Association of proinflammatory cytokines and chemotherapy-associated cognitive impairment in breast cancer patients: a multi-centered, prospective, cohort study.
BACKGROUND
Existing evidence suggests that proinflammatory cytokines play an intermediary role in postchemotherapy cognitive impairment. This is one of the largest multicentered, cohort studies conducted in Singapore to evaluate the prevalence and proinflammatory biomarkers associated with cognitive impairment in breast cancer patients.


METHODS
Chemotherapy-receiving breast cancer patients (stages I-III) were recruited. Proinflammatory plasma cytokines concentrations [interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, granulocyte-macrophage colony-stimulating factor, interferon-γ and tumor necrosis factor-α] were evaluated at 3 time points (before chemotherapy, 6 and 12 weeks after chemotherapy initiation). The FACT-Cog (version 3) was utilized to evaluate patients' self-perceived cognitive disturbances and a computerized neuropsychological assessment (Headminder) was administered to evaluate patients' memory, attention, response speed and processing speed. Changes of cognition throughout chemotherapy treatment were compared against the baseline. Linear mixed-effects models were applied to test the relationships of clinical variables and cytokine concentrations on self-perceived cognitive disturbances and each objective cognitive domain.


RESULTS
Ninety-nine patients were included (age 50.5 ± 8.4 years; 81.8% Chinese; mean duration of education = 10.8 ± 3.3 years). Higher plasma IL-1β was associated with poorer response speed performance (estimate: -0.78; 95% confidence interval (CI) -1.34 to -0.03; P = 0.023), and a higher concentration of IL-4 was associated with better response speed performance (P = 0.022). Higher concentrations of IL-1β and IL-6 were associated with more severe self-perceived cognitive disturbances (P = 0.018 and 0.001, respectively). Patients with higher concentrations of IL-4 also reported less severe cognitive disturbances (P = 0.022).


CONCLUSIONS
While elevated concentrations of IL-6 and IL-1β were observed in patients with poorer response speed performance and perceived cognitive disturbances, IL-4 may be protective against chemotherapy-associated cognitive impairment. This study is important because cytokines would potentially be mechanistic mediators of chemotherapy-associated cognitive changes.
Department of Pharmacy, National University of Singapore, Singapore Department of Pharmacy, National Cancer Centre Singapore, Singapore.
Y T
YT
Cheung
Department of Pharmacy, National University of Singapore, Singapore Department of Pharmacy, National Cancer Centre Singapore, Singapore.
T
T
Ng
Department of Pharmacy, National University of Singapore, Singapore.
M
M
Shwe
Department of Pharmacy, National University of Singapore, Singapore.
H K
HK
Ho
Department of Pharmacy.
K M
KM
Foo
Breast Centre, KK Women's and Children's Hospital, Singapore.
M T
MT
Cham
Breast Centre, KK Women's and Children's Hospital, Singapore.
J A
JA
Lee
Departments of Psychosocial Oncology, National Cancer Centre Singapore, Singapore.
G
G
Fan
Departments of Psychosocial Oncology, National Cancer Centre Singapore, Singapore.
Y P
YP
Tan
Surgical Oncology, National Cancer Centre Singapore, Singapore.
W S
WS
Yong
Surgical Oncology, National Cancer Centre Singapore, Singapore.
P
P
Madhukumar
Medical Oncology, National Cancer Centre Singapore, Singapore.
S K
SK
Loo
Medical Oncology, National Cancer Centre Singapore, Singapore.
S F
SF
Ang
Medical Oncology, National Cancer Centre Singapore, Singapore.
M
M
Wong
Medical Oncology, National Cancer Centre Singapore, Singapore.
W Y
WY
Chay
Medical Oncology, National Cancer Centre Singapore, Singapore.
W S
WS
Ooi
Medical Oncology, National Cancer Centre Singapore, Singapore Clinical Sciences, DUKE-NUS Graduate Medical School, Singapore, Singapore.
R A
RA
Dent
Medical Oncology, National Cancer Centre Singapore, Singapore.
Y S
YS
Yap
Medical Oncology, National Cancer Centre Singapore, Singapore Clinical Sciences, DUKE-NUS Graduate Medical School, Singapore, Singapore.
R
R
Ng
Department of Pharmacy, National University of Singapore, Singapore Department of Pharmacy, National Cancer Centre Singapore, Singapore Clinical Sciences, DUKE-NUS Graduate Medical School, Singapore, Singapore phaac@nus.edu.sg.
A
A
Chan
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D014408:Biomarkers, Tumor / Q000097:blood*; D001943:Breast Neoplasms / Q000097:blood / Q000150:complications* / Q000188:drug therapy* / Q000523:psychology; D003072:Cognition Disorders / Q000097:blood / Q000139:chemically induced / Q000175:diagnosis*; D016207:Cytokines / Q000097:blood*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007118:Immunoassay; D018836:Inflammation Mediators / Q000097:blood*; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D011446:Prospective Studies
D014408:Biomarkers, Tumor; D016207:Cytokines; D018836:Inflammation Mediators
FACT-Cog; breast cancer; chemobrain; cognitive disturbance; cognitive impairment; cytokines