Workshop Summary

 

 

INTRODUCTION

Recent research suggests that obesity and excess weight can play a prominent role in the incidence and progression of various cancers. Obesity results from an energy imbalance—that is, energy intake that is higher than energy expenditure—that could also influence the growth of cancers. In addition, by generating hormones and growth factors, and by fostering inflammation, fat tissue could directly fuel the growth of tumors, thereby affecting cancer incidence, progression, recurrence, and survival rates. Given the current obesity epidemic and an aging population more susceptible to cancer, there is mounting concern about the role that obesity plays in malignancies. There is also interest in exploring possible interventions to break the obesity–cancer link, especially in patients already diagnosed with cancer, who are at risk for cancer progression and recurrence and are also more susceptible to developing new cancers. Cancer survivors currently number 12 million in the United States and are rapidly increasing in number.

Recognizing the impact that current findings on obesity and cancer could have on future cancer prevention and care, the National Cancer Policy Forum (NCPF) of the Institute of Medicine (IOM) held a 2-day workshop1 on “The Role of Obesity in Cancer Survival and Recurrence,”

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1 This workshop was organized by an independent planning committee whose role was



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Workshop Summary INTRODUCTION Recent research suggests that obesity and excess weight can play a prominent role in the incidence and progression of various cancers. Obe- sity results from an energy imbalance—that is, energy intake that is higher than energy expenditure—that could also influence the growth of cancers. In addition, by generating hormones and growth factors, and by fostering inflammation, fat tissue could directly fuel the growth of tumors, thereby affecting cancer incidence, progression, recurrence, and survival rates. Given the current obesity epidemic and an aging population more suscep- tible to cancer, there is mounting concern about the role that obesity plays in malignancies. There is also interest in exploring possible interventions to break the obesity–cancer link, especially in patients already diagnosed with cancer, who are at risk for cancer progression and recurrence and are also more susceptible to developing new cancers. Cancer survivors cur- rently number 12 million in the United States and are rapidly increasing in number. Recognizing the impact that current findings on obesity and cancer could have on future cancer prevention and care, the National Cancer Policy Forum (NCPF) of the Institute of Medicine (IOM) held a 2-day workshop1 on “The Role of Obesity in Cancer Survival and Recurrence,” 1 This workshop was organized by an independent planning committee whose role was 1

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2 THE ROLE OF OBESITY IN CANCER in Washington, DC, on October 31 and November 1, 2011. At the work- shop, experts presented the latest clinical evidence on the obesity–cancer link and the molecular mechanisms that might explain that link. Clinicians, researchers, cancer survivors, and policy makers also discussed potential interventions to counter the effects of obesity on cancer, and research and policy measures needed to stem the rising tide of cancer mortality predicted by an increasingly overweight and older population worldwide. More spe- cifically, the workshop explored: • The complex web of molecular mechanisms that underlie the obesity–cancer link and whether it is obesity itself, the energy imbalance that leads to obesity, or the molecular pathways that are deregulated due to obesity, that increases the risk of cancer initiation or progression; • Clinical evidence of the obesity link to cancer incidence and out- comes and study design issues that may affect the strength of that evidence and its interpretation, as well as ways to design future stud- ies to acquire the information needed to guide patient care; • Potential interventions to counter or prevent obesity effects and/or restore energy balance, including lifestyle measures, as well as drug and surgical therapies; • What to advise cancer patients about weight loss, diet, exercise, and other measures to reduce their risk of cancer progression or recur- rence, and the challenges in inducing healthy behaviors; and • Policy suggestions related to research, education, and dissemination of the findings on obesity and cancer, as well as what the private and public sectors can do to help break the obesity–cancer link. This document is a summary of the workshop. The views expressed in this summary are those of the speakers and discussants, as attributed to them, and are not the consensus views of workshop participants or the members of the NCPF. limited to identification of topics and speakers. This workshop summary was prepared by the rapporteurs as a factual summary of the presentations and discussions that took place at the workshop. Statements, recommendations, and opinions expressed are those of individual presenters and participants, and are not necessarily endorsed or verified by the Forums or the National Academies, and they should not be construed as reflecting any group consensus.

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3 WORKSHOP SUMMARY OVERVIEW OF THE OBESITY–CANCER LINK The ancient Greek medical practitioner Hippocrates anecdotally reported the observation that a healthy balance of food intake and physi- cal activity promotes good health. But it was not until the early part of the 20th century that researchers showed tumor cells transplanted into under- fed mice did not grow as rapidly as in those fed more abundantly, noted Wendy Demark-Wahnefried, chair of nutrition sciences at the University of Alabama at Birmingham and chair of the workshop planning committee. More recently, there has been an explosion of research on obesity and cancer, with more than 2,000 papers on the topic published in the scientific literature. An extensive 2007 review of published research found convincing evidence to link obesity to the risk of endometrial, colorectal, esophageal, kidney, and pancreatic cancer as well as to postmenopausal breast cancer (World Cancer Reasearch Fund and American Institute for Cancer Research, 2007). This review found more limited evidence linking obesity to gallbladder or liver cancer, as well as accumulating evidence that obesity is linked to the risk of non-Hodgkin’s lymphoma, ovarian cancer, and aggressive prostate cancer. “There are important public health implica- tions in these findings. Obesity is the second leading risk factor for cancer,” stressed Dr. Susan Gapstur, vice president of epidemiology at the American Cancer Society. This is especially alarming considering that since the 1970s, the num- ber of Americans becoming obese or overweight has steadily risen; they now comprise more than two-thirds of the population. The obesity epidemic is also spreading internationally; the World Health Organization estimates that more than 1.5 billion adults worldwide are overweight or obese. “The obesity epidemic is not just a U.S. problem—it’s a worldwide problem,” noted Dr. Gapstur. However, there is debate over why obesity is increasing in prevalence, with several reasons posited by experts, including the rising consumption of sugar-sweetened beverages, an increase in portion size, and the decline in physical activity, in part due to increased automation. “I don’t think we can say there is any one sole factor that has led to that change,” said Dr. Rachel Ballard-Barbash, who serves as the associate director of applied research in the Division of Cancer Control and Population Sciences at the National Cancer Institute. Dr. Gapstur agreed, noting “there’s not one simple answer because it gets back to that concept of energy balance.” (See Box 1 for a discussion of energy balance.) The increasing incidence of breast cancer in developing countries

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4 THE ROLE OF OBESITY IN CANCER BOX 1 Energy Balance and Cancer Risk Dr. Wendy Demark-Wahnefried gave a brief overview of energy balance and what factors influence it and how it influences cancer risk. She noted that the energy balance in a person’s body is determined by energy intake from the diet, which can be modified by ingestion and absorption, balanced by the total calories expended. Typically, about 60 to 75 percent of energy is expended by maintaining the resting metabolic rate, 5 to 10 percent is expended as the energy needed to digest food, and 15 to 30 percent is expended through physical exercise (Figure 1). Dr. Demark-Wahnefried also noted that a gastric bypass or a lap band will induce a shift in energy balance by reducing calorie intake. The main dispeller of energy is resting metabolic rate, which is driven, in part, by lean body mass. As people age, she noted, they expend less energy because they do not have as much muscle mass. Chemotherapy and other cancer treatments can also decrease lean body mass. Resting metabolic rate is also driven by the balance of the external temperature with the body’s internal temperature, with more energy expended when the external temperature drops below 78 degrees Fahrenheit. Disease can affect body temperature as well. is thought to reflect the increase in obesity in these nations, added Dr. Ballard-Barbash. Dr. Nathan Berger, a professor of medicine and direc- tor of the Center for Science, Health, and Society at the Case Western Reserve University School of Medicine, added that “the convergence of obesity and aging is the perfect storm or tsunami in terms of increasing the overall incidence of cancer.” But obesity does not appear to have a uniform effect on all types of cancers, nor to affect cancer risk the same in men and women. One study found that obesity increases the risk of dying from all cancers by about 52 percent in men, but nearly doubled the risk of dying from any type of cancer in women (Calle et al., 2003). For some cancers, such as liver cancer, obesity was linked to about a five-fold increased risk of cancer mortality in both sexes. In contrast, the association between obesity and colon cancer mortality is not equally strong in women and men, perhaps because body mass index (BMI) is a better measure of abdominal fat in men than women,

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5 WORKSHOP SUMMARY Several researchers have attempted to assess how the various components of energy balance affect cancer risk. One study showed that calorie restriction consistently lowers the risk of cancer mortality across several species, from the mouse to the cow (Hursting et al., 2003). Stud- ies on the effects of physical exercise on cancer risk are less consistent, Dr. Demark-Wahnefried said, although a few studies suggest that when energy intake is kept constant, animals that exercise more have less cancer progression. However, one study found that expression of several genes is altered when mice are placed on caloric restriction, but there are relatively few changes in gene expression when caloric intake is kept stable while mice are exercised (Padovani et al., 2009). Dr. Demark-Wahnefried stressed “the need to disentangle effects of caloric restriction and increased physical activity, as well as obesity. Can- cer is complex and energy balance is complex. It’s really difficult to make a change in one factor without impacting another.” As she noted when people exercise a lot, their appetite tends to increase and leads them to eat more, whereas there is some evidence that moderate amounts of physical activity can actually suppress appetite. “So if you are going to conduct a physical activity intervention, then it is important to measure and control for dietary intake,” Dr. Demark-Wahnefried said. or because of hormonal factors that are protective, Dr. Gapstur pointed out (Box 2). Obesity-related breast cancer risk also varies by menopausal status. Increasing BMI levels are linked to a lower incidence of breast cancer in premenopausal women, but a greater incidence of breast cancer in post- menopausal women, Dr. Gapstur said, for reasons that are not yet clearly defined. Obesity’s influence on prostate cancer risk also varies. Although obesity is associated with a lower incidence of prostate cancer, studies sug- gest that obesity is linked to a greater risk of being diagnosed with a more aggressive form of prostate cancer, and studies have consistently shown that obesity substantially increases the risk of dying from prostate cancer. “These data suggest that one shoe doesn’t fit all, and it may be very important to separate the different disease types,” she said. Growing evidence also indicates that obesity during childhood can increase the risk of childhood cancers, such as leukemia, and young-onset brain tumors, Dr. Ballard-Barbash noted. “This is an issue that is urgent

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6 THE ROLE OF OBESITY IN CANCER ENERGY BALANCE Total Energy Expenditure (TEE) Energy Intake (Calories Out) (Calories In) Modified by inges on Res ng Metabolic Rate (RMR) and/or absorp on. (energy needed to maintain body func on at rest, ~ 60-75% TEE) Thermic Effect of Food (energy for diges on/metabolism 5-10% TEE) Physical Ac vity (15-30% TEE) FIGURE 1 Energy editable Figure 1-5, balance. Weight maintenance occurs when energy input equals energy expenditure, with gains and losses occurring when there is an imbalance. A gain of one pound occurs when approximately 3,500 calories are consumed in excess of energy needs. For most individuals, resting metabolic rate (RMR) comprises the major component of energy expenditure, accounting for 60-75 percent of energy needs (IOM, 2005; Pi-Sunyer, 2000). Resting metabolic rate is largely governed by lean tissue, which has a higher metabolic rate than adipose tissue. Neoplastic tissue also may have a higher metabolic rate, though a study of 200 cancer patients compared to 200 healthy controls found that metabolic rate was highly variable among cancer patients (50-175 percent of predicted values) and greatly influenced by tumor stage and site (Knox et al., 1983). Speculation also exists that RMR may be influenced by various cytokines, though more research is necessary (Pi-Sunyer, 2000). The Thermic Effect of Food, also known as Specific Dynamic Action, is the energy needed for digestion and metabolism of food—transient energy needs that go above and beyond normal metabolism. The Thermic Effect of Food accounts for only 5-10 percent of energy needs and is dependent upon the magnitude of dietary intake, and also may be influenced by the consumption of specific foods or food-related substances. For example, tea, capsaicin, and caffeine may increase metabolism even further (Bell and Goodrick, 2002), though more studies are needed to determine if these transient increases are clinically meaningful. Physical activity comprises the third component of energy expenditure and for individuals living in the developed world, usually accounts for 15-30 percent of energy needs. The energy expended for physical activity is the most modifiable component of energy expenditure. Furthermore, given the potential of exercise (especially resistance training) to increase lean body mass, physical activity also may act indirectly to increase RMR. SOURCE: Demark-Wahnefried presentation (October 31, 2011). Reprinted with per- mission from Wendy Demark-Wahnefried.

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7 WORKSHOP SUMMARY BOX 2 How Obesity Is Measured There are several assessments of overweight and obesity; the most common is body mass index (BMI). BMI is weight (kg)/ height squared (m2). It is frequently used in studies because it is a single measure that can be determined easily, Dr. Susan Gapstur pointed out, and is comparable among studies. Below are the World Health Organization criteria for overweight and obesity: • Underweight = BMI < 18.5 kg/m2 • Normal weight = BMI 18.5-24.9 kg/m2 • Overweight = BMI 25.0-29.9 kg/m2 • Obese = BMI 30+ kg/m2 An individual’s body fat distribution can also be assessed with anthropometric methods such as measurements of waist and hip circumference or the ratio of the two, or techniques such as air displacement or bioelectrical impedance to determine percentage of body fat. BMI correlates well with percentage of body fat in the average population, according to Dr. Gapstur. for our children, even beyond what the effect will be in their adult lives,” she said. MOLECULAR MECHANISMS The variability in how obesity affects the incidence, progression, or mortality of various cancers suggests that these effects derive from multiple mechanisms, which animal research supports. This research implies a web of interacting hormones, growth factors, cytokines, and inflammation media- tors that promote tumor initation and growth. As Dr. Berger noted, an excess of nutrients causes an imbalance in energy. This imbalance causes oxidative stress and abnormalities of fatty acid metabolism that foster inflammation and insulin resistance (Figure 2). This results in a number of processes that underlie cancer initiation and promo- tion, including DNA damage, cell division, delayed cell death, an increase in blood vessel formation, and cell migration (Figure 3). The complex interactions between all the obesity-activated hormones

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8 THE ROLE OF OBESITY IN CANCER FIGURE 2 An integrative view of obesity. SOURCE: Berger presentation (October 31, 2011). Adapted from Wisse et al. (2007). An Integrative View of Obesity. Science 318:928-929. Reprinted with permission from AAAS and Nathan Berger. and growth factors make it difficult to pinpoint targets for interventions. “It’s important to remember that if you are directing your therapy at leptin, for example, or at reducing insulin levels, all these other factors are going on simultaneously. If we really are going to attack the obesity–cancer link, it’s going to require attacking many of these components, if not all, simultane- ously,” Dr. Berger said. Dr. Berger stressed the crosstalk that occurs among several different obesity-activated pathways leading to cancers, as well as the cellular signal- ing that occurs among fat tissue, the immune system, and cancer cells. Dr. Derek LeRoith, director of the Metabolism Institute and chief of Endocri- nology, Diabetes, and Bone Diseases at the Mount Sinai School of Medi- cine, agreed, pointing out that animal models can help researchers delineate

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FIGURE 3 Putative factors involved in obesity-related carcinogenesis. Factors denoted in red text are core features in the Metabolic Syndrome. Factors denoted in blue text are additional features that may also be components of the Metabolic Syndrome. NOTE: BMI = body mass index; CRP = C-reactive protein; FFA = free fatty acid; IGF = insulin-like growth factor; IGFBPs = insulin-like growth factor binding proteins; IL = interleukin; MAC = macrophages; MCP = monocyte chemotactic protein; mito = mitochondria; PAI = plasminogen activator inhibitor; PGE = prostaglandin; ROS = reactive oxygen species; SHBG = sex hormone binding globulin; TG = triglycerides; TNF = tumor necrosis factor; VEGF = vascular epithelial growth 1-2, xed image Figure factor. 9 SOURCE: Berger presentation (October 31, 2011). Adapted from Nock and Berger, 2010. Reprinted with permission from Nathan Berger.

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10 THE ROLE OF OBESITY IN CANCER which molecules and pathways underlie the obesity–cancer link, but that those individual compounds or pathways need to be kept in context. “It’s all of them, and hitting one may be insufficient,” he said, adding that many pharmaceutical companies are trying to develop combination therapies that target two or more key molecules in different pathways simultaneously. Some of these molecular pathways could foster cancer initiation or promotion, or both. For example, Dr. Pamela Goodwin, senior scientist and Marvelle Koffler Chair in Breast Cancer Research at Mount Sinai Hospital, noted that obesity is linked to an increased risk of breast cancer progression, but not initiation in premenopausal women. Obese premenopausal women actually have a lower incidence of breast cancer than premenopausal women of normal weight, perhaps because of abnormal estrogen metabolism and/ or other factors related to having an energy imbalance, Dr. Gapstur pointed out. Dr. LeRoith suggested the low testosterone of obese men may protect them from developing prostate cancer, but once they develop this tumor, obesity and the excessive insulin production it causes could foster the aggressive growth and metastasis of prostate cancer. Dr. Stephen Hursting, professor at the University of Texas at Austin, and MD Anderson Cancer Center, pointed out that studies using a variety of animal models support the premise that obesity fosters cancer promotion, but the link between obesity and cancer initiation is more tenuous. Dr. Berger noted that the heightened metabolism of fatty acids that occurs in obese individuals might increase DNA damage due to oxidation. But little to no evidence shows that this DNA damage triggers a malignant transformation, even though DNA damage in general has been shown to cause cancer. He questioned whether obesity actually fosters the initiation of cancer, or rather causes cancer promotion so that the cancer is diagnosed earlier in life. “Data exist to support the latter for pancreatic cancer (Harvey, 2011), but for none of the other cancers. This is a really important question, because if obesity is causing one of the initial mutations, then we need to treat it early and think about how to block the mutations. But if obesity is really causing progression, then there will be whole different strategy to deal with it,” Dr. Berger said. Dr. John DiGiovanni, professor of pharmacol- ogy, toxicology, and nutrition sciences at the University of Texas at Austin, noted that the AKT-mTOR pathway that is activated in obese animals is linked to increased risk of developing a cancer, as well as to the progression of many cancers. There was general agreement, however, that cancer is a disorder whose

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11 WORKSHOP SUMMARY hallmark is abnormal regulation of the growth and survival of cells, and that fat cells generate many hormones, growth factors, and cytokines that can disrupt regulation of cell growth and survival. The key mechanistic molecular factors discussed at the workshop were estrogen, insulin, insulin- like growth factor 1 (IGF-1), leptin, adiponectin, and adipokinase, as well as several mediators of inflammation. Estrogen Seventy percent of all breast cancer patients are postmenopausal women. Most of the estrogen produced in postmenopausal women is derived from fat tissue via the enzyme aromatase, which converts adrenal androgens into estrogen. The more fat tissue there is, the greater the levels of estrogen produced and in circulation. Such estrogen can fuel the growth of estrogen receptor–positive breast cancers. Studies show that mice made obese by being fed a high-fat diet and then inoculated with breast cancer cells had significantly greater tumor growth rates than mice similarly inocu- lated, but fed a normal diet (Sabnis et al., 2009). When inoculated obese mice were given an aromatase inhibitor, the tumor growth rate was mark- edly inhibited, reported Dr. Angela Brodie, professor of pharmacology and experimental therapeutics at the Marlene and Stewart Greenbaum Cancer Center of the University of Maryland School of Medicine. Clinical studies confirm that circulating estradiol levels are linked to risk of recurrence of breast cancer, but Dr. Goodwin pointed out this mech- anism does not explain the association of obesity with premenopausal breast cancer outcomes or with estrogen receptor–negative breast cancer outcomes (Pierce et al., 2007a). Dr. Gapstur added that it also does not explain why estrogen is linked to both pre- and postmenopausal endometrial cancer risk (Reeves et al., 2007). Insulin Dr. Goodwin and others have data to suggest that another factor mak- ing obese women more susceptible to breast cancer recurrence and death is the higher than normal insulin level that is often linked to obesity. Increases in BMI correlate closely with increases in fasting insulin levels in the non- diabetic population, Dr. Goodwin noted, and greater levels of insulin are linked to increased risk of distant recurrence and death in breast cancer patients (Gallagher and LeRoith, 2011; Goodwin et al., 2002).

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70 THE ROLE OF OBESITY IN CANCER international cancer community models many of their policies according to what ASCO advocates. Dr. Wadden advocated for more educational and policy efforts being made to prevent obesity in the general population as well. “Treatment alone is clearly not the answer to the obesity epidemic. We have to do more to prevent this disorder,” he said. Dr. Partridge stressed that obesity is an interesting disease because in addition to its molecular basis, it is impacted by individual behavior, and by family, workplace, or community influences on that behavior. “I can visual- ize a system’s biomedicine approach to obesity in which you have the basic scientists, the behaviorists, the epidemiologists, and the political scientists working together in transdisciplinary teams with excellent informatics that links all that together, so you can begin to tease out the important factors at each level needed to make some progress,” he said. Mr. Kean suggested reaching out to experts who can frame the obesity and cancer policy issues within the context of the economy and jobs or other high-priority topics that are more likely to garner the interest of poli- ticians who can influence obesity policies. He also suggested collaborating with the IOM Evidence Communication Innovation Collaborative, which is currently assessing how best to communicate evidence to patients and the public at large. Dr. Morgan Downey, of the Downey Obesity Report, stressed the genetic and epigenetic components of obesity and cautioned that such factors be considered when devising health or workplace policies related to the dis- order. He said that according to obesity researcher Jeffrey Freidman, body weight is as heritable as height (Friedman, 2004), so obesity is different from a behavior such as smoking, which is more likely to be susceptible to financial disincentives or penalties. He said that some workplaces and insurers and even the Affordable Care Act are suggesting placing similar penalties on people who are overweight and obese. “We have to be careful because the types of interventions that were successful in cancer prevention via smoking I don’t think are going to prove very effective in long-term obesity reduction.” WRAPPING UP Dr. Wahnefried-Demark provided some closing remarks, noting that growing evidence from both clinical and animal studies shows that obesity increases the risk of cancer incidence, recurrence after treatment, progres- sion, and cancer death for many organ sites. This is a significant public

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71 WORKSHOP SUMMARY health concern given that an obesity epidemic is currently spreading world- wide, and obesity is the second leading risk factor for cancer incidence. Hor- mones, growth factors, and inflammation may underlie the mechanisms by which obesity increases cancer risk, with animal and human study results consistently suggesting specific interacting mechanistic pathways that vary by cancer subtype. Key molecules in those pathways could serve as targets for drugs aimed at preventing cancer or cancer recurrence or progression. There is grow- ing evidence that lifestyle measures, such as reducing weight, maintaining a healthy diet, and increasing physical activity could also lower cancer risk. Most of that evidence is observational and would be strengthened by randomized clinical trials. However, routine measurements of obesity indicators in clinical trials would aid researchers’ attempts to document the benefits of various interventions in stemming obesity and its impact on cancer risk. In the meantime, more education of oncologists, dietitians, primary care physicians, and other healthcare practitioners who work with cancer survivors and better dissemination of what is known about obesity’s influ- ence on the risk of cancer recurrence, progression, and mortality, and ways to ameliorate that risk could be beneficial. Reimbursement by health insurers for obesity treatments, including weight loss programs, and more involvement of industry and schools in pro- moting policies that help prevent obesity might also have a positive impact, not just on cancer incidence, but on the well-being of cancer patients. REFERENCES Abdelmalek, M. F., A. Suzuki, C. Guy, A. Unalp-Arida, R. Colvin, R. J. Johnson, and A. M. Diehl. 2010. Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease. Hepatology 51(6):1961-1971. Abrahamson, P. E., M. D. Gammon, M. J. Lund, J. A. Britton, S. W. Marshall, E. W. Flagg, P. L. Porter, L. A. Brinton, J. W. Eley, and R. J. Coates. 2006. Recreational physical activity and survival among young women with breast cancer. Cancer 107(8):1777- 1785. Ackermann, R. T., E. A. Finch, E. Brizendine, H. Zhou, and D. G. Marrero. 2008. Translating the Diabetes Prevention Program into the community. The DEPLOY Pilot Study. Am J Prev Med 35(4):357-363. Adams, T. D., R. E. Gress, S. C. Smith, R. C. Halverson, S. C. Simper, W. D. Rosamond, M. J. Lamonte, A. M. Stroup, and S. C. Hunt. 2007. Long-term mortality after gastric bypass surgery. N Engl J Med 357(8):753-761.

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75 WORKSHOP SUMMARY Holick, C. N., P. A. Newcomb, A. Trentham-Dietz, L. Titus-Ernstoff, A. J. Bersch, M. J. Stampfer, J. A. Baron, K. M. Egan, and W. C. Willett. 2008. Physical activity and survival after diagnosis of invasive breast cancer. Cancer Epidemiol Biomarkers Prev 17(2):379-386. Holmes, M. D., W. Y. Chen, D. Feskanich, C. H. Kroenke, and G. A. Colditz. 2005. Physical activity and survival after breast cancer diagnosis. JAMA 293(20):2479-2486. Hursting, S. D., and N. A. Berger. 2010. Energy balance, host-related factors, and cancer progression. J Clin Oncol 28(26):4058-4065. Hursting, S. D., J. A. Lavigne, D. Berrigan, S. N. Perkins, and J. C. Barrett. 2003. Calorie restriction, aging, and cancer prevention: Mechanisms of action and applicability to humans. Annu Rev Med 54:131-152. Imayama, I., C. M. Alfano, A. Kong, K. E. Foster-Schubert, C. E. Bain, L. Xiao, C. Duggan, C. Y. Wang, K. L. Campbell, G. L. Blackburn, and A. McTiernan. 2011. Dietary weight loss and exercise interventions effects on quality of life in overweight/obese postmenopausal women: A randomized controlled trial. Int J Behav Nutr Phys Act 8:118. IOM (Institute of Medicine). 2005. Dietary reference intakes for energy, carbohydrate, fiber, fat, fatty acids, cholesterol, protein, and amino acids (macronutrients). Washington, DC: The National Academies Press. IOM. 2011a. Early childhood obesity prevention policies. Washington, DC: The National Academies Press. IOM. 2011b. Legal strategies in childhood obesity prevention: Workshop summary. Washington, DC: The National Academies Press. IOM. 2011c. Leveraging food technology for obesity prevention and reduction efforts: Workshop summary. Washington, DC: The National Academies Press. IOM. 2012a. Mesuring progress in obesity prevention: Workshop report. Washington, DC: The National Academies Press. IOM. 2012b. Accelerating progress in obesity prevention: Solving the weight of the nation. Washington, DC: The National Academies Press. IOM. 2012c. Alliances for obesity prevention: Finding common ground: Workshop summary. Washington, DC: The National Academies Press. Irwin, M. L., A. McTiernan, L. Bernstein, F. D. Gilliland, R. Baumgartner, K. Baumgartner, and R. Ballard-Barbash. 2005. Relationship of obesity and physical activity with C-peptide, leptin, and insulin-like growth factors in breast cancer survivors. Cancer Epidemiol Biomarkers Prev 14(12):2881-2888. Irwin, M. L., A. W. Smith, A. McTiernan, R. Ballard-Barbash, K. Cronin, F. D. Gilliland, R. N. Baumgartner, K. B. Baumgartner, and L. Bernstein. 2008. Influence of pre- and postdiagnosis physical activity on mortality in breast cancer survivors: The health, eating, activity, and lifestyle study. J Clin Oncol 26(24):3958-3964. Irwin, M. L., K. Varma, M. Alvarez-Reeves, L. Cadmus, A. Wiley, G. G. Chung, L. Dipietro, S. T. Mayne, and H. Yu. 2009. Randomized controlled trial of aerobic exercise on insulin and insulin-like growth factors in breast cancer survivors: The Yale Exercise and Survivorship study. Cancer Epidemiol Biomarkers Prev 18(1):306-313. Irwin, M. L., C. Duggan, C. Y. Wang, A. W. Smith, A. McTiernan, R. N. Baumgartner, K. B. Baumgartner, L. Bernstein, and R. Ballard-Barbash. 2011. Fasting C-peptide levels and death resulting from all causes and breast cancer: The health, eating, activity, and lifestyle study. J Clin Oncol 29(1):47-53.

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76 THE ROLE OF OBESITY IN CANCER Jakicic, J. M., C. Winters, W. Lang, and R. R. Wing. 1999. Effects of intermittent exercise and use of home exercise equipment on adherence, weight loss, and fitness in overweight women: A randomized trial. JAMA 282(16):1554-1560. Jebb, S. A., A. L. Ahern, A. D. Olson, L. M. Aston, C. Holzapfel, J. Stoll, U. Amann-Gassner, A. E. Simpson, N. R. Fuller, S. Pearson, N. S. Lau, A. P. Mander, H. Hauner, and I. D. Caterson. 2011. Primary care referral to a commercial provider for weight loss treatment versus standard care: A randomised controlled trial. Lancet 378(9801):1485-1492. Jiralerspong, S., S. L. Palla, S. H. Giordano, F. Meric-Bernstam, C. Liedtke, C. M. Barnett, L. Hsu, M. C. Hung, G. N. Hortobagyi, and A. M. Gonzalez-Angulo. 2009. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol 27(20):3297-3302. Joshu, C. E., A. M. Mondul, A. Menke, C. Meinhold, M. Han, E. B. Humphreys, S. J. Freedland, P. C. Walsh, and E. A. Platz. 2011. Weight gain is associated with an increased risk of prostate cancer recurrence after prostatectomy in the PSA era. Cancer Prev Res (Phila) 4(4):544-551. Kakarala, M., and M. S. Wicha. 2008. Implications of the cancer stem-cell hypothesis for breast cancer prevention and therapy. J Clin Oncol 26(17):2813-2820. Kakarala, M., D. E. Brenner, H. Korkaya, C. Cheng, K. Tazi, C. Ginestier, S. Liu, G. Dontu, and M. S. Wicha. 2010a. Targeting breast stem cells with the cancer preventive compounds curcumin and piperine. Breast Cancer Res Treat 122(3):777-785. Kakarala, M., S. K. Dubey, M. Tarnowski, C. Cheng, S. Liyanage, T. Strawder, K. Tazi, A. Sen, Z. Djuric, and D. E. Brenner. 2010b. Ultra-low flow liquid chromatography assay with ultraviolet (UV) detection for piperine quantitation in human plasma. J Agric Food Chem 58(11):6594-6599. Knowler, W. C., E. Barrett-Connor, S. E. Fowler, R. F. Hamman, J. M. Lachin, E. A. Walker, and D. M. Nathan. 2002. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 346(6):393-403. Knox, L. S., L. O. Crosby, I. D. Feurer, G. P. Buzby, C. L. Miller, and J. L. Mullen. 1983. Energy expenditure in malnourished cancer patients. Ann Surg 197(2):152-162. Kroenke, C. H., W. Y. Chen, B. Rosner, and M. D. Holmes. 2005. Weight, weight gain, and survival after breast cancer diagnosis. J Clin Oncol 23(7):1370-1378. Leblanc, E. S., E. O’Connor, E. P. Whitlock, C. D. Patnode, and T. Kapka. 2011. Effectiveness of primary care-relevant treatments for obesity in adults: A systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med 155(7):434-447. LeRoith, D. 2010. Can endogenous hyperinsulinaemia explain the increased risk of cancer development and mortality in type 2 diabetes: Evidence from mouse models. Diabetes Metab Res Rev 26(8):599-601. Libby, G., L. A. Donnelly, P. T. Donnan, D. R. Alessi, A. D. Morris, and J. M. Evans. 2009. New users of metformin are at low risk of incident cancer: A cohort study among people with type 2 diabetes. Diabetes Care 32(9):1620-1625. Ligibel, J. 2011. Obesity and breast cancer. Oncology 25(11):994-1000. Ligibel, J. A., N. Campbell, A. Partridge, W. Y. Chen, T. Salinardi, H. Chen, K. Adloff, A. Keshaviah, and E. P. Winer. 2008. Impact of a mixed strength and endurance exercise intervention on insulin levels in breast cancer survivors. J Clin Oncol 26(6):907-912.

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77 WORKSHOP SUMMARY Ma, J., H. Li, E. Giovannucci, L. Mucci, W. Qiu, P. L. Nguyen, J. M. Gaziano, M. Pollak, and M. J. Stampfer. 2008. Prediagnostic body-mass index, plasma C-peptide concentration, and prostate cancer-specific mortality in men with prostate cancer: A long-term survival analysis. Lancet Oncol 9(11):1039-1047. Macedo, L. F., G. J. Sabnis, O. G. Goloubeva, and A. Brodie. 2008. Combination of anastrozole with fulvestrant in the intratumoral aromatase xenograft model. Cancer Res 68(9):3516-3522. Mai, V., L. H. Colbert, D. Berrigan, S. N. Perkins, R. Pfeiffer, J. A. Lavigne, E. Lanza, D. C. Haines, A. Schatzkin, and S. D. Hursting. 2003. Calorie restriction and diet composition modulate spontaneous intestinal tumorigenesis in Apc(Min) mice through different mechanisms. Cancer Res 63(8):1752-1755. Mancino, L., and J. Guthrie. 2009. When nudging in the lunch line might be a good thing. Amber Waves 7(1):32-38. Mason, C., K. E. Foster-Schubert, I. Imayama, A. Kong, L. Xiao, C. Bain, K. L. Campbell, C. Y. Wang, C. R. Duggan, C. M. Ulrich, C. M. Alfano, G. L. Blackburn, and A. McTiernan. 2011. Dietary weight loss and exercise effects on insulin resistance in postmenopausal women. Am J Prev Med 41(4):366-375. Menendez, J. A., S. Cufi, C. Oliveras-Ferraros, B. Martin-Castillo, J. Joven, L. Vellon, and A. Vazquez-Martin. 2011. Metformin and the ATM DNA damage response (DDR): Accelerating the onset of stress-induced senescence to boost protection against cancer. Aging 3(11):1063-1077. Meyerhardt, J. A., D. Heseltine, D. Niedzwiecki, D. Hollis, L. B. Saltz, R. J. Mayer, J. Thomas, H. Nelson, R. Whittom, A. Hantel, R. L. Schilsky, and C. S. Fuchs. 2006. Impact of physical activity on cancer recurrence and survival in patients with stage III colon cancer: Findings from CALGB 89803. J Clin Oncol 24(22):3535-3541. Meyerhardt, J. A., D. Niedzwiecki, D. Hollis, L. B. Saltz, F. B. Hu, R. J. Mayer, H. Nelson, R. Whittom, A. Hantel, J. Thomas, and C. S. Fuchs. 2007. Association of dietary patterns with cancer recurrence and survival in patients with stage III colon cancer. JAMA 298(7):754-764. Meyerhardt, J. A., J. Ma, and K. S. Courneya. 2010. Energetics in colorectal and prostate cancer. J Clin Oncol 28(26):4066-4073. Moore, T., L. Beltran, S. Carbajal, S. Strom, J. Traag, S. D. Hursting, and J. DiGiovanni. 2008a. Dietary energy balance modulates signaling through the Akt/mammalian target of rapamycin pathways in multiple epithelial tissues. Cancer Prev Res (Phila) 1(1):65-76. Moore, T., S. Carbajal, L. Beltran, S. N. Perkins, S. Yakar, D. Leroith, S. D. Hursting, and J. DiGiovanni. 2008b. Reduced susceptibility to two-stage skin carcinogenesis in mice with low circulating insulin-like growth factor I levels. Cancer Res 68(10):3680-3688. NIH (National Institutes of Health). 2000. The practical guide: Identification, evaluation, and treatment of overweight and obesity in adults. http://www.nhlbi.nih.gov/guidelines/ obesity/prctgd_c.pdf (accessed January 10, 2012). Nock, N. L., and N. A. Berger. 2010. Obesity and cancer: Overview of mechanism, in cancer and energy balance, epidemiology and overview. Edited by N. A. Berger. New York: Springer.

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