The effect of psychosocial factors on breast cancer outcome: a systematic review

Introduction We sought to review the available evidence regarding the effect of psychosocial factors on the survival of breast cancer patients. Methods We systematically searched the PubMed and PsycINFO databases to identify relevant studies. Results We identified 31 studies examining the association of various psychosocial parameters with overall breast cancer survival/disease free survival and 6 studies examining whether psychological intervention influences the disease outcome. Of the 31 studies summarized in this overview, 25 (80.6%) showed a statistically significant association between at least one psychosocial variable and disease outcome. Parameters associated with better breast cancer prognosis are social support, marriage, and minimizing and denial, while depression and constraint of emotions are associated with decreased breast cancer survival; however, the role of these factors has not been verified in all studies. Conclusion Most of the studies show a significant relationship between psychosocial factors and survival, but the actual psychosocial variables related to survival are not consistently measured across studies and the findings for many of the psychosocial variables with survival/recurrence are not consistent across studies. Thus, more research is warranted regarding the role of social support, marriage, minimizing and denial, depression and constraint of emotions on breast cancer survival.


Introduction
Breast cancer is a significant cause of morbidity and mortality among women; it is the second leading cause of death due to cancer in women, exceeded only by lung cancer (American Cancer Society 2007) [1]. The fact that patients with apparently similar tumours at the time of presentation differ significantly in the time of relapse and overall survival implies that the determinants of survival could be broader than initially assumed in the purely medical framework. The question of whether psychosocial parameters could have an effect on the clinical outcome of cancer in general has yielded a large body of research devoted to this issue and has divided the medical community into believers and non-believers. We reviewed arti-

Results
In total we identified 37 studies examining psychosocial factors and breast cancer survival; 31 descriptive analytical studies and 6 studies with psychological intervention. In Tables 1  and 2 we summarize the 31 studies regarding psychosocial/ psychological factors and survival or recurrence among patients with breast cancer . In Tables 3 and 4 we summarize the six studies regarding the impact of psychosocial intervention on survival of breast cancer patients [35][36][37][38][39][40]. In Table 5 we summarize the association of psychosocial factors with survival/recurrence. A total number of 61,611 female patients with breast cancer were examined regarding psychosocial factors and survival (52,857 of them in retrospective studies). Of the total 31 identified descriptive analytical studies, 15 were conducted in the US [5][6][7][8]10,11,15,16,22,24,26,27,31,32,34], 2 in Canada [9,29], 1 in Israel [18], 2 in Australia [23,30], 1 in Japan [19] and the rest of them in Europe (6 in the UK, [4,[12][13][14]21,25] 1 in Switzerland and Germany [17], 1 in Denmark [28], 1 in Belgium [20] and 1 in Finland [33]). Two studies examined the same cohort of women to assess the impact of psychosocial factors on survival [26] and the effect of cancer specific beliefs on survival [27]. Out of the 31 studies that did not employ psychological intervention, 12 examined patients with all stages of breast cancer [6,7,9,12,15,19,22,[26][27][28]32,34]. Five and two studies examined patients with metastatic/recurrent cancer [5,8,11,23,24] and invasive stage I or II to III cancer [20,31], respectively, whereas twelve studies examined patients with early stage cancer [4,10,13,14,[16][17][18]21,25,29,30,33] characterized either as operable, stage I and II in the TNM classification (that is, the staging system based on tumour size, lymph node involvement, and the presence of metastasis), or localized regional and non-metastatic. Fourteen studies focused on patients' reactions to having cancer and their feelings whereas nine focused on social factors (that is, marital status, social ties, religion) that can offer significant support to breast cancer patients, and seven studies focused on both. One study examines the effect of beliefs about cancer curability.

Characteristics of studies examining psychosocial factors associated with breast cancer survival
(one study [4]) and expressive activities (one study [9]) significantly reduced recurrence rates.
As seen in Table 5, for most of the separate psychosocial factors examined with regard to breast cancer survival and/or recurrence there was only one study supporting the association (either a positive or a negative impact on survival/recurrence). For several psychosocial factors (specifically, depression, social support, marriage, perceived support, stressful events, denial/avoidance, minimizing, repressive defensiveness, anger/hostility and hopelessness/helplessness) more than one study reporting a statistically significant association with breast cancer survival. For five of these eight psychosocial factors (stressful events, depression, perceived social support, anger/hostility, denial/avoidance) there are contradictory results (showing both negative and positive effects) on survival/recurrence. For example, while five studies show that depression is associated with decreased survival, there is one study where depression seems to increase survival. Perceived social support, social support, minimization and marriage were associated with prolonged survival in more than one study. Similarly, repressive defensiveness and depression are associated with decreased survival in more than one study. As far as recurrence is concerned, only stressful events appeared to reduce recurrence rates while hopelessness appeared to increase recurrence rates in more than one study.
In the 6 studies that used psychological intervention, a total of 389 female patients with breast cancer were examined (34 of them in a retrospective study). Psychological intervention varied from study to study, including group therapy, behavioral/ cognitive therapy, peer support/family therapy, counseling, mental imagery, meditation, and psychology classes. Three of these studies were conducted in the US [35,36,39], two in Canada [37,40] and one in Australia [38]. Four studies examined patients with metastatic breast cancer, one patients with early breast cancer and one patients with breast cancer of any stage. Two studies showed that there is a survival benefit for those patients that received psychological intevention [35,39], while in four studies there was no influence on survival [36][37][38]40].

Discussion
From the results of our review of the literature there are conflicting data regarding the possible association of psychosocial factors and survival. Various methodological issues of the examined studies have to be taken into account to interpret their results. Hence, while most of the examined studies in our review are prospective, the majority of the patients studied were in the retrospective studies. This means that the sample size of most of the prospective studies is relatively small. The follow-up period of the reviewed studies also differs significantly. One must be cautious when drawing conclusions from a variety of studies that used different assessment tools to evaluate the influence of psychosocial factors on the survival of patients with breast cancer. For example, in the study by Goodwin and colleagues [29] a psychosocial parameter (avoidance) was found to be important when assessed with a particular questionnaire, but this finding was not substantiated when using another questionnaire. Moreover, in the same study, the number of statistically significant associations of psychosocial factors with breast cancer survival actually found was less than that expected by chance.
Despite these limitations, some useful data regarding the role of psychosocial factors in breast cancer survival become evident. There is an overlap between studies that showed statistically significant associations and those that did not. This means that while a study may have reported a statistically sig-  Each patient was asked about the occurrence of traumatic events 5 years before the first recognition of symptoms (deaths, illnesses, divorces, unemployment). Also patients were asked questions about the extension of social involvement (marital status, participation in religious/non-religious groups).

Characteristics of studies examining psychosocial factors associated with breast cancer survival
Only women whose deaths have been recorded were included in the study Patients were asked to complete short self-administered questionnaires (90% completed within 3 months of diagnosis

Methods and outcomes of studies examining the association of psychosocial factors and breast cancer survival
Morris et al. 1992 [14] Interview at 3 months post diagnosis, further tests at 6 to 9 months post diagnosis and another interview at 12 months. Follow up at 5 years post diagnosis.    Patients answered a series of questionnaires, repeated every 3 months for up to 2 years following study entry. In this paper there is only the analysis of the initial questionnaire of each patient.

Methods and outcomes of studies examining the association of psychosocial factors and breast cancer survival
Weihs et al.

[24]
The collection and interpretation of data regarding psychological assessments begun at least 6 months after recurrence and prior to the known terminal phase (that is after the acute adjustment to breast cancer recurrence and before the effects of terminal illness

Methods and outcomes of studies examining the association of psychosocial factors and breast cancer survival
Osborne et al.
2004 [30] Hospital Anxiety and Depression Scale (HADS), Duke-UNC Functional Social Support (DUFS), Mental Adjustment to Cancer (MAC). Approximately two-thirds of the patients were interviewed between 5 and 9 months following diagnosis, the remaining one-third was interviewed 9 to 17 months following diagnosis

Methods and outcomes of studies examining the association of psychosocial factors and breast cancer survival
nificant association for a psychosocial parameter, it did not show significant correlations for other parameters. The small patient numbers in these studies may have precluded statistical significance. In the majority of the studies that showed a statistically significant association between a psychosocial factor and survival/recurrence, this association was either positive (increased survival/recurrence) or negative. For only four of the studied psychosocial parameters (depression, perceived social support, anger/hostility, denial/avoidance) were both positive and negative results evident. Thus, with regarding to depression, four studies showed increased patient mortality, five studies showed no effect at all and one study showed a contradictory effect, that is, better survival.
Parameters associated with better breast cancer prognosis are social support, marriage, minimizing and denial. Data from the literature regarding the effect of these factors on the survival of other types of cancer vary. Thus, in a recent systematic review no statistically significant influence of psychological coping on cancer survival (various types of cancer included) was found [41]. On the contrary, data from patients with melanoma show that married patients and patients adjusting with minimization also survived longer [42]. In our review, depression and constraint of emotions are associated with decreased breast cancer survival; the role of these factors has not been verified in all studies. In a prospective study of patients with various types of cancer, depression was found to

Methods and outcomes of studies examining the effect of psychological intervention on breast cancer survival
be associated with cancer prognosis after 30 months of follow-up [43].
Other studies included in our review have shown limited and/ or contradictory data for parameters such as fighting spirit, having a female child, showing adjustment, having hobbies, coping, role functioning, stressful events, stoic acceptance, fatalism, locus of control and anger.
Understanding the definitions of these psychosocial parameters is crucial. Closely related terms are not synonymous. Thus, one has to differentiate denial and minimizing (associated with better survival) from constraint of emotions (associated with shorter survival). Denial refers to the belief that one has no disease, while minimization refers to minimizing the seriousness of the disease. The constraint of emotions is not synonymous with denial/minimization. One may constrain his/ her emotions while not denying the disease.
One cannot emphasize the need for repeated evaluations of the psychosocial factor over a protracted time period. This holds true as these factors may change over time, that is, they are dynamic in nature. Chronic versus acute changes in the psychosocial factors were not a particular focus in the reviewed studies, apart from one. Neither was any specific mention of the histological type of breast cancer made in these studies. In contrast, the majority of the studies reported on breast cancer stage; it seems that no association between psychosocial factors and the stage of the neoplasm (metastatic versus non-metastatic) was evident.
When examining the effects of various psychosocial factors on the outcome of patients with breast cancer, other possibly interacting factors (either psychosocial or biological) may be deemed to be confounders. It should be kept in mind that when excluding these factors that are potentially in interplay with the examined parameter from the analysis, the effect of the psychosocial factor might not become evident. For example, in breast cancer patients with a hormone (estrogen and/ or progesterone) receptor positive status (biological factor), life events were related to recurrence of breast cancer, while such a relationship did not occur in women with hormone receptor negative breast cancer [12]. In an analogy, the effect of one psychosocial parameter may only become evident when examined in the context of other interacting psychosocial parameters. An example is shown in the study by Weihs and colleagues [24]; the effect of chronic anxiety varies when various levels of constraints of emotion are examined. Other studies do not confirm the interplay of psychosocial and biological factors [16].
The effect of various psychological interventions on the survival of breast cancer was examined in six studies and two of them showed a positive result. While psychological interventions improve the quality of life of patients with breast cancer, [35] their effect on actual survival is less obvious. Thus, it seems that psychological interventions have minimal effect on the prognosis of breast cancer patients. One has to acknowledge that the numbers of patients in the studies using psychological intervention are too small to reach definite conclusions. Data from the literature regarding the effect of psychosocial interventions on cancer survival are scarce; even data on the effects of these interventions on quality of life are contradictory [44][45][46].

Conclusion
The majority of studies show a significant relationship between psychosocial factors and survival, but the actual psychosocial variables related to survival are not consistently measured across studies and the findings for many of the psychosocial variables with survival/recurrence are not consistent across studies. In particular, more research is probably warranted Goodwin et al. 2001 [40] Women participating in the intervention group attended weekly meetings lasting 90 minutes. Therapy intended to foster support among members and encourage the expression of emotions about cancer and its effects on their lives. Patients were encouraged to attend sessions for at least 1 year. There was no significant association between psychosocial intervention and breast cancer survival Methods and outcomes of studies examining the effect of psychological intervention on breast cancer survival Table 5 Association of the examined psychosocial factors with survival/recurrence