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Stanford Report, June 28, 2000

Stress hormone may contribute to breast cancer deaths  

BY RUTHANN RICHTER

Women with advanced breast cancer who have abnormal daytime levels of cortisol, a hormone released in response to stress, are significantly more likely to die sooner than patients with normal levels of the hormone, Stanford researchers report in a newly published study. The researchers also found that women with these abnormal cortisol levels had fewer immune system cells known as natural killer cells, and this reduced immunity was associated with higher mortality.

The study involved 104 San Francisco Bay Area women with metastatic cancer, or disease that had spread beyond the breast. The researchers extracted cortisol from the saliva of the volunteers, which was taken at regular intervals during the course of three days. They then observed the women's daytime rhythms as reflected in their cortisol levels, which are generally high in the morning and then gradually decrease to a low point in the evening, said David Spiegel, MD, Stanford professor of psychiatry and behavioral sciences and principal investigator of the study. The researchers found that some of the study volunteers had abnormal patterns of cortisol secretion, with levels of the hormone that remained relatively flat or peaked at abnormal times during the day.

"We found that patients who had abnormal cortisol patterns died significantly sooner," Spiegel said. "There was no relationship in the first year. It's only down the road that it occurs. It's as if we're tapping into some physiologic system that is a marker for rapid tumor growth."

The latest study was published in the June 21 issue of the Journal of the National Cancer Institute. The work is a follow-up to an earlier, landmark study published by Spiegel and his colleagues in the journal Lancet in 1989. In that study, the researchers found that women with metastatic cancer who attended weekly support groups lived about twice as long on average as those who did not have the benefit of psychosocial intervention.

"We said, 'Look, if there is an effect of intervention, there's got to be a mechanism that mediates it,' " Spiegel said.

Based on evidence from other studies, Spiegel and Sandra Sephton, PhD, a post-doctoral fellow in his laboratory, decided to look to the cortisol system for a possible physiologic explanation for the difference in mortality. The cortisol system is one of two primary systems for responding to stress. For instance, the body may release the hormone when an individual perceives a danger. Cortisol, in turn, causes cells to release glucose so the individual has the energy to respond and fend off an attack. Cortisol also slows nonessential activities ­ including the immune system ­ so the individual can devote its full energy to fighting off the imminent threat, Spiegel said.

The researchers found that only 37 percent of the women had cortisol patterns that were normal, starting high in the morning and maintaining a steady decline into the evening. The other 63 percent of the volunteers had levels that had a relatively flat pattern or peaked abnormally later in the day. These hormone levels were directly related to survival time, the researchers found. Women with abnormal cortisol rhythms survived an average of 3.2 years, while those with normal rhythms survived an average of 4.5 years ­ more than a year longer. The difference in survival times began to emerge about a year after the testing and continued for at least six more years, the researchers reported.

Patients with a flatter cortisol pattern also had fewer natural killer cells, immune system cells that spontaneously kills abnormal cells in their vicinity, including tumor cells and infected cells. The researchers found that patients were more likely to survive longer if they had higher numbers of these cells in the blood.

After controlling for natural killer cell numbers, the researchers also found that these cells were less active among patients with flatter cortisol rhythms. Previous studies have shown that the absence of natural killer cells is related to the progression of breast cancer, Spiegel said.

"I think one of the problems these cancer patients may have is that their immune system is overregulated. Cortisol suppresses immune function and may hamper the immune system's ability to counter the spread of cancer," Spiegel said.

He said there are other, more direct ways in which cortisol might have an impact on the progression of the disease. For instance, cortisol causes normal cells to release glucose into the blood, but tumor cells ignore this signal. Thus high cortisol levels tend to favor the nourishment of tumor cells over normal ones.

The researchers explored other factors that might influence cortisol levels and found that women who were widowed, divorced or separated were more likely to have abnormal cortisol patterns. Spiegel said the abnormal cortisol profile might reflect the stress associated with loss of marital support, which has been found in other studies to be associated with poorer outcomes.

The researchers also found that women with abnormal cortisol patterns during the day were more likely to have sleep disruptions at night. It could be that the cortisol abnormalities contributed to these disturbances, or that sleep problems were a source of daytime stress for these women, Spiegel said.

Spiegel and his colleagues are now hoping to learn whether cortisol also predicts poorer disease outcomes early in the course of breast cancer. The researchers also are studying different types of group interventions offered to patients to see whether women can improve abnormal cortisol rhythms. Women interested in participating can contact project coordinator Vickie Chang at (877) 447-7457.

Spiegel's colleagues in the study are Sephton, a former Stanford postdoc who is now at the University of Louisville School of Medicine; Robert Sapolsky, PhD, Stanford professor of biological sciences; and Helena Kraemer, PhD, a Stanford professor of biostatistics in the psychiatry and behavioral sciences. SR