Researchers at the University of California, Los Angeles have defined conditions associated with disabling fatigue that persists for years in almost a third of breast cancer survivors, according to a study in the May 1 issue of Clinical Cancer Research.

The key to their fatigue stems from responses within their immune systems.

“These studies identify a biological basis for persistent fatigue in cancer survivors that is implemented by inflammation,” said Michael Irwin, M.D., director and senior research scientist, Cousins Center for Psychoneuroimmunology, UCLA Semel Institute for Neuroscience, and the UCLA Jonsson Cancer Center.

“We have detected a biological marker that is a composite of two immune response elements,” he added. “This biomarker identifies -  and can predict -  which women have long term persistent fatigue.

“These findings point the way for development of novel treatment strategies that decrease this inflammatory response and thwart the fatigue that these patients endure.”

One component of the marker, Dr. Irwin explained, is a measure of the amount of interleukin-6 receptor (IL-6R) free-floating in the blood of breast cancer survivors compared to the amount of that receptor remaining on the membranes of specific blood cells -  where the receptor normally is found and functions within the immune response.

The IL-6R is usually embedded on the surface membrane of white blood cells, or monocytes. In some survivors, however, many of the IL-6R are shed from the monocytes and are soluble within the blood plasma. Those free-floating receptors can still bind to circulating cytokine IL-6, Dr. Irwin noted, and in that form have the potential to interact with cells that normally don’t respond to cytokine/receptor activation -  such as brain cells that may regulate fatigue sensation.

IL6 is a biological chemical that helps drive initial immune responses within people. “IL-6 contributes to an activation of monocytes in the blood, and enables antigen presenting cells to activate T cells as part of the cellular immune response,” Dr. Irwin said.

The second component of the marker is an index measured by the level of T cells that are characterized by CD69, a cell membrane protein that indicates early activation of those T cells. Patients with a decreased number of CD69+ T cells along with the high ratio of serum IL-6R/monocyte-bound IL-6R were likely to experience persistent fatigue.

Battling breast cancer is a daunting challenge to women diagnosed with the disease, but with advanced screening and treatment strategies, patients with early stage breast cancer are surviving longer. Breast cancer survivors are the largest group of patients to overcome any type of cancer in the United States. While patients surviving other types of cancer also can experience the long-lasting fatigue syndrome, a greater proportion of breast cancer survivors endure the condition.

Cancer researchers had explored various possible reasons for the persistent fatigue in breast cancer survivors, Dr. Irwin said, such as different kinds of treatment, or biological events including anemia.

Dr. Irwin and his colleagues’ research is the first to document an association between biological mechanisms involved with the immune response and persistent fatigue.

“It is such an important quality of life issue. Many patients are surviving from their cancer treatments, but they are surviving with substantial impairments in their ability to carry on their lives,” Dr. Irwin said. “We’ve addressed the cancer in these survivors, and now we can also address the functional declines in the quality of life of these patients.”

Dr. Irwin defined the fatigue biomarker in collaboration with Alicia Collado-Hidalgo, Julienne E. Bower, Patricia A. Ganz, and Steve W. Cole, with the David E. Geffen School of Medicine at UCLA.

The mission of the American Association for Cancer Research is to prevent and cure cancer. Founded in 1907, AACR is the world’s oldest and largest professional organization dedicated to advancing cancer research. The membership includes more than 24,000 basic, translational, and clinical researchers; health care professionals; and cancer survivors and advocates in the United States and more than 60 other countries. AACR marshals the full spectrum of expertise from the cancer community to accelerate progress in the prevention, diagnosis and treatment of cancer through high-quality scientific and educational programs. It funds innovative, meritorious research grants. The AACR Annual Meeting attracts more than 17,000 participants who share the latest discoveries and developments in the field. Special Conferences throughout the year present novel data across a wide variety of topics in cancer research, treatment, and patient care. AACR publishes five major peer-reviewed journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Epidemiology, Biomarkers & Prevention. Its most recent publication, CR, is a magazine for cancer survivors, patient advocates, their families, physicians, and scientists. It provides a forum for sharing essential, evidence-based information and perspectives on progress in cancer research, survivorship, and advocacy.