Associations Between Breast Cancer Survivorship and Adverse Mental Health Outcomes: A Systematic Review

Abstract Background We aimed to systematically review the evidence on adverse mental health outcomes in breast cancer survivors (≥1 year) compared with women with no history of cancer. Methods Studies were identified by searching MEDLINE, PsycINFO, the Cumulative Index to Nursing and Allied Health Literature, and the Social Sciences Citation Index, and through backward citation tracking. Two researchers selected the studies, extracted data, and assessed the risk of bias. Results Sixty studies were included. Of 38 studies of depression, 33 observed more depression in breast cancer survivors; this was statistically significant in 19 studies overall, including six of seven where depression was ascertained clinically, three of four studies of antidepressants, and 13 of 31 that quantified depressive symptoms. Of 21 studies of anxiety, 17 observed more anxiety in breast cancer survivors, statistically significant in 11 studies overall, including two of four with clinical/prescription-based outcomes, and in eight of 17 of anxiety symptoms. Breast cancer survivors also had statistically significantly increased symptoms/frequency of neurocognitive dysfunction (18 of 24 studies), sexual dysfunctions (5 of 6 studies), sleep disturbance (5 of 5 studies), stress-related disorders/PTSD (2 of 3 studies), suicide (2 of 2 studies), somatisation (2 of 2 studies), and bipolar and obsessive-compulsive disorders (1 of 1 study each). Studies were heterogeneous in terms of participants’ characteristics, time since diagnosis, ascertainment of outcomes, and measures reported. Approximately one-half of the studies were at high risk of selection bias and confounding by socio-economic status. Conclusions There is compelling evidence of an increased risk of anxiety, depression and suicide, and neurocognitive and sexual dysfunctions in breast cancer survivors compared with women with no prior cancer. This information can be used to support evidence-based prevention and management strategies. Further population-based and longitudinal research would help to better characterize these associations.

1 exp Breast Neoplasms/ 2 (breast and (cancer* or carcinoma* or tumo?r* or neoplas*)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier] 3 1 or 2 4 exp catatonia/ or exp depression/ or exp self-injurious behavior/ or exp anxiety/ 5 mental disorders/ or exp anxiety disorders/ or exp "bipolar and related disorders"/ or exp "disruptive, impulse control, and conduct disorders"/ or exp dissociative disorders/ or "feeding and eating disorders"/ or anorexia nervosa/ or binge-eating disorder/ or bulimia nervosa/ or pica/ or exp mood disorders/ or exp motor disorders/ or neurocognitive disorders/ or amnesia/ or cognition disorders/ or auditory perceptual disorders/ or mild cognitive impairment/ or consciousness disorders/ or delirium/ or dementia/ or exp neurotic disorders/ or exp personality disorders/ or exp "schizophrenia spectrum and other psychotic disorders"/ or sexual dysfunctions, psychological/ or exp sleep wake disorders/ or exp somatoform disorders/ or exp substance-related disorders/ or exp "trauma and stressor related disorders"/ 6 (depressi* or dysthymia or catatonia or self-injur* or self-injury or self-injurious or selfmutilation or "self mutilation" or suicid* or self-harm or "self harm" or "self injury" or anxious* or anxiety or (panic adj1 (disorder# or attack#)) or catastrophi* or (mental adj1 (disorder or disorders)) or phobia or phobic or neurotic or (compulsive adj1 disorder) or bipolar or neurotic or (personality adj1 disorder) or psychotic or psychosis or paranoid or delusional or (sexual adj1 (disorder or dysfunction or problem#)) or insomnias or (sleep adj1 (disorder or dysfunction or problem#)) or somatoform or (substance adj3 (disorder or problem#)) or stress ajd3 disorder or (adjustment adj3 disorder)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier] 7 4 or 5 or 6 8 (prevalence# or frequenc* or incidence# or risk or rate* or ratio or odds or epidemiolog* or percent* or outcomes or hazard).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]  Table 2. Criteria used to judge the risk of bias in the systematic review studies.

Judgment Selection bias Outcome variable: information bias
Design-specific source of bias (temporality)

Confounding by age and socio-economic status
Statistical methods

Missing data Conflict of interest Low risk of bias
Describes the source and methods of selection of the participants AND Eligibility criteria given AND (Participants selected at random OR population-based study) AND Proportion of participation >50% AND/OR ≤30% of attrition (for cohort studies with a pre-defined follow up time for the entire cohort) Outcome assessed through one of the following: Psychiatric interviews OR Evidence of having been prescribed anxiolytics (for anxiety) and antidepressants (for depression) OR Record of a diagnostic code for mental health (for studies including electronic health records) OR Country's official mortality registry data (for completed suicide) OR Objective data on the trajectories of cognitive function over time (for neurocognitive dysfunction) The breast cancer diagnosis preceded the onset of the mental health outcome OR Diagnosis of the relevant outcome prior to the BC diagnosis taken into account by restriction, matching or in multivariate analysis The study attempts to minimise confounding using one or more of the following: Matching for age and for an indicator of socio-economic status (e.g. education, attending the same primary care practice, or small geographic area) AND/OR Multivariate analysis, reporting mean scores or association measures, adjusted for age and a socio-economic status indicator Appropriate use of statistics for primary analysis of effect (specific to each study design and data) ≤15% of missing data (for studies with questionnaires), with or without multiple imputation methods for missing data OR >15% of missing data, with missing data imputed using multiple imputation methods The study authors explicitly report the existence, or not, of conflicts of interests OR The study's funding source is acknowledged

High risk of bias
Participants not selected at random OR Proportion of participation ≤50% OR Women selected on the basis of a the relevant mental health outcome for this review OR >30% of attrition (for cohort studies with a pre-defined follow up time for the entire cohort) Self-reported intake of anxiolytics (for anxiety) OR antidepressants (for depression) Unclear whether the onset of the mental health outcome occurred before or after the breast cancer diagnosis OR Diagnoses of mental disorders before the onset of the BC not considered The study only reports crude measures of frequency or association (e.g. univariate association, or mean scores of the instrument) OR (There are differences between the two the group of breast cancer survivors and the women in the comparison group for age OR for an indicator of socio-economic status)   [26]; IT = immunotherapy; ND = not defined; OR = odds ratio; PR = prevalence ratio; RR = relative risk; RT = radiotherapy; SCL-90 = Anxiety subscale of the Symptoms Checklist-90 [27]; SD = standard deviation; SIR = standardised incidence ratio; Srg, C = Breast conserving surgery; Srg, ND = Surgery, not further specified; Srg, M = Mastectomy; Srg, R = Breast reconstructive surgery; STAI = State-Trait Anxiety Inventory [28]; yrs = years; 95%CI = 95% confidence interval. * There was some statistical evidence (P<0.05) for a different prevalence, risk or severity of anxiety between breast cancer survivors and women who did not have cancer. † Prevalence ratio calculated by the authors of the present study. ‡ The two studies provided results for different components of anxiety (trait and state) based on the same sample of patients.  * There was some statistical evidence (P<0.05) for a different prevalence, risk or severity of anxiety between breast cancer survivors and women who did not have cancer. † Prevalence ratio calculated by the authors of the present study.     ICD-9 codes E950-E959 and ICD-10 codes X60-X84 and Y870 --