The Double Whammy of the Obesity Epidemic: Increased Susceptibility to Cancer

Cancer. When we first think of the disease, genetics and environmental factors spring to mind. However, obesity, the other epidemic that faces the United States, has also been associated with an increased risk of numerous cancers (Figure 1). A National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) data study classified 4% of new cancer cases in men and 7% in women in 2007 to be a result of obesity.¹

Although the actual percentages of cases varied for different cancers, endometrial and esophageal cancers had the highest numbers. According to the study, even a small reduction (1%) in the body mass index (BMI) of every adult could reduce the incidence of new cancer cases by about 100,000.¹ Interestingly, although associated with an increased risk of developing such malignancies as colorectal cancer, esophageal adenocarcinoma, cancers of the gallbladder, pancreas, liver, kidney, and thyroid, non-Hodgkin lymphoma, multiple myeloma, ovarian cancer, and prostate cancer, the development of a few cancers including lung cancer, premenopausal breast cancer, and esophageal squamous cell carcinoma have been inversely associated with obesity.²

Not only are obese patients at an increased risk of developing malignancies, they have also been found to be at a significantly greater risk of dying due to the malignancy. A prospective study published back in 2003 on a large cohort (more than 900,000 adults) demonstrated that among heavy patients, with a BMI of at least 40 kg/m², death from cancer was 52% higher among men and 62% higher among women compared with their corresponding “normalweight” controls. These results, determined based on a 16-year follow-up period, identified the cancers carrying the highest risk of obesity-associated cancer death as liver and pancreatic cancer in men and uterine, kidney, and cervical cancer in women.³

Two studies that drive in the nail on the link between obesity and cancer were conducted in Sweden and in the United States. The Swedish prospective study evaluated the outcomes of bariatric surgery in 2010 patients compared with 2036 controls, after a median follow-up of 10.9 years, and identified a 40% reduction in cancer incidence.⁴ A retrospective study conducted in a single clinic in Utah that compared 7925 patients who had undergone bariatric surgery with 7925 matched controls during a follow-up period of 7.1 years revealed a 60% decrease in cancer mortality associated with bariatric surgery.⁵

Acknowledging the rise in evidence for obesity as a risk factor for cancer and other diseases, payers have recognized that a healthy body weight can reduce the incidence and complications of various diseases, which in turn would reduce medical costs and improve productivity. Mechanism of the Increased Risk Research delving into the molecular basis for the increased association of obesity with cancer risks has provided several leads. These include molecules such as estrogen, insulin, insulin-like growth factor-1, and adipokines (Figure 2). Additionally, chronic low-level inflammation, oxidative stress, and altered microbiomes are risk factors for cancer observed in obese individuals.^1,5

Breast cancer

Overweight and obese women who have not been exposed to hormone therapy develop a modest risk of postmenopausal breast cancer for estrogen and progesterone receptor—expressing tumors due to an increased level of estrogen production, but are at a reduced risk of premenopausal breast cancer. Following menopause, the ovaries stop estrogen production and the fat tissue becomes the primary source of the hormone. Obese women, with more fat tissue, have higher estrogen levels, resulting in a rapid growth of estrogenresponsive tumors.¹

A study recently presented by researchers from the German Breast Group, Neu-Isenburg, Germany, at the 9th European Breast Cancer Conference held in Glasgow, Scotland, reported that a high BMI is an adverse determinant of survival without recurrence or metastasis. However, the study, conducted in 11,000 patients with early breast cancer treated with neoadjuvant therapy, reported that HER2-positive patients did not have obesity as a risk factor. Another issue raised by the study is that obese patients were observed to have received a lower dose of chemotherapy due to a dose cap resulting from a fear of overdosing.

But this could result in a lower quality of chemotherapy in that population, which could stem a relapse.⁶ At the molecular level, a link between high caloric intake and altered breast cancer gene 1 (BRCA1) transcription has been discovered. BRCA1 plays a very important role in DNA repair, cell cycle regulation, and transcriptional regulation, and mutations or altered expression of the protein have been shown to be detrimental to the cell, leading to increased proliferation, chromosomal instability, and tumorigenesis. The transcriptional corepressor C-terminal—binding proteins (CtBP1 and CtBP2) are a part of the transcriptional machinery that binds to the BRCA1 promoter and represses expression of the gene. High caloric intake and obesity were found to disrupt the NAD+/NADH ratio, resulting in increased CtBP activity and subsequently a reduced expression of BRCA1.⁷

Colorectal cancer

Studies conducted in Europe have identified obesity as the root cause of 11% of colorectal cancer cases. Obese men seem particularly at risk, with studies showing that obesity is associated with a 30% to 70% increased risk of colon cancer in men.⁸ A high dietary glycemic load, a known risk factor for obesity, was found to be significantly associated with an increased risk of recurrence and mortality in stage 3 colon cancer patients.⁹ The prospective, observational study was conducted in 1011 stage 3 colon cancer patients receiving adjuvant chemotherapy.

The patients reported their dietary consumption during, and 6 months after, participation in the chemotherapy trial, and the impact of their glycemic load, glycemic index, fructose, and carbohydrate intake on cancer recurrence and mortality was evaluated. Significantly, the increased risk of recurrence and death with higher dietary glycemic load and total carbohydrate was primarily observed in overweight and obese patients.

A recently published study in the journal Cell Metabolism, by scientists at the National Institute of Environmental Health Sciences, identified an important role of the gene NAG-1, known to protect against colon cancer, in preventing weight gain in mice fed a high-fat diet. The scientists generated mice that expressed human NAG-1, while the control mice did not. When fed the same high-fat diet, the NAG-1—expressing mice stayed lean while the controls grew plump. Further, cells isolated from the colon of the obese mice showed altered patterns of histone acetylation, a sign of cancer progression.¹⁰

Pancreatic cancer

BMI has also been identified as a risk factor for pancreatic adenocarcinoma (PAC), the 13th-most common cancer and the 8th-leading cause of cancerrelated death in the world. Overweight or obese individuals were observed to have an increased risk of PAC, and an earlier age of onset. Further, overweight or obese older patients were also at an increased risk of dying due to the disease.¹¹

Genetic factors that regulate obesity have also been found associated with PAC. NR5A2 plays an important role in lipid and glucose metabolism, improving glucose uptake, and regulating cholesterol transport, and a significant association between NR5A2 gene variants and a decreased risk of pancreatic cancer has been identified.¹²

The Healthcare Aspect

Although Medicaid programs in most states and Medicare do not cover weight loss drugs,¹³ screening and counseling for obesity are covered by Medicare.¹⁴ Further, most private insurance companies will be forced to cover their patients’ weight loss efforts thanks to the Affordable Care Act.¹⁴

Early this year, Aetna announced the launch of a program to assess the influence of weight loss and other lifestyle improvement tools to lower medical costs, improve health outcomes, and increase workplace productivity. The agenda includes a pilot program geared for self-insured plan sponsors to evaluate 2 FDA-approved (in 2012) prescription weight loss drugs, Belviq and Qsymia, among high-risk members. Results from this pilot are expected by the end of 2014.¹⁵

When contacted for comment, Edmund Pezalla, MD, MPH, national medical director for pharmacy policy and strategy at Aetna, said in an e-mail response: “Yes, there are epidemiologic data to suggest that obesity increases the risk of cancer. We don’t know if treating obesity will reduce that risk (ie, by the time you treat, has something changed in the patient’s biology?).

We are not promising or counting on reducing cancer risk as a return on our program.” He went on to say, “Our program will not go on long enough or with enough patients to determine the reduction in risk from weight loss for many important factors, but from the existing literature we do expect to see some results:

• Short term: reduced use of medications and other improvements in the control of diabetes, high blood pressure, and cholesterol;

• Medium term: reduction in need for bariatric surgery and treatment of some other weight related disorders like gastroesophageal reflux; and

• Long term (and beyond the scope of our projects): reduction in patients progressing to diabetes, cardiac events, and other weight-related problems like need for joint replacement.”

Organizational Efforts to Combat Obesity as a Risk Factor for Cancer

The Obesity Society, based in Silver Spring, Maryland, is actively working at combating obesity, with the aim of confronting the associated comorbidities, including cancer. The society launched the Treat Obesity Seriously campaign last year to educate policy makers on the need to recognize obesity as a serious condition and provide clinicians with useful diagnostic tools.¹⁶ The society also serves as a platform to promote collaborations among members to boost cancer-obesity research at the molecular, clinical, and epidemiological levels, and to communicate the resulting information to professional and lay audiences.¹⁷

This could prove an important step in obesity prevention efforts, especially with evidence of the associated disease risks in obese individuals, including but not limited to chronic conditions such as diabetes, cardiovascular disease, and cancer. Especially for cancer, improvements in research strategies, such as the development of biologicals, have seen a rapid increase in drug prices as well as the associated treatment costs (Figure 3). It’s a bubble that is rapidly expanding and could burst anytime.

With this realization, redirecting efforts to prevent disease onset and regulating the associated risk factors is of the essence.References

1. Obesity and cancer risk (fact sheet). National Cancer Institute website. http://www.cancer.gov/cancertopics/factsheet/Risk/obesity. Accessed April 17, 2014.

2. Berger NA. Obesity and cancer pathogenesis. Ann NY Acad Sci. 2014;1311:57-76. 3. Calle EE, Rodriguez C, Walker-Thurmond W, 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.

4. Sjöström L1, Gummesson A, Sjöström CD, et al. Effects of bariatric surgery on cancer incidence in obese patients in Sweden (Swedish Obese Subjects Study): a prospective, controlled intervention trial. Lancet Oncol. 2009;10:653-662.

5. Adams TD, Gress RE, Smith SC, et al. Longterm mortality after gastric bypass surgery. N Engl J Med. 2007;357:753-761.

6. Obesity and diabetes have adverse effects on outcomes across different tumour types and should be taken into account when planning breast cancer treatment. European Cancer Organisation website. http://www.ecco-org.eu/Global/News/EBCC9-PR/2014/03/Fontanella-Obesity-and-diabetes-have-adverseeffects-on-outcomes-across-different-tumour.

aspx. Published March 20, 2014. Accessed April 15, 2014.

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