# Investigating the Trajectories of Association Between Biomarkers and Cancer-Related Cognitive Impairment in Patients with Breast Cancer: A Systematic Review

## TL;DR

This review explores how biomarkers like IL-6 and TNF-α relate to cognitive issues in breast cancer patients, highlighting the need for better studies.

## Contribution

The paper provides a systematic synthesis of biomarker-cognition associations in breast cancer patients, emphasizing treatment-specific and longitudinal research needs.

## Key findings

- Inflammatory cytokines IL-6 and TNF-α show variable associations with cognitive decline depending on timing and assessment type.
- Genetic studies suggest DNA repair and oxidative stress pathways are involved, but results for APOE, COMT, and BDNF are inconsistent.
- Biomarker-cognition associations remain heterogeneous, highlighting the need for longitudinal and harmonized studies.

## Abstract

Cancer-related cognitive impairment (CRCI) is a common and disabling consequence of breast cancer (BC) and its treatments, yet its biological underpinnings remain unclear. This systematic review synthesized evidence from 53 studies examining associations between blood or saliva biomarkers and cognitive outcomes in adults with non-metastatic BC. Most research focused on chemotherapy (ChT), while endocrine therapy (ET) and radiotherapy (RT) were less studied, and immunotherapies were rarely assessed. Assessments were largely conducted post-treatment, with few pre-treatment baselines. Biochemical findings centered on inflammatory cytokines, particularly IL-6 and TNF-α, which were variably associated with cognitive decline depending on timing and assessment type. Other markers, such as CRP, stress-axis hormones, and BDNF, showed mixed results or were associated predominantly with self-reported measures. Genetic studies implicated DNA repair and oxidative stress pathways, but results for APOE, COMT, and BDNF were inconsistent. Overall, biomarker–cognition associations remain heterogeneous, underscoring the need for longitudinal, harmonized, and treatment-specific studies.

Background/Objectives: Cancer-related cognitive impairment (CRCI) is a frequent and clinically significant consequence of breast cancer (BC) and its treatments. With rapidly evolving therapeutics and a growing body of biomarker research, a BC-specific synthesis is needed. This review aimed to evaluate associations between blood- and saliva-based biomarkers and objective and patient-reported cognitive outcomes in adults with non-metastatic BC, while accounting for treatment modality and assessment timing. Methods: This systematic review followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines and was pre-registered in the International Prospective Register of Systematic Reviews (PROSPERO, ID: CRD420251079969). PubMed, Embase, and Web of Science were searched for articles published up until April 2025. Eligible studies included adults with BC that investigated associations between blood and/or saliva biomarkers and cognitive outcomes. Results: A total of 53 studies met inclusion criteria: 31 examined biochemical biomarkers; 17, genetic; and 5, both. Assessments were predominantly post-treatment. Baseline measures were more infrequent. Chemotherapy (ChT) predominated, while endocrine therapy (ET) and radiotherapy (RT) were variably examined. Targeted therapies and immunotherapies were rarely included. IL-6 and TNF-α were most consistently linked to poorer cognition, although results varied by timing and assessment type. CRP and derived indices showed intermittent associations. Stress-axis markers and BDNF were mainly related to subjective outcomes. Genetic findings implicated DNA repair and oxidative stress pathways, while APOE, COMT, and BDNF results were inconsistent. Conclusions: Evidence for biomarker correlates of CRCI in BC is highly heterogeneous. Longitudinal, harmonized, and treatment-specific studies are needed to establish reproducible biomarker panels for risk stratification and targeted intervention.