Chemotherapy, endocrine therapy, and cognitive impairment in long-term breast cancer survivors.

523 Background: Chemotherapy and endocrine therapy have known neurobiological effects, yet evidence on their associations with long-term cognitive impairment remains limited. This study examined the relationship between prior chemotherapy, endocrine therapy, and cognitive impairment among long-term breast cancer survivors. Methods: Between July and September 2025, 1,338 participants from the Chicago Multiethnic Epidemiologic Breast Cancer Cohort were surveyed and completed the Functional Assessment of Cancer Therapy-Cognition (FACT-Cog), a validated self-report instrument assessing 4 specific domains: perceived cognitive impairment (PCI; scores 0–72), cognitive-related quality of life (QoL; scores 0–16), perceived cognitive abilities (PCA; scores 0–27), and comments-from-others (scores 0–16). Lower scores reflect worse cognitive function. Cognitive impairment was defined as a PCI score <54. Multivariable logistic regression was used to evaluate associations between chemotherapy and endocrine therapy with cognitive impairment. Multiple linear regression was used to assess associations with continuous FACT-Cog domain scores. All models were adjusted for age, race/ethnicity, radiotherapy, surgery history, and educational attainment. Results: The mean age at survey of the 1,338 study participants was 64.3 years (SD 11.7), and the median time from diagnosis to survey was 9.4 years (IQR 6.1–14.1). Overall, 299 (22.3%) met criteria for cognitive impairment. Additionally, 594 (44.4%) and 851 (63.6%) of the participants had prior chemotherapy and endocrine therapy, respectively. In adjusted analyses, chemotherapy (adjusted odds ratio [aOR] 1.39; 95% CI 1.03 to 1.89; p =0.033) and endocrine therapy (aOR 1.86; 95% CI 1.35 to 2.57; p <0.001) were significantly associated with cognitive impairment. Chemotherapy was associated with lower PCI ( β −2.11; 95% CI −3.61 to −0.61; p =0.006), and lower QoL ( β −0.60; 95% CI −1.01 to −0.19; p =0.04). Endocrine therapy was associated with lower scores in PCI ( β −2.52; 95% CI −4.02 to −1.02; p =0.001), QoL ( β −0.55; 95% CI −0.96 to −0.14; p =0.009), PCA ( β −1.54; 95% CI −2.29 to −0.79; p <0.001), and comments-from-others ( β −0.28; 95% CI −0.49 to −0.07; p =0.008). In joint models, those who received both chemotherapy and endocrine therapy (aOR 2.46; 95% CI 1.46 to 4.18; p =0.001) and those who received endocrine therapy alone (aOR 1.71; 95% CI 1.04 to 2.81; p =0.035) had significantly higher odds of cognitive impairment than participants who received neither therapy. Conclusions: In this multiethnic cohort of long-term breast cancer survivors, prior chemotherapy and endocrine therapy were independently associated with worse perceived cognitive functioning across multiple domains. These findings underscore the need for future studies to identify neuroprotective strategies and interventions to mitigate treatment-related cognitive sequelae.