Abstract
Background/Aim: This study evaluated whether a psychological inventory (Forsen inventory, FI) for measuring the severity of psychological stress (PS) could predict long-term outcomes in patients having breast carcinoma (BC) symptoms.
Patients and Methods: A total of 115 patients with BC symptoms completed the FI scale and associations between FI scale and long-term outcomes were analysed using survival models.
Results: The FI scores correlated with Beck Depression Inventory (BDI) (r=0.678, p<0.001), Montgomery-Asberg Depression Rating Scale (MADRS) (r=0.820, p<0.001), and State-Trait Anxiety inventory (STAI) (r=0.556, p<0.001) levels. In Cox regression models, higher FI scores predicted poorer 25-year relapse-free survival (RFS) in BC patients (HR=2.60, p=0.05) and poorer 25-year overall survival (OS) in patients with benign breast disease (BBD) (HR=7.79, p=0.05). Kaplan-Meier analysis showed significantly better 25-year RFS among BC patients with low FI scores (<14) compared to those with high scores (≥14) (58.3% vs. 30.0%, p=0.046), and higher 25-year OS in BBD patients with low FI scores (95.8% vs. 71.4%, p=0.022).
Conclusion: The FI scale, though underutilized, effectively captures PS and significantly predicts long-term outcomes in patients with breast disease. These findings suggest that incorporating the FI into diagnostic evaluations could enhance risk stratification and management for women with BC symptoms.
Introduction
Breast carcinoma (BC) is the most common carcinoma in women (1-5) and one of the main public health problems worldwide. Early diagnosis and treatment of women with BC represents significant health-care costs and has a substantial impact on the psychological health of women. Various BC risk factors (RFs), many of which are related to features of woman’s reproductive life, hormone physiology and life-style, have been identified (6). Therefore, BC is considered a multifactorial hormone-dependent disease that may arise from the combination of genetic, environmental, hormonal, and lifestyle factors that make women susceptible to BC (6). The RFs for BC are closely associated with the outcome and therefore assessing possible RFs for BC has been the main focus for both the prevention and early diagnosis of BC (7). Although numerous RFs have been identified, substantial gaps remain in our current knowledge of the role psychological stress (PS) plays in the etiology of BC (8). The PS events are widely thought to play a role as ‘secondary’ RFs of BC, because PS could have a less pronounced connection to outcome, and would thus not necessarily be identified as RF in some studies (8). However, a positive association between PS and BC was observed in two cohort studies (9, 10) as well as in some case-control studies (11-15). Ollonen et al. (14) conducted a case-control study of PS in women with BC symptoms admitted to BC diagnostic unit (BCDU). Their results indicated that patients with BC versus women with non-BC had significantly more severe PS in the previous 10 years preceding the investigation. Authors concluded that the findings of their study support an overall association between PS and BC risk.
The findings from the above-mentioned studies motivated us to conduct the current study with the aim of searching for an association between the features of PS detected with the Forsen psychological inventory (FI) versus the 25-year relapse-free survival (RFS) and the overall survival (OS) in women diagnosed in BCDU. To date, no studies have evaluated the impact of PS factors using the FI in relation to patient outcomes through survival model analysis.
Patients and Methods
Patients. The study cohort included 115 patients with BC symptoms diagnosed in BCDU, KUH, Finland, of whom 34 (29.6%) were patients with BC and 81 non-BC patients (70.4%) (Table I). The detailed description of the study protocol is shown in earlier reports by Ollonen et al. (14, 16-18).
Baseline characteristics and mean psychological scale scores in patients with breast symptoms.
Forsen inventory (FI) for psychological stress (PS). All patients completed the FI with 11 variables listed in Table II and each variable classified into three grades: grade 0, no PS symptoms; grade 1, moderate PS symptoms and grade 2, severe PS symptoms. A detailed description of the FI protocol is shown in earlier report (19).
Severity of psychological stress (PS) symptoms assessed by the Forsen inventory across three study groups. Each variable is divided into three grades: grade 0, no psychological stress symptoms; grade 1, moderate PS symptoms; and grade 2, severe PS symptoms.
Beck Depression Inventory (BDI). A detailed description of the BDI score protocol is shown in earlier reports (20-22).
Montgomery-Asberg Depression Rating Scale (MADRS). A detailed description of the MADRS score protocol is shown in earlier reports (23-25).
Spielberger State-Trait Anxiety inventory (STAI). A detailed description of the STAI score protocol is shown in earlier reports (26, 27).
Statistical analysis. Baseline group differences were analysed using two-sided chi-square and non-parametric Kruskall-Wallis tests. RFS was calculated from the time of diagnosis to the occurrence of the first relapse, contralateral BC, or metastatic disease. 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 FI score 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 FI scores and STAI, BDI and MADRS scale values. Data were analyzed using the IBM SPSS statistical software (IBM SPSS Statistics for Windows, version 26.0, IBM Corporation, Armonk, NY, USA).
Results
BDI, MADRS, STAI and FI scales in BC and non-BC patients. The baseline data and mean score values of BDI, MADRS, STAI and FI scales in three study groups HSP, BBD and BC are presented in Table I. The mean BDI, MADRS, STAI and FI scale (0-2 years) values between BC and non-BC patients were quite similar (p=0.70, 0.78, 0.29 and 0.99, respectively, Table I). The mean FI score (2-6 years) values were slightly higher in non-BC patients (HSP=12.5 and BBD=11.8) versus BC patients (9.8, p=0.43, Table I). The FI scale levels correlated significantly with BDI scale levels (r=0.678, p<0.001, Figure 1), MADRS (r=0.820, p<0.001, Figure 2) and STAI scale levels (r=0.556, p<0.001, Figure 3).
Scatter plot of Forsen inventory (FI) score levels (0-2 years pre-diagnosis) versus Beck Depression Inventory (BDI) score levels in patients with breast symptoms (r=0.678, p<0.001).
Scatter plot of Forsen inventory (FI) score levels (0-2 years pre-diagnosis) versus Montgomery-Asberg depression rating scale (MADRS) score levels in patients with breast symptoms (r=0.841, p<0.001).
Scatter plot of Forsen inventory (FI) score levels (0-2 years pre-diagnosis) versus state-trait anxiety inventory (STAI) score levels in patients with breast symptoms (r=0.556, p<0.001).
FI variables in BC and non-BC patients. The eleven FI variables during the prodromal periods in non-BC (HSP, BBD) and BC patients classified into three grades are shown in Table II. The women with BC had slightly more severe anxiety and severe headaches compared to non-BC women (12% and 18% versus 5% and 9%, respectively, Table II). In addition, the patients with BC also had slightly more severe tiredness than the non-BC patients during the six-year prodromal period (16% versus 11%, Table II).
The 25-year RFS and OS. In the Kaplan-Meier survival analysis using the log-rank test the FI scale predicted the long-term RFS in patients with BC (Table III). The 25-year RFS differed significantly between low FI score (<14) and high FI score (≥14) patients with BC (58.3% versus 30%, log-rank p-value=0.046, Figure 4). Additionally, in the Cox analysis, the low FI score (<14) was a significant favourable predictor of the RFS (HR=2.60, 95%CI=0.98-6.88, p=0.05, Table III) in patients with BC. A similar pattern was observed in BBD patients as the FI score predicted 25-year OS in women with BBD (Table IV). The 25-year OS rate differed significantly between low FI score (<14) and high FI score (≥14) BBD patients (95.8% versus 71.4%, log-rank p-value=0.022, Figure 5). Also, in the Cox regression analysis the low FI score (<14) was a significant favourable predictor of the OS (HR=7.79, 95%CI=0.97-62.3, p=0.05, Table IV) in patients with BBD. In all patients, the 25-year OS rate differed also between those with low FI scores (<14) and those with high FI scores (≥14), although the difference did not reach statistical significance (77.6% versus 61.4%, log-rank p-value=0.069) (Figure 6).
Association between Forsen Inventory (FI) Score and 25-year relapse-free survival (RFS). RFS rates and hazard ratios (HR) with 95% confidence intervals (CI) in relation to FI scores across healthy symptomatic patients (HSP), patients with benign breast disease (BBD), and patients with breast cancer (BC) using Cox proportional hazards models.
The Kaplan-Meier survival curves for relapse-free survival (RFS) in patients with breast cancer (n=34) according to Forsen inventory (FI) scale (2-6 years pre-diagnosis). The FI score was a continuous variable in the analysis of the study patients. The FI score had a statistically significant effect on RFS according to the log-rank test (p=0.046).
Association between Forsen Inventory (FI) Score and 25-year overall survival (OS). OS rates and hazard ratios (HR) with 95% confidence intervals (CI) across healthy symptomatic patients (HSP), patients with benign breast disease (BBD), and patients with breast cancer (BC) stratified by FI score categories using Cox proportional hazards models.
The Kaplan-Meier survival curves for overall survival (OS) in patients with benign breast disease (BBD) (n=54) according to Forsen inventory (FI) scale (0-2 years pre-diagnosis). The total FI score was a continuous variable in the analysis of the study patients. The FI score had a statistically significant effect on RFS according to the log-rank test (p=0.022).
The Kaplan-Meier survival curves for overall survival (OS) in patients with breast symptoms (n=115) according to Forsen inventory (FI) scale (0-2 years pre-diagnosis). The total Forsen score was a continuous variable in the analysis of the study patients. The FI score had almost statistically significant effect on RFS according to the log-rank test (p=0.069).
Discussion
The RFs for BC are closely associated with the outcome and therefore assessing possible RFs for BC has been the main aim for both the prevention and early diagnosis of BC (7). Although several RFs have been identified, substantial gaps remain in current knowledge of the effect of PS factors on the etiology of BC (8). Interestingly, a positive association between PS and BC was observed in two cohort studies (9, 10) and in several case-control studies (11-15). Helgesson et al. (9) studied self-reported PS levels in a cohort of Swedish women. Authors found that women with BC reporting PS during the five years preceding diagnosis had a two-fold higher rate of BC compared with women reporting no PS (HR= 2.1; 95%CI=1.2-3.7).
Lillberg et al. (10) investigated PS as a risk of BC in women from the Finnish Twin Study cohort. PS events and RFs of BC were assessed by self-administered questionnaire. The HR for BC was 1.35 (95%CI=1.09-1.67), when major life events were considered. Independently of total life events, divorce/separation (HR=2.26, 95%CI=1.25-4.07), death of a husband (HR=2.00, 95%CI=1.03-3.88), and death of a close relative or friend (HR=1.36, 95%CI=1.00-1.86) were all associated with increased risk of BC.
Forsen (11) assessed PS events preceding BC diagnosis in a case-control study of women with BC symptoms. The control group of women was selected from the general female population and matched for sex, age and number of child-births. The findings showed that patients with BC had significantly more PS events, important losses, and difficult life situations prior BC diagnosis. Their analysis indicated that important losses during a 6-year prodromal period of BC diagnosis were associated with enhanced BC risk. The association persisted after adjustment for marital status, education, and social class.
Chen et al. (12) performed a case-control study with 119 women, who were referred for biopsy of a suspicious breast lesion (BC=41 and non-BC=78). Authors reported that PS events increased the risk of BC three-fold (HR=3.2, 95%CI=1.35-7.6). After adjustment for age, menopause and other potential confounders, the HR for BC rose almost 4-fold (HR=11.6, 95%CI=3.1-43.7). However, non-severe life events and long-term difficulties had no significant association with enhanced BC risk. The authors concluded that there is significant association between PS events and risk of BC.
Kruk et al. (13) assessed, in a case-control study, whether PS could enhance BC risk. The women in their study filled a questionnaire including questions on lifetime physical activity, diet, reproductive history and experience of PS. The women in their study reported PS events, stress of daily activity and experience of stress at work. After adjustment for age and other potential confounders, the authors found that women with PS events, stress of daily activity and depression had significantly higher risk for BC (HR=3.70; 95%CI=2.61-5.26). The authors concluded that their findings suggest an association between PS events and BC risk. The same authors (15) also studied the association of severe life events with the risk of BC. Their case-control study was based on examination of patients with BC and women matched for age and place of residence as controls. Data on PS events, reproductive factors and lifestyle habits were collected using a self-administered questionnaire. After adjustment for potential RFs for BC, women with four to six PS events had 5.33 times higher risk for BC, compared with women in the lowest quartile of PS events. Several PS events (death of a close family member, personal injury or illness, imprisonment/trouble with the law, retirement) were significantly associated with BC risk. These findings suggest that major life events can play an important role in the etiology of BC.
Ollonen et al. (14) conducted a case-control study of PS events in women with BC symptoms admitted to BCDU and they completed BDI, MADRS and STAI questionnaires. The women with BC reported clearly enhanced PS (p =0.02) and more losses (p<0.001) in comparison to non-BC patients. Their results indicated that patients with BC had significantly more severe PS events in the previous 10 years preceding the diagnosis compared to non-BC women. The authors concluded that a severe PS load and significant personal losses could significantly enhance BC risk. The same authors also studied the PS events, psychiatric medications and the risk of BC in 115 women with BC symptoms before any diagnostic procedures (19). This study might indicate a weak association between PS events detected with the FI scale and risk of BC. Unfortunately, the cohort of patients with psychiatric medications was too small to detect a link between medications and increased BC risk (19).
The findings from the above-mentioned studies motivated us to conduct the current study with the aim of searching for an association between PS events detected with FI scoring and the 25-year outcome with RFS and OS in women with BC symptoms diagnosed in BCDU. No previous studies are available where the outcome of the PS events with the FI approach had been estimated using survival models.
Taken together, the aim was to investigate the characteristics of the PS events detected with the FI model in women with BC symptoms and to report their association with outcome. The results showed that the PS events detected with the FI scale correlate with the 25-year RFS and OS in women with BC symptoms. The present data indicate that the FI scale seem to have the potential to enhance the diagnostic accuracy (DA) of the PS testing in women with BC symptoms.
Different types of environmental stress, including PS, affect organisms every day, sometimes resulting in substantial detrimental changes in the functioning of living cells (28, 29). Exposure to different stressors can trigger molecular and cellular processes that underlie DNA and protein damage, oxidative stress, and energy metabolism disturbances, all of which may contribute to the development and progression of BC (28, 29). This article draws attention to the problem of cancer-related PS and proposes a novel FI scale approach for patients with BC symptoms. Even though the PS in patients with BC symptoms during their visit at BCDU seems to be rather negative, the PS-related neuroendocrine, metabolic and immune reactions during BCDU-visit remains unclear (30, 31). However, recently published studies demonstrated increased plasma levels of the biomarkers of oxidative stress glutathione peroxidase and superoxide dismutase (SOD1) following surgery in patients with cancer and benign disease (32, 33). In addition, Kärkkäinen et al. (34) reported enhanced SOD1 plasma levels post-surgery in gallstone patients, while Saimanen et al. (35) assessed cell damage, oxidative stress, and inflammation by measuring the plasma concentration of the nitrosative stress biomarker nitrotyrosine (NT) in patients with gallstone disease and cancer. Although, this study seems to be significant in the light of a comprehensive analysis of PS in patients with BC symptoms, more attention should be paid on the PS during the visit at BCDU. Diagnosis and treatment of patients with BC should be accompanied by appropriate PS testing and psychological support to prevent the negative impact of PS on the psychological health of women with BC symptoms (36, 37). In addition to PS testing, analysis of modern omics-based blood biomarkers may open new ways to understand the connection of PS with BC development and progression in the future (38-40).
Conclusion
Early diagnosis and treatment of women with BC represents significant health-care costs and has a substantial impact on the psychological health of women. Various RFs of BC have been identified, many of which are related to woman’s reproductive life, hormone physiology, and life-style. To date, the studies assessing the effect of PS events on the outcome of women with BC have not used the FI scale. Until now, the lack of long follow-up time of women with BC has delayed the advance in survival model calculations. The follow-up of women with BC symptoms enables us to detect the 25-year outcome and to assess the association of RFS and OS with PS events detected with the FI scale using survival models. The present study showed that the PS events detected with the FI scale significantly correlate to the 25-year RFS in patients with BC and 25-year OS in patients with BBD. Therefore, the use of the FI scale detecting PS events should be considered as a useful part of the diagnostic decision tree of patients with BC symptoms.
Footnotes
Authors’ Contributions
All Authors contributed to the collection and analysis of data, drafting and revising the manuscript, and read and approved the final article.
Conflicts of Interest
The Authors report no conflicts of interest or financial ties regarding this study.
Artificial Intelligence (AI) Disclosure
No AI tools, including large language models or machine learning software were used in the preparation, analysis or presentation of this manuscript.
- Received May 30, 2025.
- Revision received June 16, 2025.
- Accepted June 17, 2025.
- Copyright © 2025 The Author(s). Published by the International Institute of Anticancer Research.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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