SCIENTIFIC ABSTRACT Background: Women with locally advanced breast cancer (LABC), and women with high risk (T2-3/N+4, triple negative) yet operable breast cancer, undergo combined treatment including chemotherapy, surgery, irradiation, and hormonal treatment. These treatments decrease the chance of recurrence of cancer, but are associated with several side effects, including cognitive difficulties. About one third of breast cancer patients treated with chemotherapy report sustained decline in thinking abilities ('chemofog') after treatment. The causes for cognitive declines are not known. However there is recent information that: (i) people with cancer may have high levels of cytokines and other inflammatory molecules in the blood; (ii) injection of cytokines into animals, and their use to treat some human diseases, can lead to problems in memory and other cognitive abilities; (iii) some survivors of breast cancer have very high cytokine levels with no evidence that their cancer is still active and (iv) in some advanced cancers different cytokines and other inflammatory markers have prognostic information for disease outcome. Genetic polymorphisms of neuronal proteins (APOe, BDNF, COMT) are predictive for cognitive decline in non-cancer population). Objective: This longitudinal study will determine whether serum levels of cytokines and other inflammatory markers are related to 1) cognitive dysfunction; and 2) recurrence of disease in women with LABC/High Risk. Method: In 120 women with LABC/High risk relation of cytokines and inflammatory markers to cancer recurrence will be evaluated; blood will be drawn pre-chemotherapy, pre-surgery and then 1 and 2 years after diagnosis. In a subset of 60 women with LABC/high risk, cognitive performance will be evaluated at similar times as blood will be drawn. Similarly, a control group of 60 healthy women will be evaluated for cytokines and cognitive performance. We will also evaluate the predictive role of polymorphisms in genes encoding the neuronal proteins APOe, BDNF, and COMT for cognitive impairment. Data Analysis: The impact of cytokine levels and other inflammatory markers on cognitive performance over time will be evaluated using mixed model regression. Multivariate model will be applied to assess the impact of LABC/high risk and chemotherapy on cognitive functions. Cox proportional-hazard model will evaluate the relationship of cytokines and other blood markers on Time-To-Progression to identify variables that predict reoccurrence. Hypotheses: Cytokines and inflammatory markers are related to cognitive impairment and in disease outcome in women with locally advanced and high risk operable breast cancers. Genetic polymorphisms of neuronal proteins (APOe, BDNF, and COMT) are predictive for increased cognitive decline after diagnoses and treatment of these cancers. Implications: Increased knowledge about the causes of cognitive problems in women with breast cancer should allow development of strategies to prevent or minimize these unpleasant symptoms. Cytokines and other biomarkers might be predictive for disease outcome in women with breast cancer and used in tailoring of adjuvant treatment and as potential targets in development of new therapies.