Introduction

The prevalence of obesity, defined as body mass index (BMI) ≥ 30 kg/m², has reached epidemic levels in the United States. Approximately one in three adults living in the United States is considered obese.¹ Obesity has long been known to increase the risk of developing a variety of health conditions, including coronary heart disease, stroke, and type 2 diabetes, and has also been associated with an increased risk of mortality, accounting for 19% of premature deaths.² More recently, obesity has also been linked to an increased risk of developing and dying from cancer. This review provides a synopsis of the most recent evidence linking obesity to cancer incidence and outcomes, discusses the obesity initiative that was recently launched by the American Society of Clinical Oncology (ASCO), and describes a novel partnership between ASCO and the American College of Cardiology (ACC) to unify and accelerate our understanding of obesity.³

Obesity and Cancer Risk

Obesity is associated with an increased risk of developing multiple types of cancer. It is estimated that up to 20% of all cancers are caused by obesity.⁴ In the past 30 years, there have been hundreds of epidemiologic studies that have examined the relationship between obesity and cancer risk. In 2016, the International Agency for Research on Cancer (IARC) concluded that obesity was associated with an increased risk of 13 types of cancer, including breast (post-menopausal), colorectal, endometrial, esophageal (adenocarcinoma), gall bladder, gastric cardia, kidney (renal cell), liver, meningioma, multiple myeloma, ovary, pancreas, and thyroid (Table 1).⁵ Evidence also suggests that weight gain during adulthood is associated with an elevated risk of developing post-menopausal breast, colorectal, endometrial, kidney, and high-risk or fatal prostate cancers when compared with adults whose weight remains stable.⁶

Table 1: Obesity-Related Cancers⁵

Breast (post-menopause)

Colorectal

Endometrial

Esophageal (adenocarcinoma)

Gastric cardia

Gall bladder

Kidney (renal cell)

Liver

Meningioma

Multiple myeloma

Ovarian

Pancreatic

Thyroid

There is less evidence from observational studies regarding the relationship between weight loss and cancer risk. The best evidence to date comes from the bariatric surgery literature that shows that individuals who undergo bariatric surgery have a 27-59% lower risk of developing malignancy compared with weight- and age-matched controls who do not undergo surgery.⁷ The benefits of bariatric surgery may be limited to obesity-related cancers, such as that of the breast and endometrium, for which average risk reduction is 38% (p < 0.0001). Conversely, among non-obesity-related cancers, such as that of the lung and bladder, the benefits of bariatric surgery are much more modest at 9%; this magnitude of risk reduction is not different from individuals who do not undergo bariatric surgery (p = 0.37).⁸

Obesity and Cancer Prognosis

Obesity is also associated with an increased risk of recurrence and cancer-specific mortality among individuals diagnosed with several types of early-stage cancers.⁹ The emergence of data on obesity and recurrence and cancer-specific mortality has been more recent, relative to the data on obesity and cancer incidence. In a meta-analysis of 82 studies of breast cancer survivors, obesity was associated with a 35% and 41% increase in the risk of breast cancer-specific and all-cause mortality, respectively.¹⁰ In a meta-analysis of 18 studies of colorectal cancer survivors, obesity was associated with a 14% increase in both colorectal cancer-specific and all-cause mortality.¹¹ In a meta-analysis of 6 studies of prostate cancer survivors, each 5 kg/m² increase in BMI was associated with a 21% and 20% increase in the risk of biochemical recurrence and prostate cancer-specific mortality, respectively.¹² Though in smaller volume, there is emerging evidence that obesity is associated with death from a variety of other cancers, including esophageal, gallbladder, gastric, kidney, liver, multiple myeloma, non-Hodgkin's lymphoma, ovarian, and pancreatic.¹³ Evidence also suggests that weight gain after cancer diagnosis may increase the risk of recurrence of breast and prostate cancers.^14,15 It is noteworthy that the relationship between obesity and recurrence or cancer-specific mortality is independent of known prognostic factors such as clinicopathologic tumor features, cancer treatments, age, smoking status, and pre-diagnosis characteristics.

It is currently unknown if purposeful weight loss reduces the risk of developing disease recurrence and cancer-specific mortality among individuals diagnosed with early-stage cancer. Several large randomized trials of weight loss, physical activity, and dietary modification to prevent disease recurrence and mortality among early-stage breast cancer survivors are underway. BWEL (Breast Cancer Weight Loss Study) is a randomized phase III trial being conducted in the United States and Canada to determine the efficacy of weight loss on invasive-disease-free survival among 3,136 early-stage breast cancer survivors with a baseline BMI ≥ 27 kg/m². Two trials in Europe will also examine how lifestyle modification influences breast cancer recurrence and survival. The SUCCESS C (Docetaxel Based Anthracycline Free Adjuvant Treatment Evaluation, as Well as Life Style Intervention) trial will examine weight loss, and the DIANA-5 (Diet and Androgens) trial will examine a Mediterranean diet and physical activity.^16,17 Several other large lifestyle trials are being conducted in other cancer sites. The LIVES (Lifestyle Intervention for Ovarian Cancer Enhanced Survival) trial will examine the impact of diet and physical activity on progression-free survival among women with advanced ovarian cancer.¹⁸ The CHALLENGE (Colon Health and Life-Long Exercise Change) trial will examine how moderate-intensity physical activity may reduce the risk of recurrence and mortality among colon cancer survivors.¹⁹ The INTERVAL (Intense Exercise for Survival Among Men With Metastatic Castrate-Resistant Prostate Cancer) trial will examine how vigorous-intensity aerobic and muscle strengthening can prolong overall survival in men with advanced prostate cancer.²⁰ Together these clinical trials will clarify the role of lifestyle modification in the management of cancer.²¹

Biologic Mechanisms Linking Obesity and Cancer

The specific biologic mechanisms that link obesity to cancer risk and prognosis have not been completely elucidated. Obesity is often characterized by the presence of low-grade systemic inflammation, perturbations in sex steroid signaling, and elevated concentrations of insulin/insulin-like growth factors.²² It is hypothesized that these obesity-related metabolic abnormalities create a host environment that may promote malignant cell growth and progression. The 2016 IARC review concluded that there is strong evidence to implicate inflammation and sex steroid signaling and moderate evidence to implicate insulin/insulin-like growth factors as physiological mediators in the relationship between obesity and cancer risk and prognosis.⁵ Research is needed to validate intermediate physiological biomarkers of cancer risk and prognosis to expedite future studies. This approach has the potential to rapidly advance obesity and cancer research, just as hypertension and hyperlipidemia accelerated research for cardiovascular disease.

The ASCO Obesity Initiative

In 2013, ASCO launched an initiative focused on obesity and cancer. Key goals of the initiative follow:

• Increasing awareness of the evidence linking obesity and cancer
• Providing tools and resources to help oncology providers address obesity with their patients
• Building and fostering a robust research agenda to study the relationship between obesity and cancer and the impact of weight-management programs on cancer outcomes
• Advocating for policy and systems change to increase access to weight-management programs for cancer survivors²³

To date, this initiative has facilitated the development of patient and provider resources to promote healthy weight management, worked to build awareness of the relationship between obesity and cancer in the oncology community, and developed a set of recommendations for future obesity research in cancer populations (Table 2).²⁴

Table 2: Key Priority Areas, Ongoing and Planned Activities, and Products From the ASCO Obesity and Cancer Initiative³

Priority Area	ASCO Ongoing and Planned Activities and Products
Education and Awareness	Develop curriculum to highlight the role of obesity/diet/physical activity as an essential component of cancer prevention Integrate educational sessions on obesity at ASCO meetings and forums Develop a special series in the Journal of Clinical Oncology focused on obesity and cancer (to appear in fall of 2016) Develop a comprehensive set of resources for patients on weight management, diet, and physical activity (available at www.cancer.net)
Clinical Guidance, Tools, Resources	Develop and promote obesity toolkits: Obesity and Cancer: A Guide for Oncology Providers Managing Your Weight After Cancer Diagnosis: A Guide for Patients and Families
Promotion of Research	Host summit on obesity clinical trials to foster collaboration among obesity researchers and establish a common set of research priorities Advocate for increased funding for research in key areas Promote obesity research through various foundation and philanthropic agencies Increase oncologist awareness of the need for patient participation in obesity research studies
Policy, Advocacy	Advocate for workplaces and communities to decrease obesity Promote coverage and access to obesity screening, diagnosis, and treatment services Encourage Centers for Medicare & Medicaid Services to add obesity to chronic diseases eligible for the Complex Chronic Care Management Services payments Encourage the Department of Health and Human Services to explicitly define access to obesity treatment services in new health care exchange plans Encourage coverage and reimbursement for efficacious interventions in the cancer population to reduce cancer recurrence as evidence becomes available

The next phase of the ASCO Obesity and Cancer Initiative will focus on building partnerships with other groups that are engaged in provider education, public awareness, and research and advocacy in obesity-related areas. As part of this endeavor, ASCO assembled a work group in early 2016 focused on addressing obesity through multidisciplinary collaboration. It includes members from 17 other medical professional organizations, and its goal is to develop guidance to inform how these distinct organizations can work jointly to reduce the public health burden of obesity. A white paper summarizing recommendations from this meeting is currently in development. As another part of its collaborative efforts, ASCO established a work group with the ACC in 2015 with the goal of leveraging the unique strengths of oncology and cardiology to deal with common problems, such as the cardiotoxicity of oncology agents, and common risk factors, such as obesity.³ It was agreed that both specialties could benefit from better evidence regarding the implementation of weight-management interventions into the clinical care setting. This joint work group will develop educational curricula, publish position articles and guidelines, and repurpose existing disease registries to identify and characterize care patterns and outcomes over time. The successful partnership between ASCO and ACC established a productive platform on which to broaden partnerships.

Conclusion

Obesity is a risk factor for developing and dying from multiple forms of cancer. Obesity is a complex, multifactorial public health problem that will require carefully coordinated efforts from various medical and research specialties to generate, translate, and disseminate research; educate stakeholders; and refine policy practices. These coordinated efforts will require significant time and effort on the parts of many organizations, but investments such as these are necessary to overcome the enormous health burden that obesity places upon our society.

References

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Keywords: Adenocarcinoma, Androgens, Anthracyclines, Biomarkers, Body Mass Index, Cardiotoxicity, Chronic Disease, Breast Neoplasms, Colonic Neoplasms, Colorectal Neoplasms, Coronary Disease, Diabetes Mellitus, Type 2, Hyperlipidemias, Hypertension, Meningioma, Obesity, Prostatic Neoplasms, Ovarian Neoplasms, Risk Factors, Risk Reduction Behavior, Smoking, Somatomedins, Stroke, Weight Gain, Weight Loss

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