Chemotherapy-related cognitive impairment (CRCI), widely known as “chemobrain,” has become a major survivorship challenge among women treated for breast cancer. A substantial proportion of patients-estimated between 30% and 75%-report difficulties in attention, memory, executive functioning, and processing speed during or after systemic treatment [1,2]. These cognitive difficulties may persist long after completion of therapy and have been linked to impaired daily functioning, decreased work productivity, reduced social engagement, and lower overall quality of life [3,4]. As global survival rates for breast cancer continue to improve, understanding the long-term cognitive and psychosocial consequences of treatment has become an essential component of comprehensive oncological care.

The etiology of CRCI is multifactorial, involving complex biological and psychosocial mechanisms. Proposed pathways include neuroinflammation, oxidative stress, alterations in hormonal regulation, disruption of white matter microstructure, and impaired neurogenesis [2,5]. At the same time, demographic and psychological moderators-such as age, education, cognitive reserve, distress, and fatigue-may influence both the severity and the subjective experience of cognitive decline [6,7]. Importantly, subjective cognitive complaints often only partially correlate with objective neuropsychological performance, underlining the value of patient-reported outcomes in capturing the lived experience of cancer survivors [8].

Although CRCI is well-documented across North America, Western Europe, and parts of Asia, research from Central and Eastern Europe remains markedly limited. In Bulgaria, there are currently no published empirical studies systematically assessing chemotherapy-related cognitive impairment or its influence on quality of life in women with breast cancer. The absence of national data presents a significant knowledge gap, as cultural factors, differences in healthcare pathways, levels of psychological support, sociodemographic characteristics, and attitudes toward symptom reporting may shape the perception and expression of cognitive difficulties in meaningful ways. The lack of local evidence restricts the development of tailored psychological, psychosocial, and rehabilitative interventions within the Bulgarian healthcare context.

Patient-reported outcome measures are essential for evaluating cognitive complaints in real-world clinical environments. Among them, the Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog v3) is one of the most widely used and psychometrically robust instruments for assessing perceived cognitive impairment and its impact on quality of life [9,10]. Despite its extensive international application, FACT-Cog has not previously been used in a structured scientific study in Bulgaria, and no comparative analysis across clinical groups has been performed.

Despite the growing international evidence on CRCI, Bulgaria lacks national epidemiological or psychosocial data describing cognitive outcomes among breast cancer survivors. The absence of structured screening practices and limited access to psycho-oncological services further restrict the development of evidence-based survivorship strategies. Understanding the cognitive and functional needs of Bulgarian women is therefore essential for designing culturally appropriate interventions and improving long-term supportive care.

Given these gaps, there is a clear need to generate foundational evidence regarding cognitive functioning and quality of life among Bulgarian women with breast cancer. The present study addresses this need by conducting the first pilot, single-center, three-group investigation comparing: (1) women treated with chemotherapy, (2) women with breast cancer who have not undergone chemotherapy, and (3) healthy controls. Through this design, the study provides an essential first step in characterizing CRCI within the Bulgarian population and offers initial insights into the relationship between cognitive complaints, sociodemographic factors, and quality-of-life outcomes. These findings aim to lay the groundwork for future longitudinal, multicenter, and multimodal research and to support the development of evidence-based psychosocial care for oncology patients in Bulgaria.

Study Design and Setting

A cross-sectional, comparative pilot study was conducted in a single tertiary oncology center in Bulgaria. The study was carried out between 2022 and 2023 in the outpatient department of medical oncology. This investigation represents the first structured assessment of chemotherapy-related cognitive impairment (CRCI) and quality of life among Bulgarian women with breast cancer.

Participants

A total of 62 women were enrolled and assigned to one of three groups:

1. Chemotherapy group (CT+)-women diagnosed with stage I-III breast cancer who had completed at least three cycles of adjuvant or neoadjuvant chemotherapy.
2. Non-chemotherapy group (CT-)-women with stage I-III breast cancer who had not received chemotherapy.
3. Healthy control group (HC)-women without a history of cancer or neurological/psychiatric illness.

Inclusion Criteria

• Female sex, ≥18 years
• Minimum primary education
• Ability to read and complete self-report questionnaires independently
• For CT+: completion of chemotherapy wi-hin the past 6–24 months
• For HC: no oncological or chronic neurological disease history

Exclusion Criteria

• Prior diagnosis of neurological disorders (e.g., epilepsy, traumatic brain injury, dementia)
• Severe psychiatric illness (major depression, bipolar disorder, psychotic disorders)
• Current CNS metastases or prior cranial radiotherapy
• Substance abuse or cognitive impairment interfering with participation
• Inability to provide informed consent

These criteria align with commonly applied standards in CRCI research and minimize confounding factors.

Measures

Sociodemographic and Clinical Data

Participants completed a structured questionnaire including age, education, employment status, menopausal status, comorbidities, and detailed cancer-treatment characteristics (where applicable).

Cognitive Functioning

Perceived cognitive functioning was evaluated using the Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog v3), a standardized and internationally validated 37-item questionnaire that assesses:

• Perceived Cognitive Impairments (PCI)
• Perceived Cognitive Abilities (PCA)
• Comments from Others (Oth)
• Impact on Quality of Life (QoL)

Higher scores reflect better cognitive functioning or quality of life.

Quality of Life

FACT-Cog’s QoL subscale served as the primary indicator of the effect of cognitive changes on participants’ daily functioning and overall well-being.

Procedure

Eligible participants were recruited consecutively during routine clinical visits (CT+ and CT– groups) or via community outreach (HC group). After informed consent, questionnaires were completed in a quiet room with the assistance of a trained psychologist when needed. Data collection for all groups followed the same standardized protocol.

Ethical Considerations

The study was conducted in accordance with the Declaration of Helsinki. All participants provided informed consent. Permission for the use of the FACT-Cog questionnaire was obtained from the copyright holders. All data were anonymized and handled confidentially.

Statistical Analysis

Data were analyzed using SPSS (v. Version 26.0; IBM Corp., Armonk, NY, USA).

• Descriptive statistics summarized sociodemographic and clinical variables.
• Group differences were examined using Kruskal-Wallis tests, followed by Mann-Whitney U post-hoc analyses.
• Associations between cognitive outcomes and QoL were assessed using Spearman’s rho correlations.
• A multiple linear regression model was constructed to identify predictors of QoL, including age, education, employment, and cognitive impairment scores.
• Statistical significance was set at p < .05 (two-tailed).

This analytical framework aligns with international methodological standards for pilot CRCI research.

Sample Characteristics

A total of 62 women participated in the study: 21 in the chemotherapy group (CT+), 21 in the non-chemotherapy breast cancer group (CT–), and 20 healthy controls (HC). The three groups were comparable in age distribution and general sociodemographic profiles. Menopausal status and use of hormonal therapy differed as expected between clinical groups, reflecting treatment-related characteristics. A summary of the sample distribution across key variables is presented in Table 1.

Group Differences in Perceived Cognitive Functioning

Overall Cognitive Complaints

Across all FACT-Cog domains, women in the CT+ group reported the highest levels of cognitive difficulties.

• Memory problems, difficulty concentrating, slowed thinking, and word-finding difficulties were notably more frequent in the CT+ group.
• These symptoms were less pronounced in the CT– group and lowest in the HC group.

For example, memory-related complaints were reported by over one-third of women in the CT+ group, compared with approximately 2.5% in the CT– group and 3.8% in the HC group.

Specific Cognitive Domains

A detailed item-level analysis revealed clear domain patterns:

• Difficulty concentrating: Most prominent in the CT+ group, suggesting challenges with sustained attention and mental focus.
• Slowed thinking: Frequently reported among CT+ participants, indicative of reduced processing speed and longer time needed for decision-making.
• Word-finding problems: Present across groups but markedly elevated in the CT+ group.
• Verbal expression and short-term memory: Also notably affected in CT+ participants, consistent with typical CRCI symptom clusters.

Group Comparisons on FACT-Cog Total and Subscale Scores

The FACT-Cog total score and subscale scores (Perceived Cognitive Impairments, Perceived Cognitive Abilities, Comments from Others, and Impact on Quality of Life) demonstrated a consistent group pattern:

• CT+ group: Worst cognitive scores across all subscales
• CT– group: Intermediate performance
• HC group: Best cognitive functioning

Kruskal-Wallis tests indicated statistically significant differences across the three groups on most cognitive dimensions. Post-hoc analyses using the Mann-Whitney U test confirmed that the CT+ group differed significantly from both CT– and HC groups, while differences between CT– and HC were smaller and domain-specific.

Impact of Cognitive Difficulties on Quality of Life

Women in the CT+ group reported the strongest negative QoL impact associated with cognitive symptoms. FACT-Cog’s QoL subscale showed:

• Substantial QoL reduction in CT+
• Moderate reduction in CT–
• Minimal impact in HC

These results support the hypothesis that CRCI exerts a clinically meaningful effect on daily functioning and well-being.

Statistical Summary

Kruskal–Wallis analyses demonstrated significant differences among the three groups across the primary cognitive domains (H values significant at p < .05). Post-hoc Mann–Whitney U comparisons confirmed that the chemotherapy group scored significantly lower than both the non-chemotherapy and healthy control groups across all core FACT-Cog indices (all p < .05).

Spearman correlations indicated a moderate negative association between perceived cognitive impairment and quality of life (ρ ≈ –0.40, p < .01).

Multiple linear regression analysis identified perceived cognitive impairment as a significant independent predictor of quality of life (β significant at p < .05), whereas age and education contributed non-significantly to the model.

Correlation Analysis

Spearman correlations demonstrated:

• The relationship between perceived cognitive abilities and QoL showed a trend toward significance (p = .099).
• Sociodemographic variables such as age, education, and employment status demonstrated small-to-moderate associations with cognitive scores.

These findings indicate that cognitive complaints are meaningfully tied to functional outcomes, although moderated by demographic characteristics.

Regression Analysis

A multiple linear regression model tested predictors of QoL. Variables entered into the model included age, education, employment status, and FACT-Cog cognitive impairment scores.

• Perceived cognitive impairment emerged as the only significant independent predictor of QoL.
• Age and education showed weak non-significant contributions.
• The model’s predictive power was modest, suggesting the influence of additional unmeasured factors (e.g., psychological distress, fatigue), consistent with CRCI literature.

Summary of Key Findings

1. Chemotherapy-treated women reported significantly higher cognitive difficulties compared with both clinical and healthy controls.
2. The CT– group showed mild cognitive complaints, indicating that cancer itself and associated stressors may contribute to cognitive symptoms.
3. QoL was most adversely affected in the chemotherapy group.
4. Cognitive impairment predicted QoL independently of demographic factors.
5. These results provide the first national evidence of chemotherapy-related cognitive difficulties in Bulgarian women.

Table 1: Sociodemographic and Clinical Characteristics of the Sample (N = 62).

The present study provides the first empirical evidence of chemotherapy-related cognitive impairment (CRCI) among Bulgarian women with breast cancer. Consistent with international findings, the chemotherapy group reported significantly greater perceived cognitive difficulties across memory, concentration, processing speed, and verbal expression when compared with both non-chemotherapy patients and healthy controls. These results reinforce the robust body of literature indicating that systemic cancer treatment is associated with a measurable subjective decline in cognitive functioning [1,2]. Importantly, our findings extend this knowledge to a previously unexamined population in Central and Eastern Europe, highlighting both the universality of CRCI and the relevance of examining it within diverse sociocultural contexts.

These findings are consistent with international trends observed in North American, Western European, and Asian cohorts, suggesting that CRCI manifests similarly across diverse sociocultural contexts. This convergence supports the global generalizability of CRCI patterns and highlights that cognitive vulnerabilities following chemotherapy may be driven by shared biological mechanisms, irrespective of healthcare system differences.

A notable outcome of this study is the central role of subjective cognitive complaints. Similar to prior research, participants treated with chemotherapy reported substantial cognitive changes even in the absence of objective neuropsychological assessment. This aligns with evidence suggesting that subjective cognitive impairment reflects complex interactions among biological alterations, psychological distress, fatigue, and metacognitive awareness. Subjective complaints are often more sensitive to real-world functional limitations than formal cognitive tests and have been shown to predict long-term psychosocial outcomes, work-related challenges, and reduced quality of life [4]. Thus, patient-reported cognitive symptoms should be viewed as clinically meaningful indicators in survivorship care, rather than secondary or less reliable metrics.

The mechanisms underlying CRCI are multifactorial and likely involve a dynamic interplay between neurobiological and psychosocial factors. From a biopsychosocial perspective, chemotherapy-induced neuroinflammation, oxidative stress, hormonal dysregulation, and alterations in white matter microstructure may contribute to cognitive inefficiencies. Psychosocial contributors-including emotional distress, sleep disturbances, attentional load, and illness-related uncertainty-may further amplify cognitive vulnerability. In the Bulgarian context, additional systemic factors such as limited access to psycho-oncological services, sociocultural expectations regarding illness, and stigma related to cognitive complaints may also shape symptom perception and reporting.

A particularly important finding in this study is the moderating role of cognitive reserve, represented through educational level and employment status. Women with higher education or sustained occupational engagement tended to report fewer cognitive difficulties and better quality-of-life outcomes. This is consistent with the cognitive reserve hypothesis [6], which posits that enriched cognitive activity buffers against neurocognitive decline. These results suggest that cognitive and social enrichment may serve as protective factors in Bulgarian cancer survivors and underscore the importance of integrating cognitive-supportive interventions into survivorship programs.

From a clinical perspective, the findings highlight several implications for oncology care in Bulgaria. First, cognitive symptoms should be routinely screened using validated patient-reported outcome measures such as FACT-Cog, particularly for women undergoing systemic therapy. Second, the high burden of cognitive complaints emphasizes the need for accessible psycho-oncological and cognitive rehabilitation services. Currently, such services remain underdeveloped in Bulgaria, and the present findings provide a compelling rationale for strengthening integrated survivorship care. Third, educational and occupational status may help clinicians identify individuals at higher risk for CRCI and guide targeted support strategies.

Finally, this pilot, single-center study serves as a foundational step toward more comprehensive research on CRCI in Bulgaria. Although preliminary, the results clearly indicate that cognitive impairments represent a meaningful survivorship challenge and justify the development of systematic longitudinal and multicenter studies. These future investigations should incorporate multimodal methodologies, combining subjective assessments with objective neuropsychological testing, neuroimaging, and biological markers to deepen understanding of CRCI trajectories and mechanisms.

Clinical Implications

The findings of this pilot study underscore the need for routine cognitive screening in Bulgarian oncology settings, particularly for women undergoing chemotherapy. Incorporating validated patient-reported measures such as FACT-Cog into standard follow-up assessments may facilitate early identification of patients experiencing cognitive difficulties. Given the observed association between cognitive impairment and lower quality of life, integrating psycho-oncological support, cognitive rehabilitation strategies, and patient education into survivorship care pathways may help mitigate the negative functional impact of CRCI. Additionally, recognizing the protective role of cognitive reserve highlights the importance of promoting cognitive engagement interventions, vocational reintegration, and tailored psychosocial support for at-risk patients.

Limitations

This study has several limitations that should be considered when interpreting the findings. First, it was conducted in a single oncology center, which may limit generalizability to the broader Bulgarian population. Second, the study relied exclusively on subjective patient-reported measures of cognitive function. Although highly relevant for functional and psychosocial outcomes, subjective measures may not fully correspond to objective neurocognitive performance. Third, the design was cross-sectional, preventing conclusions regarding causality or temporal patterns of cognitive change. Comprehensive longitudinal studies are needed to assess pre-treatment baseline functioning and cognitive trajectories over time. Finally, objective neuropsychological testing and biological or imaging markers were not included, which will be important components of future investigations aiming to clarify underlying mechanisms.

This study presents the first empirical data on chemotherapy-related cognitive impairment among Bulgarian women with breast cancer. Chemotherapy was associated with significantly greater subjective cognitive difficulties and reduced quality of life compared with both non-chemotherapy patients and healthy controls. These findings emphasize the importance of recognizing cognitive symptoms as a meaningful aspect of survivorship, with implications for daily functioning, emotional well-being, and social participation. Early psychological support, routine cognitive screening, and integration of cognitive-focused interventions into oncology care pathways may help mitigate these effects. The results highlight the need for continued research and the development of evidence-based survivorship care tailored to Bulgarian patients.

Future Directions

Future research should build upon these pilot findings by employing:

1. Longitudinal designs capturing cognitive functioning before, during, and after chemotherapy to track changes over time.
2. Objective neuropsychological testing integrated with patient-reported measures to better characterize cognitive profiles.
3. Neurobiological markers (e.g., inflammatory cytokines, neuroimaging) to elucidate mechanisms underlying CRCI.
4. Multicenter studies to enhance generalizability and capture regional differences across Bulgarian oncology settings.
5. Intervention trials, including cognitive training, mindfulness-based programs, and psychoeducational approaches aimed at mitigating CRCI and improving quality of life.
6. Cultural Considerations - Future research should examine how cultural beliefs, communication norms, and attitudes toward psychological symptoms influence the reporting and interpretation of cognitive complaints among Bulgarian women. Understanding culturally specific patterns of symptom expression may help tailor psycho-oncological interventions and improve screening accuracy in this population.

Strengths

This study has several notable strengths. It is the first investigation to systematically examine chemotherapy-related cognitive impairment in Bulgarian women with breast cancer. The inclusion of two clinical groups and a healthy control group provides a robust comparative design, allowing differentiation between cancer-related and treatment-related effects. The use of a validated and internationally recognized patient-reported outcome measure (FACT-Cog v3) enhances the reliability and external comparability of the findings. Additionally, focusing on sociodemographic moderators provides novel insights relevant for individualized survivorship care in Bulgaria.

This research is supported by the Ministry of Education and Science under National Program "Young Scientists and Postdoctoral Fellows -2".

1. Ahles TA, Root JC. Cognitive effects of cancer and cancer treatments. Annual Review of Clinical Psychology. 2018; 14: 425-451.
2. Wefel JS, Kesler SR, Noll KR, Schagen SB. Clinical characteristics, pathophysiology, and management of noncentral nervous system cancer-related cognitive impairment in adults. CA: A Cancer J for Clinicians. 2015; 65: 123-138.
3. Reid-Arndt SA, Hsieh C, Perry MC. Neuropsychological functioning and quality of life during the first year after completing chemotherapy for breast cancer. Psycho-Oncology. 2010; 19: 535-544.
4. Von Ah D, Habermann B, Carpenter JS, Schneider BL. Impact of perceived cognitive impairment in breast cancer survivors. European J Oncology Nursing. 2013; 17: 236-241.
5. Janelsins MC, Kesler SR, Ahles TA, Morrow GR. Prevalence, mechanisms, and management of cancer-related cognitive impairment. Int Review of Psychiatry. 2014; 26: 102-113.
6. Stern Y. Cognitive reserve. Neuropsychologia. 2009; 47: 2015-2028.
7. Ahles TA, Root JC, Ryan EL. Cancer- and treatment-associated cognitive change: An update on the state of the science. J Clinical Oncology. 2012; 30: 3675-3686.
8. Henneghan AM, Stuifbergen AK. Perceived cognitive deficits in women with breast cancer: A review of the literature. Cancer Nursing. 2010; 33: E1-E17.
9. Wagner LI, Sweet JJ, Butt Z, Lai JS, Cella D. Measuring patient self-reported cognitive function: Development of the Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) instrument. J Supportive Oncology. 2009; 7: W32-W39.
10. Joly F, Lange M, Rigal O, Correia H, Giffard B, Beaumont JL, et.al. French version of the Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) questionnaire: Validation and norms. J Pain and Symptom Management. 2012; 43: 105-114.