Breast Cancer Survivors with Fatigue have Immune Systems that Fail to Shut Down

UCLA<br>Michael Irwin

Breast cancer survivors who suffer from persistent, debilitating fatigue years after their diagnosis have something in common: their immune systems don’t shut down following treatment, according to researchers at UCLA’s Jonsson Cancer Center.

This constant immune system activation, which researchers discovered by measuring specific proteins in blood samples from survivors, may be causing the fatigue, UCLA researchers theorize. Their discovery may lead to behavioral interventions such as tai chi and yoga that will help alleviate persistent fatigue, which affects about a third of breast cancer survivors for years after they complete treatment.

The study is the first to look at the cellular basis for immune activation in fatigued breast cancer survivors, said Dr. Michael Irwin, a researcher at UCLA’s Jonsson Cancer Center and the study’s lead author. The research appears in the May 1 issue of Clinical Cancer Research, the peer-reviewed journal of the American Association of Cancer Research.

“Without knowing why this fatigue happens at the cellular level, we can’t develop efficient therapies to treat it,” said Irwin, who also serves as director of the Cousins Center for Psychoneuroimmunology at the Semel Institute for Neuroscience and Human Behavior at UCLA.

“Breast cancer survivors can be severely disabled by fatigue and that can dramatically impact their quality of life. That’s the tragedy of our treatments for cancer,” Irwin said. “We have focused on treating the disease, but we should also focus on the patient’s well being later. Right now, we have no treatment for cancer-related fatigue and we need something that will allow patients to return to their prior level of functioning.”

Dr. Patricia Ganz, a nationally renowned expert who has studied quality of life in breast cancer survivors for two decades, agrees that fatigue is a serious problem for survivors, a fact that their primary care physicians don’t always understand.

“When breast cancer survivors talk to their physicians about being tired and how it affects their lives, they’re often told that they survived cancer, so they should be grateful to be alive,” said Ganz, one of the co-authors of the study. “But their fatigue is a very real problem that needs to taken seriously and addressed.”

A small study at UCLA had previously demonstrated abnormalities in immune activation in breast cancer survivors. If researchers could determine the biological factors underlying this activation, and therefore fatigue, they could uncover a biomarker for the condition that could help them predict which patients would suffer from fatigue and which would not, Irwin said.

Irwin and his colleagues took blood samples from breast cancer survivors one to five years out from diagnosis and placed them into two groups, those who suffered from persistent fatigue and those who did not. The researchers measured the levels of a pro-inflammatory cytokine protein in their blood – levels that indicated the immune system was turned on. Irwin said the pro-inflammatory protein levels were significantly different between the two groups. Those with persistent fatigue had 30 percent more of the proteins circulating in their blood. Additionally, their immune cells produced more cytokines in laboratory analyses than the cells from survivors without fatigue, and those cytokines were more efficient at producing the pro-inflammatory proteins driving the immune response.

“This study proved that there is an aberrant immune response in breast cancer survivors with persistent fatigue,” Irwin said. “With this information, we may now be able to identify those patients at greatest risk for persistent fatigue and implement interventions early on that will lessen the severity and duration of the fatigue.”

The immune systems of women undergoing treatment for breast cancer are activated at high levels to help them fight disease and help the body recover from the side effects of chemotherapy and radiation. Some data suggest that survivors who develop fatigue might have immune system changes before the cancer and the treatments may be exacerbating that. Further studies are needed to understand how this immune activation occurs and what clinical factors predispose to it, Irwin said

“We know from studies that animals with immune activation and cytokines circulating in their blood don’t move around a lot, they don’t eat, they don’t engage in sexual activity,” Irwin said. “From our study, we believe that the severity of fatigue in breast cancer survivors is not related to the type of treatment they received or its duration, but rather that the fatigue is driven by constant immune activation. Their immune systems simply don’t shut down after treatment.”

Irwin and his team studied 32 breast cancer survivors with persistent fatigue and compared their blood samples to 18 survivors who did not suffer from fatigue. The pro-inflammatory proteins in the blood of fatigued cancer survivors could be used as a biomarker to classify those women who may suffer from fatigue after treatment. In those who appear to be predisposed to fatigue – the women whose immune systems have not shut off as they should – it may be possible in the future to provide interventions can right away that might eliminate or, at the least, alleviate the severity and duration of the fatigue.

While there are drugs such as statins that can be used to dampen immune response, future studies by Irwin and his team will focus on behavioral interventions such as tai chi and yoga. Exercise and meditation, Irwin said, have been shown to decrease levels of pro-inflammatory cytokine expression in the blood.

“If we can identify survivors at greatest risk of persistent fatigue, we can implement interventions early on to help them,” Irwin said. “That would be good news for the increasing numbers of women who are surviving breast cancer every year.”

The number of breast cancer survivors is steadily increasing due to advances in screening and treatment strategies. More patients are being diagnosed with early stage breast cancer and are surviving longer. In fact, breast cancer survivors are the largest group of patients to overcome any type of cancer in the United States. It is estimated that there are more than 2 million breast cancer survivors in the U.S. today.