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Cancer Risk Among Immunosuppressed Populations

, by Alyssa M. Voss, M.P.H.

Since the influence of the HIV epidemic on cancer was first observed in the 1980s, investigators in the Infections and Immunoepidemiology Branch (IIB) have examined how oncogenic viruses and other opportunistic infections affect individuals with compromised immune systems. Today, DCEG’s research portfolio on cancer among immunocompromised patients involves two distinct, yet related, study populations: (1) organ transplant recipients and (2) HIV-infected individuals and persons with AIDS. Organ transplants have increased in recent decades for certain organ types (see Figure 1), and recipients must take immunosuppressive drugs for the remainder of their lives to prevent organ rejection. Both groups provide valuable populations in which to study the interconnected roles of infections, environmental exposures, inflammation, and the immune response in the development of cancer. DCEG senior investigator Eric A. Engels, M.D., M.P.H. (IIB), leads the Transplant Cancer Match (TCM) Study and the HIV/AIDS Cancer Match (HACM) Study, two large and complementary registry linkage studies on cancer among immunosuppressed populations.

Transplant-related Immunosuppression and Cancer

More than five years ago, Dr. Engels met with officials from the Health Resources and Services Administration (HRSA), the Department of Health and Human Services agency that oversees the U.S. organ transplant program, to discuss the creation of a resource linking the U.S. transplant registry with multiple cancer registries. “It was an exciting opportunity to take an unprecedented look at the cancer burden among solid organ transplant recipients,” Dr. Engels noted, “but it was also daunting because of the logistics involved in getting all the approvals from the cancer registries.” It took six years to get the study off the ground, but the efforts were well worth the time. The TCM Study now combines data from HRSA’s Organ Procurement and Transplantation Network and 15 population-based state or regional cancer registries, making it the largest study of its kind.

Dr. Engels and other TCM Study researchers published the study’s first article, which provides the most comprehensive description to date of the cancer burden among solid organ transplant recipients, in the November 2011 issue of the Journal of the American Medical Association. The authors assessed linked registry data from 175,732 solid organ transplant recipients, who represented roughly 40 percent of the U.S. transplant recipient population between 1987 and 2008, and measured the risk of individual cancer types among recipients of all types of organs. The researchers found a twofold increased risk of cancer among transplant recipients. This finding confirmed results from earlier, smaller studies, but the large size of the TCM Study also allowed the investigators to evaluate the risk of rare cancer types.

“We were surprised to find that this population is at increased risk for a large number of different cancers—32 different types of cancer, including some that we don’t commonly associate with HIV and immunosuppression,” Dr. Engels noted. For example, the four most common cancers among transplant recipients and that occur more commonly in these individuals than in the general population were non-Hodgkin lymphoma (NHL) and cancers of the lung, kidney, and liver. NHL also is common among HIV-infected individuals and is associated with immunosuppression and Epstein-Barr virus, whereas liver cancer is associated with hepatitis B and C. However, researchers do not generally believe that lung and kidney cancers are associated with infection.

Having such a large, valuable resource as the TCM Study also permits swift follow-up studies on interesting leads. For example, Todd M. Gibson, Ph.D., a postdoctoral fellow, and Lindsay M. Morton, Ph.D., an investigator, both in the Radiation Epidemiology Branch, conducted an analysis of diffuse large B-cell lymphoma, a common and highly aggressive form of NHL. They observed an almost 14-fold elevation in the risk of this NHL subtype among transplant recipients compared with the general population. Dr. Gibson recently presented the findings of this study at the 2012 Annual Meeting of the American Association for Cancer Research.

Dr. Engels and his team plan to pursue these leads in order to characterize the proportion of cancers related to infection and impaired immune response as well as to shed light on other possible mechanisms, especially for cancers not linked to infection. 

HIV and Cancer

DCEG’s HACM Study is an example of a unique resource that has permitted the examination of cancer trends among the HIV and AIDS population over time. James J. Goedert, M.D. (IIB), and Dr. Robert Biggar (formerly of DCEG) initiated the HACM Study in 1990. The study now links data from 14 state and metropolitan HIV/AIDS registries across the United States with corresponding cancer registries. DCEG researchers have been able to show how AIDS-related cancer trends in the United States have changed since the HIV epidemic began, including the impact of the introduction of highly active antiretroviral therapy in 1996, through the mid-2000s. Over this time, individuals with HIV have experienced dramatic improvements

in survival and are now reaching ages when cancer is commonly diagnosed. The population of U.S. residents living with HIV quadrupled between 1991 and 2005, and the average age of this group has risen substantially. Recent DCEG work is focusing on the long-term effects of chronic HIV infection and the ways in which cancer affects individuals with HIV as they age.

Meredith Shiels, Ph.D., a research fellow in IIB, recently described the new landscape of cancer risk and burden among the HIV-infected population in the United States (Journal of the National Cancer Institute, May 2011, see Figure 2). Based on an analysis of data from the HACM Study, she showed that the number of AIDS-defining cancers (Kaposi sarcoma, NHL, and cervical cancer) has declined threefold (from 34,580 to 10,320 cases), while the number of other non–AIDS-defining cancers has tripled (from 3,200 to 10,000 cases). “We know that some of the more common non–AIDS-defining cancers diagnosed in this population are due to viral co-infection, such as hepatitis B or C viruses or human papillomavirus, or are related to smoking, which is much more common among the HIV/AIDS population than the general U.S. population,” said Dr. Shiels. “The results underscore the magnitude of the cancer burden that will continue to rise as this population ages and the need for surveillance and screening grows.”

To define these trends further, Drs. Engels and Shiels are working with Ruth M. Pfeiffer, Ph.D., Biostatistics Branch, and other scientists to take a closer look at how HIV has influenced overall cancer rates in the general population. They recently estimated that 28 percent of anal cancer cases in men and 1 percent of cases in women in the United States between 2001 and 2005 occurred among the HIV-infected population. Anal cancer is rare in the United States, but its rates have been rising steadily for several decades. The large size of the HACM Study allowed investigators to estimate general population incidence rates with and without HIV-infected cases and to show for the first time that the rates of anal cancer over time in men have been influenced substantially by HIV-infected cases.

Examining cancer trends in large registry-based resources has been critical for understanding cancer risk in immunosuppressed populations in the United States, Dr. Engels stated. “There’s still a lot we’re trying to learn about what’s driving the increased risk for certain cancers, and hopefully we can identify mechanisms so that the cancer risks in these populations can be minimized.”

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