At present, there is few evidence for any biological assumption through which life events with psychosocial stress (PS) could predict the etiology or outcome in breast carcinoma (BC). Stressful experiences include physical stressors such as pathogens and toxins, and PS factors such as major life events, trauma, abuse, or factors related to the environment in the home, workplace, family, or at neighborhood (1, 2). Several PS mechanisms have been suggested, most of these hypotheses implicate neuroendocrine responses or hormonal status of patients (3-11). Neuroendocrine responses can impact immune, angiogenic, and inflammatory pathways that contribute to the incidence, progression and control of cancer. The responses are mainly regulated by the hypothalamic–pituitary–adrenal (HPA) axis and the sympathetic nervous system (SNS) that release stress hormones: glucocorticoids and catecholamines (3, 5-7). Prolactin, growth hormone, and nerve growth factor are also linked to BC pathogenesis (11). It seems that BC-related PS responses can be found in many other psychosocial disorders also.

The studies focusing on stressful events in life due to losses and deficit are less studied than other adverse events and their role remains unclear in etiology and outcome of BC (13-26). Earlier reports have found some relationship of losses, deficit and stress (LDS) events with BC (14-16, 24, 25) including loss of a family member, divorce, job loss, physical, sexual, or psychological abuse. Hilakivi-Clarke et al. (9, 10) reported the effects of social isolation on BC and suggested deficit in social connections as risk factor for BC. The previously published results of the Kuopio Breast Cancer Study (KBCS) (18) support a weak association between LDS events in adulthood and the risk of BC. Furthermore, the same authors (19) reported that female patients with BC had higher mean score for loss and deficit in childhood than the non-BC patients. Patients with BC had also significantly more severe deficit in childhood than women without BC. The authors concluded that female patients with BC tended to have more LDS events than non-BC patients. However, the biological explanation for such an association is unclear and it might be that the LDS events impact indirectly on BC risk (18, 19). Unfortunately, the impact of LDS events on long-term outcome of patients with BC symptoms has not been reported.

Patients. The study cohort included 115 patients with BC symptoms diagnosed in Breast Cancer Diagnostic Unit (BCDU), Kuopio University Hospital (KUH), Finland (Table I). The Kuopio Breast Cancer Study (KBCS) (27-30) follows the protocol of the International Collaborative Study of Breast and Colorectal Cancer coordinated by the European Institute of Oncology and was initiated as a SEARCH program of the International Agency for Research on Cancer (31).

Losses, deficit and stressful events inventory (LDSI). The LDS events were evaluated over the whole lifespan, especially the previous ten years before admission. The LDS events and the context surrounding them were marked on the ‘life line paper’ during the interview. After the interviews, the LDS events were rated according to the degree of threat or stress they were likely to pose, and each LDS event was graded on a five-point scale, grade I (one point) indicating non-threatening event and grade V (five points) a severely threatening event. The defences used were also assessed on a five-point scale: grade I (one point) indicating very defensive, in denial and grade V (five points) non-defensive. The ‘working through and actively confronting the LDS event’ variable was also rated on a five-point scale: grade I (one point) indicating not resolved and grade V (five points) fully resolved. These measurements were put together in the final statement, one to two points on the scale meant little or mild loss or stress, and five meant very hard loss or stress. A detailed description of the LDSI protocol is shown in earlier reports (18, 19).

Wirsching Psychosocial Risk Scale (WPRS). We used a modified WPRS for psychosocial risk assessment with 10 scales and a detailed description of the WPRS protocol is shown in earlier reports (32-34).

A detailed description of the classical psychosocial scales, Sifneos Alexithymia Inventory (SAI), Forsen Inventory (FI), Beck Depression Inventory (BDI), Montgomery-Asberg Depression Rating Scale (MADRS), Spielberger State-Trait Anxiety inventory (STAI) is provided in earlier reports (35-48).

Statistical analysis. Baseline group differences were analysed by two-sided chi-square and non-parametric Kruskall-Wallis tests. Scores are presented as mean values and standard deviation. Scores were compared between the two groups using Student’s t-test. The relapse-free survival (RFS) was calculated from the time of diagnosis to the occurrence of the first relapse, contralateral BC, or metastatic disease. The overall survival (OS) was assessed as the time from the date of diagnosis to the date of last follow-up or death of the patient. The effect of the LDSI approach on the RFS and OS were calculated using the Kaplan-Meier survival analysis and the difference between the groups was assessed using the log-rank test. The p-values and the hazard ratios (HRs) with their 95% confidence intervals (CI) were calculated using the Cox proportional hazard models. Pearson’s method was used to test for correlation between LDSI approach and the classical psychosocial scale levels. Data were analyzed using the IBM SPSS statistical software (IBM SPSS Statistics for Windows, version 26.0, IBM Corporation Armonk, NY, USA).

BDI, MADRS, STAI, FI, SAI, WPRS and LDSI levels in BC and non-BC patients. Table I shows the baseline data and values of BDI, MADRS, STAI, FI, SAI, WPRS and LDSI scales in healthy study participants (HSP), benign breast disease (BBD) and breast carcinoma (BC). The mean BDI, MADRS, STAI, FI scale (0-2 years), FI scale (2-6 years), LDSI and number of LDS events (nLDSI) values between female patients with BC and women without BC were quite similar (p=0.70, 0.78, 0.29, 0.99, 0.43, 0.41 and 0.47, respectively, Table I). The mean SAI levels were significantly higher in women without BC (HSP=27.2 and BBD= 28.7) versus women withBC (24.0, p=0.003, Table I), whereas the mean WPRS values in patients with BC were higher than in non-BC patients (BC=19.4 versus HSP=17.2 and BBD=17.6, p=0.05). However, there were no significant differences between the mean LDSI scores of losses (Table II) and deficits with stress (Table III) at adulthood among non-cancer women and female patients with BC using Student’s t-test.

LDSI correlation to classical tests. The LDSI levels correlated with BDI (r=0.37, p<0.001; Figure 1), MADRS (r=0.51, p<0.001; Figure 2), STAI (r=0.29, p=0.002; Figure 3), and FI 0-2 years (r=0.50, p<0.001; Figure 4), FI 2-6 years (r=0.52, p<0.001), SAI (r=–0.52, p<0.001) and WPRS (r=0.34, p<0.001; Figure 5) (Table IV).

The 25-year RFS and OS. In the Cox model, the LDSI predicted the 25-year RFS in all women with BC symptoms (HR=2.37, p=0.05, Table V) and the RFS in female patients with BC (HR=5.02, p=0.01). In the Kaplan-Meier survival analysis by the log-rank test, the 25-year relapse level differed between low LDSI (<83) and high LDSI (≥83) in women with BC symptoms; though the difference was not statistically significant (27.9% versus 54.5%, log-rank p-value=0.098; Figure 6). Also, the low LDSI (<83) was a favourable predictor of the RFS (HR=5.02, 95% CI=1.42-17.8, p=0.01) in patients with BC. The 25-year OS rate differed between low LDSI (<83) andhigh LDSI score (≥83) in women with BC symptoms (19.8% versus 36.8%, log-rank p-value=0.048; Figure 7). A similar figure was seen in female patients with BC as the LDSI predicted 25-year OS in patients with BC (44.4% versus 71.4%, HR=2.59, 95% CI 0.90-7.40, p=0.076; Table VI).

BC is one of the main public health problems in women worldwide (49-52) and several PS factors for BC have been identified, while LDS events are less studied than other adverse events and their role remains unclear in etiology and outcome of BC (13-26). Earlier reports have found some relationship between the LDS events and BC, including loss of a family member, divorce, job loss, physical, sexual, or psychological abuse; (14-16, 24, 25, 53, 54). Forsen (38) assessed the PS events and the findings indicated that female patients with BC had losses, and difficult life situations preceding BC diagnosis. The authors concluded that significant losses preceding BC diagnosis could enhance BC risk in women with BC symptoms (38).

Chen et al. (53) reported that PS events enhanced the risk of BC in women with BC symptoms 3-fold and after adjustment for menopause and age, the risk for BC rose almost 4-fold in women with BC symptoms. The authors concluded that there is a significant association between severe PS events and risk of BC in women with BC symptoms.

Duijts et al. (13) conducted a meta-analysis to examine the association between the PS events and BC risk. They included the following PS events: death of spouse, death of relative or friend, personal or nonpersonal health difficulties, change in marital status, change in financial status and change in environmental status. The authors found a statistically significant effect of stressful life events (RR=1.77), death of spouse (RR=1.37) and death of a relative or friend (OR=1.35). Unfortunately, publication bias was detected in two PS variables; in the stressful life events and in the death of relative or friend categories. Therefore, only a modest association could be identified between death of spouse and risk of BC in women with BC symptoms.

Lillberg et al. (14) investigated retrospectively the PS events in BC by a self-administered questionnaire and found that the risk of BC was associated with the following life events: divorce (RR=2.2), death of spouse (RR=2.00), and death of a close relative or friend (RR=1.36). The authors suggest that major life events can play a significant role in the etiology of BC.

Kruk (15, 54) reported that women with a high number of PS events, four to six PS events, had over 5-fold increased risk for BC compared to women with low number of PS events. The authors found that the risk of BC is enhanced after high number of PS events and following death of a family member, personal injury or illness, imprisonment/trouble with the law, and retirement.

Chiriac et al. (23) performed a systematic review including all studies from 1966 to 2016 assessing the relationship between stress and the risk of BC. They found 17 retrospective, 20 limited prospective and 15 prospective studies for their review and the number of patients exceeded 29,000, for a total number of more than 700,000 women recruited from hospital, screening cohorts or population registers. They identified 26 ‘positive results’ articles linking personal traits and stressful events to BC, 18 ‘negative results’ articles that did not confirm their hypothesis and eight articles that could not be classified. They found heterogeneity and possible study bias factors such as: study design, information gathering, stress type, moment of exposure, individual susceptibility and personality. Authors concluded, that their qualitative analysis of articles revealed a possible association between stress and risk of BC, especially regarding stressful life events. However, without meta-analysis, their results are difficult to interpret and the role of chance is difficult to exclude.

Fischer et al. (24) studied stressful life events that occurred prior to BC diagnosis and found that they were associated with increased BC risk (RR=1.63, 95% CI=1.00-2.66). Conversely, non-stressful events did not have a significant impact on BC risk. Previous personal illness was directly related to increased BC risk, whether perceived as stressful (RR=2.84, 95%CI=1.96-4.11) or non-stressful (RR=3.47, 95% CI=1.34-8.94). Authors concluded that their study underscores the importance to pay attention to PS events when determining BC risk.

Bahri et al. (25) conducted a review and meta-analysis to investigate the relation between PS events and the risk of BC. Out of 168 publications, 11 documents met the inclusion criteria of their study and the results showed that history of the PS events slightly enhanced the risk of BC (RR=1.11, 95% CI=1.03-1.19). The authors concluded, that history of PS events could be associated with a moderate increase in the risk of BC.

Moayedi-Nia et al. (55) examined life-stress due to losses (death of a family member, divorce/separation) and socioeconomic events (job loss, major income reduction, or a move to a new city) as risk factors for lung cancer (LC) in a case-control study. They found that the high impact loss events enhanced significantly LC risk (RR=1.84, 95% CI=0.97-3.49).

In addition, the previously published results of the Kuopio Breast Cancer Study (KBCS) (26) showed association between the LDS events in adulthood and the risk of BC. Furthermore, the same authors (27) reported that patients with BC had higher mean score for deficit and loss at childhood than non-BC patients. Their results indicated that the women with BC tended to have more LDS events than non-BC women. However, the weakness of their BC study is that they had no data on the impact of LDS events on long-term outcome. At present, the relationship between PS events and BC has been widely studied; however, most existing research is characterized by a weak methodological structure and contradictory findings. However, the evidence is quite low for any biological assumption through which the PS factors could predict the etiology or outcome in patients with BC. Furthermore, the ability to adjust to repeated stress is also determined by the way a person perceives a situation. The determination of the role of stress in cancer has faced many difficulties such as the health habits or stage of cancer (1, 2). In addition, individuals who are stressed and depressed are more likely to have health behavior that puts them at higher risk, including worse sleep, excessive use of alcohol and drug abuse, worse nutrition, and less exercise – health habits that have immunological and endocrinological consequences (1, 2). Reducing the effect of the PS events through social support, including the presence of a social network or psychological intervention, has been shown to increase survival time and decrease the rate of metastasis (1, 2). Here, we report the characteristics of the PS events with the LDSI model in women with BC symptoms and their link with the long-term outcome. The LDS events should be identified by a doctor who is considering patients’ potential risk of future BC. This study found significant long-term outcome effects for LDS events of both women with BC symptoms and patients with BC. In addition, we observed significant associations between BDI, MADRS, STAI, FI, SAI and WPRS scales and LDSI levels. These findings suggest that further research is needed to substantiate, whether LDSI could be an important addition to the PS events screening criteria for preventative or early breast cancer care. The results indicated that PS events detected with LDSI scale correlate with the 25-year RFS in women with BC symptoms and the RFS in women with BC. Also, low LDSI (<83) demonstrated as a favourable predictor of the RFS in women with BC. The 25-year OS rate differed between low LDSI (<83) and high LDSI score (≥83) women with BC symptoms. A similar figure was seen in BC as LDSI predicted 25-year OS in women with BC. The present data indicate that reducing the effect of the PS events at the prediagnostic phase could decrease the rate of relapse (RFS) and increase OS time.

The studies to date assessing PS events of women with BC have not considered LDSI versus outcome. The 25-year long follow-up time of women with BC symptoms permits us to assess the RFS and OS. The PS events observed with the LDSI significantly correlate with the 25-year OS in women with BC and in women with BC symptoms. Therefore, the use of the LDSI observing PS events should be considered a useful tool in BCDU. Moreover, one can believe that all attempts aimed at suppressing the PS response, both pharmacologically and psychologically, have the potential to positively influence the outcome of women with BC symptoms.

The Authors report no conflicts of interest or financial ties regarding this study.

All Authors contributed to the collection and analysis of data, drafting and revising the manuscript, and read and approved the final article.

No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.