Associations Between Breast Cancer Survivorship and Adverse Mental Health Outcomes

A Systematic Review

Helena Carreira; Rachael Williams; Martin Müller; Rhea Harewood; Susannah Stanway; Krishnan Bhaskaran

Disclosures

J Natl Cancer Inst. 2018;110(12):1311-1327. 

In This Article

Discussion

Anxiety, depression, neurocognitive dysfunction, sexual dysfunction, and suicide appear to be more common in breast cancer survivors compared with noncancer groups. Scarcer data were available for other adverse mental health outcomes, but they were also reported as increased among breast cancer survivors. Common limitations of the current available evidence include use of nonprobabilistic samples, cross-sectional study designs making temporality of events difficult to assess, lack of power, and lack of consideration for important confounders such as socio-economic status.

Strengths of this review include the extensive search of multiple databases, the duplicated screening of the references and data extraction, and the systematic evaluation of the quality of the studies. The restriction to studies involving nonhospitalized samples and the inclusion of studies with in situ tumors allowed for a more generalizable characterization of the long-term burden of mental disorders in women in the community who have had breast cancer. We aimed to reduce the potential for information bias in the outcomes by considering only studies in which outcomes were assessed clinically or with validated instruments. However, this review also has limitations. Studies that reported mood assessments as secondary outcomes may not have been identified in the searches of electronic publication databases if the mental health outcome was not mentioned in the title, abstract, keywords, or indexing terms. This problem should have been minimized by our use of the four largest and most relevant databases in this field, supplemented by manual searches of all reference lists to further reduce the chances of major studies being missed. The comparability of clinically diagnosed outcomes over time may be limited by the changes in the diagnostic criteria, especially in cases such as sexual dysfunction where the criteria became narrower over time.[87] We defined explicit criteria to evaluate the risk of bias in the studies, but our assessment may have been affected by the quality of the reporting of the original studies. We considered that confounding by age and socio-economic status had been accounted for when the studies matched participants for these factors, even though we acknowledge that matching per se may not completely remove the confounding effect.[88]

The population-based studies included in this review consistently described more depression and anxiety in breast cancer survivors compared with the general population when these outcomes were clinically assessed. The group of breast cancer patients who receive a psychiatric diagnosis or who contact clinical services in relation to their mental health are likely to represent the most severe cases only; these patients are likely to benefit from medical treatment. Studies using receipt of antidepressants and anxiolytics prescriptions to define depression and anxiety, respectively, are likely to capture the specific group of patients who were thought to benefit from pharmacological intervention, which is only a subset of all patients with anxiety and depression. The indication of these drugs was not explored in any of the original studies, and misclassification of the outcome may have occurred because some of these drugs have other indications and are routinely used to manage vasomotor symptoms secondary to breast cancer treatments.[89,90] In addition, we cannot rule out that patients with breast cancer history may have been more likely to be diagnosed with a mental health outcome due to increased contact with the health services compared with participants who did not have cancer.

The results from the original studies involving self-assessment scales, especially to assess symptoms of anxiety and depression, need to be interpreted with caution. These were often small, low-powered, cross-sectional studies using nonprobabilistic samples. Several of the original studies excluded women with psychiatric conditions and relied on voluntary participation. This may have resulted in an overrepresentation of psychologically healthier women, because diseased people are less likely to volunteer to participate in epidemiological studies;[91,92] it is unclear if this would be differential between breast cancer survivors and control groups. The clinical profile of the patents included in these studies may also have been more favorable, because 45% of the studies included only patients with no recurrence and who were disease free at recruitment. In addition, misclassification of the outcome may have occurred, because these scales are screening tools and not suitable to establish definitive diagnoses. For example, the Hospital Anxiety and Depression Scale had only 50% sensitivity as a screening test for major depressive disorder in breast cancer survivors compared with the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders.[93] Despite these limitations, scales are widely used in psychiatric epidemiology and in psycho-oncology research, and their results in this review are helpful to show the consistency of the results across methods of assessment.

For all methods of outcome definition, selective reporting in the original studies cannot be ruled out. Information on missing data was rarely well reported, and there was limited adjustment for potentially important confounders such as age and socio-economic status; residual confounding is still likely to be present in the studies that adjusted for education only.

Clinically relevant symptoms of anxiety and stress-related/adjustment disorders are common shortly after diagnosis,[94] which is an expected response to a stressor that may be perceived as life-threatening and considering the uncertainty about the future that women may feel at this point.[95] Declining trajectories of anxiety suggest that most women adjust to the diagnosis over time,[96] but clinically relevant symptoms may persist in subgroups of women. Evidence on long-term trajectories of outcomes is scarce and needs to be further explored. Reported determinants of anxiety included younger age at diagnosis and having comorbidities; this is consistent with literature reporting that young breast cancer survivors have specific concerns, for example, fertility issues for women who want more children or weight gain during and after treatments.[10] The increased symptoms of posttraumatic stress is consistent with a meta-analysis reporting that 10% of breast cancer survivors have posttraumatic stress disorder.[97] Results for somatic and obsessive-compulsive symptoms must be interpreted with caution because they come from a small number of studies.

The increased frequency of depression in breast cancer survivors is plausible considering that many report unmet needs in several domains that affect quality of life,[98] including impact on relationships, lifestyle changes induced by the cancer, lack of psychological support, and difficulties obtaining understandable information about the physical long-term effects of the treatments.[99–101] Risk factors for depression in breast cancer patients appear to be similar to those for the general female population, including less social support and lower socio-economic status.[46] Suicide almost always occurs among people suffering from a mental health disorder, most often depression.[102,103] The increased risk of suicide in breast cancer survivors is likely to be underestimated, because suicide is often classified under other causes of death, and this may happen more often in women who have had cancer.

Neurocognitive dysfunction, also known as chemo-fog, has been linked to the neurotoxic effects of chemotherapy.[104] Other determinants of neurocognitive dysfunction recently postulated include posttraumatic stress disorder[59] and exposure to hormone therapy due the effects of estrogen deprivation in the neuronal structures.[82] Impairments for one or more domains of neurocognitive function (eg, memory[65,83] and processing speed[77,81]) were often described, but the methodological heterogeneity of the studies[105] as well as the challenge to measure neurocognitive function[106] hamper comparisons, and it is currently debatable which specific domains are impaired.

The narrow inclusion/exclusion criteria in some eligible studies of sexual dysfunction preclude generalizability to the general population of breast cancer survivors. For example, Safarinejad et al.[39] excluded women who did not attempt sexual intercourse weekly and Boehmer et al.[47] included only in lesbian or bisexual women. The aetiology of sexual dysfunction in women with a history of breast cancer is thought to be multifactorial. Vaginal dryness is a common iatrogenic effect of hormone therapy or chemotherapy-induced ovarian failure and may lead to dyspareunia.[14] However, impaired sexual function, compared with healthy women, has also been reported in women treated with surgery only,[48] indicating that factors other than the physical ones may be involved. Indeed, the distress in partnered relationships,[107–110] body image concerns,[111,112] depressive feelings,[113] younger age at diagnosis,[113] and presence of comorbidities[114] have all been reported amongst the most important determinants of female sexual dysfunction.

Mitchell et al.[115] systematically reviewed studies providing data for depression and anxiety in survivors from several types of cancer (>2 years since diagnosis) and in healthy subjects. The results indicated that anxiety, but not depression, may be increased among cancer survivors.[115] This conclusion arose from the meta-analysis of nine studies that provided data for anxiety and included patients diagnosed with breast, colorectal, prostate, testicular, and cervical cancers or Hodgkin's lymphomas as well as patients diagnosed with cancers during adolescence and young adulthood. It is currently unknown if, and how, the risk of anxiety and depression varies by cancer type, and thus we cannot directly compare our results. Other systematic reviews on the topic assessed the prevalence of anxiety and depressive symptoms in cancer survivors,[11,116–118] including studies without a comparison group. Maass et al.[11] described a higher frequency of depressive symptoms among breast cancer survivors (>1 year since diagnosis) compared with normative data found in the literature. The results for cognitive dysfunction are in accordance with those reported by Jim et al.,[119] who found small but increased cognitive deficits in breast cancer survivors treated with chemotherapy compared with noncancer and cancer controls.

Several studies have reported no differences in most domains of health-related quality of life (HRQoL) between long-term breast cancer survivors and women in the general population.[120–122] The interpretation of our results in the context of the literature for HRQoL is not straightforward, and the apparent difference is likely to be explained by the combination of several factors, including the differential participation of psychologically healthier women in HRQoL surveys and positive effects of surviving breast cancer. Patients with adverse mental health outcomes, especially those with the most severe categories, may be less likely to participate in HRQoL surveys. This contrasts with the studies in this review that included women with a clinical diagnosis and/or treated for a mental health disorder and were thus likely to capture the most severe cases. In addition, long-term breast cancer survivors report changes in several aspects of their lives, but not all of them are negative. Women in the survivorship period have described feeling improved empathy, closer relationships, and a greater appreciation for life.[123] This phenomenon of heightened well-being after a stressful event—known as posttraumatic stress growth—has been described to affect up to 60% of breast cancer survivors.[124] Quality of life reflects how women perceive their current status, and the occurrence of posttraumatic growth may offset some of the negative feelings associated with breast cancer.[125] In addition, studies of HRQoL often reported mean scores of overall and domain-specific measures of HRQoL; subgroups that have a different trajectory of symptoms can be hard to disentangle based on standard analyses.

This study has several implications for clinical practice. It is important to raise awareness amongst health care professionals acting at various levels of the health care system of the increased risk of mental health symptoms among breast cancer survivors, in particular anxiety, depression, and neurocognitive and sexual dysfunctions. Screening for mental health disorders in some or all of the breast cancer survivor population may be warranted. Predictors of distress among breast cancer survivors include having perceived functioning limitations, fatigue, younger age, lower socioeconomic status, and psychiatric history, and modifiable factors such as vasomotor symptoms, pain, less social support, physical activity, and cigarette smoking.[126] As such, screening for anxiety and depression may be especially relevant for younger patients, and all those within the first few years of survivorship, with co-morbidities, living alone, or diagnosed with more advanced disease; patients with depression should be assessed for suicidal ideation. Patients who experienced treatment-induced menopause are likely to benefit from being asked about their sexual function, because they may avoid this topic with their clinicians; patients who received chemotherapy may also benefit from assessment for clinically significant cognitive impairments. Psychosocial support and routine monitoring of patient-reported outcomes during survivorship care are likely to help reduce the burden of these conditions. Differentiated psychological services are becoming the norm in specialized breast cancer clinics; however, only a fraction of the breast cancer survivors are followed-up in these settings.[127] The holistic approach to the patients' unmet needs also requires equipping health care professionals with evidence-based information on the optimal management strategies. For example, treatment for sexual dysfunction may require not only management of anxiety and depressive symptoms, but also vaginal dryness, which may be undertreated in women with history of estrogen-receptor positive breast cancer due to concerns over the effect of hormonal vaginal treatments[128] and unawareness of the recommendations for lubricants and moisturizers.[129] Patients' education on common changes post breast cancer, and the strategies available to manage these, may help women to better understand and cope with their disease, increase patients' awareness of common symptomatology, and help to decrease the stigma associated with mental health disorders.

Our review also identified areas for further research. There is a pressing need for studies evaluating clinically diagnosed adverse mental health outcomes in samples of women likely to represent the cohort of survivors in the general population and with sufficient numbers to allow effects to be detected. Further research is particularly needed to better characterize the trajectories of mental health outcomes over time, particularly of anxiety, depression, and neurocognitive dysfunction. The long-term risk of sleep disorders needs clarification, because breast cancer treatments such as chemotherapy and steroids have been suggested to be associated with impaired sleep,[130,131] possibly due to increased risk of vasomotor symptoms that affect the sleep quality and quantity.[132] Evidence on the long-term effect of being diagnosed in situ vs invasive tumors and on having undergone breast reconstructive surgery is scarce despite the increasing numbers of ductal carcinoma in situ diagnoses and aesthetics surgeries performed. The role of systemic treatments other than chemotherapy on neurocognitive function also needs clarification, including the role of the different types of hormonal treatments (selective oestrogen receptors modulators vs aromatase inhibitors). Efforts should be made to employ standardized definitions of the outcomes, because the heterogeneity of diagnostic codes and psychometric instruments hampers comparability of results across studies. Further research is also needed on the performance of commonly used scales for anxiety and depression as screening tools for these conditions in breast cancer survivors. Studies should also consider that the incidence of mental health disorders after a breast cancer diagnosis may vary with age, socio-economic status, time, stage of disease, recurrence, type of treatment, and sequelae from cancer among other factors. The inclusion of a comparison group is essential to estimate the excess risk of the breast cancer survivorship.

In conclusion, women with a history of breast cancer appear to be at higher risk of a wide range of adverse mental health outcomes up to several years post diagnosis and treatment compared with women who did not have cancer. The evidence was particularly compelling for anxiety, depression and neurocognitive and sexual dysfunctions, and suicide, which were most often studied. However, there is a pressing need for more population-based research to better characterize the association between breast cancer history and mental health. Our results can be used to inform prevention and management strategies directed at tackling the burden of adverse mental health outcomes in breast cancer survivors.

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