6/20/00
MEDIA CONTACT: Ruthann Richter, (650) 725-8047, [email protected], or M.A. Malone, (650) 723-6912, [email protected]
FOR COMMENT: David Spiegel, MD, (650) 723-6421
EDITORS NOTE: This release corresponds with publication in the Journal of the National Cancer Institute
BREAST CANCER PATIENTS WITH ABNORMAL STRESS HORMONE LEVELS ARE MORE LIKELY TO DIE SOONER, STANFORD STUDY FINDS
STANFORD - 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, professor of psychiatry and behavioral sciences at the Stanford University School of Medicine 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 course of 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 is 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 their counterparts 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 non-essential activities - including the immune system - so the individual can devote its full energy to fighting off the imminent threat, Spiegel said.
The researchers were able to obtain cortisol samples from the study volunteers through a method developed by German researchers. The women were asked to collect their saliva four times daily using a plastic tube with a cotton swab held in the mouth for a few minutes. The researchers then were able to extract cortisol from the saliva and reliably measure levels of the hormone, Spiegel said. The researchers also obtained blood samples in order to measure specific types of immune system cells.
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, a type of immune system cell that spontaneously kills abnormal cells in its 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 circulating 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. Also, it is already known that the hormone estrogen stimulates cancer growth, acting through estrogen receptors on tumor cells.
"It's also possible that cortisol weakly reacts with these receptors," Spiegel said.
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. The researchers did not find any link between the cortisol patterns in the women and their experiences with pain or depression, he said.
Spiegel and his colleagues are now expanding on their research on the connections between stress and breast cancer, looking at cortisol and its relationship to physical and emotional well-being in women with recently diagnosed disease. They hope 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 in the community to see whether the 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 postdoctoral fellow at Stanford 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 Department of Psychiatry and Behavioral Sciences.
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