Survival analyses from an RCT confirmed that breast cancer patients randomized to receive a psychologic intervention had reduced risk for breast cancer recurrence and death compared with patients who did not receive the intervention. These effects were observed above and beyond the contribution of known predictors of disease progression in breast cancer, such as lymph node status, receptor status, histology, and others. Furthermore, treatment quality was high for patients in both arms because the majority (83%) of patients received cancer treatment and follow-up at an NCI-designated comprehensive cancer center, and community care and follow-up were comparable. The benefits to the intervention patients were evidenced both in the reduced likelihood of an event occurring and in extended event-free time (ie, fewer patients randomized to the Intervention arm were diagnosed with a recurrence, and if they were, they had been cancer-free an average of 6 months longer than the patients in the Assessment only arm [a 45% reduced risk]. In addition, fewer patients in the Intervention arm died of breast cancer, and those who did survived >1 year longer after disease recurrence than did the patients in the Assessment only arm [a 56% reduced risk]).
As is possible, these patients will continue to be observed. The 5-year survival rate for the stage II patients in the current trial was 90%, which compares favorably with the same estimates for the state of Ohio (84%) and the surrounding county (Franklin) for Columbus, Ohio (83%).17
The 30-year risk of death from breast cancer is in the range of .47.18
However, the majority of the risk of recurrence (.37) occurs in the first 10 years of follow-up18
; this is a time point already passed by greater than half of the sample. Because of the potential implications of these findings, the methods used require replication by our and other laboratories. At the current time, the prior findings from the trial provide a complimentary scientific context within which the survival data stand. We will also make comparisons with previous RCTs testing psychotherapy interventions and breast cancer survival19–22
and identify mechanism(s) and moderators of the survival finding. We discuss 3 possible mechanisms here.
The significant psychologic improvements and positive behavioral changes observed for the patients in the Intervention arm may have been critical. Previously, we reported that the significant distress reduction achieved for the Intervention arm at 4 months subsequently predicted significant, positive improvements in health at 12 months.6,10
Recent analyses shed light on this particular effect as well as others.11
Specifically, we found that patients in the Intervention arm with the greatest reductions in distress and physical symptoms were also those who practiced progressive muscle relaxation frequently (daily) and those who understood and remembered (daily) that continued stress could adversely affect their health and that it could be controlled/reduced by using the intervention techniques. Moreover, the benefits from these techniques were greatest for patients vulnerable to poor outcomes (ie, those with the highest levels of cancerspecific stress) (unpublished data). These data suggest that the relation between patients’ use of particular intervention strategies and their subsequent heath was important.
A recent meta-analysis implicates stress in poorer survival and higher cancer mortality.1
Considering biologic mechanisms, stress may have impacted disease processes via endocrine and immune pathways. For the first path, studies using animal models (often with mammary cell tumor lines) have provided evidence of the effects of stress on tumor proliferation/angiogenesis,23
and adhesion in organs or vessel wall structures,27
and there is evidence that these effects are directly mediated by stress hormones (eg, catecholamines).3
For example, administration of epinephrine mimicked the tumorpromoting effects produced by behavioral stress (eg, restraint, isolation), whereas administration of β-adrenergic antagonists blocked the effects of behavioral stress. For humans, an emerging literature notes the effects of stress hormones on tumor growth.28,29
To our knowledge there are few data, but β-adrenergic receptors have been observed on human breast and ovarian tumor cells,24,30
suggesting similar pathways to those observed in animals.
Immune changes secondary to stress hormones may promote cancer growth or metastasis. Neuroendocrine effects on immune dysregulation include impaired diurnal cortisol rhythms, which have been associated with impairments of immune cell function, inflammation, and poorer survival.31–34
Similarly, tumor progression via stress modulation of the immune system (eg, compromised natural killer [NK] cell or T cell function) has been shown and replicated. 35,36
We hypothesized immunity as a mechanism that might covary with psychologic and behavioral variables and disease progression. We first demonstrated that as patients entered the trial, their high stress covaried with lowered immunity, found with multiple indices of NK cell cytotoxicity and lower T lymphocyte proliferative responses.37
Next, we observed that as the patients in the Intervention arm reported significant declines in emotional distress and were found to have reduced symptoms and treatmentrelated toxicities, simultaneously their T cell blastogenesis was stabilized or improving, but this was on a downward trajectory for patients in the Assessment –only arm.6,10
Thus, added immune control of disease processes, particularly early—when patients were recovering from surgery and receiving adjuvant cancer therapies—may have occurred with the declining stress. If so, the impact appears after approximately 20 months, the time at which the groups began to diverge ().
A related possibility is that arising from the stress-related release of proinflammatory cytokines. 38,39
Inflammatory processes appear to promote tumor growth both in clinical studies and in murine models.38,40
This may be because of the ability of proinflammatory factors to induce angiogenesis, stimulate the accumulation of myeloid suppressor cells, or promote an antiapoptotic tumor phenotype.41–43
As a period of tumor growth precedes its clinical detection, we hypothesized that inflammatory processes might be operative during this period. Enabled by the continuous data collection, we explored the possibility that patients in the trial who were to develop disease recurrence might demonstrate reliable biobehavioral alterations beforehand.44
At the time of the latter analysis, the 48 trial patients who had recurred (R; n= 48) were compared with trial patients remaining disease-free (DF; n= 48), with the 2 groups matched on demographic characteristics, prognostic factors and cancer treatments received when initially diagnosed, study arm, and duration of disease-free follow-up. Data were examined from 3 assessments, occurring on average 17 months, 11 months, and 4 months before the recurrence was detected clinically, with equivalent time points for the disease-free group.
Full details are available, but we briefly note here that in the 17 months before detection, patients who were to develop disease recurrence were found to have significantly higher white blood cell, neutrophil, lymphocyte, and natural killer cell counts compared with DF patients. R patients also demonstrated higher cortisol, worse physical functioning, fatigue, and quality of life during this period. Although the immune and behavioral effects may be independent, they may also arise from a common mechanism. It has been hypothesized that fatigue among cancer patients can result from a “cytokine cascade,” triggered by post-treatment elevation of the proinflammatory cytokines tumor necrosis factor-α, interleukin-1β (IL-1β), and IL-6.45
IL-2, also a proinflammatory cytokine, is known to produce fatigue, depressed mood, and other “sickness behaviors” in addition to the enhanced immune function (particularly NK cytotoxicity).46,47
A psychologic intervention that reduces stress could conceivably interrupt the inflammatory process, thereby mediating the intervention effect to limit disease progression.42
In conclusion, an RCT accruing women with regional breast cancer found that a 1-year, 26-session psychologic intervention was associated with improved survival 11 years later. Considered in context, in the last 30 years, hundreds of randomized psychologic intervention trials have shown mental health improvements for cancer patients in comparison with those in control conditions,48,49
although dissemination of interventions to the 1.4 million cancer patients diagnosed annually remains a goal rather than reality. Indeed, policy makers and oncology professionals in the US and around the world (eg, Committee of the Institute of Medicine,50
Central European Cooperative Group51
) recommend making efforts to treat cancer patients, and in particular those diagnosed with breast cancer,52
for their psychologic distress. If efficacious psychologic interventions to reduce stress are delivered early, they will improve mental health, health and treatment-relevant behaviors, and potentially, biologic outcomes. If so, there is the possibility for improved survivorship and survival for cancer patients.