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Simple Summary Superparamagnetic iron oxide (SPIO) nanoparticles have comparable performance to the combination of radioisotope and blue dye (RI + BD) for sentinel lymph node (SLN) biopsy in breast cancer. In this multicenter prospective study, lower SPIO doses (undiluted 1.5 vs. 1.0 mL) in different timeframes (perioperative vs. 1-7 days preoperative) and injection sites (subareolar vs. peritumoral) were compared to the previous standard (diluted 2.0 mL perioperatively) from the earlier Nordic trial. RI + BD were co-administered as background. In total, 534 patients were analyzed. SPIO SLN detection rates were similar (97.5% vs. 100% vs. 97.6%, p = 0.11) and respectively non-inferior to the dual technique. Significantly more SLNs were retrieved in the preoperative 1.0 mL cohort compared with 1.5 mL and the Nordic cohorts (2.18 vs. 1.85 vs. 1.83, p = 0.003). Thus, SPIO at 1.5 and 1.0 mL was non-inferior to both Sienna+(R) and the dual technique for SLN detection. Superparamagnetic iron oxide nanoparticles (SPIO) are non-inferior to radioisotope and blue dye (RI + BD) for sentinel lymph node (SLN) detection. Previously, 2 mL SPIO (Sienna+(R)) in 3 mL NaCl was used. In this dose-optimizing study, lower doses of a new refined SPIO solution (Magtrace(R)) (1.5 vs. 1.0 mL) were tested in different timeframes (0-24 h perioperative vs. 1-7 days preoperative) and injections sites (subareolar vs. peritumoral). Two consecutive breast cancer cohorts (n = 328) scheduled for SLN-biopsy were included from 2017 to 2019. All patients received isotope +/- blue dye as back-up. SLNs were identified primarily with the SentiMag(R) probe and thereafter a gamma-probe. The primary endpoint was SLN detection rate with SPIO. Analyses were performed as a one-step individual patient-level meta-analysis using patient-level data from the previously published Nordic Trial (n = 206) as a third, reference cohort. In 534 patients, the SPIO SLN detection rates were similar (97.5% vs. 100% vs. 97.6%, p = 0.11) and non-inferior to the dual technique. Significantly more SLNs were retrieved in the preoperative 1.0 mL cohort compared with 1.5 and the 2.0 mL cohorts (2.18 vs. 1.85 vs. 1.83, p = 0.003). Lower SPIO volumes injected up to 7 days before the operation have comparable efficacy to standard SPIO dose and RI + BD for SLN detection. Funding Agencies|Uppsala University; Vastmanland Cancer Foundation

Breast cancer (BC) intrinsic subtype classification is based on the expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and proliferation marker Ki-67. The expression of these markers depends on both the genetic background of the cancer cells and the surrounding tumor microenvironment. In this study, we explore macrophage traits in cancer cells and intra-tumoral M2-macrophage infiltration (MI) in relation to intrinsic subtypes in non-metastatic invasive BC treated with breast conserving surgery, with and without postoperative radiotherapy (RT). Immunostaining of M2-macrophage-specific antigen CD163 in cancer cells and MI were evaluated, together with ER, PR, HER2, and Ki-67-expression in cancer cells. The tumors were classified into intrinsic subtypes according to the ESMO guidelines. The immunostaining of these markers, MI, and clinical data were analyzed in relation to ipsilateral local recurrence (ILR) as well as recurrence-free (RFS) and disease-free specific (DFS) survival. BC intrinsic subtypes are associated with T-stage, Nottingham Histologic Grade (NHG), and MI. Macrophage phenotype in cancer cells is significantly associated with NHG3-tumors. Significant differences in macrophage infiltration were observed among the intrinsic subtypes of pT1-T2 stage BC. Shorter RFS was observed in luminal B HER2neg tumors after RT, suggesting that this phenotype may be more resistant to irradiation. Ki-67-expression was significantly higher in NHG3 and CD163-positive tumors, as well as those with moderate and high MI. Cancer cell ER expression is inversely related to MI and thus might affect the clinical staging and assessment of BC. Electronic supplementary material The online version of this article (10.1007/s00428-019-02563-3) contains supplementary material, which is available to authorized users.