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Workshop Summary
Pages 1-80

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From page 1...
... 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.
From page 2...
... 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 specifically, 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.
From page 3...
... 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.
From page 4...
... Dr. Nathan Berger, a professor of medicine and director 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.
From page 5...
... Obesity's influence on prostate cancer risk also varies. Although obesity is associated with a lower incidence of prostate cancer, studies suggest 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.
From page 6...
... to increase lean body mass, physical activity also may act indirectly to increase RMR. SOURCE: Demark-Wahnefried presentation (October 31, 2011)
From page 7...
... This research implies a web of interacting hormones, growth factors, cytokines, and inflammation mediators that promote tumor initation and growth.
From page 8...
... 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.
From page 9...
... 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.
From page 10...
... 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.
From page 11...
... 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)
From page 12...
... Unlike most people who have insulin resistance, the experimental mice were not obese, giving the researchers the opportunity to assess the role that high levels of insulin without concurrent obesity plays in fueling breast cancer growth. The breast cancers that developed in the mice with elevated insulin levels were much more aggressive and had greater tumor growth than those that developed in the mice with normal insulin levels.
From page 13...
... • Adiponectin, a hormone that regulates sugar uptake and the break down of fats mainly by upregulating AMP kinase. Adiponectin is linked to greater energy expenditure, and weight loss increases the amount of this hormone.
From page 14...
... The importance of the leptin/adiponectin ratio was confirmed in other studies conducted by Dr. Hursting, which showed that transplanted tumors do not grow in genetically obese mice that have high insulin levels, but low IGF-1 levels and a low leptin/adiponectin ratio (Zheng et al., 2011)
From page 15...
... . The inflammation seen in abdominal and breast fat is induced by the breakdown of lipids into fatty acids, which can activate immune system cells called macrophages, via a receptor called NF-kappaB (NF-kB)
From page 16...
... Dannenberg examined normal breast tissue removed from women undergoing breast surgery. He found that the crown-like structures seen in the fat tissue of obese mice also occurred in about three-quarters of the breast fat tissue removed from overweight and obese women, but in less than 10 percent of the breast fat tissue removed from women of normal weight.
From page 17...
... "The mechanisms that are involved in the dietary energy balance effects in prostate cancer are complex and involve many pathways," Dr. DiGiovanni said.
From page 18...
... Dr. Madhuri Kakarala, clinical lecturer at the University of Michigan School of Medicine, related this stem cell hypothesis to how obesity might increase cancer risk.
From page 19...
... The Role of Diet There was some discussion at the workshop about whether the type of diet, especially the fat and carbohydrate content, was more important for cancer risk than the total number of calories. This is an important issue, Dr.
From page 20...
... of an inner energy imbalance that more directly heightens cancer risk due to altered metabolism and specific cell signaling pathways. In other words, is obesity a symptom of an underlying long-term energy imbalance that heightens cancer risk, or a more direct cause of that elevated risk?
From page 21...
... Jennifer Ligibel, assistant professor and attending physician at Dana-Farber Cancer Institute and Harvard School of Medicine. In addition to the general clinical evidence linking obesity to cancer risk, as previously summarized in the introduction, several presenters elaborated on the evidence linking obesity to the risk of incidence, recurrence, progression, and death for three common cancers: breast, prostate, and colon.
From page 22...
... Several studies show that elevated insulin levels or fasting glucose levels are linked to increased risk of distant
From page 23...
... separated more aggressive fatal disease from disease that is more indolent," she said. She noted that the timing of body fatness might be critical in determining prostate cancer risk.
From page 24...
... . CLINICAL STUDY DESIGN ISSUES When conducting clinical studies assessing the link between obesity and cancer and possible interventions to weaken that link, it can be difficult to parse the effects of obesity and other tightly interconnected factors such as energy balance, physical activity, diet, and timing of weight gain or loss.
From page 25...
... This is especially true, Dr. Platz added, if the cancer risk linked to obesity differs before or after diagnosis because of differential effects on causing cancer or causing an aggressive cancer subtype before diagnosis versus causing cancer progression after diagnosis.
From page 26...
... Demark-Wahnefried added. Accelerometers can help in physical activity assessments, but they are not perfect, said Dr.
From page 27...
... Dr. Platz noted that extreme obesity can make complete prostate removal technically difficult so obese men diagnosed with prostate cancer may be less likely to have prostatectomies than men of normal weight.
From page 28...
... showing that when the dose of the aromatase inhibitor Arimidex (Anastrozole) was adjusted according to BMI, there was no increased risk of breast cancer recurrence in obese women compared to normal weight women (Macedo et al., 2008)
From page 29...
... Dr. Rock also said that for clinical trials assessing the effects of weight loss, researchers frequently fail to make the distinction between intentional weight loss due to diet and/or exercise versus involuntary weight loss that might be due to an advanced cancer.
From page 30...
... symposium on sleep and disease, there was interest in how circadian rhythms, especially those that individual organs appear to have, might influence changes in cell cycling and related factors that may influence cancer risk.
From page 31...
... Several speakers pointed out that this behavioral clustering makes it difficult to determine from observational data what factors (such as diet, exercise, or weight loss) are associated with the outcome.
From page 32...
... Dr. Ballard-Barbash added that in the medical literature on cancer incidence, there are few studies on obesity or BMI adjusted for physical activity.
From page 33...
... . Given the mounting mechanistic evidence for how obesity increases cancer risk in certain subtypes of people, several experts suggested designing studies to include subset analyses and including large enough numbers of those subtypes so that studies are adequately powered to do subtype analyses.
From page 34...
... • acilitate ongoing contact with health care or other profes F sionals to maintain weight loss. • nclude biomarkers for energy balance and undertake cor I relative science.
From page 35...
... She suggested considering competing risk when analyzing data to sort out the heightened risk of cancer mortality in obese patients from the heightened risk of mortality from the various comorbidities that obese cancer patients, especially those who are older, tend to have. Such an analysis is especially important for studies that include a wide age range of patients, she said.
From page 36...
... She conducted a study in non-cancer patients that linked weight loss to a decrease in white blood cells, which might be problematic for patients recovering from chemotherapy who typically have depressed immune function (Imayama et al., 2011)
From page 37...
... " Dr. Kerry Courneya, Canada Research chair in physical activity and cancer at the University of Alberta, responded that the American College of Sports Medicine has recommendations for patient risk and a risk stratification approach that stipulates, for example, that patients at high risk may need medical supervision or electrocardiogram monitoring.
From page 38...
... Dr. Goodwin added that she conducted a weight loss study that excluded participants with BMIs greater than 40 because of the supposition that the intervention would not be sufficient for women with higher BMIs, who should be referred to more focused interventions that might include bariatric surgery.
From page 39...
... Weight Loss/Diet Changes Clinical studies in cancer patients have not yet firmly established if or how much weight loss is necessary to reduce cancer risk. However, studies in other patient populations suggest just a 10 percent weight loss, regardless of starting weight, is enough to generate health benefits, including lower insulin levels and fewer diabetes complications, Dr.
From page 40...
... while increasing intake of fruits and vegetables to induce a weight loss of 1 or 2 pounds per week; • xercise -- brisk walking or various types of aerobic exercise E and resistance training -- for more than 150 min/week; and • ecord food intake, physical activity, and weight, and R receive feedback on weight loss progress. A diet plan in which meals and snacks are consumed at regu lar, established intervals is generally recommended.
From page 41...
... Studies indicate that one can attain only about a 2- to 3-kg weight loss over a year with just exercise, and similar findings have been seen in cancer patients and survivors, she said. The large, randomized Women's Intervention Nutrition Study found that postmenopausal women with early-stage breast cancer who were assigned to a low-fat diet had a significantly reduced risk of relapse compared to control women who did not change their diets.
From page 42...
... We have to carefully consider the pros and cons of bariatric surgery in cancer survivors." Diet also appears to affect colon cancer outcomes. Colon cancer patients who tended to eat more meats, processed meats and grains, and sugary foods had significantly worse disease-free survival compared to those who ate less of these foods, a study by Dr.
From page 43...
... By the second year, monthly behavioral support sessions are mandatory, although they can be by telephone or face-to-face, and monthly supervised physical activity sessions are recommended. So far, most participants prefer to have monthly supervised exercise sessions, and monthly face-to-face behavioral support sessions, according to Dr.
From page 44...
... "We know from the data looking at the determinants of exercise that the perceived enjoyment of the activity is the strongest correlate of whether or not they are going to continue," he said, adding that he has done some preliminary research about what makes exercise fun for patients and has applied his findings in the CHALLENGE guidebook and behavioral session designs. Several observational studies have shown the benefits of exercise in reducing colorectal cancer risk, consistent with experimental results in an animal model of colon cancer in which exercise, especially voluntary exercise, reduced polyps by 25 percent, Dr.
From page 45...
... . Most exercise effects are small to moderate, he added, with TABLE 1 Observational Evidence Suggests a Link Between Physical Activity and Breast Cancer Prognosis Timing of Study N Patient Population Exercise Results NHS 2,987 Pre- and 2+ years Breast cancer death postdiagnosis postdiagnosis RR=0.50 (95% CI, 0.31-0.32)
From page 46...
... Exercise Versus or in Combination with Diet and/or Weight Loss Some debate took place at the workshop on which lifestyle interventions or combinations of lifestyle measures, such as diet, exercise, and weight loss, were most important in lowering cancer risk.
From page 47...
... We really don't have the randomized data to determine which of these factors are more important. The closest we have to that randomized data are WINS and WHEL, which suggest that weight loss or a low-fat diet may be important in breast cancer survivors."
From page 48...
... Wolfe, professor of surgery at the Oregon Health & Science University, reported that a long-term Swedish study found that a 15 to 30 percent weight loss due to bariatric surgery can be maintained over a period of many years (Sjostrom et al., 2007)
From page 49...
... Metformin Metformin attracted cancer researchers' attention when it was found to be associated with a lower risk of breast cancer risk in observational studies of diabetic patients, Dr. Goodwin reported (Bodmer et al., 2010; Bosco et al., 2011; Currie et al., 2009; Decensi et al., 2010; Libby et al., 2009)
From page 50...
... Figure 1-6, xed image, box around gure coverd the findings from their labs and others that suggest low doses of rapamycin are as effective as calorie restriction for lifespan extension in several different strains of mice, and can mitigate the effects of obesity on cancer risk (Checkley et al., 2011; Harrison et al., 2009)
From page 51...
... . But cancer stem cells are able to pump out chemotherapy compounds Hedgehog TGFβ Family Notch EGF Family Wnt Self-Renewal l Prolac n Estrogen and LIF Progesterone Stem Cell FIGURE 7 Regulation of stem cell self-renewal and clonal expansion.
From page 52...
... These drugs have already been shown in randomized clinical trials to extend breast cancer survival and help prevent breast cancer recurrence. CHALLENGES IN STUDYING OR INDUCING LIFESTYLE CHANGES IN PATIENTS Many speakers and workshop participants noted obstacles to inducing potential cancer risk-reducing lifestyle changes in patients, as well as ways to overcome those obstacles.
From page 53...
... Wadden suggested several measures to improve adherence to weight loss interventions, including portion control, group treatment, and ongoing contact with health care providers or other professionals. He said diets that provide a fixed amount of food with known calorie content are critical because, for example, "If you consume a Slim Fast or Boost shake, you know you are getting 200 to 220 calories and when the can is empty, your lunch is over and it is time to stop eating." Similar results can be achieved by using frozen food entrees, such as Lean Cuisine, he added.
From page 54...
... . He suggested teaching patients to maintain their weight loss by weighing themselves regularly, engaging in high levels of physical activity, and continuing to eat a low-calorie diet.
From page 55...
... One study found that wellness instructors at the YMCA induced a 6 percent weight loss in participants at 1 year, which is near what the DPP trial was able to achieve. But the YMCA treatment cost $300 per patient, compared to $1,400 per patient treated similarly at academic medical centers (Ackermann et al., 2008)
From page 56...
... Dr. McTiernan noted several studies that found that group plus individual diet and/or exercise interventions had greater effectiveness, in terms of weight loss, in breast cancer survivors than individual interventions alone, and the least effective were home-based interventions (Table 2)
From page 57...
... TABLE 2 Weight Loss Interventions in Breast Cancer Survivors Mean Baseline % Weight Loss: % Weight Loss: Study Type of Intervention Body Mass Index N 6 Months 12 Months Djuric Individual + group 35 48 9.8 Rock (HWMS) Group + phone 31 85 7 (4 mos.)
From page 58...
... Ganz pointed out that most cancer patients are older, overweight, and with comorbidities that would benefit from weight loss and/or increased exercise. Consequently, there is a valid need to encourage health promotion in cancer survivors.
From page 59...
... There is also the potential that weight loss and/ or physical activity might prevent the occurrence of secondary cancers for which cancer survivors are at increased risk, especially if they have certain hereditary forms of cancers, Dr. Ganz pointed out.
From page 60...
... In addition, she noted not enough is known about combination therapy to counter obesity effects, such as weight loss combined with metformin or hormonal therapy, nor is enough known about the additive effects of physical activity in addition to losing weight.
From page 61...
... Alternatively, researchers could develop better markers for rodent stem cells so they could be injected into obese mice, she added. "This would help us elucidate the links between obesity and stem cell biology," she said.
From page 62...
... Linda Nebeling, chief of the Health Promotion Research Branch at NCI, suggested more policy-specific research that addresses diet, physical activity, and other energy balance behaviors, and how such behaviors can be influenced by manipulating the environment to support lifestyles less likely to lead to obesity. She also suggested supporting more comprehensive behavioral and health outcomes research that has greater integration of biomarkers to reveal the effectiveness of certain interventions.
From page 63...
... • evelop cancer rehabilitation programs to help cancer sur D vivors stay physically active. • ncourage health insurers to cover weight loss programs E and cancer rehabilitation.
From page 64...
... The centers included scientists from multiple disciplines and encompassed projects spanning the basic biology and genetics of behavioral, sociocultural, and environmental influences on nutrition, physical activity, weight, energy balance, energetics, and cancer risk. The Coordination Center facilitated interactions across and between the Research Centers and the NCI.
From page 65...
... Dr. Ruth Patterson at the University of California, San Diego, is conducting a similar study on breast cancer survivors, although the interventions she is studying are weight loss or metformin or the combination of both.
From page 66...
... Ms. Murphy stressed that overwhelming percentages of cancer patients are willing to donate tissue, not only to their existing trials, but also for future research.
From page 67...
... Dr. Kakarala suggested focusing obesity prevention efforts in the school food environment.
From page 68...
... Dr. Wadden suggested that health insurers pay for weight loss programs.
From page 69...
... . We clearly have a disconnect here -- we have the evidence, but we are not getting people to the services that they need," she said, adding that rehabilitation programs should be part of cancer survivorship care plans.
From page 70...
... 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, progression, and cancer death for many organ sites. This is a significant public
From page 71...
... 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 influence 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 promoting policies that help prevent obesity might also have a positive impact, not just on cancer incidence, but on the well-being of cancer patients.
From page 72...
... 2010. Pre- to postoperative physical activity changes in bariatric surgery patients: Self report vs.
From page 73...
... 2008. Bariatric surgery reduces cancer risk in morbidly obese patients.
From page 74...
... 2006. Effect of physical activity and body size on survival after diagnosis with colorectal cancer.
From page 75...
... 2005. Relationship of obesity and physical activity with C-peptide, leptin, and insulin-like growth factors in breast cancer survivors.
From page 76...
... 2011. Primary care referral to a commercial provider for weight loss treatment versus standard care: A randomised controlled trial.
From page 77...
... 2011. Dietary weight loss and exercise effects on insulin resistance in postmenopausal women.
From page 78...
... 2009. Correlates of circulating C-reactive protein and serum amyloid A concentrations in breast cancer survivors.
From page 79...
... 2010. An update of controlled physical activity trials in cancer survivors: A systematic review and meta analysis.
From page 80...
... 2007. Food, nutrition, physical activity, and the prevention of cancer: A global perspective.


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