A new exploratory study sheds light on the biological mechanisms that may contribute to cognitive dysfunction in postmenopausal women with early-stage, hormone receptor-positive breast cancer—even before the initiation of adjuvant therapy. The study highlights key epigenetic differences linked to both objectively and subjectively assessed cognitive function (CF), pointing to divergent biological pathways.

A total of 109 patients were included in the epigenome-wide association study (EWAS), where researchers analyzed whole blood samples obtained at the time of study enrollment, prior to any adjuvant treatment. Participants were rigorously phenotyped for objective CF across 7 domains, each assessed using multiple neuropsychological tests, and for subjective CF using the Patient’s Assessment of Own Functioning Inventory (PAOFI).

The analysis identified distinct differentially methylated regions associated with each CF phenotype. Pathway-level insights from Ingenuity Pathway Analysis revealed the axonal guidance signaling pathway as significantly linked to the objective domain of processing speed. In contrast, the synaptogenesis signaling pathway was the most significant in relation to PAOFI total scores, which reflect self-reported cognitive function.

"Axonal guidance and synaptogenesis are both important to normal brain function," the study notes, "therefore it makes sense that these pathways would surface in a discovery-based manner as being important to CF."

These findings mark a critical advancement in understanding the etiology of cognitive impairment in breast cancer patients. Importantly, the data suggest that objective and subjective cognitive impairments may arise from biologically distinct mechanisms, which may in turn influence patient management.

"Finding that different pathways may play different roles in objective CF versus subjective CF hints that patient reported CF may be biologically distinct from objectively measured CF," the authors write.

This distinction holds potential clinical implications. If subjective cognitive complaints and objectively measurable cognitive deficits are driven by separate biological processes, interventions to prevent or treat cognitive decline may need to be tailored accordingly. It also underscores the importance of utilizing both objective and subjective assessments when evaluating CF in oncology patients.

In conclusion, this study supports the growing recognition that cognitive changes in cancer patients may begin prior to treatment and are biologically mediated. Continued research into epigenetic markers and pathway-specific mechanisms may be key to developing targeted interventions for cancer-related cognitive decline.

Source:

Conley Y, Liu S, Weeks D, Shaffer J, Erickson K, Bender C. Data-driven epigenomic analyses reveal different signaling pathways for subjective and objective cognitive function in early-stage breast cancer. Presented at the 50th Annual ONS Congress; April 9-12, 2025. Denver, CO.