Abstract PS4-16: Symptoms of cold discomfort are reduced in breast cancer patients with a composite cytokine pattern associated with increased anti-tumor immunity
Authors: Gandhi Shipra , Sarma Maithreyi , Attwood Kristopher , Ambrosone Christine B. , Repasky Elizabeth A. , Hong Chi-Chen 
Published: February 2021

Abstract
Background: In preclinical models of breast cancer (BC), chronic stress enhances tumor growth and metastasis through β-adrenergic signaling as part of the “fight or flight” stress response pathway. These effects involve norepinephrine-mediated sympathetic regulation of cancer-related immunity. In a novel discovery, adrenergic stress in tumor-bearing mouse models of BC was associated with symptoms of intense cold discomfort, reduced CD8+ T cells, and higher immunosuppressive myeloid derived suppressor cells (MDSC) and regulatory T cells. BC survivors often experience heightened sympathetic activation and anecdotally report symptoms of feeling overly cold. Based on preclinical findings, symptoms of cold discomfort reported by BC survivors are hypothesized to identify those with reduced anti-cancer immunity and increased immunosuppression. Methods: Women with incident stage I to III BC were prospectively enrolled into the Women’s Health after Breast Cancer Study prior to BC treatment at Roswell Park Comprehensive Cancer Center. Participants provided blood samples and completed a survey assessing BC risk factors at the time of diagnosis and survivorship outcomes one-year post. Symptoms of being persistently and inappropriately cold as well as the occurrence of hot flashes and sweats were assessed using a Likert scale patterned on the validated Multidimensional Assessment of Fatigue Scale. A total of 424 women who had questionnaire data and plasma samples were included in the study. A panel of 27 Th1, Th2, Th9, and Th17 cytokines were assayed using a multiplex Luminex bead-based approach. Perceived symptoms of thermal discomfort were evaluated using logistic regression over cytokine tertiles (T1, T2, T3). Principal component analysis (PCA) was used to identify clusters of cytokines associated with symptoms of thermal discomfort. Cytokine composite scores were further refined based on their role with anti-tumor or pro-tumor activity. Multivariate models were adjusted for age, race, menopausal status, body mass index, stage, estrogen receptor status, grade, and treatment received. Results: Forty-six percent (195/424) of patients reported symptoms of feeling cold while 65% (275/424) experienced hot flashes and night sweats. There were no differences in patient or tumor characteristics between women who reported feeling cold versus those who did not, with women receiving chemotherapy more likely to report feeling cold (p = 0.01). Importantly, menopausal onset occurring after BC diagnosis or receipt of hormonal therapy were not associated with symptoms of feeling cold, but as expected were associated with experiencing hot flashes indicating that feeling cold is a distinct symptom from hot flashes. Higher pre-treatment levels of IL-6 was associated with 40-55% lower risk of feeling inappropriately cold 1-year post-diagnosis (T3 vs T1: OR=0.58, 95% CI: 0.34-1.00, p=0.01). PCA analysis identified a composite cytokine score at 1-year post diagnosis, which included the Th1 cytokines IL-12p70 and TNFα, IL-9 and IL-21 as cytokines involved in Th9 antitumor immunity, and the type 3 interferon IFN-λ2/IL-28α, which are all associated with increased CD8+ T cell activity. Increased scores were associated with reduced odds of feeling cold (T3 vs T1: OR=0.42, 95% CI: 0.23-0.77, p=0.02). Hot flashes in contrast were not associated with individual cytokine levels or composite scores. Conclusions: Symptoms of cold discomfort are less likely to be reported by BC survivors with a composite cytokine pattern associated with increased anti-tumor immunity. Further research is needed to determine if this symptom is associated with increased adrenergic stress and worse BC outcomes as observed in preclinical models.
Citation Format: Shipra Gandhi, Maithreyi Sarma, Kristopher Attwood, Christine B. Ambrosone, Elizabeth A. Repasky, Chi-Chen Hong. Symptoms of cold discomfort are reduced in breast cancer patients with a composite cytokine pattern associated with increased anti-tumor immunity [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS4-16.