COMMENTARY

Psychological Stress and Breast Cancer: Is There a Link?

Linda Brookes, MSc

Disclosures

June 09, 2017

Medscape spoke about the challenges in treating stress with Monique Gary, DO, a breast surgeon and specialist in benign and malignant breast disease at Grand View Hospital in Sellersville, Pennsylvania. Dr Gary has initiated a local community program focusing on the effects of stress on survivorship but also addressing stress in high-risk previvors—individuals who are predisposed to cancer but have not had the disease.

Psychological stress—the behavioral or physiologic responses of an individual to environmental demands that challenge or exceed their perceived ability to cope—has been implicated in the development of a range of diseases, including cancer.[1,2] Increasing evidence has demonstrated the adverse biological effects of stress on tumor progression, but the association between psychosocial stress and cancer risk is less clear.[3,4,5] Patient information on stress issued by national cancer organizations and agencies such as the American Cancer Society® and the National Cancer Institute underlines the inconsistency of evidence for a link. Despite this, about half of all women with breast cancer cite stress, especially stressful life events, among the risk factors for their disease.[6] Sixteen studies published between 1984 and 2011 found that women identified stress as one of the causes of their breast cancer and as the leading cause in five of the studies.[7] "That impacts providers, because whether or not we believe it, patients believe that stress causes cancer and they are looking for ways to mitigate stress in their lives," Dr Gary states. "Even if we don't buy into it, we must be able to fully address our patients in a way that they desire, because they are looking for a holistic approach."

The most obvious effect of stress in women with breast cancer and those at risk is the initiation of negative health behavioral responses such as increased smoking and alcohol consumption, poor eating habits, and lack of exercise and sleep, all of which are associated with increased cancer risk. Although the pathophysiologic effects of stress have been well documented, researchers in the field tend to be cautious about linking them with the initiation of breast cancer, although they do not exclude the possibility, acknowledging that "stress makes your body more susceptible to cancer."[8] Chronic stress is regarded as particularly detrimental, whether it arises from brief events that continue to cause stress after they have ended (such as an assault) or situations that persist for weeks, months, or years (such as long-term work stress or unemployment).

Biological Evidence for Tumor Effects

Psychological stress and affective responses, including depression and anxiety, are known to produce neuroendocrine responses that can alter important immune, angiogenic, and inflammatory pathways in the development, progression, and control of cancer.[3] Activation of the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous systems (SNS) releases stress hormones such as glucocorticoids and catecholamines. These have been shown to modulate tumor initiation and development by suppression of cellular immune responses important in the defense against malignant cells.[5] These responses include changes in the number and type of lymphocytes in circulation and the ratio of helper to suppressor T cells, decreased lymphocyte proliferation, increased macrophage infiltration, changes in natural killer (NK) cell number and activity, and impaired antibody responses.

Norepinephrine is also known to increase levels of proinflammatory molecules such as C-reactive protein (CRP), a prognostic marker in certain cancers, and interleukin 6 (IL-6), a cytokine that plays an important role in tumor progression by inducing angiogenesis. Corticosteroids, found in high concentrations during stress, reduce inflammation and induce immune suppression via nuclear factor (NF)-κB-, AP1-, Raf-, and MAPK-mediated signaling.[2] NF-kB, which is proinflammatory, is known to be widely involved in the regulation of breast cancer initiation, proliferation, angiogenesis, and metastasis, and the crosstalk between NF-kB and glucocorticoid receptors is regarded as important in determining the survival or apoptosis of breast cancer cells.[9] In humans, stress is seen to blunt the normal diurnal cortisol pattern, which has been implicated as a risk factor for tumor initiation and progression.[10,11]. Stress hormones are also known to play a role in DNA damage and repair in breast cancer cells, which also has implications for breast cancer initiation and progression.[12]

[C]ells make mistakes when they are stressed, cellular mistakes get reproduced, and this leads to uncontrolled cell growth and to cancer.

"At the most basic cellular level, cells make mistakes when they are stressed, cellular mistakes get reproduced, and this leads to uncontrolled cell growth and to cancer," Dr Gary summarizes. It is unclear whether it is possible to extrapolate this to breast cancer specifically versus other cancers, she cautions, but the main point is that "the more stress that you have and the fewer ways that you have to mitigate that stress, the more at risk your body is to create a milieu that is conducive to cellular damage and mistakes."

Epidemiologic Studies Inconclusive

Initial epidemiologic investigations into the potential links between stress and breast cancer were mainly case-control or cohort studies with smaller numbers of participants, using different measures of stress and study methods, and which produced a wide range of findings. Earlier studies reported no evidence for an association between stress caused by adverse life events such as bereavement, divorce, and change in financial circumstances.[13,14] It was suggested that the effects might be dependent on the specific type or length of time of stress exposure.[15] A rigorous analysis of studies that followed women for at least 10 years found a 50% increased risk for breast cancer in women who had experienced stressful life events and a twofold increased risk in those who experienced the highest-stress events.[16]

Larger, prospective cohort studies, which were initially expected to give more definitive answers, have also produced mixed results. The most recent study, from the United Kingdom, looked at over 106,000 women and concluded, after controlling for all other breast cancer risk factors, that there was no statistically significant association between frequency of stress experienced and risk for breast cancer.[17] There was also no consistent evidence of an association with having had an adverse life event during the 5 years preceding the study, similar to findings from two other large studies.[18,19] "Nobody was surprised by these data," Dr Gary comments. "We already knew that it might be difficult to quantify. When you break out the data, there is no way to say that at a certain point of psychosocial stress, you are more prone to develop a specific type of cancer versus even a general type of cancer." Prospective studies in which the patients are stratified by socioeconomic groups and other risk factors might show differences, she suggests.

Need for Intervention in Previvors as Well as Survivors

Psychosocial interventions, including cognitive-behavioral, mindfulness, supportive, and stress management approaches, all have the potential to improve the care, well-being, and survival of individuals with cancer.[20] "In our survivorship program, we place a heavy emphasis on the relationship between stress and healing at each stage of cancer treatment," Dr Gary says. Similarly, physicians need not be afraid to address psychosocial stressors as part of a comprehensive, integrated cancer risk and prevention program, she believes. "Psychosocial interventions such as mindfulness, meditation, yoga, exercise, etc, have cross-discipline benefits that extend to most chronic and preventable diseases as well as to breast cancer."

"Physicians may be apprehensive about tackling the psychosocial stress or stressors that are associated with increased cancer risk because it is so nebulous and it is very difficult to reproduce," Dr Gary points out. "In population studies, you could take 100,000 women who are at increased risk for breast cancer and look at their associated stressors to see who might develop breast cancer, and there would be no distinctive pattern because it relates to support systems or coping mechanisms," she says. Clinicians must be willing to extrapolate from the hard science, "because there's no tipping point that hallmarks the transition from a distressed body to a diseased one; rather, there is a gradual degradation of immune barriers coupled with the heightened fight-or-flight response that triggers cellular changes that create the right milieu for proliferation or preservation of abnormal cells responsible at a very fundamental level for cancer initiation and progression."

[Psychological stress] is that 'Pandora's box' that physicians may be reluctant to open.

Psychosocial stress "is a huge umbrella term for a myriad of stimuli that can include socioeconomic or interpersonal or involve work-life balance stressors," Dr Gary points out. "It is that 'Pandora's box' that physicians may be reluctant to open, because they don't know what they are going to find and they don't know whether they have the resources to address it," she suggests. "But if we are waiting for the data to show us the need, we will be waiting a long time," she cautions. "Patients are showing us that they have the desire to know about coping mechanisms, and to prevent cancer we have to get ahead of the curve—we can't be behind it."

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