title: Elevated ARG1 expression in primary monocytes-derived macrophages as a predictor of radiation-induced acute skin toxicities in early breast cancer patients.
abstract: Radiation therapy (RT) the front-line treatment after surgery for early breast cancer patients is associated with acute skin toxicities in at least 40% of treated patients. Monocyte-derived macrophages are polarized into functionally distinct (M1 or M2) activated phenotypes at injury sites by specific systemic cytokines known to play a key role in the transition between damage and repair in irradiated tissues. The role of M1 and M2 macrophages in RT-induced acute skin toxicities remains to be defined. We investigated the potential value of M1 and M2 macrophages as predictive factors of RT-induced skin toxicities in early breast cancer patients treated with adjuvant RT after lumpectomy. Blood samples collected from patients enrolled in a prospective clinical study (n = 49) were analyzed at baseline and after the first delivered 2Gy RT dose. We designed an ex vivo culture system to differentiate patient blood monocytes into macrophages and treated them with M1 or M2-inducing cytokines before quantitative analysis of their "M1/M2" activation markers, iNOS, Arg1, and TGFß1. Statistical analysis was performed to correlate experimental data to clinical assessment of acute skin toxicity using Common Toxicity Criteria (CTC) grade for objective evaluation of skin reactions. Increased ARG1 mRNA significantly correlated with higher grades of erythema, moist desquamation, and CTC grade. Multivariate analysis revealed that increased ARG1 expression in macrophages after a single RT dose was an independent prognostic factor of erythema (p = 0 .032), moist desquamation (p = 0 .027), and CTC grade (p = 0 .056). Interestingly, multivariate analysis of ARG1 mRNA expression in macrophages stimulated with IL-4 also revealed independent prognostic value for predicting acute RT-induced toxicity factors, erythema (p = 0 .069), moist desquamation (p = 0 .037), and CTC grade (p = 0 .046). To conclude, our findings underline for the first time the biological significance of increased ARG1 mRNA levels as an early independent predictive biomarker of RT-induced acute skin toxicities.
authors.affiliation: a Department of Oncology ; University of Alberta ; Edmonton , Canada.
authors.forename: Karen
authors.initials: K
authors.lastname: Jung
authors.affiliation: a Department of Oncology ; University of Alberta ; Edmonton , Canada.|b Department of Oncology ; McGill University ; Montreal , Canada.|f These authors equally contributed to this work.
authors.forename: Siham
authors.initials: S
authors.lastname: Sabri
authors.affiliation: c Cross Cancer Institute; University of Alberta ; Edmonton , Canada.
authors.forename: John
authors.initials: J
authors.lastname: Hanson
authors.affiliation: a Department of Oncology ; University of Alberta ; Edmonton , Canada.|b Department of Oncology ; McGill University ; Montreal , Canada.
authors.forename: Yaoxian
authors.initials: Y
authors.lastname: Xu
authors.affiliation: a Department of Oncology ; University of Alberta ; Edmonton , Canada.
authors.forename: Ying Wayne
authors.initials: YW
authors.lastname: Wang
authors.affiliation: a Department of Oncology ; University of Alberta ; Edmonton , Canada.|d Department of Laboratory Medicine and Pathology ; University of Alberta ; Edmonton , Canada.|e DynaLIFEDx Medical Laboratories ; Edmonton , Canada.
authors.forename: Raymond
authors.initials: R
authors.lastname: Lai
authors.affiliation: a Department of Oncology ; University of Alberta ; Edmonton , Canada.|b Department of Oncology ; McGill University ; Montreal , Canada.|f These authors equally contributed to this work.
authors.forename: Bassam S
authors.initials: BS
authors.lastname: Abdulkarim
mesh_terms: D001119:Arginase / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000201:enzymology / Q000532:radiotherapy*; D018270:Carcinoma, Ductal, Breast / Q000201:enzymology* / Q000532:radiotherapy; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008264:Macrophages / Q000201:enzymology*; D008875:Middle Aged; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011379:Prognosis; D011832:Radiation Injuries / Q000201:enzymology*; D012871:Skin Diseases / Q000201:enzymology*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D016212:Transforming Growth Factor beta; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D001119:Arginase
keywords: 3D-CRT, 3D-conformal RT; AI, aromatase inhibitor; ARG1, arginin1; BC, breast cancer; CI, confidence interval; CTC, Common Toxicity Criteria; CTC-AE, CTC-adverse events; DCIS, ductal carcinoma in situ; ER, estrogen receptor; HER-2. Human epidermal receptor; Arginase-1; M1/M2 polarization; Macrophages; acute skin toxicities; breast cancer; radiation therapy