Published OnlineFirst June 13, 2012; DOI: 10.1158/1055-9965.EPI-12-0485 Cancer Epidemiology, Review Biomarkers & Prevention The Role of Obesity in Cancer Survival and Recurrence Wendy Demark-Wahnefried1, Elizabeth A. Platz2, Jennifer A. Ligibel3, Cindy K. Blair1, Kerry S. Courneya4, Jeffrey A. Meyerhardt3, Patricia A. Ganz5, Cheryl L. Rock6, Kathryn H. Schmitz7, Thomas Wadden8, Errol J. Philip9, Bruce Wolfe10, Susan M. Gapstur11, Rachel Ballard-Barbash12, Anne McTiernan15, Lori Minasian13, Linda Nebeling14, and Pamela J. Goodwin16 Abstract Obesity and components of energy imbalance, that is, excessive energy intake and suboptimal levels of physical activity, are established risk factors for cancer incidence. Accumulating evidence suggests that these factors also may be important after the diagnosis of cancer and influence the course of disease, as well as overall health, well-being, and survival. Lifestyle and medical interventions that effectively modify these factors could potentially be harnessed as a means of cancer control. However, for such interventions to be maximally effective and sustainable, broad sweeping scientific discoveries ranging from molecular and cellular advances, to developments in delivering interventions on both individual and societal levels are needed. This review summarizes key discussion topics that were addressed in a recent Institute of Medicine Workshop entitled, "The Role of Obesity in Cancer Survival and Recurrence"; discussions included (i) mechanisms associated with obesity and energy balance that influence cancer progression; (ii) complexities of studying and interpreting energy balance in relation to cancer recurrence and survival; (iii) associations between obesity and cancer risk, recurrence, and mortality; (iv) interventions that promote weight loss, increased physical activity, and negative energy balance as a means of cancer control; and (v) future directions. Cancer Epidemiol Biomarkers Prev; 21(8); 1244–59. Ó2012 AACR. Introduction past century have significantly improved our understand- The hazards of obesity were first noted by the ancient ing of the interrelationships between overweight/obesity, Greeks. Hippocrates (460–370 BC), the "Father of Medi- energy balance and cancer risk, as well as cancer recur- cine" and the first to characterize the crab-like structure of rence and survival (2). Consensus now exists that obesity cancer that he termed "karkinos," warned of the dangers of is a risk factor for cancers of the endometrium, colorectum, too much food and too little exercise (1). Almost 2 mil- kidney, esophagus, breast (postmenopause), and pancre- lennia later, Robert Thomas chronicled the link between as, and evidence continues to mount about associations obesity and endometrial cancer (2). Discoveries over the with cancers of the thyroid, gallbladder, liver, ovary, and aggressive forms of prostate cancer, as well as non- Hodgkin lymphoma (3, 4). Moreover, obesity is increas- Authors' Affiliations: 1Department of Nutrition Sciences, University of ingly recognized as a poor prognostic factor for several Alabama at Birmingham, Birmingham, Alabama; 2Department of Epidemi- common malignancies (5–8). The effects of obesity on ology, Johns Hopkins Bloomberg School of Public Health, Baltimore, cancer incidence and poor outcomes in patients with Maryland; 3Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; 4Faculty of Physical Education and Recreation, University cancer are especially worrisome in light of the obesity of Alberta, Edmonton, Canada; 5Schools of Medicine and Public Health, epidemic (9). Worldwide, estimates indicate that 1.5 bil- University of California–Los Angeles, Los Angeles; 6Department of Family and Preventive Medicine, University of California, San Diego, La Jolla, lion adults are overweight [body mass index (BMI): 25– 2 2 California; 7Department of Biostatistics and Epidemiology, 8Center for 29.9 kg/m ] and 500 million are obese (BMI 30 kg/m ; Weight and Eating Disorders, University of Pennsylvania, Philadelphia, ref. 10). Also, with the earlier onset of overweight and Pennsylvania; 9Department of Psychiatry & Behavioral Sciences, Memorial Sloan-Kettering Cancer Center, New York; 10Department of Surgery, obesity often occurring during childhood, there is con- Oregon Health and Science University, Portland, Oregon; 11Epidemiology siderable concern, as the life-time effects of obesity on 12 Research Program, American Cancer Society, Atlanta, Georgia; Applied cancer outcomes are yet unknown. Research Program, 13Community Oncology and Prevention Trials Research Group, 14Behavioral Research Program, National Cancer Insti- In a recent workshop convened by the Institute of tute, Bethesda, Maryland; 15Fred Hutchinson Cancer Research Center, Medicine’s (IOM) National Cancer Policy Forum (October Seattle, Washington; and 16Department of Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada 31–Nov 1, 2011), experts in the fields of cancer survivor- ship and obesity met to discuss converging trends and the Corresponding Author: Wendy Demark-Wahnefried, Department of Nutri- tion Sciences, University of Alabama at Birmingham, 1675 University Blvd, research gaps that exist (11). Discussions included (i) Room 346, Birmingham, AL 35294. Phone: 205-975-4022; Fax: 205-975- mechanisms associated with obesity and energy balance 2592; E-mail: [email protected] that influence cancer progression; (ii) complexities of doi: 10.1158/1055-9965.EPI-12-0485 studying and interpreting energy balance in relation to Ó2012 American Association for Cancer Research. cancer recurrence and survival; (iii) associations between 1244 Cancer Epidemiol Biomarkers Prev; 21(8) August 2012 Downloaded from cebp.aacrjournals.org on September 28, 2021. © 2012 American Association for Cancer Research. Published OnlineFirst June 13, 2012; DOI: 10.1158/1055-9965.EPI-12-0485 Obesity and Cancer Survival (especially resistance training) or decreases as with sar- Resting metabolic rate copenia resulting from cancer treatments, such as chemo- Energy needed to maintain body function at rest. Accounts therapy (13). This is important because lean body mass Energy Balance for approximately 60% to 75% of expenditure. Modified by determines RMR. This relationship is worth noting Body weight lean body mass (age), and because it is unknown whether obesity per se drives Stable external/internal temperature. Physical activity cancer progression, or whether components of energy Gain Loss Energy needed for activity. Usually accounts for balance (i.e., too much energy consumed or too little 15% to 30% of expenditure, but energy expended) have a greater impact, and which most modifiable component Thermic effect of food factors hold promise for cancer control. Calorie Intake Energy needed for digestion or Modified by ingestion and/or metabolism. Accounts for <10% absorption (e.g., changes in of expenditure. Modified Potential mechanisms by which positive energy microflora, surgery, somewhat by digestibility, pharmacologic agents) capsaicin, caffeine. balance contributes to cancer progression Energy intake Total energy expenditure All of the putative mechanisms whereby obesity drives (energy in) (energy out) the progression of cancer are not yet known; however the process is acknowledged as complex. Earlier work focused on associations between obesity and higher levels Figure 1. The complex dynamic nature of energy balance: Energy balance of free circulating sex hormones (e.g., estradiol) and their occurs when energy intake (measured in kilocalories) equals total energy impact on hormonally linked cancers (14–17), such as expenditure (RMR þ physical activity þ thermic effect of food), with gains cancer of the breast. Now a multitude of other mechan- and losses occurring when there is an imbalance. A gain of one pound isms are being elucidated. Preclinical data indicate that occurs when approximately 3,500 calories are consumed in excess of energy needs. energy balance may affect genomic instability, dysregu- lated growth signaling and cellular energetics, inhibition of apoptosis and immune surveillance, and angiogenesis obesity and cancer risk, recurrence, and mortality; (iv) (18). Moreover, myriad factors interact in an intricate interventions that promote weight loss and negative signaling network to accelerate neoplasia. Data now exist energy balance as a means of cancer control; and (v) for several factors including energy-driven signaling via future directions. A review of these topics is reported insulin, insulin-like growth factor-1 (IGF-1; cross-talk herein. with EGF), phosphatidylinositol 3-kinase, and AMP- activated protein kinase, and many other entities. Com- Energy balance ponents of insulin resistance syndrome have been well Historically, cancer has been a disease associated with studied in both breast (19–23) and colorectal cancer (24– cachexia (hypermetabolic state marked by anorexia and 31). For example, in nondiabetic breast cancer patients, profound wasting), a problem that remains today for more higher levels of fasting insulin have been associated with a advanced cancers (12). However, with more cancers diag- 2- to 3-fold increased risk of mortality (19–23, 32). Over- nosed at earlier stages when cure is possible and with the expression of insulin receptors, notably the fetal insulin discovery that more cancers are being initiated or promot- receptor (IRa) on breast cancer cells, provides a biologic edbyobesity(especially againstthebackdropoftheobesity basis for this