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Neal Freedman: Investigating the Role of Lifestyle and Metabolism in Cancer

November 2013 - Linkage Newsletter

by Wendy Schneider-Levinson

If you ask Neal D. Freedman, Ph.D., M.P.H., how he became an epidemiologist, he’ll tell you that he started out far from that discipline. Neal D. Freedman, Ph.D.In fact, Dr. Freedman earned his Ph.D. in biomedical sciences, and he initially worked in a molecular biology and biochemistry laboratory. “As I went along in the Ph.D. process,” he said, “I realized that I wanted to do something more directly related to human health.”

After many Google searches and lots of networking, he eventually learned about the Cancer Prevention Fellowship Program at NCI, which is designed to train individuals with diverse backgrounds in the field of cancer prevention and control. Dr. Freedman joined the program in 2004 and earned a master’s degree in public health at the Harvard School of Public Health in Boston, Massachusetts. In 2005, Dr. Freedman joined the Nutritional Epidemiology Branch (NEB), where he received an in-depth introduction to epidemiology and biostatistics from NEB mentors Christian C. Abnet, Ph.D., M.P.H., and Sanford M. Dawsey, M.D.

Since becoming a tenure-track investigator in NEB in 2009, Dr. Freedman has conducted multidisciplinary epidemiologic studies on the roles of lifestyle and metabolism in cancer, concentrating on three areas: liver cancer, gastrointestinal (GI) diseases and hormones, and tobacco products.

Exploring the Risk of Liver Cancer

Liver cancer is the third leading cause of cancer-related mortality worldwide and has poor five-year survival. Incidence rates of liver cancer have increased substantially in the United States, tripling over the past 30 years. Although much of this increase is likely due to infection with the hepatitis C (HCV) virus, scientists believe that other risk factors are also important.

While serving as an NCI fellow, Dr. Freedman became interested in the numerous hypotheses linking metabolism, diet, and lifestyle to liver cancer. Since becoming a tenure-track investigator, he has evaluated a number of these hypotheses in collaboration with Katherine A. McGlynn, Ph.D., M.P.H., Deputy Chief of the Hormonal and Reproductive Epidemiology Branch, and other researchers, leveraging complementary studies to address the following three key challenges:

  1. Because liver cancer has a poor survival rate and occurs in a metabolically essential organ, it is important to conduct prospective studies that assess exposure to liver cancer risk factors prior to cancer diagnosis. However, most prospectively conducted studies include few cases of liver cancer. 
  2. Existing studies often lack assessment of hepatitis B and C viruses (HBV and HCV), which are strong risk factors for liver cancer.
  3. Finally, liver cancer tends to occur among individuals with chronic underlying liver disease, which most likely affects their lifestyle and metabolism; however, gaining information about the early stages of liver disease in the general population is difficult.

In his research, Dr. Freedman has used the very large NIH-AARP Diet and Health Study, which includes more than 600 incident liver cancers but lacks biological samples, along with smaller cohorts that have biological samples—such as the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study; the Linxian Nutrition Intervention Trials in China; and the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial—in which he can assess the important risk factors of HBV and HCV. Using data from the ATBC Study, Dr. Freedman has been investigating the association of serum levels of insulin and glucose with subsequent risk of liver cancer, controlling for other liver cancer risk factors including HBV, HCV, excessive alcohol intake, and tobacco smoking.

Dr. Freedman also has taken advantage of the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial, funded by the National Institute of Diabetes and Digestive and Kidney Diseases, which includes repeat liver biopsies and detailed clinical information on liver disease in a cohort of HCV-positive patients. Using these resources, Dr. Freedman has made several novel findings.


Within the HALT-C Trial, Dr. Freedman found that coffee drinkers were more likely to respond to HCV therapy (Gastroenterology 2011) and less likely to progress toward end-stage liver disease, including liver cancer (Hepatology 2009). These associations were independent of both clinical and histologic markers of underlying liver disease, providing strong evidence that previously observed associations between coffee and liver cancer were not due to reverse causality. These and other observations led Dr. Freedman, in collaboration with Rashmi Sinha, Ph.D., Deputy Chief of NEB, and other researchers, to conduct an analysis within the NIH-AARP cohort, in which they found that coffee was inversely associated with overall mortality and several major causes of death (N Engl J Med 2012).

“Being willing to follow and study the unexpected is a large part of what it takes to conduct high-risk, high-impact research.”

Dr. Freedman is now focusing on improving the assessment of coffee and its effect on health. He is investigating which of the 1,000+ compounds comprising coffee may be beneficial to humans, and by what mechanism, and whether the methods of preparation (e.g., boiled, filtered, espresso) affect possible health effects.

Red and White Meat

Meat intake is another potentially important cause of liver cancer. Dr. Freedman found evidence in the NIH-AARP study of inverse associations between intake of white meat and subsequent liver cancer but positive associations between intake of red meat and of saturated fat and the development of liver cancer (J Natl Cancer Inst 2010).

The GI System and the Role of GI Hormones in Cancer

The GI system is a major metabolic and endocrine organ. Disorders of the GI system can increase the risk of certain diseases, including cancers that grow locally in the GI tract. However, a growing body of evidence suggests that disorders of the GI system also may affect the risk of cancers occurring elsewhere in the body.

Relatively few studies have systematically examined the associations of GI disorders with different cancer types. Because these conditions are often uncommon, scientists must evaluate such associations within very large studies. Using NCI’s Surveillance, Epidemiology and End Results (SEER)-Medicare program, which links cancer data from SEER registries with claims data from Medicare, Dr. Freedman, in collaboration with Eric A. Engels, M.D., M.P.H., Infections and Immunoepidemiology Branch (IIB), and other scientists, has evaluated the associations between GI disorders, such as diabetes, pernicious anemia, and ulcers, with cancers both inside and outside of the GI tract.

In addition, while hormones in the GI tract are essential for metabolism and for maintaining homeostasis in response to environmental changes, the role of GI hormones in cancer is largely unstudied. Using data from the ATBC Study, Dr. Freedman and his colleagues, in particular Gwen Murphy, Ph.D., M.P.H. (NEB), observed that low circulating levels of ghrelin, a hormone produced in the stomach, were associated with an increased risk of gastric cancer as well as with increased risks of esophageal cancer J Natl Cancer Inst 2011, Gut 2012). Dr. Freedman plans to continue examining ghrelin and cancer in other study populations and will investigate other GI hormones, including gastrin and cholecystokinin.

Tobacco Use and the Future Risk of Cancer

Dr. Freedman’s third focus of research is on tobacco use and the way that tobacco has continued to affect cancer risk as use patterns and tobacco products themselves have changed (see The Changing Role of Tobacco in Cancer, in this issue). For example, in the United States, women now start smoking tobacco at a similar age as men do and smoke similar amounts as well, such that now women and men have similar risks for mortality and many cancers, including lung cancer (Lancet Oncol 2008, N Engl J Med 2013) and bladder cancer (JAMA 2011).

Scientists have found that filtered and low-tar cigarettes, which have been touted to reduce carcinogenicity, may actually have a higher concentration of certain carcinogens. In addition, new types of tobacco and tobacco-related products, such as flavored mini cigars, electronic cigarettes, and hookah (water pipes), are becoming popular among young adults, who do not necessarily regard these products as carcinogenic.

Some of these new products have characteristics that differ from those of traditional cigarettes, and Dr. Freedman is investigating ways to evaluate the products‘ carcinogenicity. For example, he is working with Meredith Shiels, Ph.D., and Anil K. Chaturvedi, Ph.D., and other colleagues in IIB to evaluate circulating inflammatory markers as possible biomarkers of tobacco use. In addition, Dr. Freedman is working with Dr. Abnet, Dr. Chaturvedi, and other scientists to characterize the impact of different tobacco products on the oral microbiome of participants in the National Health and Nutrition Examination Survey, a project funded by a competitive grant from the U.S. Food and Drug Administration’s Center for Tobacco Products.

Mentoring Activities

Training and mentoring fellows is a responsibility that Dr. Freedman not only enjoys but also takes quite seriously, as evidenced by his receiving the DCEG Outstanding Mentor Award in 2011, an honor bestowed by the fellows themselves. “I try to counsel the fellows I mentor to build some time into their research schedules so that if an unexpected or unusual result shows up in a study, they can explore it to see where it leads,” Dr. Freedman said. “Science is fun and the most intriguing results are often unexpected. Being willing to follow and study the unexpected is a large part of what it takes to conduct high-risk, high-impact research.”

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