessing an entire dietary pattern4 to attempting to identify a specific individual nutrient or phytochemical as being important in carcinogenesis. Because of the potential for confounding by other factors (both dietary and nondietary), the definitive proof of causation for a specific component may ultimately require randomized trials (along with animal/mechanistic studies), as noted below.
Despite their limitations, observational studies have contributed important information on the relationships between food, nutrition, and cancer. As an example, evidence strongly suggests that a rapid growth rate in childhood leading to greater adult height increases risk of breast, colon, prostate, and other cancers, and accumulation of body fat in adulthood is related to cancers of the colon, kidney, pancreas, and endometrium, as well as postmenopausal breast cancer.5,6 The aspect of diet related to energy balance and related hormones (eg, insulin, insulinlike growth factors, sex steroids) is likely to be one of the strongest contributors of diet and nutrition to cancer risk.7 Multiple dietary variables, as well as genetic and epigenetic factors, independent of energy intake, that affect these hormones may also influence cancer risk.
The role of specific individual nutrients (eg, folate, calcium) on cancer risk, largely suggested based on promising findings from observational studies,8 has been more difficult to establish. Challenges include measuring these adequately, capturing the relevant dose-response and induction or latency period, and accounting for correlated factors in the context of an overall dietary pattern, including dietary and nondietary behaviors. More recently, recommendations for cancer prevention from the American Institute for Cancer Research and other organizations have focused on food groupings (eg, folate-rich foods instead of folate intake; foods of plant origin) rather than specific nutrients, in part to deal with the issue of correlated nutrients.
Because of the known limitations with observational data, ultimate recommendations involving diet should be based on a convergence of the mechanistic understanding, animal data, observational data, and randomized interventions whenever this is feasible.
Randomized Clinical Trials
In a randomized clinical trial (RCT), the exposure (nutrient intake or dietary pattern) is assigned randomly to persons within a recruited population, and cancer incidence and mortality can be tracked over time and compared between the intervention group and a comparison group of recruited persons that was assigned randomly to the placebo or to the usual diet. Although the RCT is often considered the criterion standard of medical research, it also has both strengths and weaknesses. In brief, the major advantages of the RCT design are the ability to control confounding by both measured and unmeasured variables through the process of randomization, as well as to provide a structure for unbiased ascertainment of study outcomes (thus simultaneously controlling for confounding, selection bias, and surveillance and/or detection bias). Yet RCTs are reliant on basic research, clinical studies, and observational epidemiologic studies for the generation of hypotheses and even refinement of the intervention, such as the optimal dose to be tested or the critical time interval for the intervention. Moreover, RCTs have the following additional constraints: compliance with the intervention may be suboptimal; usually only 1 dose (or intensity) of an intervention can be tested; the study population may already be replete in a nutrient (with intakes above a threshold for efficacy); long latency periods may limit feasibility; other lifestyle factors such as smoking might unexpectedly affect the efficacy of the nutrient; and the costs tend to be much higher than for other study designs. Thus, it should be evident that observational and intervention research (along with basic and translational research) has complementary and synergistic roles in advancing knowledge on the role of diet and cancer.
Examples of this scientific exchange between different types of research include the hypothesis that a low-fat dietary pattern can reduce the risk of breast and colorectal cancer (later tested in the Women's Health Initiative9-12), observational studies of antioxidant vitamins and folic acid/B vitamins suggesting cancer risk reductions (later tested in a number of RCTs13-15), and the extensive observational evidence for a relationship between higher serum 25-hydroxyvitamin D levels and a reduced risk of colorectal and other site-specific cancers (now being tested in VITAL [VITamin D and OmegA-3 TriaL]16 and in other RCTs of vitamin D supplementation17).
Given the important interplay between observational studies and RCT research, and the increasing incorporation of biomarkers into clinical research, some researchers have recommended a "phased" approach to evaluating scientific hypotheses that would leverage the advantages of RCTS but at a much lower cost and study duration. This approach is dependent on the availability of well-validated "intermediate outcomes," such as biomarkers (serum, proteomic, metabolomic, or other), imaging results (such as mammographic breast density), colorectal adenomas, or other surrogate markers. Promising hypotheses in bench research, animal studies, and observational studies could then move to RCTs with carefully selected intermediate outcomes that require smaller sample sizes and shorter durations of treatment and follow-up. Those that continue to look promising in terms of intermediate outcomes would move forward to full-scale RCTs. This approach may not be appropriate for many of the scientific questions of interest and may also have disadvantages related to false positives and false negatives, so it will require careful consideration before adoption on a broader scale.
Animal Models, in Vitro Model, and Transdisciplinary Studies
As noted earlier, although observational evidence suggests that many human cancers could be prevented with prudent dietary change, causal relationships between specific dietary factors and cancer are challenging to establish using human research approaches alone.18 Animal models can play important roles in multidisciplinary nutrition and cancer prevention research, particularly in establishing causal connections and understanding underlying mechanisms, but there are several strengths and limitations that must be considered in order to maximize the contributions of animal research to the field.19 Focusing on rodent models (which are commonly used in nutrition and cancer research), key strengths include (1) rodents are relatively simple and inexpensive to generate and manage under controlled conditions; (2) inbred strains with well-characterized genetics facilitate development of relevant models via genetic manipulation, genetic crosses, isogenic transplants, and so on; (3) causal relationships and underlying mechanisms can be established; (4) the entire life course is ~2.5 years, and often less, facilitating the development of rapid models; (5) combination studies of multiple nutrients/agents and studies of stage-specific effects of interventions can be easily performed; and finally (6) parallel animal and human trials to elucidate underlying mechanisms, establish biologic plausibility, and inform human studies can be conducted. Key limitations of rodent studies include (1) mice/rats are not people-rodent cancer can be different than human cancer (eg, rodents are generally poor models for metastasis); (2) diet is generally very different from humans; (3) gene sequences/functions/redundancy may be different than in humans; (4) the pharmacokinetics and pharmacodynamics of nutrients and nonnutrients, as well as carcinogenic agents, can be quite different than in humans, because of differences in cytochromes P450, and so on; (5) the microbiota of relevant tissues such as the skin, oral cavity, and intestine that may impact nutritional status and carcinogenesis may be different from humans; (6) typically young animals are used to study late-life diseases; and (7) genetically defined strain differences can be large and must be considered. Given these and other limitations, it is important to molecularly profile/pathologically characterize tumors/preneoplastic lesions relative to human lesions to understand what, relative to the human disease, is being modeled. It is also important to establish positive (and negative) predictive value of a model-does the model respond similarly to known suppressors or enhancers of human tumors and not respond to interventions that have null effects in humans? Finally, as it is generally accepted that there will never be 1 single, perfect mouse model for each disease, it is advantageous to use more than 1 animal model whenever possible to study different aspects of a given disease.20
An example of the utility of animal models in supporting and extending observational or clinical research can be found in studies establishing causal relationships between several obesity-related local or systemic factors and the risk and/or progression of multiple cancer types.21,22 These factors include several hormones (such as insulin and insulinlike growth factor 1), adipokines, and inflammatory regulators. Each of these energy balance-related factors impacts critical cellular nutrient sensing and survival pathways, such as the mammalian target of rapamycin (mTOR) pathway. Recent research using a series of transgenic mouse models of colon, prostate, skin, mammary, and pancreatic cancers has shown that the mTOR pathway (which was initially identified as a cancer therapeutic target in preclinical studies) appears central to many of the effects of energy balance on cancer.23-26 Furthermore, it has been established that dietary or pharmacologic inhibitors of components of the mTOR pathway can modulate the energy balance-cancer link.23,24,26 This has led to studies in high-risk human subjects in parallel with relevant animal models to further elucidate relevant mechanisms, biomarkers, and effective interventions for offsetting the effects of obesity on breast, prostate, and endometrial cancer. Such transdisciplinary research approaches that combine animal models with epidemiologic, clinical, and/or behavioral studies should accelerate the development and translation of nutritional strategies for cancer prevention.
The in vitro studies and their relevance to the field of diet and cancer also deserve attention. Studies of malignant cells, immortalized normal cells, or primary cultures cannot provide strong evidence to guide public health recommendations. Cells in culture bypass many of the critical in vivo processes that have an impact on how a nutrient or nonnutrient phytochemical may impact a target tissue to alter cancer risk, including digestion, bioavailability, absorption processes, systemic metabolism by the host or microflora, and relevant distribution mechanisms (eg, lipoprotein delivery of carotenoids). However, studies of cells can provide very precise knowledge regarding the molecular and cellular targets modulated by nutrients and other dietary components. Studies can be conducted on rapidly and potentially relevant interactions between dietary agents, and relevant growth factors or hormones may be elucidated to drive the design of mechanistically driven in vivo studies. These approaches provide evidence for biological plausibility for specific diet, nutrition, and cancer hypotheses while also providing guidance for the development of relevant biomarkers that may be useful in rodent and human studies.
CONCLUSIONS
As discussed in this brief overview, observational studies, RCTs, and basic animal and translational research have complementary and synergistic roles in advancing knowledge on food, nutrition, and cancer. In most cases, a single study (of any type) is unlikely to provide sufficient evidence of causal associations, and the entire available body of data from various perspectives and disciplines is likely to provide the best evidence for the relationship between a dietary factor and cancer risk. To illustrate with but one example, the convergence of evidence supporting obesity and obesity-related biomarkers as risk factors for cancer, based on both human and animal studies, supports the priority public health recommendation that persons "be as lean as possible, within the normal range of body weight."1
Susan T. Mayne, PhD, is the C.-E.A. Winslow Professor of Epidemiology and chair of the Department of Chronic Disease Epidemiology at the Yale School of Public Health, New Haven, Connecticut. She is also associate director for Population Sciences for the Yale Cancer Center, New Haven, Connecticut.
Edward Giovannucci, MD, ScD, is professor of nutrition and epidemiology in the Departments of Nutrition and Epidemiology at the Harvard School of Public Health, Boston, Massachusetts. He is also associate professor of Medicine at Harvard Medical School.
JoAnn E. Manson, MD, DrPH, is a professor of medicine, Harvard Medical School, and chief,Division of PreventiveMedicine, Brighamand Women's Hospital Boston, Massachusetts. She is also professor of epidemiology in the Department of Epidemiology at the Harvard School of Public Health, Boston, Massachusetts.
Stephen D. Hursting, PhD, MPH, is a professor and Margaret McKean Love Chair, Division of Nutritional Sciences, University of Texas at Austin. He is also a member of the Department of Molecular Carcinogenesis, UT-MD Anderson Cancer Center.
Steven K. Clinton,MD, PhD, is a professor, Division of Medical Oncology, Department of Internal Medicine, the Ohio State University and the James Cancer Hospital, Columbus. He is also professor in the Department of Human Nutrition, the Ohio State University, Columbus.
The authors have no conflicts of interest to disclose.
Correspondence: Susan T. Mayne, PhD, Yale School of Public Health, PO Box 208034, 60 College St, New Haven, CT ([email protected]).
References
1. World Cancer Research Fund American Institute for Cancer Research. Food, Nutrition, Physical Activity, and the Prevention of Cancer: A Global perspective. Washington, DC: The Second Expert Report; 2007.
2. Rose DP, Boyar AP, Wynder EL. International comparisons of mortality rates for cancer of the breast, ovary, prostate, and colon, and per capita food consumption. Cancer. 1986;58:2263-2271.
3. Ziegler RG, Hoover RN, Pike MC, et al. Migration patterns and breast cancer risk in Asian-American women. J Natl Cancer Inst. 1993;85:1819-1827.
4. Slattery ML, Boucher KM, Caan BJ, Potter JD, Ma KN. Eating patterns and risk of colon cancer. Am J Epidemiol. 1998;148(1):4-16.
5. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003;348:1625-1638.
6. Giovannucci E, Ascherio A, Rimm EB, Colditz GA, Stampfer MJ, Willett WC. Physical activity, obesity, and risk for colon cancer and adenoma in men. Ann Intern Med. 1995;122:327-334.
7. Giovannucci E. Nutrition, insulin, insulin-like growth factors and cancer. Hormone Metab Res. 2003;35(11-12):694-704.
8. Cho E, Smith-Warner SA, Spiegelman D, et al. Dairy foods and calcium and colorectal cancer: a pooled analysis of 10 cohort studies. J Natl Cancer Inst. 2004;96:1015-1022.
9. Prentice RL, Caan B, Chlebowski RT, et al. Low-fat dietary pattern and risk of invasive breast cancer. The Women's Health Initiative Randomized Controlled Dietary Modification Trial. JAMA. 2006;295:629-642.
10. Beresford SAA, Johnson KC, Ritenbaugh C, et al. Low-fat dietary pattern and risk of colorectal cancer. The Women's Health Initiative Randomized Controlled Dietary Modification Trial. JAMA. 2006;295:643-654.
11. Howard BV, Manson JE, Stefanick ML, et al. Low-fat dietary pattern and weight change over 7 years. The Women's Health Initiative Dietary Modification Trial. JAMA. 2006;295(1):39-49.
12. Prentice RL, Thomson CA, Caan B, et al. Low-fat dietary pattern and cancer incidence in the Women's Health Initiative Dietary Modification Randomized Controlled Trial. J Natl Cancer Inst. 2007;99(20):1534-1543.
13. Blot WJ, Li JY, Taylor PR, et al. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst. 1993;85(18):1483-1492.
14. Gaziano JM, Glynn RJ, Christen WG, et al. Vitamins E and C in the prevention of prostate and total cancer in men. The Physicians' Health Study II Randomized Controlled Trial. JAMA. 2009;301(1):52-62.
15. Zhang SM, Cook NR, Albert CM, Gaziano JM, Buring JE, Manson JE. Effect of combined folic acid, vitamin B6, and vitamin B12 on cancer risk: results from a randomized trial. JAMA. 2008;300(17):2012-2021.
16. Manson JE, Bassuk SS, Lee IM, Cook NR, Albert MA, et al. The VITamin D and OmegA-3 TriaL (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease. Contemp Clin Trials. 2012;33:159-171.
17. Manson JE, Mayne ST, Clinton SK. Vitamin D and prevention of cancer-ready for prime time? N Engl J Med. 2011;364:1385-1387.
18. Forman M, Hursting SD, Umar A, Barrett JC. Nutrition and cancer prevention: a multidisciplinary perspective on human trials. Annu Rev Nutr. 2004;24:223-254.
19. Hursting SD, Lashinger LM, Brown P, Perkins SN. The utility of transgenic mouse models for cancer prevention research. In: Teichee B, ed. Transgenic Animal Models in Cancer Research. 2nd ed. Totowa, NJ: Humana Press, Inc; 2010. Chapter 18.
20. European Commission Workshop Executive Summary. Are mice relevant models for human disease? 2010. http://ec.europa.eu/research/health/pdf/summary-report-25082010_en.pdf.
21. Hursting SD, Berger N. Energy balance, host-related factors and cancer progression. J Clin Oncol. 2010;28:4058-4065.
22. Hursting SD, Lashinger LM, Wheatley KW, et al. Reducing the weight of cancer: mechanistic targets for breaking the obesity-carcinogenesis link. Best Pract Res Clin Endocrinol Metab. 2008;22:659-669.
23. Lashinger LM, Malone LM, Brown GW, et al. Rapamycin partially mimics the anticancer effects of calorie restriction in a murine model of pancreatic cancer. Cancer Prev Res. 2011;4:1041-1051.
24. Nogueira LM, Smith SM, Ford NA, Hursting SD. Calorie restriction and rapamycin, but not exercise, inhibit MMTV-Wnt-1 mammary tumor growth in a mouse model of postmenopausal obesity. Endocr Relat Cancer. 2011. In press.
25. Moore T, Beltran LD, Carbajal S, et al. Dietary energy balance modulates signaling through the Akt/mammalian target of rapamycin pathway in multiple epithelial tissues. Cancer Prev Res. 2008;1:65-76.
26. Zhu J, Thompson MD, McGinley JN, Thompson HJ. Metformin as an energy restriction mimetic agent for breast cancer prevention. J Carcinogenesis. 2011;10 (17):1-15.
Current Nutritional Issues in Cancer Treatment and Survivorship
Authors: Cheryl L. Rock, PhD, RD; John A. Milner, PhD; Carla Prado, PhD; Ralph Green, MD, PhD, FRCPath; Bette J. Caan, Dr PH; Leena A. Hilakivi-Clarke, PhD
Running Title: Cancer Treatment and Survivorship
ABSTRACT
Nutritional factors can have an important role in the management of cancer, across the spectrum from the initial phases of treatment and recovery through the continuum of survivorship. The majority of Americans diagnosed with cancer survive more than 5 years, and more than 12 million people in the United States are now cancer survivors. Several important nutritional issues in this population are recognized. Cancer cachexia is a syndrome of progressive weight loss characterized by muscle wasting with or without loss of fat mass associated with cancer and cancer treatments. This is associated with poorer prognosis, particularly shorter median survival time. Nutritional support with an emphasis on adequate energy and protein intakes and as part of a multimodal treatment designed to counteract both reduced dietary intake and hypercatabolism appears to be the strategy most likely to improve body composition and physical function in managing cancer cachexia. The nervous system is particularly sensitive to micronutrient deficiencies associated either with tumor growth or with the use of antimetabolites, and complications associated with cancer or cancer treatments may affect either or both the central and peripheral nervous system. Current epidemiologic evidence suggests that concerns that soy food intake may adversely affect prognosis following the diagnosis and treatment of breast cancer may be unwarranted, although more preclinical and intervention studies are needed. Incorporating nutritional care into the management of the cancer patient, based on continued research, may contribute to increased quality and/or quantity of life for the millions of individuals who are diagnosed with cancer each year.
This presentation was part of the program at the AICR Annual Research Conference in Washington, DC, November 3-4, 2011, which is an annual event organized by the American Institute for Cancer Research.
INTRODUCTION
Cancer is a major health concern in the United States, as well as throughout the world.1 Although cancer death rates decreased 22.9% in men and 15.3% in women in the United States between 1990/1991 and 2008,2 1 in 4 deaths in this country is currently due to cancer. Because of advances in early detection and treatment, 68% of Americans diagnosed with cancer now live more than 5 years, and more than 12 million people in the United States are now classified as cancer survivors.
Nutritional factors can have a significant role in the management of cancer patients, across the spectrum from the initial phases of diagnosis, treatment, and recovery, through the continuum of lifelong survivorship, in which the goals are to prevent recurrence, reduce risk for comorbid disease, and increase likelihood of survival. Maintaining good nutritional status during the initial postdiagnosis treatment phase may enable the successful completion of prescribed treatments, reduce time to recovery, and improve quality of life of the patient. Observational studies of cohorts of individuals who have been diagnosed with cancer suggest that dietary and nutritional factors also may influence the long-term prognosis and overall survival.1
Several nutritional issues are particularly relevant to the management of cancer and are active areas of research. These include the prevention and treatment of cancer cachexia, the unique vulnerability of the nervous system to both tumor- and treatment-related complications, and identifying whether bioactive constituents in specific foods, such as soy, may have a beneficial or deleterious effect on progression in breast cancer.
The Impact of Nutrition Intervention in Cancer Cachexia
Cancer cachexia is a syndrome of progressive weight loss and muscle wasting with or without loss of fat mass that is associated with cancer and cancer progression treatments.3
Key Point
* As noted in early clinical series reports,3 substantial weight loss and cachexia can occur in patients at the time of cancer diagnosis and during treatment, although the prevalence of weight loss and malnutrition varies widely across cancer types.3,4 When grouped by cancer type, tumor extent, and activity level, median survival time has been observed to be shorter in those who experience weight loss and cachexia compared with those who did not.5
Nutritional status is an important prognostic factor in cancer cachexia research. The assessment of nutritional status, and specifically body composition, has recently emerged as an important predictor of cancer-related outcomes.6 Advances in body composition research have also changed the traditional expectation of extreme wasting in patients with cancer cachexia, showing that body weight or body mass index alone no longer depicts a state of nutritional deficit.6,7 In fact, cachexia may be observed in individuals with normal or even high body mass index. This concept will affect the design and interpretation of future cachexia clinical trials, which have mainly relied on changes in body weight as the primary outcome. Importantly, in order to assess the impact of nutrition intervention in cancer cachexia, it is essential to determine whether these patients possess a therapeutic window for anabolic response throughout the course of their disease trajectory.
As cancer cachexia is a complex syndrome, stand-alone nutritional interventions have had only limited success. Nonetheless, nutritional support as part of a multimodal treatment may help to improve metabolism, specific cellular processes such as immunocompetence, and body composition as well as physical function, all of which ultimately affect survival.8 Providing adequate energy and protein intake remains the hallmark nutritional intervention in cancer cachexia. However, it is becoming increasingly clear that a multitude of bioactive constituents in foods can influence key cellular processes associated with cancer and thus influence survival. Nutritional factors such as specific amino acids and fatty acids and their effects on metabolic response are being actively investigated. Fish oil and omega-3 fatty acids are one of the more widely investigated food components, but study results are conflicting and have precluded recommending them for use in cancer cachexia therapy. Glutamine is a well-tolerated and effective amino acid associated with an overall improvement in clinical condition in response to administration.9 Although branched-chain amino acid supplementation may lead to a reduced length of hospital stay, improvement in survival and quality of life has not been convincingly demonstrated.9
At this time, there is no agreed-upon successful nutritional intervention for cancer cachexia. Promotion of good nutritional status should be directed toward capturing the patient's anabolic potential while promoting an increase in food intake and modulation of inflammation, and other critical cancer-related processes, to improve the quality and duration of life.
Micronutrient Status and the Nervous System in Cancer: A Balance Between Feeding the Host and Starving the Tumor
The framework for host-tumor interaction is complex and multifaceted, but it is, in large measure, competitive. One important arena for host-tumor competition is nutrient availability. An adequate supply of critical micronutrients is essential for the maintenance of both normal and malignant cellular growth, development, function, and proliferation. In general, tumor cells are highly effective in competing with normal cells for available micronutrients, largely as a result of high expression on their cell surfaces of receptors for micronutrients and their carrier proteins. This may contribute to conditions of host nutrient deficiencies, which, if not corrected, can cause morbidities of varying severity10 but, if corrected or overcorrected, may result in the undesirable effect of further promoting tumor growth. Similar considerations apply to "antimetabolite" cancer chemotherapy, directed specifically at a micronutrient-dependent metabolic pathway and designed to interdict the growth and proliferation of rapidly dividing tumor cells. However, inhibition of the same nutrient-dependent pathway may have undesirable effects on normal tissues as well, and various strategies need to be used to protect or "rescue" the normal cells from sustaining serious or irreparable damage from the effects of disruption of the nutrient-dependent pathway.
The nervous system is particularly vulnerable to nutrient deprivation associated either with tumor growth or with the use of antimetabolites.11 Complications associated with cancer may affect either or both the central and peripheral nervous systems. Central neurotoxicity effects range from mild cognitive impairment to encephalopathy with dementia and even coma.12,13 Peripheral neurotoxicity usually consists of peripheral neuropathy and is particularly troublesome in patients who already have neuropathic symptoms due to underlying diabetes mellitus, hereditary, or other neuropathies. The overall goal of cancer treatment is to greatly reduce and, if possible, to eradicate the tumor cell population, while preserving, maintaining, and, when possible, enhancing the health of the host's normal cells, including the sensitive, often irreparable and currently irreplaceable cells of the nervous system. In terms of the metaphor of warfare in which cancer is considered to be the enemy combatant, the essence of the tactical approach to the conflict is to inflict maximum damage on cancer cells while avoiding or keeping to a minimum any collateral damage to normal cells. The strategy of managing cancer patients with respect to maintenance of optimum health in the context of good nutritional status is therefore to achieve a desirable balance between feeding the host and starving the tumor. Disruption of normal micronutrient status affecting the nervous system has been reported in the context of cancer treatment. The classic and best known example of this situation is seen with the use of high doses of methotrexate and other antifolates, particularly when they are administered intrathecally (into the brain) as in the treatment of acute lymphoblastic leukemia in childhood, where serious and irreversible effects on intellectual development would occur without folic acid rescue.
Other micronutrient deficiencies that can occur in cancer include deficiencies in vitamin B12 or thiamine, giving rise to neurological complications that affect both the central and peripheral nervous system.10 It is important to distinguish whether such neurological complications are caused by the systemic effects of the cancer, associated micronutrient deficiencies, or complications arising from anticancer drugs that can closely mimic the manifestations of micronutrient deficiencies. Nutritional and dietary supplements should be used prudently, because their inappropriate or excessive administration to cancer patients may lead to tumor progression, although the evidence for this is not terribly compelling.
Soy Intake for the Breast Cancer Survivor: Evidence From the Epidemiological Literature
Found mainly in soy foods, isoflavones are part of a larger class of flavonoid compounds. Isoflavones are structurally similar to 17[beta]-estradiol, the primary endogenous estrogen, and have been demonstrated to have both antiestrogenic and estrogen-like properties, depending on the endogenous estrogen environment of the woman. Soy foods also demonstrate other anticancer properties and have been mostly associated with a lower risk of breast cancer, especially in Asian populations where soy consumption is more prevalent and is typically begun at earlier ages.14
However, soy foods also exhibit estrogen-like properties and therefore can compete for binding to estrogen receptors (ERs) in the breast. In fact, in contrast to the chemopreventive effects of soy, animal studies have demonstrated that genistein, one of the main components of soy, can stimulate tumor development and cell growth.15
Further, experimental studies suggest that soy isoflavones may interact with tamoxifen therapy. Some studies show a potential benefit for combined dietary isoflavone intake and tamoxifen therapy use on the inhibition of breast tumor growth,16 whereas other studies have reported reduction of the anticancer effects of tamoxifen on breast tissue.17 These data have raised concern regarding soy food consumption among breast cancer survivors, and in some cases, physicians in the United States may caution women who are receiving tamoxifen against consuming soy foods and/or soy supplements.
The epidemiologic data on the impact of soy foods for the breast cancer survivor are limited. To date, there have been 4 individual studies: 2 in US populations,18,19 2 in Chinese populations,20,21 and 1 report from a pooling project.22 In none of the individual studies was an increased risk of either recurrence or breast cancer death observed in association with soy consumption. In fact, although there were large differences in levels of soy consumption across populations, all of them demonstrated to some degree that soy food intake after diagnosis may improve prognosis among breast cancer survivors. Furthermore, several of the studies demonstrated that benefits of soyconsumption were greatest among women with ER and/or progesterone receptor-positive breast cancer who received tamoxifen. Results from the pooled analysis of 4 cohorts of more than 9500 breast cancer survivors confirmed findings from the individual studies and found that women who consumed 10 mg/d or more of isoflavones had a 25% reduced risk of recurrence. Further, among women with ER-positive tumors, the inverse association appeared to be limited to tamoxifen users. Although the associations were statistically significant among breast cancer survivors in China, the inverse association of soy intake and breast cancer outcomes was present in both the United States and Chinese cohorts.
Contrary to soy being harmful, these reports and the pooled results suggest no adverse effects and, although variable, possible benefits for breast cancer survivors. Continued research is needed to further understand the potential benefits, who may benefit most, and the interactions of soy consumption in combination with adjuvant therapies. Nevertheless, these studies, taken together, which vary in racial/ethnic composition and by level and type of soy consumption, provide evidence that clinicians likely do not need to advise against soy food consumption for women diagnosed with breast cancer.
Biological Factors Involved in Mediating the Effects of Soy Foods on Breast Cancer Survivors
Because of the apparent estrogenicity of genistein from soybeans, there has been some concern whether breast cancer survivors should consume soy foods. As discussed above, results obtained in observational studies indicate that soy intake is associated with either a reduced risk of breast cancer recurrence or it has no effect. However, there are no human studies available that have investigated whether initiating soy food consumption after a breast cancer diagnosis affects prognosis. There are several reasons why breast cancer survivors may consider starting to consume soy foods after diagnosis: lifestyle changes are common in survivors; observational studies suggest that soy food consumers have low risk of recurrence, and genistein may be believed to help reduce menopausal symptoms triggered by antiestrogen treatments for breast cancer. However, there also are findings that raise concerns about starting soy intake after a breast cancer diagnosis: genistein promotes the growth of human breast cancer cells in in vitro or in vivo preclinical models and can increase the probability that the cells metastasize.23 It is possible that genistein has different effects on breast cancer survivors who have consumed soy throughout their lifetime than on those who have not.
Only 20% to 30% of non-Hispanic white women in the United States consume soy foods. Average soy intake in this country corresponds to 1 to 6 mg/d isoflavones, whereas the intake is 20 to 50 mg/d isoflavones among Asian women. Most non-Hispanic white women start consuming soy foods as adults, in contrast to Asian women who consume soy foods throughout their lifetimes. Results from both human (reviewed in Hilakivi-Clarke et al15) and animal studies (reviewed in Warri et al24) suggest that soy intake may need to start early in life; that is, before puberty, to provide protection against the development of breast cancer. This protection may extend beyond breast cancer diagnosis and reduce the likelihood of recurrence. Evidence to support this idea comes from the data showing that prepubertal genistein consumption causes a persistent down-regulation of progesterone receptor and its downstream target RANKL in the mammary gland and estrogen receptor (ER-[alpha]) and progesterone receptor in mammary tumors.25 In addition, prepubertal genistein exposure reduces amphiregulin expression. Amphiregulin is a downstream target of ER-[alpha] and mediates its proliferative actions by activating EGFR26; no changes in ER-[beta] were seen.25 It is not known how early-life genistein exposure induces long-lasting changes in the mammary gland and tumors, but it may be related to genistein-induced up-regulation of tumor suppressor gene BRCA1.27 Results from both human28 and animal studies25 indicate that intake of genistein or soy during childhood reduces the expression of oncogene HER2 in the breast tumors. Additional mechanistic studies are needed to determine whether there are different groups of breast cancer survivors who might benefit most or possibly be placed at risk by continuing or starting isoflavone intake.
The possibility that childhood exposure to genistein determines the effect of adult soy intake on breast cancer recurrence has not yet been studied. Results from laboratory studies show that mammary tumors in rats exposed to a synthetic estrogen early in life respond differently to the antiestrogen tamoxifen than do tumors in control animals, although neither histopathology nor ER-[alpha] expression of the tumors is altered. The difference in the tamoxifen response may be related to altered gene signaling in the mammary glands and perhaps tumors. Ongoing studies may reveal whether the findings obtained in observational studies, indicating that soy consumption reduces the risk of recurrence, are applicable to individuals with breast cancer who have not consumed soy before diagnosis.
SUMMARY AND CONCLUSIONS
Nutritional care and guidance are important aspects of the management of the cancer patient across the continuum from the immediate postdiagnosis period of initial treatment and recovery through long-term survival. However, many issues relating to care and guidance in this population are unresolved and under study. Nutritional support as part of a multimodal treatment, with an emphasis on adequate energy and protein intakes, appears to be the strategy most likely to improve body composition and physical function in the management of cancer cachexia. Cancer treatments can result in micronutrient inadequacies, and complications that affect the central and peripheral nervous system can result. However, inappropriate use of nutritional supplements carries a risk of promoting tumor progression. Recent epidemiologic evidence suggests that soy foods are unlikely to adversely affect prognosis following the diagnosis and treatment of breast cancer, although laboratory studies are currently exploring whether isoflavone exposure over the lifetime may affect response to tamoxifen and recurrence of mammary cancer. Continued probing investigations are needed to resolve issues related to the best practices for cancer survivors.
Cheryl L. Rock, PhD, RD, is a professor, Department of Family and Preventive Medicine and the Cancer Prevention and Control Program, University of California, San Diego, School of Medicine. She also leads the Nutrition Shared Resource of the Moores University of California, San Diego, Comprehensive Cancer Center.
John A. Milner, PhD, is the director of and a senior scientist at the U.S. Department of Agriculture Beltsville Human Nutrition Center, Beltsville, MD.
Carla Prado, PhD, is an assistant professor, Department of Nutrition, Food and Exercise Sciences, the Florida State University, Tallahassee.
Ralph Green, MD, PhD, FRCPath, is a professor of pathology and medicine at the University of California, Davis, where he served as chair of the Department of Medical Pathology and Laboratory Medicine from 1996 to 2009.
Bette J. Caan, Dr PH, is a senior research scientist at the Division of Research (DOR), Kaiser Permanente Northern California, Davis. Her research focus is nutritional epidemiology.
Leena A. Hilakivi-Clarke, PhD, is a professor,Department ofOncology, Lombardi Cancer Center, Georgetown University, Washington, DC.
The authors have no conflicts of interest to disclose.
Correspondence: Cheryl L. Rock, PhD, RD, Moores UCSD Cancer Center, 3855 Health Sciences Dr, La Jolla, CA 92093 ([email protected]).
References
1. World Cancer Research Fund (WCRFL)/American Institute for Cancer Research. Food, Nutrition, and the Prevention of Cancer: A Global Perspective, 2nd Expert Report. Washington, DC: American Institute for Cancer Research; 2007.
2. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012 [published online ahead of print January 4, 2012]. CA Cancer J Clin.
3. Fearon K, Strasser F, Anker SD, et al. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol. 2011;12:489-495.
4. Bozetti F, Mariani L, Lo Vullo S, et al. The nutritional risk in oncology: a study of 1,453 cancer outpatients [published online ahead of print February 2, 2012]. Support Care Cancer.
5. DeWys WD, Begg C, Lavin PT, et al. Prognostic effect of weight loss prior to chemotherapy in cancer patients. Am J Med. 1980;69:491-497.
6. Prado CM, Birdsell LA, Baracos VE. The emerging role of computerized tomography in assessing cancer cachexia. Curr Opin Support Palliat Care. 2009;3:269-75.
7. Prado CM, Lieffers JR, McCargar LJ, et al. Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours of the respiratory and gastrointestinal tracts: a population-based study. Lancet Oncol. 2008;9:629-35.
8. Bosaeus I. Nutritional support in multimodal therapy for cancer cachexia. Support Care Cancer. 2008;16:447-451.
9. Paccagnella A, Morassutti I, Rosti G. Nutritional intervention for improving treatment tolerance in cancer patients. Curr Opin Oncol. 2011;23:322-330.
10. Baz R, Alemany C, Green R, Hussein MA. Prevalence of vitamin B12 deficiency inpatients with plasma cell dyscrasias: a retrospective review. Cancer. 2004;101(4):790-795.
11. Khasraw M, Posner JB. Neurological complications of systemic cancer. Lancet Neurol. 2010;9(12):1214-1227.
12. Sioka C, Kyritsis AP. Central and peripheral nervous system toxicity of common chemotherapeutic agents [published online ahead of print November 25, 2008]. Cancer Chemother Pharmacol. 2009;63(5):761-767.
13. Verstappen CC, Heimans JJ, Hoekman K, Postma TJ. Neurotoxic complications of chemotherapy in patients with cancer: clinical signs and optimal management [review]. Drugs. 2003;63(15):1549-1563.
14. Dong JY, Qin LQ. Soy isoflavones consumption and risk of breast cancer incidence or recurrence: a meta-analysis of prospective studies. Breast Cancer Res Treat. 2011;125:315-323.
15. Hilakivi-Clarke L, Andrade JE, Helferich W. Is soy consumption good or bad for the breast? J Nutr. 2010;140:2326S-2334S.
16. Tanos V, Brzezinski A, Drize O, Strauss N, Peretz T. Synergistic inhibitory effects of genistein and tamoxifen on human dysplastic and malignant epithelial breast cells in vitro. Eur J Obstet Gynecol Reprod Biol. 2002;102:188-194.
17. Ju YH, Doerge DR, Allred KF, Allred CD, Helferich WG. Dietary genistein negates the inhibitory effect of tamoxifen on growth of estrogen-dependent human breast cancer (MCF-7) cells implanted in athymic mice. Cancer Res. 2002;62:2474-2477.
18. Guha N, Kwan ML, Quesenberry CP Jr, Weltzien EK, Castillo AL, Caan BJ. Soy isoflavones and risk of cancer recurrence in a cohort of breast cancer survivors: the Life After Cancer Epidemiology study. Breast Cancer Res Treat. 2009;118:395-405.
19. Caan BJ, Natarajan L, Parker B, et al. Soy food consumption and breast cancer prognosis. Cancer Epidemiol Biomarkers Prev. 2011;20:854-858.
20. Shu XO, Zheng Y, Cai H, et al. Soy food intake and breast cancer survival. JAMA. 2009;302:2437-2443.
21. Kang X, Zhang Q, Wang S, Huang X, Jin S. Effect of soy isoflavones on breast cancer recurrence and death for patients receiving adjuvant endocrine therapy. CMAJ. 2010;182:1857-1862.
22. Nechuta S. Postdiagnosis soy food intake and breast cancer survival: report from the After Breast Cancer Pooling Project [abstract]. Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research. 2011.
23. Helferich WG, Andrade JE, Hoagland MS. Phytoestrogens and breast cancer: a complex story. Inflammopharmacology. 2008;16:219-226.
24. Warri A, Saarinen NM, Makela SI, Hilakivi-Clarke L. The role of early life genistein exposures in modifying breast cancer risk. Br J Cancer. 2008;98:1288-1291.
25. de Assis S, Warri A, Hilakivi-Clarke L. The protective effects of prepubertal genistein exposure on mammary tumorigenesis are dependent on up-regulation BRCA1. Cancer Prev Res. 2011;4:1436-1448.
26. Ciarloni L, Mallepell S, Brisken C. Amphiregulin is an essential mediator of estrogen receptor alpha function in mammary gland development. PNAS. 2007;104:5455-5460.
27. Cabanes A, Wang M, Olivo S, et al. Prepubertal estradiol and genistein exposures up-regulate BRCA1 mRNA and reduce mammary tumorigenesis. Carcinogenesis. 2004;25:741-748.
28. Maskarinec G, Erber E, Verheus M, et al. Soy consumption and histopathologic markers in breast tissue using tissue microarrays. Nutr Cancer. 2009;61:708-716.
Physical Activity, Sedentary Behavior, and Cancer: Review of the Evidence and Directions for Future Research
Authors: Christine M. Friedenreich, PhD; Lee W. Jones, PhD; Charles E. Matthews, PhD; June Stevens, PhD; Neville Owen, PhD
Running Title: Sedentary behavior
INTRODUCTION
Over the past 20 years, considerable research has focused on the role of physical activity as a means of reducing cancer incidence and cancer-related mortality, and systematic reviews and public health guidelines have been published by several national and international agencies. More recently, the potential deleterious effect of sedentary behavior on cancer incidence has been studied. The American Institute of Cancer Research 2011 Conference included a session on physical activity and sedentary behavior. Four presentations reviewed the epidemiologic evidence on associations of physical activity and sedentary behavior with cancer risk and the role of structured physical activity interventions in cancer rehabilitation and survival. There was a special focus on the underlying biologic mechanisms involved and on making recommendations for future research. This article summarizes this symposium.
Observational Epidemiologic Evidence on Physical Activity and Cancer Risk
A framework for research on physical activity in cancer control1 divides the cancer experience into prediagnosis, diagnosis, and postdiagnosis-specifically addressing how physical activity can improve cancer prevention, detection, treatment preparation/coping, treatment effectiveness, recovery/rehabilitation, disease prevention/health promotion, palliation, and survival.
At present, the evidence regarding the association between physical activity and risk of colon and breast cancers is classified as "convincing" and for endometrial cancer as "probable" based on the strength and consistency of the evidence, the dose-response effect, and the biologic plausibility of such associations. There have now been a large number of studies conducted on these three cancer sites (ranging from 40-90 studies), and the magnitude of the risk reduction is 25% to 30% for the highest versus lowest activity groups, with clear evidence for a dose-response relation with increasing physical activity levels and decreasing risk (Table).2 The evidence for an association between physical activity and prostate and lung cancers can be classified as "possible," and for ovarian cancer as "insufficient."2 For the remaining cancer sites, the evidence is still insufficient.
Several methodological challenges exist, however, in conducting research on physical activity in cancer control, particularly with respect to physical activity assessment.2 With improvements in physical activity measurement methods, providing more precise exposure metrics, the nature of these relations will become more apparent.
The effects of physical activity appear to be stronger for recreational, sustained, and at least moderate-intensity activity. Given the consistent and strong evidence for a role of physical activity in reducing the risk of several major cancer sites, a call to action was made for exercise intervention trials that would, among other objectives, elucidate the biologic mechanisms whereby physical activity reduces cancer risk.3 Four randomized controlled exercise intervention trials examining breast3-5 and colon cancer prevention6 have found promising evidence that physical activity reduces several hypothesized biomarkers involved in the etiology for different cancer sites such as body fat, endogenous sex hormones, insulin resistance, inflammation, and oxidative stress. No intervention trials have been conducted with cancer incidence as the primary outcome, although proposals for this type of large-scale research have been made. Ongoing research studies are now examining questions of the optimal type and dose of activity needed to influence surrogate markers for cancer risk reduction, as well as the respective roles of exercise in combination with diet for cancer prevention.
Exercise Rehabilitation Following a Cancer Diagnosis: Physiologic, Psychological, and Prognostic Outcomes
Supervised exercise-based rehabilitation combined with comprehensive risk factor modification is recommended as "first-line" treatment for a broad range of cardiovascular pathologies including myocardial infarction, stroke, peripheral artery disease, and chronic obstructive pulmonary disease. In clinical settings, exercise rehabilitation has been shown to improve functional capacity and cardiovascular symptoms, as well as reduce cardiovascular events. In stark contrast, the notion of exercise rehabilitation following a diagnosis of cancer has, until recently, received scant attention.7 Despite significant advances in these therapies, cytotoxic chemotherapy and endocrine, radiation, and biologic therapies remain associated with a broad range of toxicities that can directly impair various components of the cardiovascular-oxidative capacity axis together with increased physical inactivity and weight gain, cumulating in impaired cardiovascular fitness.8 Indeed, increasing evidence indicates that cancer patients have marked reductions in cardiorespiratory fitness across the entire cancer survivorship continuum. In response, several research groups have investigated the safety, feasibility, and efficacy of structured exercise interventions on a broad range of physiological and psychosocial outcomes before, during, and/or following adjuvant therapy.
Systematic reviews9 and meta-analyses10,11 conclude that structured exercise is a safe and well-tolerated intervention associated with improvements in cancer-related symptoms and functional outcomes. Based on these early results, ongoing trials are investigating the most effective type and intensity of exercise training and the physiologic mechanisms underlying the association between exercise training and cardiorespiratory fitness in persons with cancer.
Another major question of interest is whether the benefits of exercise extend beyond functional status and patient-reported outcomes to impact prognosis. In cancer survivors, exercise has the potential to reduce the risk of cancer recurrence as well as risk of competing causes of mortality, primarily cardiovascular disease. A total of 27 observational studies have examined the association between self-reported exercise and prognosis following a diagnosis of operable breast (17 studies), colorectal (6 studies), prostate (2 studies), ovarian (1 study), and primary glioma (1 study).12 Overall, 20 studies (74%) reported a significant inverse relationship between exercise and prognosis (cancer-specific or all-cause mortality) with an average risk reduction of 25% for breast and 48% for colon cancer-specific mortality. These findings are yet to be confirmed in randomized trials, although at least 1 trial is currently ongoing. Specifically, the CHALLENGE (Colon Health and Life-Long Exercise Change) trial is a phase III trial investigating the effects of regular exercise on recurrence and cancer-specific mortality in 962 colorectal cancer patients.13
Given the demonstrated efficacy of exercise rehabilitation on secondary prevention of cardiovascular disease, it appears reasonable to speculate that there are analogous benefits in cancer survivors at high risk of therapy-induced cardiovascular disease. The effects on cancer-specific disease outcomes are less certain, although biologically plausible.
Sedentary Behaviors and Cancer: Possible Risks and Biologic Mechanisms
Sedentary behavior (too much sitting, as distinct from too little exercise) is a newly identified behavioral risk for cancer. In the last 50 years, time spent in a variety of sedentary behaviors has increased dramatically in daily life, which has resulted in prolonged periods spent sitting, with substantial overall reductions in daily activity levels. Adolescents and adults in the United States currently spend about 60% of their waking time-as much as 9 hours or more each day-sedentary.14 The impact of such high levels of sedentary behavior on cancer risk is unknown, but recent studies indicating that prolonged sitting is positively associated with early mortality and other chronic diseases, independent of many benefits of regular exercise,15,16 suggest that the impact on cancer risk may be substantial.
Early studies designed to test the physical activity-cancer hypothesis often examined differences in cancer risk between individuals in sedentary occupations and those in professions that required more physical activity. Many later studies were designed to test the hypothesis that modifiable physical activity behaviors believed to be health-enhancing (ie, moderate-vigorous activity) were associated with reduced risk. The potential opposing effects of sedentary behaviors and lower-intensity activities on risk remained unexplored, in part because of the difficulties in measuring these behaviors in epidemiologic studies. Recently, observational studies have examined the hypothesis that sedentary behaviors are independently associated with cancer risk. Initial studies, often using crude measures of sedentary behavior, suggest that prolonged sedentary time may be associated with colon, endometrial, and ovarian cancer.17 To date, evidence for an association with breast and prostate cancer is inconsistent.17
In support of these findings, there is considerable evidence that prolonged sitting time may adversely affect many biological pathways implicated in obesity-related cancers. Both cross-sectional and intervention studies indicate adverse effects for higher levels of sedentary behavior on overall physical activity levels, energy balance, fat and carbohydrate metabolism, physical fitness, and body composition.15 Prolonged TV viewing time is associated with components of the metabolic syndrome18 and with markers of systemic inflammation.19 Studies from the Australian Diabetes, Obesity and Lifestyle Study and the US National Health and Nutrition Examination Survey using device-based measurement (via accelerometers) confirm TV-time findings.20 Accelerometer studies also show that frequent short breaks from sitting appear to have a beneficial effect on these cardiometabolic biomarkers.20
Hence, there is considerable potential for high levels of sedentary behavior to have an impact on several biological pathways linked to increased cancer risk (Figure). Results from a number of ongoing studies examining the effect of interventions to reduce sedentary behavior on these metabolic outcomes are eagerly awaited.
Future Research Directions
Future research needs to expand the work on physically active and sedentary behaviors and cancer, to include more cancer sites, continue to investigate the type and intensity of activity that may provide benefit, as well as further study of additional underlying mechanisms of action related to physical activity and cancer risk (and prognosis), and to elucidate the role of genetic predisposition in these associations. With respect to cancer rehabilitation, current evidence provides initial promising evidence that structured exercise may be a central component of multidisciplinary rehabilitation to prevent and/or mitigate functional impairment and improve symptom control in persons with cancer. Results of ongoing and planned trials will address several outstanding questions regarding the use of exercise rehabilitation as an integral component of the treatment and management of cancer patients. The roles of physical activity and exercise in cancer risk, rehabilitation, and survivorship have an increasingly strong evidence base, but gaps still remain in translating this evidence into practice across the cancer spectrum.
In contrast, sedentary behavior in cancer risk is less well understood. Several topics were identified as high priorities for future research in sedentary behavior and cancer. For cancer prevention and survivorship, studies on determinants of sedentary behavior and interventions are of priority. The specificity of contextual and behavioral focus provided by ecological models can be helpful.20 Although accelerometer-based measurement provides potentially greater precision in assessing exposures, self-report methods remain an important method for elucidating the type and intensity of activity that may provide benefit, as well as for identifying relationships with behavioral determinants.21 Relevant evidence is emerging on the correlates of sedentary behavior22-24 and on the efficacy and effectiveness of interventions that target the relevant determinant factors.23 In addition to future etiologic studies, the research agenda for sedentary behaviors in the context of cancer prevention and survivorship include the following:
1. identification of determinants of prolonged sitting time in different settings (home, workplace, neighborhoods, transportation);
2. examination of sedentary behaviors within studies of environment/physical activity relationships; by using accelerometer measures, it is feasible to identify sedentary time, breaks in sedentary time, and their predictors in such studies;
3. conduct intervention trials to determine the feasibility of changing sedentary behaviors for different population subgroups and for cancer-survivor groups in different settings with interventions; and
4. investigation of changes in sedentary behaviors (and, ideally adiposity and other biomarker changes) from "natural experiments" such as height-adjustable workstations, changes in community transport, and recreational infrastructure;
5. amassment of evidence from multiple countries, where environmental, social, and cultural attributes influencing sedentary behaviors will differ so that the influence of broader variations in the determinants of sedentary behaviors can be examined.
In all these types of studies, advances in measurement methods25 and increasingly sophisticated data-analytic capacities will strengthen the understanding of these behavioral exposure variables in relation to cancer risk, their links to contextual and other determinants, and the outcomes of interventions. With such evidence, improved programs and policies will follow.
In summary, evidence is accumulating that physical activity and sedentary behaviors may be independently associated with cancer risk, and there is compelling evidence regarding the underlying biological mechanisms involved in these etiologic associations. The ultimate objective of this research is clear public health guidelines on the type and dose of physical activity in combination with the safe level of sedentary behavior that will be required to decrease cancer risk and improve cancer rehabilitation and survival.
Christine M. Friedenreich, PhD, is a cancer epidemiologist with the Department of Population Health Research of Alberta Health Services and an adjunct professor in the Faculties of Medicine and Kinesiology of the University of Calgary, Alberta Health Services-Cancer Care, Canada.
Lee W. Jones, PhD, is an associate professor in the Department of Radiation Oncology and scientific director of Cancer Survivorship at Duke University MedicalCenter,DukeCancer Institute,Durham,NorthCarolina.
Charles E. Matthews, PhD, is physical activity epidemiologist and investigator in the Nutritional Epidemiology Branch in National Cancer Institute's Division of Cancer Epidemiology and Genetics, Bethesda, Maryland.
June Stevens, PhD, is chair of the Department of Nutrition at the University of North Carolina at Chapel Hill and the American Institute for Cancer Research, and distinguished professor, Department of Nutrition, University of North Carolina, Chapel Hill.
Neville Owen, PhD, is head of the Behavioral Epidemiology Laboratory at the Baker IDI Heart and Diabetes Institute in Melbourne, a National Health and Medical Research Council of Australia senior principal research fellow and professor of health behavior at the University of Queensland, Melbourne, Australia.
The authors have no conflicts of interest to disclose.
Correspondence: Christine M. Friedenreich, PhD, Department of Population Health Research, Alberta Health Services, 2202 2nd St SW, Calgary, AB, Canada T2S 3C3 ([email protected]).
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2. Courneya KS, Friedenreich CM, eds. Physical Activity and Cancer. Heidelberg: Springer-Verlag; 2011.
3. McTiernan A, Schwartz RS, Potter J, Bowen D. Exercise clinical trials in cancer prevention research: a call to action. Cancer Epidemiol Biomarkers Prev. 1999;8:201-207.
4. Friedenreich CM, Woolcott CG, McTiernan A, et al. Alberta physical activity and breast cancer prevention trial: sex hormone changes in a year-long exercise intervention among postmenopausal women. J Clin Oncol. 2010;28:1458-1466.
5. Monninkhof EM, Velthuis MJ, Peeters PH, et al. Effect of exercise on postmenopausal sex hormone levels and role of body fat: a randomized controlled trial. J Clin Oncol. 2009;27:4492-4499.
6. McTiernan A, Yasui Y, Sorensen B, et al. Effect of a 12-month exercise intervention on patterns of cellular proliferation in colonic crypts: a randomized controlled trial. Cancer Epidemiol Biomarkers Prev. 2006;15:1588-1597.
7. Jones LW, Peppercorn J. Exercise research: early promise warrants further investment. Lancet Oncol. 2010;11:408-410.
8. Jones LW, Eves ND, Haykowsky M, et al. Exercise intolerance in cancer and the role of exercise therapy to reverse dysfunction. Lancet Oncol. 2009;10:598-605.
9. Schmitz KH, Courneya KS, Matthews CE, et al. American College of Sports Medicine roundtable on exercise guidelines for cancer survivors. Med Sci Sports Exerc. 2010;42:1409-1426.
10. Jones LW, Liang Y, Pituskin EN, et al. Effect of exercise training on peak oxygen consumption in patients with cancer: a meta-analysis. Oncologist. 2011;16:112-120.
11. Speck R, Courneya K, Masse LC, et al. An update of controlled physical activity trials in cancer survivors: a systematic review and meta-analysis. J Cancer Surviv. 2010;4:87-100.
12. Ballard-Barbash R, Friedenreich CM, Courneya KS, et al. Physical activity, biomarkers, and disease outcomes in cancer survivors: a systematic review. J Natl Cancer Inst. 2012. In press.
13. Courneya KS, Booth CM, Gill S, et al. The Colon Health and Life-Long Exercise Change trial: a randomized trial of the National Cancer Institute of Canada Clinical Trials Group. Curr Oncol. 2008;15:279-285.
14. Matthews CE, Chen KY, Freedson PS, et al. Amount of time spent in sedentary behaviors-United States 2003-2004. Am J Epidemiol. 2008;167:875-881.
15. Thorp AA, Owen N, Neuhaus M, Dunstan DW. Sedentary behaviors and subsequent health outcomes in adults: a systematic review of longitudinal studies, 1996-2011. Am J Prev Med. 2011;41:207-215.
16. Matthews CE, George SM, Moore SC, et al. Amount of time spent in sedentary behaviors and cause-specific mortality in US adults. Am J Clin Nutr. 2012. In press.
17. Lynch BM. Sedentary behavior and cancer: a systematic review of the literature and proposed biological mechanisms. Cancer Epidemiol Biomarker Prev. 2010;19:2691-2709.
18. Owen N, Healy GN, Matthews CE, Dunstan DW. Too much sitting: the population health science of sedentary behavior. Exerc Sport Science Rev. 2010;38:105-113.
19. Anuradha S, Dunstan DW, Healy GN, et al. Physical activity, television viewing time, and retinal vascular caliber. Med Sci Sport Exerc. 2011;43:289-86.
20. Healy GN, Matthews CE, Dunstan DW, et al. Sedentary time and cardio-metabolic biomarkers in US adults: NHANES 2003-06. Eur Heart J. 2011;32:590-597.
21. Troiano RP, Pettee G, Welk G, et al. Physical activity and sedentary behavior: why do you ask? J Phys Act Health. 2012. In press.
22. Van Dyck D, Cardon G, Deforche B, et al. Socio-demographic, psychosocial and home-environmental attributes associated with adults' domestic screen time. BMC Public Health. 2011;11:668.
23. Sugiyama T, Salmon J, Dunstan DW, et al. Neighborhood walkability and TV viewing time among Australian adults. Am J Prev Med. 2007;33:444-449.
24. King AC, Goldberg JH, Salmon J, et al. Identifying subgroups of U.S. adults at risk for prolonged television viewing to inform program development. Am J Prev Med. 2010;38:17-26.
25. Schatzkin A, Subar AF, Moore S, et al. Observational epidemiologic studies of nutrition and cancer: the next generation (with better observation). Cancer Epidemiol Biomarkers Prev. 2009;18:1026-1032.
Vitamin D and Cancer: Visions of Panacea or Icarus?
Authors: Steven K. Clinton, MD, PhD; Demetrius Albanes, MD; James C. Fleet, PhD; Glenville Jones, PhD; Susan T. Mayne, PhD
Running Title: Vitamin D and Cancer
This article summarizes a session presented as part of the program at the American Institute for Cancer Research Annual Research Conference in Washington, DC, November 3-4, 2011. The conference is an annual event organized by the American Institute for Cancer Research (http://www.aicr.org).
CONFUSION FOR THE PUBLIC AND MEDICAL PROFESSION
Greek mythology describes Panacea as the goddess of healing, who provides a poultice or potion that heals countless ailments. Variations of this tale permeate the lore of many diverse historic cultures. In modern times, we use the term panacea figuratively as a simple solution to large and multifaceted problems. In the last decade, the popular press, media, and many other sources have promoted the concept that vitamin D inadequacy is a common syndrome and that enhancing vitamin D status will safely and meaningfully reduce the burden of heart disease, multiple autoimmune syndromes, many types of cancer, and a variety of other afflictions, particularly those conditions associated with aging. Indeed, a modern-day panacea.
Key Points
* Greek mythology describes Panacea as the goddess of healing, who provides a poultice or potion that heals countless ailments.
* The Institute of Medicine Committee, charged with determining population requirements for vitamin D, concluded that the evidence linking vitamin D status with many nonskeletal outcomes, including cancer, was inconsistent and inconclusive as to causality.
The Institute of Medicine Committee, charged with determining population requirements for vitamin D, concluded that the evidence linking vitamin D status with many nonskeletal outcomes, including cancer, was inconsistent and inconclusive as to causality.1 Only bone health provided sufficient data for determining public health requirements for vitamin D known as DRIs (Dietary Reference Intakes).1 In brief, the committee used an evidence-based review methodology to comprehensively examine relevant epidemiologic literature, including observational studies of vitamin D intake and vitamin D status as assessed by serum 25-hydroxyvitamin D (25-OHD), along with intervention trials.1-3 After systematically reviewing a vast literature, the committee concluded that there was a well-established role for vitamin D in bone health (rickets, osteomalacia, osteoporosis), but insufficient evidence for defining a dietary requirement in regard to other conditions, including the vast array of common cancers.1,4,5 Thus, the DRIs for vitamin D (Table), defined as public health guidelines, are based on bone health across the life cycle, and the committee strongly encouraged additional research in other areas potentially linked to vitamin D status.1 Importantly, the DRI committee also defined the adequate serum concentration of 25-OHD as 20 ng/mL (50 nmol/L), a value lower than the level championed by many advocates (>30 ng/mL or 75 nmol/L). Thus, the prevalence of vitamin D inadequacy in North Americans is commonly overestimated1,5,6 and has led to excessive laboratory testing, high-dose supplementation, and pharmacologic administration of vitamin D preparations to otherwise healthy individuals. However, it is estimated that 8% of Americans have serum concentrations of 25-OHD less than 12 ng/mL (30 nmol/L), placing them at risk of deficiency, with 24% at risk of inadequacy (12-20 ng/mL or 30-49 nmol/L).7
Key Point
* It is estimated that 8% of Americans have serum concentrations of 25-hydroxyvitamin D (25-OHD) less than 12 ng/mL (30 nmol/L), placing them at risk of deficiency, with 24% at risk of inadequacy (12-20 ng/mL or 30-49 nmol/L).7
The American Institute for Cancer Research symposium was organized to carefully evaluate the diverse types of scientific evidence regarding vitamin D and cancer and to provide insight into the present conundrum. The potential of vitamin D metabolites to have an impact on carcinogenesis within a number of tissues is firmly grounded in basic laboratory science derived from in vitro cellular and molecular biology. Similarly, a growing number of studies in laboratory models of carcinogenesis provide support for an in vivo role for dietary vitamin D in modulating carcinogenesis. However, the impact of variations in vitamin D status over critical phases of the human life span and its impact on human cancer risk are enormously complex and poorly understood.
CELLULAR AND MOLECULAR INSIGHTS
A detailed understanding of the synthesis, metabolism, and mechanism of action of vitamin D has emerged in recent decades.1,8,9 Indeed, it is clear that neither vitamin D nor the metabolite 25-OHD is biologically active but must be further metabolized to the hormone 1,25-dihydroxyvitamin D [1,25-(OH)2D] to influence human biology. This metabolite acts through a specific nuclear vitamin D receptor (VDR) in the familiar target tissues of the intestine, kidney, and bone to tightly orchestrate the hormonal network that maintains calcium and phosphate homeostasis, which is so critical for optimal bone mineralization and the control of serum calcium levels within the narrow range required for many life functions.1,8,9 We now appreciate that the VDR is present in dozens, if not all, tissues and that signaling through the VDR is responsible for many biological actions unrelated to bone and mineral metabolism. The bioactivity of 1,25-(OH)2D in target tissues controlling bone and mineral metabolism depends on exposure to 1,25-(OH)2D produced in the kidney and released into the circulation. However, increasingly, investigations suggest that local tissue synthesis of 1,25-(OH)2D via extrarenal 1[alpha]-hydroxylase (CYP27B1) metabolism of 25-OHD derived from the circulation may also be a critical means for regulating the functions of specific tissues, especially for non-bone-related end points. This would account for why serum 25-OHD concentrations (rather than circulating 1,25(OH)2 D levels) may be associated with disease risk. In addition, inactivation of 1,25-(OH)2D by the catabolic enzyme, CYP24A1 (24-hydroxylase), plays a key role to tightly regulate the actions of 1,25-(OH)2D in target tissues.10 Yet, direct in vivo evidence demonstrating extrarenal production of 1,25-(OH)2D has remained elusive.
Extensive in vitro studies of cancer cells demonstrate that 1,25-(OH)2D binding to the VDR has an impact on many processes relevant to carcinogenesis and tumor biology, by regulating the transcription of genes involved in cell proliferation, sensitivity to apoptosis/autophagy, and cell differentiation.8-11 It is now well established that 1,25-(OH)2D is growth inhibitory in a vast array of tumor-derived cell lines and that the VDR mediates this activity.8-11 Among the mechanisms elucidated, the expression of key cell-cycle regulatory proteins including cyclins are typically decreased, whereas CDK (cyclin-dependent kinase) inhibitors (p21 or p27) may be increased.8-11 Involvement of 1,25-(OH)2D in restraining various growth factor-related signal transduction cascades, such as the PIP3/AKT pathway, in cancer cells reflects a role that 1,25-(OH)2D plays in normal cell biology.8-11 1,25-Dihydroxyvitamin D may also act by down-modulating the cancer promoting effects of hormonal, autocrine, or paracrine growth factor networks, such as estrogen, insulinlike growth factor 1, and bioactive lipids (eg, prostaglandins) while up-regulating those associated with terminal differentiation and homeostasis, including transforming growth factor [beta].8-11 Indeed, genomic sequencing and global gene expression technology have shown that hundreds of mammalian genes contain the VDR response element in their promoter regions, including genes encoding transcription factors that may activate or repress additional downstream gene expression programs.9,11 These studies suggest that 1,25-(OH)2D or vitamin D analogs may also regulate a variety of processes that inhibit cancer, such as the antioxidant defense system, DNA repair, bioactive lipid metabolism, and stem cell biology.9 Accordingly, our greater understanding of the molecular actions of 1,25-(OH)2D in cell cycling, cell differentiation, and cellular function supports the hypothesis that maintaining adequate vitamin D exposure could contribute to cancer prevention, provided 1,25-(OH)2D can be produced and act locally.
CANCER AND HOST INTERACTIONS
Studies in rodent models and humans provide a level of complexity that far exceeds studies of cells in culture. Scientists are beginning to appreciate that vitamin D may have an impact on cancer risk, not only through direct action on the nascent or established tumor cell, but indirectly through actions upon the host, both systemically and within the tumor microenvironment. The modern concept of tumor growth incorporates a complex expansion of heterogeneous and continually evolving cancer cells, along with a constant coevolution and dynamic interplay with the contiguous mesenchyme composed of the extracellular matrix, stromal cells, infiltrating immune cells, and the vasculature.
Tumor-associated angiogenesis is one essential process for the progression and dissemination of cancer, providing nutrients and oxygen for growth, removal of metabolic toxins, and serving as a conduit for metastatic spread. Evidence is accumulating that 1,25-(OH)2D may exert antiangiogenic actions directly upon the cancer cells and indirectly via the vascular endothelial cells.9 The inhibition of proangiogenic cytokines and growth factor expression such as interleukin 8, VEGF (vascular endothelial growth factor), and platelet-derived growth factor by cancer cells in response to 1,25-(OH)2D may be in part related to reduced activity of the key transcription factor hypoxia-inducible factor 1.9 Studies with vascular endothelial cells suggest that 1,25-(OH)2D inhibits proliferation and vascular sprouting in response to VEGF, a major proangiogenic growth factor elaborated by cancer cells.9 Although our understanding is currently modest, it appears likely that 1,25-(OH)2D may participate in the coordination of normal and malignant angiogenesis.
There is also accumulating evidence that 1,25-(OH)2D regulates immune functions, and this suggests that 1,25-(OH)2D signaling may impact 2 critical aspects of carcinogenesis. 1,25-Dihydroxyvitamin D demonstrates many anti-inflammatory activities by orchestrating an optimal immune response to pathogens and reducing proinflammatory cascades that typically promote carcinogenesis, in part due to local oxidative stress and DNA damage. Perhaps more critical, yet poorly understood, is the emerging role of vitamin D signaling in immunosurveillance and as an inhibitor of tumor cell-mediated immunosuppression. These are vital areas for future research. Thus, rodent and human studies allow investigators to consider hypotheses that integrate the impact of vitamin D status on many host factors that impact cancer risk as well as the direct impact of vitamin D metabolites on the target tissue.
RODENT CANCER MODELS
The ability to manipulate mouse genes via knockout or transgenic approaches to disrupt VDR expression and the synthesis (1-[alpha]-hydroxylase deletion) has been applied to alter vitamin D signaling in vivo. As predicted, severe alterations in bone morphology are observed in these rodent models, yet further examination of VDR knockout mice indicates an additional action for 1,25-(OH)2D signaling in the regulation of cell turnover and differentiation.9,11,12 For example, targeted disruption of the VDR in the prostate increases rates of epithelial proliferation while reducing apoptosis.13 This phenomenon was observed in the prostate epithelial compartment from normal animals and in mice genetically programmed for prostate carcinogenesis.12 Similar procarcinogenic biological phenomena following genetic disruption of VDR signaling have been reported in colonic and breast tissue.8,9,11
The direct effects of 1,25-(OH)2D on cells in culture or the genetic manipulations of vitamin D metabolism and signaling in mice represent the most dramatic impact or severe phenotype possible. In contrast, dietary effects would be predicted to be more modest, particularly when the homeostatic regulation of vitamin D metabolism, tissue distribution, and activation is considered. In many cases, dietary vitamin D depletion is associated with greater risk of carcinogenesis or enhanced tumor growth.9,10 Yet there are remarkably few studies of dietary vitamin D in rodent models of experimental carcinogenesis over the wide range of intake relevant to human dietary exposures. In addition, many studies are lacking in precise documentation of serum vitamin D concentrations, data that can greatly aid investigators as they attempt to interpret relevance to human exposures. Adding to the biological plausibility that vitamin D may impact cancer risk is the extensive array of in vitro and rodent data using pharmacologic analogs of vitamin D under development for cancer therapy with reduced calcemic activity compared with 1,25-(OH)2D.8-11 Clearly, rodent cancer models represent an enormous increase in biological complexity compared with in vitro studies and therefore have the potential to greatly inform our understanding of vitamin D and cancer relationships and impact the optimal design of definitive human studies. Rodent cancer models have many important characteristics, providing investigators with opportunities to contribute significantly to our understanding of dietary vitamin D status and cancer risk. The ability to precisely control dietary intake, monitor 25-OHD status, and examine in vivo mechanisms of action during specific phases of carcinogenesis while simultaneously evaluating potential toxicities and relevant end points is of great value as we try to understand the complexities of vitamin D and cancer relationships in humans.
HUMAN STUDIES
Despite the fanfare provided in the media as newly published studies purporting a role of vitamin D in chronic disease prevention or cancer are paraded to the public, the totality of the evidence is far from conclusive. Results of observational and intervention studies vary widely across organ sites with respect to a number of investigations available, actual population concentrations and categories used for risk estimation, blood 25-OHD levels and categorization, and even the direction of associations.1-4 The majority of scientifically rigorous epidemiologic studies are statistically null, with respect to measured vitamin D status in relation to risk of specific cancers, whereas some suggest protective effects, and several others raise concerns for adverse outcomes for higher vitamin D status.1-4 Case-control investigations nested within prospective cohorts have been the observational method of choice because they can utilize a measure of vitamin D status (serum 25-OHD) in blood samples, ideally collected years in advance of the development of cancer, thereby reducing the influence of illness on nutritional status (ie, reverse causality). Yet, a single value may not represent the individual's status over a lifetime or at the critical times relevant to carcinogenesis in a given tissue, for example, at puberty or during childbearing years with regard to breast cancer. Furthermore, low serum 25-OHD is often confounded by other factors related to cancer risk, such as obesity, low physical activity, dark skin pigmentation, and dietary supplement practices.1
Among the common malignancies, perhaps the strongest case for vitamin D in preventing cancer relates to colorectal cancer.1-4 For this cancer organ site, the majority of observational studies provide compelling evidence for a relationship between adequate vitamin D status and lower risk.1-4,14 Yet, there is substantial variation across studies, including for colon versus rectum and for the actual 25-OHD concentrations contributing to lower risk. Interestingly, however, controlled trials have not demonstrated colorectal cancer prevention in response to vitamin D supplementation; for example, 400 IU/d combined with calcium and given to women for 7 years.15 In contrast to colorectal cancer, investigations of prostate cancer and breast cancer are substantially more heterogeneous and inconsistent.1-4,16 For example, a recent study reports that the risk of prostate cancer may be increased among men with higher 25-OHD blood levels beyond those considered adequate.17 With regard to breast cancer, greater risk for low vitamin D status has been observed in retrospective case-control studies, which collect the blood samples at the time of diagnosis (or some time later, including during cancer treatments), but not in cohort nested case-control studies, which measure 25-OHD concentrations in blood collected years in advance of the cancer diagnosis.14 The Cohort Consortium Vitamin D Pooling Project (VDPP) of less common cancers prospectively examined a total of 5500 cases from 10 collaborating cohorts for lymphoma and cancers of the pancreas, esophagus, stomach, endometrium, kidney, and ovary. Together, these cancers account for approximately half of all cancers worldwide, and no clear association with vitamin D status emerged with the exception of pancreatic cancer, which showed significantly higher risk for men and women with very high blood concentrations of 25-OHD (ie, >100 nmol/L).18,19 Much-needed randomized trial evidence is remarkably limited and often confounded by the coadministration of vitamin D and calcium.1-4
ASSESSMENT AND RECOMMENDATIONS
We began with the reference to the mythological Greek goddess Panacea and conclude with the story of Icarus, who was the son of the inventor Daedalus. In order to escape from island imprisonment, Daedalus constructed wings for himself and Icarus using wax and string to fasten feathers to reeds imitating the curves of birds' wings. Daedalus warned Icarus to fly at medium altitude. If he flew too high, the sun could melt the wax of his wings, and the sea could dampen the feathers if he flew too low, in either case placing his escape in jeopardy. However, once in flight, Icarus became exhilarated; ignoring his father's words of prudence, flying higher until the sun melted the wax, and the boy fell into the sea and drowned.
The history of vitaminology, pharmacology, and toxicology provides us with concepts reminiscent of the tale of Icarus. Too little of an essential nutrient is characterized by a well-defined and correctable deficiency syndrome. Yet, all substances exhibit toxicity at excessive exposures. Clearly, deficiency of vitamin D places individuals at significant risks for bone disease2 and the Institute of Medicine report1 and subsequent articles4,5 thoroughly review the literature and provide justification for current public health DRIs to prevent deficiency. It is also clear that insufficient and inconsistent scientific evidence exists to guide DRI development or define optimal ranges of serum 25-OHD for minimizing the lifetime overall cancer risk or in regard to malignancies at specific sites.1-5 Indeed, cancer research in the genomic era continues to elucidate the complex and heterogeneous etiologies of human cancer, suggesting that a single dietary "panacea" for cancer prevention is an unlikely scenario. Yet, the vitamin D and cancer literature, ranging from cell biology to experimental models and human studies, is very provocative. Many viable hypotheses remain to be thoroughly tested in regard to cancers at specific sites. The Institute of Medicine DRI Committee and the nutrition research community enthusiastically support expanded investment in high-quality research regarding vitamin D and cancer risk or as an adjunct to therapy, the results of which will enhance our ability to provide public health guidelines through the DRI process and develop targeted interventions for those at risk of specific cancers in our medical practice. Studies involving a wide range of dietary exposures to vitamin D in experimental models and human intervention studies are particularly important and must be undertaken.
The authors conclude with a word of caution, much like that of Daedalus in his advice to his son. It is appreciated that large doses of vitamin D may cause hypercalcemia and associated sequelae.1,20 This knowledge, coupled with emerging data suggesting the possibility that chronically high vitamin D status may increase overall mortality or risks of certain cancers and other diseases of aging, suggests that a word of caution is appropriate. Higher levels of intake beyond those sufficient for bone health have not been proven to confer greater health benefits, such as lower risks of cancer.1-5 Thus, the tale of Icarus underscores the value of the evidence-based approach taken in the recent DRI process in defining public health recommendations regarding vitamin D.
Steven K. Clinton, MD, PhD, is a professor, Division of Medical Oncology, Department of Internal Medicine, the Ohio State University and the James Cancer Hospital, Columbus. He is program leader of Molecular Carcinogenesis and Chemoprevention of the Ohio State University Comprehensive Cancer Center, Columbus.
Demetrius Albanes, MD, is senior investigator in the Division of Cancer Epidemiology and Genetics in the US National Cancer Institute, Bethesda, Maryland.
James C. Fleet, PhD, is a professor in the Department of Foods and Nutrition and the director of the Interdepartmental Nutrition Program for graduate training in nutrition at Purdue University, West Lafayette, Indiana.
Glenville Jones, PhD, is a professor of biochemistry and medicine, Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
Susan T. Mayne, PhD, is the C.-E.A. Winslow Professor of Epidemiology and chair of the Department of Chronic Disease Epidemiology at the Yale School of Public Health, New Haven, Connecticut. She is also associate director for Population Sciences for the Yale Comprehensive Cancer Center, New Haven, Connecticut.
The authors have no conflicts of interest to disclose.
Correspondence: Steven K. Clinton, MD, PhD, Division of Medical Oncology, the Ohio State University, A456 Starling Loving Hall, 320 W 10th Ave, Columbus, OH 43210 ([email protected]).
References
1. Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press; 2011.
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