Tumor-associated neutrophils are a negative prognostic factor in luminal breast cancers lacking immunosuppressive macrophage recruitment

Tumor-associated neutrophils are a negative prognostic factor in luminal breast cancers lacking immunosuppressive macrophage recruitment | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Tumor-associated neutrophils are a negative prognostic factor in luminal breast cancers lacking immunosuppressive macrophage recruitment Eva Schmidt, Luitpold Distel, Ramona Erber, Maike Büttner-Herold, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4012034/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Tumor-associated neutrophils (TAN) are important modulators of the tumor microenvironment with opposing functions which can promote and inhibit tumor progression. The prognostic role of TANs in the luminal breast cancer subtype is unclear. Methods: A total of 144 patients were treated for early-stage hormone receptor positive breast cancer as part of an Accelerated Partial Breast Irradiation (APBI) phase II trial. Resection samples from multiple locations were processed into tissue microarrays and sections thereof immunohistochemically stained for CD66b+ neutrophils. CD66b+ neutrophil density was measured separately in the stromal and intraepithelial compartment. Results: High stromal and intraepithelial CD66b+ TAN density was a negative prognostic factor in central tumor samples. In addition, neutrophil density in adjacent normal breast tissue and lymph node samples also correlated with reduced disease-free survival. TAN density correlated with CD163+ M2-like tumor-associated macrophage (TAM) density, which we analyzed in a previous study. A combined analysis of TAM and TAN density revealed that TANs were only prognostically relevant in tumors with an elevated M1/M2 TAM ratio, while there was no impact on patient outcome in tumors with a low M1/M2 ratio. Conclusions: In conclusion, numerous CD66b+ neutrophils in tumor tissue, normal breast tissue and lymph nodes are a negative prognostic factor in early-stage luminal breast cancer. TAN recruitment might act as a compensatory mechanism of immunoevasion and disease progression in tumors which are unable to sufficiently attract and polarize TAMs. breast cancer luminal tumor-associated neutrophils CD66b tumor-associated macrophages Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Immune evasion is an essential capability of malignant tumors, which has become highly relevant to clinical practice with the introduction of immune checkpoint inhibitors [1]. A better understanding of the dynamics of the tumor microenvironment is fundamental for the development of new therapeutic approaches [2]. Tumor-infiltrating lymphocytes (TILs) and other tumor-infiltrating inflammatory cells (TIICs) are key actors in the tumor microenvironment and can have a crucial role both in disease progression and in tumor control [3-5]. In this regard, not only the type of immune cell is of importance, but also its localization and distribution patterns within the tumor. Within the context of different immune phenotypes, diverse mechanisms of intratumoral immunosuppression come into play and one type of immune cell may exert completely opposite functions [6-8]. Tumor-associated neutrophil granulocytes (TANs) are an important example of differing roles of a single type of inflammatory cell. Traditionally, TANs were considered an anti-tumor component of the tumor microenvironment due to their cytotoxic abilities like H 2 O 2 secretion. However, in recent years, numerous progression-promoting mechanisms have been described: TANs contribute to tumorigenesis and tumor growth, promote angiogenesis, engage in immunosuppression and inhibit cytotoxic T cells, contribute to the formation of the premetastatic niche, and use neutrophil extracellular traps (NETs) to direct circulating tumor cells to distant organ sites [9]. Due to these opposing functions, a classification into two distinct polarization states similar to those of tumor-associated macrophages has been established. Under the influence of TGF-beta and G-CSF, the tumor-promoting N2 phenotype is expressed, whereas IFN-beta promotes the anti-tumor N1 phenotype [10]. However, in contrast to TAMs, no reliable single markers exist for these two phenotypes, preventing a direct immunohistochemical detection of the polarization status of a TAN population. Consequently, it is not surprising that increased infiltration with TANs has been associated with both improved and reduced prognosis in various solid tumors. Overall, however, studies have found TANs to predominate as a negative prognostic factor in most cancers and TANs are frequently described as a potential biomarker [11]. This is also the case in breast cancer, where especially the triple-negative subtype is often the focus of immunological research. This subtype is considered more immunogenic and has a higher rate of treatment failure [12, 13]. The much more common luminal subtype is less frequently investigated due to better prognosis and an unclear impact of immunological factors on disease outcome [14]. Contrary to this hypothesis, we already demonstrated a clear prognostic relevance of TAMs as well as a number of other TIICs in a cohort of patients with early hormone receptor positive breast cancer[15, 16]. Therefore, the goal of the current study was to expand this analysis and assess the density of CD66b+ TANs in tumor epithelium and stroma in tissue samples from luminal breast cancer. Of special interest was the question of prognostic relevance as well as possible conclusions about interactions with other TIICs and mechanisms of immunosuppression. To our knowledge, this is the first study to evaluate the prognostic relevance of neutrophils exclusively in the early luminal subtype. Materials And Methods Patients and Clinical Data A total of 144 patients were treated for early stage, hormone receptor positive breast cancer at Universitätsklinikum Erlangen as part of the German-Austrian Accelerated Partial Breast Irradiation (APBI) phase II trial [17]. As previously reported, main trial inclusion criteria were histopathologically confirmed invasive breast carcinoma of any histologic subtype of ≤3 cm in diameter, clear resection margins of ≥ 2 mm in any direction, hormone sensitivity (oestrogen receptor positive (ER+) / progesterone receptor positive (PR+), ER+/PR−, ER−/PR+), histologic grade 1 or 2, no lymph vessel and no blood vessel invasion, no or only microscopically involved axillary nodes (pN0/pNmi), no distant metastases, and age ≥35 years [18, 19]. Interstitial multicatheter pulsed dose rate (PDR) or high dose rate (HDR) brachytherapy were performed in all patients after breast conserving surgery [20]. Resection samples were used for tissue microarray (TMA) construction. Most patients (90.3%) received hormone therapy, ten (6.9%) were treated with chemotherapy and eight patients received both treatments (Table 1). Written informed consent was obtained “front door” from all patients for collection of their tissue and clinical data. The use of formalin fixed paraffin-embedded material from the Archive of the Institute of Pathology was approved by the Ethics Committee of the Friedrich-Alexander-University of Erlangen-Nuremberg on 24 January 2005 (21_ 19 B), waiving the need for additional consent for using the existing archived material. TMA Construction and Immunohistochemistry Tissue microarrays with a diameter of 2 mm per core were processed from each of the 144 paraffin-embedded tumour resections. Samples originated from the central tumour (CT), the invasive front of the tumor (IF), normal tissue in tumour proximity (prox), normal tissue distant from the tumour (dist) and resected lymph nodes. Tissue sections (2 µm) were de-paraffinized in xylene and rehydrated with graded ethanol. CD66b immunohistochemical stainings were performed using a mouse monoclonal anti-human CD66b antibody (clone G10F5, dilution 1:200) (555723, BD Biosciences, Heidelberg, Germany) and a goat anti-mouse IgM secondary antibody (Vector Laboratories, Newark, CA, USA) as described previously [21]. Stained TMAs were digitalised on a high throughput scanner (Mirax Scan, Zeiss, Göttingen, Germany) and processed digitally in Pannoramic Viewer (3D Histech, Budapest, Hungary). While samples were available from 144 patients in total, some biopsies only contained stromal or epithelial tissue, resulting in fewer available datasets than the total number of patients. Especially the staining process of normal tissue biopsies which often contained a high degree of fat led to a very low number of evaluable samples. The definitions released by the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer were used to classify intrinsic breast cancer subtypes [22]. Ki67 expression levels of ≥ 20% were described as an unfavorable prognostic factor in early breast cancer by Fasching et al. [23]. Quantification of neutrophils As described previously CD66b cell densities were counted semi-automatically with image processing software (Biomas, Erlangen, Germany). Inclusion criteria were size, morphology and color. The respective areas of the stromal and intraepithelial compartments were registered and cell densities were analyzed for each compartment separately. Cell densities of other tumor-infiltrating inflammatory cells Data on cell densities of M1-like (CD68+/CD163 -) and M2-like (CD68+/CD163+) TAMs, CD4+ T helper cells, CD45RO+ memory T cells CD1a+ dendritic cells and CD20+ B cells in this cohort of patients has been published previously [15, 16]. Statistical Analyses Statistical analyses were performed in SPSS version 27 (IBM Inc., Chicago, IL, USA). Correlations were identified through Spearman’s Rho and Chi-squared test. Mean values of cell densities were compared with Student’s t-test for independent samples and Welch’s test. Cox proportional hazards model was used to calculate hazard ratios. Covariates with p < 0.15 in univariate analysis were included in multivariate analyses. The proportional hazards assumption was verified by visual examination of the log-minus-log curves. Optimal cut-off points for prognostic groups based on CD66b+ cell density were calculated for disease-free survival (DFS) through receiver operating characteristic (ROC) curve analysis and confirmed via X-tile software (Yale School of Medicine, New Haven, CT, USA) [24]. The Kaplan–Meier method was used to plot survival curves. Estimated survival times were compared with the log-rank test. P-values < 0.05 were considered to be statistically significant. Results CD66b+ cell density in different locations The cohort studied consisted of 144 patients with early-stage breast cancer and mainly T1, N0 / UICC I stage (Table 1)[18]. Immunohistochemically stained CD66b+ neutrophils and total epithelial and stromal areas were detected in biopsies from central tumor and invasion front (Figure 1A), resected lymph nodes, (Figure 1B), and adjacent normal tissue in the immediate vicinity of the tumor (prox) or at the margin of the resected tissue (dist) (Figure 1C). A high variance in measured cell densities was observed in all localizations (Figure 1D). In both the central tumor (median 4.0 cells/mm 2 , SD: 185.2 cells/mm 2 ) and the invasion front (median 4.3 cells/mm 2 , SD: 265.4 cells/mm 2 ), significantly higher CD66b+ cell densities were measured in the stroma compared to the tumor epithelium (p < 0.05). The highest median cell density was measured in lymph nodes with 25.1 cells/mm 2 (SD: 53.1 cells/mm 2 ). Correlations with clinical characteristics Intratumoral neutrophil density only had an inverse correlation with the presence of DCIS, otherwise there were no correlations with clinical parameters. High CD66b+ cell density in lymph nodes, on the other hand, correlated significantly with luminal B subtype, high proliferation index and lobular histology (Table 2). CD66b+ cell density in lymph nodes and normal tissue did not correlate with TAN density in tumor samples (data not shown). CD66b+ neutrophils as a prognostic factor For the subgroup of patients of the German-Austrian APBI trial that was studied here, disease-free survival (DFS) at 10 years was 87.2% (15-yr DFS: 81.4%) and in-breast recurrence free survival (IBRFS) was 92.7% (15-yr IBRFS: 86.4%) (Figure 2A). Cut-off points for prognostic groups based on CD66b+ cell density were calculated through receiver operating characteristic (ROC) curve analysis. Elevated TAN density (≥ 74.8 cells/mm²) in lymph nodes identified a small group of patients (n = 9) with a strongly increased risk of local recurrence or distant metastasis (Figure 2B). In normal tissue samples from tumor proximity (n = 30), high stromal CD66b+ cell density was a negative prognostic factor (p = 0.037) (Figure 2C), while in normal tissue from the periphery of resected tissue, only a weak trend towards worse prognosis was observed (p = 0.250) (Figure 2D). In central tumor samples, both high stromal (p < 0.001) and intraepithelial (p = 0.025) densities of CD66b+ cells were associated with significantly reduced disease-free survival (Figure 3A, 3B). In samples from the invasive front, only a trend to this effect could be detected (stromal: p = 0.215, intraepithelial: p = 0.155) (Figure 3C, 3D). Correlations with other tumor-infiltrating inflammatory cells CD66b+ cell densities were correlated with those of other inflammatory cells measured in previous studies in central tumor and the invasive front samples in this cohort. These inflammatory cells included M1-like (CD68+/CD163-) and M2-like (CD68+/CD163+) TAMs, CD4+ T helper cells, CD45RO+ memory T cells, CD1a+ dendritic cells and CD20+ B cells. Intraepithelial and stromal CD66b+ cell densities in central tumor and invasion front correlated most consistently with M2-like macrophage densities. A correlation of neutrophils with CD4+ T helper cells, CD45RO+ memory T cells and CD20+ B cells was observed in the stromal compartment of central tumor samples (Table 3). Prognostic impact according to macrophage polarization status We divided the cohort according to stromal and intraepithelial macrophage polarization status, which we defined in our previous work and thus established two groups: a prognostically favorable group with a high M1/M2 ratio (stromal and intraepithelial median M1/M2 ratio: 0.061 and 0.103, respectively) and an overall prognostically very unfavorable group with a low M1/M2 ratio (stromal and intraepithelial median M1/M2 ratio: 0.00 and 0.007, respectively)[15]. Average stromal and intraepithelial neutrophil density (Figure 4B) was higher in the M1/M2 low group, but there was no statistically significant difference in cell density distribution. In central tumor samples with a high ratio of M1/M2 macrophages TANs remained a negative prognostic factor (stromal p < 0.001, intraepithelial p = 0.032) (Figure 4B, 4C), while in tumors with a low M1/M2 ratio no prognostic relevance of stromal and intraepithelial CD66b+ cell densities was observed (Figure 4D, 4E). Multivariate Cox Regression analysis In multivariate Cox regression that included macrophage polarization status, only intraepithelial macrophage polarization status (p = 0.038) was an independent prognostic factor (Table 4). Cohort size was not sufficient for Cox regression of subgroups according to M1/M2 ratio. Discussion The disease modulating properties of tumor-infiltrating lymphocytes (TILs) and other inflammatory cells (TIICs) continue to be of great research interest in breast cancer, both on a mechanistic level and as prognostic biomarkers [25, 26]. Although triple-negative breast cancer (TNBC) is more frequently addressed in this context, we have already been able to demonstrate a surprisingly strong prognostic relevance of various TIICs in the cohort of patients with early luminal breast cancer investigated here [12, 14-16]. In the present study we extended this analysis with the addition of CD66b+ tumor associated neutrophil granulocytes (TANs). TANs, similar to TAMs, can exhibit different polarization states and thus exert both pro- and anti-tumor effects in the tumor microenvironment [10]. In multiple solid cancers, a high density of TANs has been described as a negative prognostic factor [11]. Data on their prognostic relevance in breast cancer is mixed and further clarification is needed: Boissiere-Michot et al. reported no prognostic relevance of CD66b+ TANs in a mixed subtype as well as a triple-negative cohort [27, 28]. Geng et al. showed that in tumors treated with neoadjuvant chemotherapy, an increase in CD66b+ cells was prognostically unfavorable, but there were no conclusive results regarding pretherapeutic TAN density [29]. Wang et al. showed a negative prognostic effect, especially in TNBC, of parenchymal CD66b+ TANs, only [30]. Two other studies also found a correlation between CD66b+ TAN density and worsened prognosis in cohorts with mixed subtypes [30, 31]. A consistent finding of the above-mentioned studies was that the various molecular subtypes of breast cancer displayed different degrees of TAN infiltration, and that infiltration was most pronounced in TNBC. This highlights that an evaluation of prognostic relevance as well as the establishment of cut-off values for prognostic groups should be performed separately according to subtypes. To our knowledge, this is the first study to evaluate the prognostic relevance of CD66b+ TANs exclusively in the early luminal subtype, which is the most frequently treated subtype and stage. The results of our work suggest that increased CD66b+ cell density both in the stromal and intraepithelial compartment of central tumor tissue from early luminal breast cancers is a negative predictive factor associated with tumor progression. This is consistent with the above-mentioned results of studies in other subtypes of breast cancer [27, 28, 30, 31]. In addition, we also made intriguing novel observations in tissue beyond the primary tumor: Although there was limited availability of normal tissue samples in this study, a negative prognostic relevance of CD66b+ cells was also observed in these samples. And even in surgically removed lymph nodes, which were free from metastasis, we could identify a small group of patients with strongly increased CD66b+ cell density and significantly elevated long-term risk for recurrence or distant metastasis. Correlation of cell densities with clinical parameters also revealed that neutrophil infiltration in lymph nodes correlated with more aggressive clinical parameters. Thus, in the luminal subtype of breast carcinoma, increased infiltration with CD66b+ neutrophils in the primary tumor itself, as well as in adjacent normal tissue and lymph nodes, was associated with worse disease outcome. This suggests that the ability of breast cancers to recruit neutrophil granulocytes and to influence their behavior may extend far beyond the classical tumor microenvironment. The mechanisms by which TANs contribute to cancer progression have been a subject of ongoing oncoimmunological interest in recent years. They include immunosuppression as well as promotion of tumor growth, angiogenesis and distant metastasis, which is mediated via a CD90-TIMP-1 loop and the G-CSF-RLN2-MMP-9 axis in breast cancer [9, 30, 31]. Moreover, estrogen alters the activity and gene expression of neutrophils to contribute to tumor formation and growth [32, 33]. Furthermore, TANs might also play a role in resistance to radiotherapy, which is a key element of breast-conserving treatment strategies in breast cancer [34]. We were particularly interested in the aspect of immunosuppression and possible interactions with other inflammatory cells, which we already quantified in previous studies. We found the most consistent intratumoral correlation between M2-like TAM density and CD66b+ TAN density. This is in contrast to the results of Boissiere-Michot et al. who could not report any association between the density of TAMs and TANs in their work [27]. However, in their study, the pan-macrophage marker CD68 was applied, whereas here CD163 was used to specifically identify immunosuppressive M2-like TAMs. Thus, there may be a dependency or mutual recruitment between M2-like TAMs and TANs, a process which has also been described in literature [35]. In hepatocellular cancer, Zhou et al. reported the recruitment of tumor-associated macrophages by TANs as a mechanism of tumor progression [36]. Tumor-induced G-CSF release, which as described by Sheng et al. promotes metastasis in TANs via the G-CSF-RLN2-MMP-9 axis, also affects the polarization of TAMs to the immunosuppressive M2-like phenotype [31]. One of the main observations of our previous work on TAMs was that in early luminal breast cancer, a combined analysis of cytotoxic M1-like and immunosuppressive M2-like TAMs, i.e. the overall polarization status of the macrophage population, had the most pronounced association with prognosis [15]. A particularly unfavorable constellation of macrophage polarization was the combination of high M2-like density and low M1-like density (M2-shifted) or, in other words, a low M1-like/M2-like ratio. This was contrasted by patients with tumors with a higher M1/M2 ratio and almost ideal response to therapy. Interestingly, dividing the cohort into two groups based on M1/M2 ratio in our present study revealed that within the group with a low M1/M2 ratio, CD66b+ TAN density was no longer prognostically relevant. In the remaining tumors with higher M1/M2 ratios, CD66b+ TANs were still significantly associated with reduced disease-free survival. This may reflect alternative primary mechanisms of immunosuppression: While some tumors succeed in recruiting and repolarizing the macrophage population to the suppressive M2-like phenotype (low M1/M2 ratio, Type A), others primarily utilize the progression-promoting properties of TANs (Type B) (Figure 5). These tumors express a prognostically favorable M1/M2 ratio but the anti-tumor effects of the M1-like TAM phenotype is counteracted by suppressive TANs. In experimental studies in both cervical carcinoma and pancreatic adenocarcinoma, results suggest that there is a complementary immunosuppressive dynamic between the two myeloid cell types [37, 38]. Macrophage depletion via CCR2 blockade led to compensatory influx of neutrophils into the tumor, and only blockade of both cell types led to initiation of a tumor-directed immune response. A similar mechanism may also be relevant in early luminal breast cancer. Due to the immunohistochemical methodology of the present study, this hypothesis is of course speculative at this point and requires experimental confirmation. Strengths of this study were the precise detection of cell densities separately in the stromal and intraepithelial compartments, as well as the uniform clinical characteristics of the patient cohort with exclusively luminal breast carcinoma, which were treated within the framework of a clinical trial. The relatively small cohort of patients with a low number of recurrences and metastases entailing a degree of statistical uncertainty was the major weakness of our analysis. Conclusion Increased density of CD66b + TANs in the central tumor, but also in adjacent normal tissue and lymph nodes, were predictive of reduced disease-free survival in early luminal breast cancer. CD66b + neutrophil density in lymph nodes was associated with more aggressive disease characteristics. Intratumoral neutrophil density correlated with M2-like TAM density. A combined analysis revealed that neutrophil infiltration was only associated with poor prognosis in tumors with an increased M1/M2 ratio. Declarations Acknowledgments We thank the Tumor Centre at the Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany for providing us with patient data. The present work was performed in fulfilment of the requirements for obtaining the degree “Dr. med. dent.”. Author Contributions: Conceptualization, L.D., R.F., M.H., M.B-H.; methodology, S.S., L.D.; software, L.D.; validation, S.S., L.D.; formal analysis, E.S., S.S., L.D.; investigation, E.S., S.S., O.J.O., V.S., M.-C.R.; resources, O.J.O., V.S., A.H., R.E., M.B.-H., M.W.B., R.F., M.H., L.D.; data curation, S.S., L.D. M.-C.R.; writing—original draft preparation, E.S., S.S.; L.D., writing—review and editing, S.S., L.D., E.S., R.E., M.W.B., M.H., O.J.O., M.B.-H., ; visualization, E.S., S.S., L.D.; supervision, L.D., R.F., A.H., M.W.B., M.H., M.B.-H.; project administration, R.F., L.D.; All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. 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Tumor-Associated Macrophages and Neutrophils in Tumor Microenvironment. Mediators Inflamm, 2016. 2016: p. 6058147. Zhou SL, et al. Tumor-Associated Neutrophils Recruit Macrophages and T-Regulatory Cells to Promote Progression of Hepatocellular Carcinoma and Resistance to Sorafenib. Gastroenterology. 2016;150(7):1646–e165817. Pahler JC, et al. Plasticity in tumor-promoting inflammation: impairment of macrophage recruitment evokes a compensatory neutrophil response. Neoplasia. 2008;10(4):329–40. Nywening TM, et al. Targeting both tumour-associated CXCR2(+) neutrophils and CCR2(+) macrophages disrupts myeloid recruitment and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma. Gut. 2018;67(6):1112–23. Tables Table 1: Clinical characteristics of the studied patient cohort. Age (yr) mean: 59.0; < 50: 28 (19.4%); ≥ 50: 116 (80.6%) T category pT1a: 9 (6.3%); pT1b: 37 (25.7%); pT1c: 82 (56.9%); pT1mic: 6 (4.2%); pT2: 10 (6.9%) N category N0: 141 (97.9%); N1: 3 (2.1%) Stage UICC I: 132 (91.7%); UICC II: 12 (8.3%) Tumor size (mm) 20: 10 (6.9%) Histological grading G1: 37 (25.7%); G2: 100 (69.4%); G3: 4 (2.8%); n.a. 3 (2.1%) Histological typing lobular: 22 (15.3%); no special type: 100 (69.4%); other: 22 (15.3%) Ki67 (%) <20: 109 (75.7%); ≥20: 31 (21.5%); n.a.: 4 (2.8%) ER status positive: 139 (96.5%); negative: 1 (0.7%); n.a.: 4 (2.8%) PR status positive: 130 (90.3%); negative: 11 (7.6%); n.a.: 3 (2.1%) Her2 status positive: 7 (4.9%); negative: 132 (91.7%); n.a.: 5 (3.5%) Subtype Luminal A: 96 (66.7%); Luminal B: 43 (29.9%); n.a.: 5 (3.5%) Hormone therapy Yes: 130 (90.3%); No: 14 (9.7%) Chemotherapy Yes: 10 (6.9%); No: 134 (93.1%) Table 2: Association between clinicopathological characteristics and CD66b+ neutrophil density in both tumor compartments of central tumor samples and lymph nodes. Stromal (N=108) Intraepithelial (N=107) Lymph node (N=112) N (total) CD66b+ TIN density low CD66b+ TIN density high p CD66b+ TIN density low CD66b+ TIN density high p CD66b+ TIN density low CD66b+ TIN density high p Age (yr) 0.52 0.48 0.37 <50 28 22 (24 %) 2 (13 %) 14 (20 %) 10 (26 %) 18 (17 %) 3 (33 %) ≥50 116 70 (76 %) 14 (87 %) 55 (80 %) 28 (74 %) 85 (83 %) 6 (67 %) Stage 0.64 1.00 0.18 UICC I 132 84 (91 %) 14 (88 %) 63 (91 %) 36 (95 %) 95 (92 %) 7 (78 %) UICC II 12 8 (9 %) 2 (12 %) 6 (9 %) 2 (5 %) 8 (8 %) 2 (22 %) Tumor size (mm) 1.00 0.71 0.50 <20 134 85 (92 %) 15 (94 %) 62 (93 %) 36 (92 %) 96 (93 %) 8 (89 %) ≥20 10 7 (8%) 1 (6 %) 5 (7 %) 3 (8 %) 7 (7 %) 1 (11 %) Histological grading 1.00 0.07 0.11 G1 37 26 (29 %) 4 (25 %) 24 (35 %) 6 (17 %) 27 (26 %) 0 (0 %) G2+G3 104 63 (71 %) 12 (75 %) 44 (65 %) 30 (83 %) 76 (74 %) 9 (100 %) n.a. 3 Histological typing 0.67 0.54 0.04 non lobular 122 83 (90 %) 14 (88 %) 65 (94 %) 32 (84 %) 88 (85 %) 5 (56 %) lobular 22 9 (10 %) 2 (12 %) 4 (6 %) 6 (16 %) 15 (15 %) 4 (44 %) DCIS 0.02 0.20 0.48 no 76 38 (46 %) 12 (80 %) 31 (48 %) 20 (63 %) 58 (61 %) 7 (78 %) yes 56 44 (54 %) 3 (20 %) 34 (52 %) 12 (37 %) 37 (39 %) 2 (22 %) n.a. 12 Ki67 0.74 0.62 0.03 <20% 109 70 (80 %) 12 (75 %) 55 (81 %) 25 (71 %) 83 (81 %) 4 (44 %) ≥20% 31 18 (20 %) 4 (25 %) 13 (19 %) 10 (29 %) 20 (19 %) 5 (56 %) n.a. 4 Her2 status 1.00 0.61 0.46 neg 132 85 (97 %) 16 (100 %) 65 (97 %) 34 (94 %) 96 (94 %) 8 (89 %) pos 7 3 (3 %) 0 (0 %) 2 (3 %) 2 (6 %) 6 (6 %) 1 (11 %) n.a. 5 Subtype 1.00 0.82 0.03 Luminal A 96 62 (71 %) 11 (69 %) 48 (71 %) 23 (68 %) 73 (72 %) 3 (33 %) Luminal B 43 25 (29 %) 5 (31 %) 20 (29 %) 11 (32 %) 29 (28 %) 6 (67 %) n.a. 5 n.a. = not available Table 3: Correlation analysis between CD66b tumor-associated neutrophil (TAN) densities and cell densities of other tumor-infiltrating inflammatory cells in different tumor locations. M1 M2 CD4 CD45RO CD1a CD20 Stromal CD66b+ TAN density in central tumor samples Correlation coefficient -0.020 0.370 ** 0.475 ** 0.240 * 0.005 0.343 ** p 0.836 <0.001 <0.001 0.012 0.956 <0.001 n 107 107 108 108 107 107 Intraepithelial CD66b+ TAN density in central tumor samples Correlation coefficient 0.032 0.239 * 0.106 -0.067 -0.263 * 0.086 p 0.748 0.015 0.293 0.506 0.012 0.417 n 103 103 100 100 91 91 Stromal CD66b+ TAN density in invasive front samples Correlation coefficient -0.099 0.414 ** 0.325 ** 0.038 -0.055 0.119 p 0.295 <0.001 <0.001 0.682 0.563 0.207 n 115 115 116 116 114 114 Intraepithelial CD66b+ TAN density in invasive front samples Correlation coefficient 0.024 0.325 ** 0.081 -0.066 0.052 0.061 p 0.808 0.001 0.425 0.519 0.623 0.560 n 103 103 98 98 93 93 Correlation coefficient = Spearman's ρ Table 4: Univariate and multivariate analysis of disease-free survival according to Cox's proportional hazards model. Univariate analysis Multivariate analysis Variable Hazard ratio 95% C.I. p Hazard ratio 95% C.I. p Age (yr) (<50 [n = 28] v. ≥50 [n = 116 ]) 0.96 0.32 - 2.89 0.947 --- --- --- Stage (UICC I [n = 132] v. UICC II [n = 12 ]) 2.03 0.59 - 6.93 0.26 --- --- --- Tumor size (mm) (9999 0.953 Histological typing (non-lobular [n = 122] v. lobular [n = 22 ]) 0.81 0.24 - 2.79 0.738 --- --- --- DCIS (no [n = 76] v. yes [n = 56 ]) 0.68 0.26 - 1.84 0.452 --- --- --- Ki67 (<20 [n = 109] v. ≥20 [n = 31 ]) 2.24 0.91 - 5.50 0.078 1.23 0.41 - 3.75 0.712 Her2 status (negative [n = 132] v. positive [n = 7 ]) 0.05 0 - 269.89 0.486 --- --- --- Luminal (A [n = 96] v. B [n = 43 ]) 1.94 0.80 - 4.69 0.142 --- --- --- Hormone therapy (No [n = 14] v. Yes [n = 130 ]) 2.02 0.27 - 15.06 0.495 --- --- --- Chemotherapy (No [n = 134] v. Yes [n = 10 ]) 2.38 0.70 - 8.17 0.167 --- --- --- Stromal TAM polarization status (other [n = 78] v. M2-shifted [n = 44 ]) 3.53 1.39 - 8.99 0.008 1.67 0.56 - 4.97 0.36 Intraepithelial TAM polarization status (other [n = 84] v. M2-shifted [n = 34 ]) 5.25 1.96 - 14.04 <.001 3.56 1.07 - 11.81 0.038 Stromal CD66b+ TIN density (low [n = 92] v. high [n = 16 ]) 5.02 1.90 - 13.24 0.001 1.67 0.46 - 6.08 0.44 Intraepithelial CD66b+ TIN density (low [n = 69] v. high [n = 38 ]) 2.98 1.09 - 8.09 0.033 1.80 0.56 - 5.85 0.326 Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4012034","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":276611694,"identity":"261e0d7a-423f-41ad-bf61-b77250ae8b17","order_by":0,"name":"Eva Schmidt","email":"","orcid":"","institution":"Erlangen University Hospital Department of Radiation Oncology: Universitatsklinikum Erlangen Strahlenklinik","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Eva","middleName":"","lastName":"Schmidt","suffix":""},{"id":276611695,"identity":"7caa3822-6ff9-487c-8331-f9d09c04153c","order_by":1,"name":"Luitpold Distel","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0002-8040-3226","institution":"Erlangen University Hospital Department of Radiation Oncology: Universitatsklinikum Erlangen Strahlenklinik","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Luitpold","middleName":"","lastName":"Distel","suffix":""},{"id":276611696,"identity":"53f5f2be-f265-4d7d-9cea-a927128e5950","order_by":2,"name":"Ramona Erber","email":"","orcid":"","institution":"Universitatsklinikum Erlangen Pathologisches Institut","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ramona","middleName":"","lastName":"Erber","suffix":""},{"id":276611697,"identity":"647508df-97cf-409b-86d7-70a407a44184","order_by":3,"name":"Maike Büttner-Herold","email":"","orcid":"","institution":"Universitatsklinikum Erlangen Pathologisches Institut","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Maike","middleName":"","lastName":"Büttner-Herold","suffix":""},{"id":276611698,"identity":"64f67026-b0bc-4f97-958d-e1ac41c8290b","order_by":4,"name":"Marie-Charlotte Rosahl","email":"","orcid":"","institution":"Erlangen University Hospital Department of Radiation Oncology: Universitatsklinikum Erlangen Strahlenklinik","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Marie-Charlotte","middleName":"","lastName":"Rosahl","suffix":""},{"id":276611699,"identity":"6f86a44b-764d-4531-b5a0-6157598a9f56","order_by":5,"name":"Oliver J. 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Hack","email":"","orcid":"","institution":"Erlangen University Hospital Department of Obstetrics and Gynaecology: Universitatsklinikum Erlangen Frauenklinik","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Carolin","middleName":"C.","lastName":"Hack","suffix":""},{"id":276611702,"identity":"9273032e-4af0-4eb1-8d16-819ed01c7535","order_by":8,"name":"Arndt Hartmann","email":"","orcid":"","institution":"Universitatsklinikum Erlangen Pathologisches Institut","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Arndt","middleName":"","lastName":"Hartmann","suffix":""},{"id":276611703,"identity":"04a22251-0ab8-4228-9ebb-3bc0b8bf7671","order_by":9,"name":"Markus Hecht","email":"","orcid":"","institution":"Saarland University Hospital and Saarland University Faculty of Medicine Clinic for Radiotherapy and Radiation Oncology: Universitatsklinikum des Saarlandes und Medizinische Fakultat der Universitat des Saarlandes Klinik fur Strahlentherapie und Radioonkologie","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Markus","middleName":"","lastName":"Hecht","suffix":""},{"id":276611704,"identity":"c13dff4d-3c45-4f1d-9d29-2865716f6c68","order_by":10,"name":"Rainer Fietkau","email":"","orcid":"","institution":"Erlangen University Hospital Department of Radiation Oncology: Universitatsklinikum Erlangen Strahlenklinik","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Rainer","middleName":"","lastName":"Fietkau","suffix":""},{"id":276611705,"identity":"ca8cc339-f42d-4c7d-b7e7-a6e1084412e9","order_by":11,"name":"Sören Schnellhardt","email":"","orcid":"","institution":"Saarland University Hospital and Saarland University Faculty of Medicine Clinic for Radiotherapy and Radiation Oncology: Universitatsklinikum des Saarlandes und Medizinische Fakultat der Universitat des Saarlandes Klinik fur Strahlentherapie und Radioonkologie","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Sören","middleName":"","lastName":"Schnellhardt","suffix":""}],"badges":[],"createdAt":"2024-03-04 14:31:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4012034/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4012034/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":52196586,"identity":"f8100a6f-64a3-457e-b65c-2c3bc1785e00","added_by":"auto","created_at":"2024-03-07 20:04:36","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":15835000,"visible":true,"origin":"","legend":"\u003cp\u003eRepresentative images of sections of breast cancer tissue microarray cores with immunohistochemical CD66b staining. (a) Invasive front sample with stromal neutrophil infiltration (brown). Example of intraepithelial compartment segmentation (green) via BIOMAS software. (b) Tissue microarray cores of lymph node sample and (c) normal tissue sample with immunohistochemical CD66b staining. (d) Box plots of stromal and intraepithelial CD66b+ cell density distribution in different locations. Horizontal black bars signify p \u0026lt; 0.05 in Student’s t-test\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-4012034/v1/8dbe5f4a398f350cec437199.png"},{"id":52196204,"identity":"9aafea2e-a215-4cad-8c13-564e2724645f","added_by":"auto","created_at":"2024-03-07 19:56:36","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1987534,"visible":true,"origin":"","legend":"\u003cp\u003e(a) Disease-free survival and in-breast recurrence-free survival rate of the studied patient cohort analyzed with the Kaplan-Meier method and log-rank test. (b) Disease-free survival according to stromal CD66b+ neutrophil density in lymph nodes. (c, d) Disease-free survival according to stromal CD66b+ neutrophil density in normal tissue from tumor proximity (c) and normal tissue from the periphery of the resection (d)\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-4012034/v1/3c29ac7094afe3af9f7aa991.png"},{"id":52196203,"identity":"8822a3e5-8fdf-4822-b57d-87f53f6ce61c","added_by":"auto","created_at":"2024-03-07 19:56:35","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":2007341,"visible":true,"origin":"","legend":"\u003cp\u003e(a, b) Disease-free survival rate according to stromal (a) and intraepithelial (b) CD66b+ neutrophil density in central breast tumor samples analyzed with the Kaplan-Meier method and log-rank test. (c, d) Disease-free survival rate according to stromal (a) and intraepithelial (b) CD66b+ neutrophil density in invasive front samples\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-4012034/v1/df5456ac05bc42cbcb47ad79.png"},{"id":52196207,"identity":"7a202fe1-f8d7-45bc-9328-7eefbbe834b3","added_by":"auto","created_at":"2024-03-07 19:56:36","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":2582972,"visible":true,"origin":"","legend":"\u003cp\u003e(a) Box plots of stromal (blue) and intraepithelial (red) CD66b+ cell density distribution in patients with high versus low M1/M2 ratio. Carets signify outliers. (b, c) Disease-free survival rate according to stromal (b) and intraepithelial (c) CD66b+ neutrophil density in central breast tumor samples in patients with a high M1/M2 ratio analyzed with the Kaplan-Meier method and log-rank test. (d, e) Disease-free survival according to stromal (d) and intraepithelial (e) CD66b+ neutrophil density in central tumor samples in patients with a low M1/M2\u003c/p\u003e","description":"","filename":"Fig4.png","url":"https://assets-eu.researchsquare.com/files/rs-4012034/v1/6145c6e8d1b465e61998281d.png"},{"id":52196205,"identity":"62bbb383-53b5-4f3b-9862-567a154138dd","added_by":"auto","created_at":"2024-03-07 19:56:36","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":1042980,"visible":true,"origin":"","legend":"\u003cp\u003eProposed model of cellular mechanisms of immunosuppression in early luminal breast cancer. Type A tumors are capable of polarizing tumor-associated macrophages (TAMs) towards the immunosuppressive M2-like state (low M1/M2 ratio), resulting in inactivation of anti-tumor elements like cytotoxic T cells. Tumor-associated neutrophils (TANs) are numerous but play a subordinate role, possibly due to contrary effects of anti-tumor N1-like TANs and suppressive N2-like TANs in this scenario. Type B tumors are not capable of macrophage repolarization (high M1/M2 ratio) and utilize the immunosuppressive properties of TANs which are most likely polarized towards the N2-like state. Figure created with Biorender.com\u003c/p\u003e","description":"","filename":"Fig5.png","url":"https://assets-eu.researchsquare.com/files/rs-4012034/v1/e490ea0db737b87cb34eba42.png"},{"id":61912012,"identity":"8055fea3-5f42-483a-aa8e-d9c4cb98018a","added_by":"auto","created_at":"2024-08-07 03:29:31","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":27186080,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4012034/v1/b54ee002-ef62-443c-843b-6c7272bb0705.pdf"}],"financialInterests":"","formattedTitle":"Tumor-associated neutrophils are a negative prognostic factor in luminal breast cancers lacking immunosuppressive macrophage recruitment","fulltext":[{"header":"Introduction","content":"\u003cp\u003eImmune evasion is an essential capability of malignant tumors, which has become highly relevant to clinical practice with the introduction of immune checkpoint inhibitors\u0026nbsp;[1]. A better understanding of the dynamics of the tumor microenvironment is fundamental for the development of new therapeutic approaches\u0026nbsp;[2].\u003c/p\u003e\n\u003cp\u003eTumor-infiltrating lymphocytes (TILs) and other tumor-infiltrating inflammatory cells (TIICs) are key actors in the tumor microenvironment and can have a crucial role both in disease progression and in tumor control\u0026nbsp;[3-5]. In this regard, not only the type of immune cell is of importance, but also its localization and distribution patterns within the tumor. Within the context of different immune phenotypes, diverse mechanisms of intratumoral immunosuppression come into play and one type of immune cell may exert completely opposite functions\u0026nbsp;[6-8].\u003c/p\u003e\n\u003cp\u003eTumor-associated neutrophil granulocytes (TANs) are an important example of differing roles of a single type of inflammatory cell. Traditionally, TANs were considered an anti-tumor component of the tumor microenvironment due to their cytotoxic abilities like H\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e secretion. However, in recent years, numerous progression-promoting mechanisms have been described: TANs contribute to tumorigenesis and tumor growth, promote angiogenesis, engage in immunosuppression and inhibit cytotoxic T cells, contribute to the formation of the premetastatic niche, and use neutrophil extracellular traps (NETs) to direct circulating tumor cells to distant organ sites\u0026nbsp;[9].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDue to these opposing functions, a classification into two distinct polarization states similar to those of tumor-associated macrophages has been established. Under the influence of TGF-beta and G-CSF, the tumor-promoting N2 phenotype is expressed, whereas IFN-beta promotes the anti-tumor N1 phenotype\u0026nbsp;[10]. However, in contrast to TAMs, no reliable single markers exist for these two phenotypes, preventing a direct immunohistochemical detection of the polarization status of a TAN population.\u003c/p\u003e\n\u003cp\u003eConsequently, it is not surprising that increased infiltration with TANs has been associated with both improved and reduced prognosis in various solid tumors. Overall, however, studies have found TANs to predominate as a negative prognostic factor in most cancers and TANs are frequently described as a potential biomarker\u0026nbsp;[11]. This is also the case in breast cancer, where especially the triple-negative subtype is often the focus of immunological research. This subtype is considered more immunogenic and has a higher rate of treatment failure\u0026nbsp;[12, 13]. The much more common luminal subtype is less frequently investigated due to better prognosis and an unclear impact of immunological factors on disease outcome\u0026nbsp;[14].\u003c/p\u003e\n\u003cp\u003eContrary to this hypothesis, we already demonstrated a clear prognostic relevance of TAMs as well as a number of other TIICs in a cohort of patients with early hormone receptor positive breast cancer[15, 16]. Therefore, the goal of the current study was to expand this analysis and assess the density of CD66b+ TANs in tumor epithelium and stroma in tissue samples from luminal breast cancer. Of special interest was the question of prognostic relevance as well as possible conclusions about interactions with other TIICs and mechanisms of immunosuppression. To our knowledge, this is the first study to evaluate the prognostic relevance of neutrophils exclusively in the early luminal subtype.\u003c/p\u003e"},{"header":"Materials And Methods","content":"\u003cp\u003e\u003cstrong\u003ePatients and Clinical Data\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 144 patients were treated for early stage, hormone receptor positive breast cancer at Universit\u0026auml;tsklinikum Erlangen as part of the German-Austrian Accelerated Partial Breast Irradiation (APBI) phase II trial\u0026nbsp;[17]. As previously reported, main trial inclusion criteria were histopathologically confirmed invasive breast carcinoma of any histologic subtype of \u0026le;3 cm in diameter, clear resection margins of \u0026ge; 2 mm in any direction, hormone sensitivity (oestrogen receptor positive (ER+) / progesterone receptor positive (PR+), ER+/PR\u0026minus;, ER\u0026minus;/PR+), histologic grade 1 or 2, no lymph vessel and no blood vessel invasion, no or only microscopically involved axillary nodes (pN0/pNmi), no distant metastases, and age \u0026ge;35 years\u0026nbsp;[18, 19]. Interstitial multicatheter pulsed dose rate (PDR) or high dose rate (HDR) brachytherapy were performed in all patients after breast conserving surgery\u0026nbsp;[20]. Resection samples were used for tissue microarray (TMA) construction. Most patients (90.3%) received hormone therapy, ten (6.9%) were treated with chemotherapy and eight patients received both treatments (Table 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained \u0026ldquo;front door\u0026rdquo; from all patients for collection of their tissue and clinical data. The use of formalin fixed paraffin-embedded material from the Archive of the Institute of Pathology was approved by the Ethics Committee of the Friedrich-Alexander-University of Erlangen-Nuremberg on 24 January 2005 (21_ 19 B), waiving the need for additional consent for using the existing archived material.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTMA Construction and Immunohistochemistry\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTissue microarrays with a diameter of 2 mm per core were processed from each of the 144 paraffin-embedded tumour resections. Samples originated from the central tumour (CT), the invasive front of the tumor (IF), normal tissue in tumour proximity (prox), normal tissue distant from the tumour (dist) and resected lymph nodes. Tissue sections (2 \u0026micro;m) were de-paraffinized in xylene and rehydrated with graded ethanol. CD66b immunohistochemical stainings were performed using a mouse monoclonal anti-human CD66b antibody (clone G10F5, dilution 1:200) (555723, BD Biosciences, Heidelberg, Germany) \u0026nbsp;and a goat anti-mouse IgM secondary antibody (Vector Laboratories, Newark, CA, USA) as described previously\u0026nbsp;[21].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eStained TMAs were digitalised on a high throughput scanner (Mirax Scan, Zeiss, G\u0026ouml;ttingen, Germany) and processed digitally in Pannoramic Viewer (3D Histech, Budapest, Hungary).\u003c/p\u003e\n\u003cp\u003eWhile samples were available from 144 patients in total, some biopsies only contained stromal or epithelial tissue, resulting in fewer available datasets than the total number of patients. Especially the staining process of normal tissue biopsies which often contained a high degree of fat led to a very low number of evaluable samples.\u003c/p\u003e\n\u003cp\u003eThe definitions released by the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer were used to classify intrinsic breast cancer subtypes\u0026nbsp;[22]. Ki67 expression levels of \u0026ge; 20% were described as an unfavorable prognostic factor in early breast cancer by Fasching et al.\u0026nbsp;[23].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eQuantification of neutrophils\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs described previously CD66b cell densities were counted semi-automatically with image processing software (Biomas, Erlangen, Germany). Inclusion criteria were size, morphology and color. The respective areas of the stromal and intraepithelial compartments were registered and cell densities were analyzed for each compartment separately.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCell densities of other tumor-infiltrating inflammatory cells\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData on cell densities of M1-like (CD68+/CD163 -) and M2-like (CD68+/CD163+) TAMs, CD4+ T helper cells, CD45RO+ memory T cells CD1a+ dendritic cells and CD20+ B cells in this cohort of patients has been published previously\u0026nbsp;[15, 16].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analyses\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStatistical analyses were performed in SPSS version 27 (IBM Inc., Chicago, IL, USA). Correlations were identified through Spearman\u0026rsquo;s Rho and Chi-squared test. Mean values of cell densities were compared with Student\u0026rsquo;s t-test for independent samples and Welch\u0026rsquo;s test. Cox proportional hazards model was used to calculate hazard ratios. Covariates with p \u0026lt; 0.15 in univariate analysis were included in multivariate analyses. The proportional hazards assumption was verified by visual examination of the log-minus-log curves. Optimal cut-off points for prognostic groups based on CD66b+ cell density were calculated for disease-free survival (DFS) through receiver operating characteristic (ROC) curve analysis and confirmed via X-tile software (Yale School of Medicine, New Haven, CT, USA)\u0026nbsp;[24]. The Kaplan\u0026ndash;Meier method was used to plot survival curves. Estimated survival times were compared with the log-rank test.\u0026nbsp;P-values \u0026lt; 0.05 were considered to be statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eCD66b+ cell density in different locations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe cohort studied consisted of 144 patients with early-stage breast cancer and mainly T1, N0 / UICC I stage (Table 1)[18]. Immunohistochemically stained CD66b+ neutrophils and total epithelial and stromal areas were detected in biopsies from central tumor and invasion front (Figure 1A), resected lymph nodes, (Figure 1B), and adjacent normal tissue in the immediate vicinity of the tumor (prox) or at the margin of the resected tissue (dist) (Figure 1C).\u003c/p\u003e\n\u003cp\u003eA high variance in measured cell densities was observed in all localizations (Figure 1D). In both the central tumor (median 4.0 cells/mm\u003csup\u003e2\u003c/sup\u003e, SD: 185.2 cells/mm\u003csup\u003e2\u003c/sup\u003e) and the invasion front (median 4.3 cells/mm\u003csup\u003e2\u003c/sup\u003e, SD: 265.4 cells/mm\u003csup\u003e2\u003c/sup\u003e), significantly higher CD66b+ cell densities were measured in the stroma compared to the tumor epithelium (p \u0026lt; 0.05). The highest median cell density was measured in lymph nodes with 25.1 cells/mm\u003csup\u003e2\u003c/sup\u003e (SD: 53.1 cells/mm\u003csup\u003e2\u003c/sup\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorrelations with clinical characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIntratumoral neutrophil density only had an inverse correlation with the presence of DCIS, otherwise there were no correlations with clinical parameters. High CD66b+ cell density in lymph nodes, on the other hand, correlated significantly with luminal B subtype, high proliferation index and lobular histology (Table 2). CD66b+ cell density in lymph nodes and normal tissue did not correlate with TAN density in tumor samples (data not shown).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCD66b+ neutrophils as a prognostic factor\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor the subgroup of patients of the German-Austrian APBI trial that was studied here, disease-free survival (DFS) at 10 years was 87.2% (15-yr DFS: 81.4%) and in-breast recurrence free survival (IBRFS) was 92.7% (15-yr IBRFS: 86.4%) (Figure 2A).\u003c/p\u003e\n\u003cp\u003eCut-off points for prognostic groups based on CD66b+ cell density were calculated through receiver operating characteristic (ROC) curve analysis. Elevated TAN density (\u0026ge;\u0026nbsp;74.8 cells/mm\u0026sup2;) in lymph nodes identified a small group of patients (n = 9) with a strongly increased risk of local recurrence or distant metastasis (Figure 2B). In normal tissue samples from tumor proximity (n = 30), high stromal CD66b+ cell density was a negative prognostic factor (p = 0.037) (Figure 2C), while in normal tissue from the periphery of resected tissue, only a weak trend towards worse prognosis was observed (p = 0.250) (Figure 2D). \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn central tumor samples, both high stromal (p \u0026lt; 0.001) and intraepithelial (p = 0.025) densities of CD66b+ cells were associated with significantly reduced disease-free survival (Figure 3A, 3B). In samples from the invasive front, only a trend to this effect could be detected (stromal: p = 0.215, intraepithelial: p = 0.155) (Figure 3C, 3D).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorrelations with other tumor-infiltrating inflammatory cells\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCD66b+ cell densities were correlated with those of other inflammatory cells measured in previous studies in central tumor and the invasive front samples in this cohort. These inflammatory cells included M1-like (CD68+/CD163-) and M2-like (CD68+/CD163+) TAMs, CD4+ T helper cells, CD45RO+ memory T cells, CD1a+ dendritic cells and CD20+ B cells.\u003c/p\u003e\n\u003cp\u003eIntraepithelial and stromal CD66b+ cell densities in central tumor and invasion front correlated most consistently with M2-like macrophage densities. A correlation of neutrophils with CD4+ T helper cells, CD45RO+ memory T cells and CD20+ B cells was observed in the stromal compartment of central tumor samples (Table 3).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrognostic impact according to macrophage polarization status\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe divided the cohort according to stromal and intraepithelial macrophage polarization status, which we defined in our previous work and thus established two groups: a prognostically favorable group with a high M1/M2 ratio (stromal and intraepithelial median M1/M2 ratio: 0.061 and 0.103, respectively) and an overall prognostically very unfavorable group with a low M1/M2 ratio (stromal and intraepithelial median M1/M2 ratio: 0.00 and 0.007, respectively)[15]. Average stromal and intraepithelial neutrophil density (Figure 4B) was higher in the M1/M2 low group, but there was no statistically significant difference in cell density distribution.\u003c/p\u003e\n\u003cp\u003eIn central tumor samples with a high ratio of M1/M2 macrophages TANs remained a negative prognostic factor (stromal p \u0026lt; 0.001, intraepithelial p = 0.032) (Figure 4B, 4C), while in tumors with a low M1/M2 ratio no prognostic relevance of stromal and intraepithelial CD66b+ cell densities was observed (Figure 4D, 4E).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMultivariate Cox Regression analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn multivariate Cox regression that included macrophage polarization status, only intraepithelial macrophage polarization status (p = 0.038) was an independent prognostic factor (Table 4). Cohort size was not sufficient for Cox regression of subgroups according to M1/M2 ratio.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe disease modulating properties of tumor-infiltrating lymphocytes (TILs) and other inflammatory cells (TIICs) continue to be of great research interest in breast cancer, both on a mechanistic level and as prognostic biomarkers\u0026nbsp;[25, 26]. Although triple-negative breast cancer (TNBC) is more frequently addressed in this context, we have already been able to demonstrate a surprisingly strong prognostic relevance of various TIICs in the cohort of patients with early luminal breast cancer investigated here\u0026nbsp;[12, 14-16]. In the present study we extended this analysis with the addition of CD66b+ tumor associated neutrophil granulocytes (TANs).\u003c/p\u003e\n\u003cp\u003eTANs, similar to TAMs, can exhibit different polarization states and thus exert both pro- and anti-tumor effects in the tumor microenvironment\u0026nbsp;[10]. In multiple solid cancers, a high density of TANs has been described as a negative prognostic factor\u0026nbsp;[11]. Data on their prognostic relevance in breast cancer is mixed and further clarification is needed: Boissiere-Michot et al. reported no prognostic relevance of CD66b+ TANs in a mixed subtype as well as a triple-negative cohort\u0026nbsp;[27, 28]. Geng et al. showed that in tumors treated with neoadjuvant chemotherapy, an increase in CD66b+ cells was prognostically unfavorable, but there were no conclusive results regarding pretherapeutic TAN density\u0026nbsp;[29]. Wang et al. showed a negative prognostic effect, especially in TNBC, of parenchymal CD66b+ TANs, only\u0026nbsp;[30]. Two other studies also found a correlation between CD66b+ TAN density and worsened prognosis in cohorts with mixed subtypes\u0026nbsp;[30, 31].\u003c/p\u003e\n\u003cp\u003eA consistent finding of the above-mentioned studies was that the various molecular subtypes of breast cancer displayed different degrees of TAN infiltration, and that infiltration was most pronounced in TNBC. This highlights that an evaluation of prognostic relevance as well as the establishment of cut-off values for prognostic groups should be performed separately according to subtypes. To our knowledge, this is the first study to evaluate the prognostic relevance of CD66b+ TANs exclusively in the early luminal subtype, which is the most frequently treated subtype and stage.\u003c/p\u003e\n\u003cp\u003eThe results of our work suggest that increased CD66b+ cell density both in the stromal and intraepithelial compartment of central tumor tissue from early luminal breast cancers is a negative predictive factor associated with tumor progression. This is consistent with the above-mentioned results of studies in other subtypes of breast cancer\u0026nbsp;[27, 28, 30, 31]. In addition, we also made intriguing novel observations in tissue beyond the primary tumor: Although there was limited availability of normal tissue samples in this study, a negative prognostic relevance of CD66b+ cells was also observed in these samples. And even in surgically removed lymph nodes, which were free from metastasis, we could identify a small group of patients with strongly increased CD66b+ cell density and significantly elevated long-term risk for recurrence or distant metastasis. Correlation of cell densities with clinical parameters also revealed that neutrophil infiltration in lymph nodes correlated with more aggressive clinical parameters. Thus, in the luminal subtype of breast carcinoma, increased infiltration with CD66b+ neutrophils in the primary tumor itself, as well as in adjacent normal tissue and lymph nodes, was associated with worse disease outcome. This suggests that the ability of breast cancers to recruit neutrophil granulocytes and to influence their behavior may extend far beyond the classical tumor microenvironment.\u003c/p\u003e\n\u003cp\u003eThe mechanisms by which TANs contribute to cancer progression have been a subject of ongoing oncoimmunological interest in recent years. \u0026nbsp; They include immunosuppression as well as promotion of tumor growth, angiogenesis and distant metastasis, which is mediated via a CD90-TIMP-1 loop and the G-CSF-RLN2-MMP-9 axis in breast cancer\u0026nbsp;[9, 30, 31]. Moreover, estrogen alters the activity and gene expression of neutrophils to contribute to tumor formation and growth\u0026nbsp;[32, 33]. Furthermore, TANs might also play a role in resistance to radiotherapy, which is a key element of breast-conserving treatment strategies in breast cancer\u0026nbsp;[34]. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe were particularly interested in the aspect of immunosuppression and possible interactions with other inflammatory cells, which we already quantified in previous studies. We found the most consistent intratumoral correlation between M2-like TAM density and CD66b+ TAN density. This is in contrast to the results of Boissiere-Michot et al. who could not report any association between the density of TAMs and TANs in their work\u0026nbsp;[27]. However, in their study, the pan-macrophage marker CD68 was applied, whereas here CD163 was used to specifically identify immunosuppressive M2-like TAMs. Thus, there may be a dependency or mutual recruitment between M2-like TAMs and TANs, a process which has also been described in literature\u0026nbsp;[35]. In hepatocellular cancer, Zhou et al. reported the recruitment of tumor-associated macrophages by TANs as a mechanism of tumor progression\u0026nbsp;[36]. Tumor-induced G-CSF release, which as described by Sheng et al. promotes metastasis in TANs via the G-CSF-RLN2-MMP-9 axis, also affects the polarization of TAMs to the immunosuppressive M2-like phenotype\u0026nbsp;[31].\u003c/p\u003e\n\u003cp\u003eOne of the main observations of our previous work on TAMs was that in early luminal breast cancer, a combined analysis of cytotoxic M1-like and immunosuppressive M2-like TAMs, i.e. the overall polarization status of the macrophage population, had the most pronounced association with prognosis\u0026nbsp;[15]. A particularly unfavorable constellation of macrophage polarization was the combination of high M2-like density and low M1-like density (M2-shifted) or, in other words, a low M1-like/M2-like ratio. This was contrasted by patients with tumors with a higher M1/M2 ratio and almost ideal response to therapy. Interestingly, dividing the cohort into two groups based on M1/M2 ratio in our present study revealed that within the group with a low M1/M2 ratio, CD66b+ TAN density was no longer prognostically relevant. In the remaining tumors with higher M1/M2 ratios, CD66b+ TANs were still significantly associated with reduced disease-free survival. This may reflect alternative primary mechanisms of immunosuppression: While some tumors succeed in recruiting and repolarizing the macrophage population to the suppressive M2-like phenotype (low M1/M2 ratio, Type A), others primarily utilize the progression-promoting properties of TANs (Type B) (Figure 5). These tumors express a prognostically favorable M1/M2 ratio but the anti-tumor effects of the M1-like TAM phenotype is counteracted by suppressive TANs.\u003c/p\u003e\n\u003cp\u003eIn experimental studies in both cervical carcinoma and pancreatic adenocarcinoma, results suggest that there is a complementary immunosuppressive dynamic between the two myeloid cell types\u0026nbsp;[37, 38]. Macrophage depletion via CCR2 blockade led to compensatory influx of neutrophils into the tumor, and only blockade of both cell types led to initiation of a tumor-directed immune response. A similar mechanism may also be relevant in early luminal breast cancer. Due to the immunohistochemical methodology of the present study, this hypothesis is of course speculative at this point and requires experimental confirmation.\u003c/p\u003e\n\u003cp\u003eStrengths of this study were the precise detection of cell densities separately in the stromal and intraepithelial compartments, as well as the uniform clinical characteristics of the patient cohort with exclusively luminal breast carcinoma, which were treated within the framework of a clinical trial. The relatively small cohort of patients with a low number of recurrences and metastases entailing a degree of statistical uncertainty was the major weakness of our analysis.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIncreased density of CD66b\u0026thinsp;+\u0026thinsp;TANs in the central tumor, but also in adjacent normal tissue and lymph nodes, were predictive of reduced disease-free survival in early luminal breast cancer. CD66b\u0026thinsp;+\u0026thinsp;neutrophil density in lymph nodes was associated with more aggressive disease characteristics.\u003c/p\u003e \u003cp\u003eIntratumoral neutrophil density correlated with M2-like TAM density. A combined analysis revealed that neutrophil infiltration was only associated with poor prognosis in tumors with an increased M1/M2 ratio.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the Tumor Centre at the Friedrich-Alexander University Erlangen-N\u0026uuml;rnberg, Erlangen, Germany for providing us with patient data. The present work was performed in fulfilment of the requirements for obtaining the degree \u0026ldquo;Dr. med. dent.\u0026rdquo;.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u003c/strong\u003e Conceptualization, L.D., R.F., M.H., M.B-H.; methodology, S.S., L.D.; software, L.D.; validation, S.S., L.D.; formal analysis, E.S., S.S., L.D.; investigation, E.S., S.S., O.J.O., V.S., M.-C.R.; resources, O.J.O., V.S., A.H., R.E., M.B.-H., M.W.B., R.F., M.H., L.D.; data curation, S.S., L.D. M.-C.R.; writing\u0026mdash;original draft preparation, E.S., S.S.; L.D., writing\u0026mdash;review and editing, S.S., L.D., E.S., R.E., M.W.B., M.H., O.J.O., M.B.-H., ; visualization, E.S., S.S., L.D.; supervision, L.D., R.F., A.H., M.W.B., M.H., M.B.-H.; project administration, R.F., L.D.; All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e This research received no external funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest:\u003c/strong\u003e The authors declare no conflict of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eHanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646\u0026ndash;74.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVonderheide RH, Domchek SM, Clark AS. Immunotherapy Breast Cancer: What Are We Missing? 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PLoS ONE. 2016;11(4):e0152500.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBense RD et al. Relevance of Tumor-Infiltrating Immune Cell Composition and Functionality for Disease Outcome in Breast Cancer. J Natl Cancer Inst, 2017. 109(1).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBoissiere-Michot F et al. Prognostic Value of CXCR2 in Breast Cancer. Cancers (Basel), 2020. 12(8).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBoissiere-Michot F et al. CXCR2 Levels Correlate with Immune Infiltration and a Better Prognosis of Triple-Negative Breast Cancers. Cancers (Basel), 2021. 13(10).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGeng SK, et al. Tumor infiltrating neutrophil might play a major role in predicting the clinical outcome of breast cancer patients treated with neoadjuvant chemotherapy. BMC Cancer. 2021;21(1):68.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang Y, et al. Tumor-Contacted Neutrophils Promote Metastasis by a CD90-TIMP-1 Juxtacrine-Paracrine Loop. Clin Cancer Res. 2019;25(6):1957\u0026ndash;69.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSheng Y, et al. Tumor-activated neutrophils promote metastasis in breast cancer via the G-CSF-RLN2-MMP-9 axis. J Leukoc Biol. 2023;113(4):383\u0026ndash;99.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLim CL, Lin VC. Estrogen markedly reduces circulating low-density neutrophils and enhances pro-tumoral gene expression in neutrophil of tumour-bearing mice. BMC Cancer. 2021;21(1):1017.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChung HH, et al. Estrogen reprograms the activity of neutrophils to foster protumoral microenvironment during mammary involution. Sci Rep. 2017;7:46485.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWisdom AJ, et al. Neutrophils promote tumor resistance to radiation therapy. Proc Natl Acad Sci U S A. 2019;116(37):18584\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKim J, Bae JS. \u003cem\u003eTumor-Associated Macrophages and Neutrophils in Tumor Microenvironment.\u003c/em\u003e Mediators Inflamm, 2016. 2016: p. 6058147.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhou SL, et al. Tumor-Associated Neutrophils Recruit Macrophages and T-Regulatory Cells to Promote Progression of Hepatocellular Carcinoma and Resistance to Sorafenib. Gastroenterology. 2016;150(7):1646\u0026ndash;e165817.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePahler JC, et al. Plasticity in tumor-promoting inflammation: impairment of macrophage recruitment evokes a compensatory neutrophil response. Neoplasia. 2008;10(4):329\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNywening TM, et al. Targeting both tumour-associated CXCR2(+) neutrophils and CCR2(+) macrophages disrupts myeloid recruitment and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma. Gut. 2018;67(6):1112\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1: Clinical characteristics of the studied patient cohort.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"605\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.3801652892562%\" valign=\"top\"\u003e\n \u003cp\u003eAge (yr)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"65.6198347107438%\" valign=\"top\"\u003e\n \u003cp\u003emean: 59.0; \u0026lt; 50: 28 (19.4%); \u0026ge; 50: 116 (80.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.3801652892562%\" valign=\"top\"\u003e\n \u003cp\u003eT category\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"65.6198347107438%\" valign=\"top\"\u003e\n \u003cp\u003epT1a: 9 (6.3%); pT1b: 37 (25.7%); pT1c: 82 (56.9%);\u0026nbsp;\u003c/p\u003e\n \u003cp\u003epT1mic: 6 (4.2%); pT2: 10 (6.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.3801652892562%\" valign=\"top\"\u003e\n \u003cp\u003eN category\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"65.6198347107438%\" valign=\"top\"\u003e\n \u003cp\u003eN0: 141 (97.9%); N1: 3 (2.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.3801652892562%\" valign=\"top\"\u003e\n \u003cp\u003eStage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"65.6198347107438%\" valign=\"top\"\u003e\n \u003cp\u003eUICC I: 132 (91.7%); UICC II: 12 (8.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.3801652892562%\" valign=\"top\"\u003e\n \u003cp\u003eTumor size (mm)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"65.6198347107438%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;10: 38 (26.4%); 10-20: 96 (66.7%); \u0026gt;20: 10 (6.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.3801652892562%\" valign=\"top\"\u003e\n \u003cp\u003eHistological grading\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"65.6198347107438%\" valign=\"top\"\u003e\n \u003cp\u003eG1: 37 (25.7%); G2: 100 (69.4%); G3: 4 (2.8%); n.a. 3 (2.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.3801652892562%\" valign=\"top\"\u003e\n \u003cp\u003eHistological typing\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"65.6198347107438%\" valign=\"top\"\u003e\n \u003cp\u003elobular: 22 (15.3%); no special type: 100 (69.4%); other: 22 (15.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.3801652892562%\" valign=\"top\"\u003e\n \u003cp\u003eKi67 (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"65.6198347107438%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;20: 109 (75.7%); \u0026ge;20: 31 (21.5%); n.a.: 4 (2.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.3801652892562%\" valign=\"top\"\u003e\n \u003cp\u003eER status\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"65.6198347107438%\" valign=\"top\"\u003e\n \u003cp\u003epositive: 139 (96.5%); negative: 1 (0.7%); n.a.: 4 (2.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.3801652892562%\" valign=\"top\"\u003e\n \u003cp\u003ePR status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"65.6198347107438%\" valign=\"top\"\u003e\n \u003cp\u003epositive: 130 (90.3%); negative: 11 (7.6%); n.a.: 3 (2.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.3801652892562%\" valign=\"top\"\u003e\n \u003cp\u003eHer2 status\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"65.6198347107438%\" valign=\"top\"\u003e\n \u003cp\u003epositive: 7 (4.9%); negative: 132 (91.7%); n.a.: 5 (3.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.3801652892562%\" valign=\"top\"\u003e\n \u003cp\u003eSubtype\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"65.6198347107438%\" valign=\"top\"\u003e\n \u003cp\u003eLuminal A: 96 (66.7%); Luminal B: 43 (29.9%); n.a.: 5 (3.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.3801652892562%\" valign=\"top\"\u003e\n \u003cp\u003eHormone therapy\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"65.6198347107438%\" valign=\"top\"\u003e\n \u003cp\u003eYes: 130 (90.3%); No: \u0026nbsp;14 (9.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.3801652892562%\" valign=\"top\"\u003e\n \u003cp\u003eChemotherapy\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"65.6198347107438%\" valign=\"top\"\u003e\n \u003cp\u003eYes: 10 (6.9%); No: 134 (93.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2: Association between clinicopathological characteristics and CD66b+ neutrophil density in both tumor compartments of central tumor samples and lymph nodes.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"771\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.305699481865284%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.383419689119171%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"27.590673575129532%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eStromal (N=108)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.295336787564768%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eIntraepithelial (N=107)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.424870466321245%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eLymph node (N=112)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.305699481865284%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"7.383419689119171%\" valign=\"top\"\u003e\n \u003cp\u003eN (total)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003eCD66b+ TIN density low\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.398963730569948%\" valign=\"top\"\u003e\n \u003cp\u003eCD66b+ TIN density high\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.347150259067358%\" valign=\"top\"\u003e\n \u003cp\u003ep\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.362694300518134%\" valign=\"top\"\u003e\n \u003cp\u003eCD66b+ TIN density low\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003eCD66b+ TIN density high\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.0880829015544045%\" valign=\"top\"\u003e\n \u003cp\u003ep\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003eCD66b+ TIN density low\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003eCD66b+ TIN density high\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.7357512953367875%\" valign=\"top\"\u003e\n \u003cp\u003ep\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.305699481865284%\" valign=\"top\"\u003e\n \u003cp\u003eAge (yr)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.383419689119171%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.398963730569948%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.347150259067358%\" valign=\"top\"\u003e\n \u003cp\u003e0.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.362694300518134%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.0880829015544045%\" valign=\"top\"\u003e\n \u003cp\u003e0.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.7357512953367875%\" valign=\"top\"\u003e\n \u003cp\u003e0.37\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.305699481865284%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.383419689119171%\" valign=\"top\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e22 (24 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.398963730569948%\" valign=\"top\"\u003e\n \u003cp\u003e2 (13 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.347150259067358%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.362694300518134%\" valign=\"top\"\u003e\n \u003cp\u003e14 (20 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e10 (26 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.0880829015544045%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e18 (17 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e3 (33 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.7357512953367875%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.305699481865284%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026ge;50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.383419689119171%\" valign=\"top\"\u003e\n \u003cp\u003e116\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e70 (76 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.398963730569948%\" valign=\"top\"\u003e\n \u003cp\u003e14 (87 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.347150259067358%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.362694300518134%\" valign=\"top\"\u003e\n \u003cp\u003e55 (80 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e28 (74 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.0880829015544045%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e85 (83 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e6 (67 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.7357512953367875%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.305699481865284%\" valign=\"top\"\u003e\n \u003cp\u003eStage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.383419689119171%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.398963730569948%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.347150259067358%\" valign=\"top\"\u003e\n \u003cp\u003e0.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.362694300518134%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.0880829015544045%\" valign=\"top\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.7357512953367875%\" valign=\"top\"\u003e\n \u003cp\u003e0.18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.305699481865284%\" valign=\"top\"\u003e\n \u003cp\u003eUICC I\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.383419689119171%\" valign=\"top\"\u003e\n \u003cp\u003e132\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e84 (91 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.398963730569948%\" valign=\"top\"\u003e\n \u003cp\u003e14 (88 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.347150259067358%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.362694300518134%\" valign=\"top\"\u003e\n \u003cp\u003e63 (91 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e36 (95 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.0880829015544045%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e95 (92 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e7 (78 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.7357512953367875%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.305699481865284%\" valign=\"top\"\u003e\n \u003cp\u003eUICC II\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.383419689119171%\" valign=\"top\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e8 (9 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.398963730569948%\" valign=\"top\"\u003e\n \u003cp\u003e2 (12 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.347150259067358%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.362694300518134%\" valign=\"top\"\u003e\n \u003cp\u003e6 (9 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e2 (5 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.0880829015544045%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e8 (8 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e2 (22 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.7357512953367875%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.305699481865284%\" valign=\"top\"\u003e\n \u003cp\u003eTumor size (mm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.383419689119171%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.398963730569948%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.347150259067358%\" valign=\"top\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.362694300518134%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.0880829015544045%\" valign=\"top\"\u003e\n \u003cp\u003e0.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.7357512953367875%\" valign=\"top\"\u003e\n \u003cp\u003e0.50\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.305699481865284%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.383419689119171%\" valign=\"top\"\u003e\n \u003cp\u003e134\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e85 (92 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.398963730569948%\" valign=\"top\"\u003e\n \u003cp\u003e15 (94 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.347150259067358%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.362694300518134%\" valign=\"top\"\u003e\n \u003cp\u003e62 (93 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e36 (92 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.0880829015544045%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e96 (93 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e8 (89 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.7357512953367875%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.305699481865284%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026ge;20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.383419689119171%\" valign=\"top\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e7 (8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.398963730569948%\" valign=\"top\"\u003e\n \u003cp\u003e1 (6 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.347150259067358%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.362694300518134%\" valign=\"top\"\u003e\n \u003cp\u003e5 (7 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e3 (8 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.0880829015544045%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e7 (7 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e1 (11 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.7357512953367875%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.305699481865284%\" valign=\"top\"\u003e\n \u003cp\u003eHistological grading\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.383419689119171%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.398963730569948%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.347150259067358%\" valign=\"top\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.362694300518134%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.0880829015544045%\" valign=\"top\"\u003e\n \u003cp\u003e0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.7357512953367875%\" valign=\"top\"\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.305699481865284%\" valign=\"top\"\u003e\n \u003cp\u003eG1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.383419689119171%\" valign=\"top\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e26 (29 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.398963730569948%\" valign=\"top\"\u003e\n \u003cp\u003e4 (25 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.347150259067358%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.362694300518134%\" valign=\"top\"\u003e\n \u003cp\u003e24 (35 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e6 (17 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.0880829015544045%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e27 (26 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.7357512953367875%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.305699481865284%\" valign=\"top\"\u003e\n \u003cp\u003eG2+G3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.383419689119171%\" valign=\"top\"\u003e\n \u003cp\u003e104\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e63 (71 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.398963730569948%\" valign=\"top\"\u003e\n \u003cp\u003e12 (75 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.347150259067358%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.362694300518134%\" valign=\"top\"\u003e\n \u003cp\u003e44 (65 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e30 (83 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.0880829015544045%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e76 (74 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e9 (100 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.7357512953367875%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.305699481865284%\" valign=\"top\"\u003e\n \u003cp\u003en.a.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.383419689119171%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.398963730569948%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.347150259067358%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.362694300518134%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.0880829015544045%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.7357512953367875%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.305699481865284%\" valign=\"top\"\u003e\n \u003cp\u003eHistological typing\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.383419689119171%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.398963730569948%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.347150259067358%\" valign=\"top\"\u003e\n \u003cp\u003e0.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.362694300518134%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.0880829015544045%\" valign=\"top\"\u003e\n \u003cp\u003e0.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.7357512953367875%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.04\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.305699481865284%\" valign=\"top\"\u003e\n \u003cp\u003enon lobular\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.383419689119171%\" valign=\"top\"\u003e\n \u003cp\u003e122\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e83 (90 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.398963730569948%\" valign=\"top\"\u003e\n \u003cp\u003e14 (88 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.347150259067358%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.362694300518134%\" valign=\"top\"\u003e\n \u003cp\u003e65 (94 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e32 (84 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.0880829015544045%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e88 (85 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e5 (56 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.7357512953367875%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.305699481865284%\" valign=\"top\"\u003e\n \u003cp\u003elobular\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.383419689119171%\" valign=\"top\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e9 (10 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.398963730569948%\" valign=\"top\"\u003e\n \u003cp\u003e2 (12 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.347150259067358%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.362694300518134%\" valign=\"top\"\u003e\n \u003cp\u003e4 (6 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e6 (16 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.0880829015544045%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e15 (15 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e4 (44 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.7357512953367875%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.305699481865284%\" valign=\"top\"\u003e\n \u003cp\u003eDCIS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.383419689119171%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.398963730569948%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.347150259067358%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.02\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.362694300518134%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.0880829015544045%\" valign=\"top\"\u003e\n \u003cp\u003e0.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.7357512953367875%\" valign=\"top\"\u003e\n \u003cp\u003e0.48\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.305699481865284%\" valign=\"top\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.383419689119171%\" valign=\"top\"\u003e\n \u003cp\u003e76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e38 (46 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.398963730569948%\" valign=\"top\"\u003e\n \u003cp\u003e12 (80 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.347150259067358%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.362694300518134%\" valign=\"top\"\u003e\n \u003cp\u003e31 (48 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e20 (63 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.0880829015544045%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e58 (61 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e7 (78 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.7357512953367875%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.305699481865284%\" valign=\"top\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.383419689119171%\" valign=\"top\"\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e44 (54 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.398963730569948%\" valign=\"top\"\u003e\n \u003cp\u003e3 (20 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.347150259067358%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.362694300518134%\" valign=\"top\"\u003e\n \u003cp\u003e34 (52 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e12 (37 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.0880829015544045%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e37 (39 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e2 (22 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.7357512953367875%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.305699481865284%\" valign=\"top\"\u003e\n \u003cp\u003en.a.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.383419689119171%\" valign=\"top\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.398963730569948%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.347150259067358%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.362694300518134%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.0880829015544045%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.7357512953367875%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.305699481865284%\" valign=\"top\"\u003e\n \u003cp\u003eKi67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.383419689119171%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.398963730569948%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.347150259067358%\" valign=\"top\"\u003e\n \u003cp\u003e0.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.362694300518134%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.0880829015544045%\" valign=\"top\"\u003e\n \u003cp\u003e0.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.7357512953367875%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.03\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.305699481865284%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;20%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.383419689119171%\" valign=\"top\"\u003e\n \u003cp\u003e109\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e70 (80 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.398963730569948%\" valign=\"top\"\u003e\n \u003cp\u003e12 (75 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.347150259067358%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.362694300518134%\" valign=\"top\"\u003e\n \u003cp\u003e55 (81 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e25 (71 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.0880829015544045%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e83 (81 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e4 (44 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.7357512953367875%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.305699481865284%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026ge;20%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.383419689119171%\" valign=\"top\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e18 (20 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.398963730569948%\" valign=\"top\"\u003e\n \u003cp\u003e4 (25 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.347150259067358%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.362694300518134%\" valign=\"top\"\u003e\n \u003cp\u003e13 (19 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e10 (29 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.0880829015544045%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e20 (19 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e5 (56 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.7357512953367875%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.305699481865284%\" valign=\"top\"\u003e\n \u003cp\u003en.a.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.383419689119171%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.398963730569948%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.347150259067358%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.362694300518134%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.0880829015544045%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.7357512953367875%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.305699481865284%\" valign=\"top\"\u003e\n \u003cp\u003eHer2 status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.383419689119171%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.398963730569948%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.347150259067358%\" valign=\"top\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.362694300518134%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.0880829015544045%\" valign=\"top\"\u003e\n \u003cp\u003e0.61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.7357512953367875%\" valign=\"top\"\u003e\n \u003cp\u003e0.46\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.305699481865284%\" valign=\"top\"\u003e\n \u003cp\u003eneg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.383419689119171%\" valign=\"top\"\u003e\n \u003cp\u003e132\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e85 (97 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.398963730569948%\" valign=\"top\"\u003e\n \u003cp\u003e16 (100 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.347150259067358%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.362694300518134%\" valign=\"top\"\u003e\n \u003cp\u003e65 (97 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e34 (94 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.0880829015544045%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e96 (94 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e8 (89 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.7357512953367875%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.305699481865284%\" valign=\"top\"\u003e\n \u003cp\u003epos\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.383419689119171%\" valign=\"top\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e3 (3 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.398963730569948%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.347150259067358%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.362694300518134%\" valign=\"top\"\u003e\n \u003cp\u003e2 (3 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e2 (6 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.0880829015544045%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e6 (6 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e1 (11 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.7357512953367875%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.305699481865284%\" valign=\"top\"\u003e\n \u003cp\u003en.a.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.383419689119171%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.398963730569948%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.347150259067358%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.362694300518134%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.0880829015544045%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.7357512953367875%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.305699481865284%\" valign=\"top\"\u003e\n \u003cp\u003eSubtype\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.383419689119171%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.398963730569948%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.347150259067358%\" valign=\"top\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.362694300518134%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.0880829015544045%\" valign=\"top\"\u003e\n \u003cp\u003e0.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"6.7357512953367875%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.03\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.305699481865284%\" valign=\"top\"\u003e\n \u003cp\u003eLuminal A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.383419689119171%\" valign=\"top\"\u003e\n \u003cp\u003e96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e62 (71 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.398963730569948%\" valign=\"top\"\u003e\n \u003cp\u003e11 (69 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.347150259067358%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.362694300518134%\" valign=\"top\"\u003e\n \u003cp\u003e48 (71 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e23 (68 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.0880829015544045%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e73 (72 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e3 (33 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.7357512953367875%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.305699481865284%\" valign=\"top\"\u003e\n \u003cp\u003eLuminal B\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.383419689119171%\" valign=\"top\"\u003e\n \u003cp\u003e43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e25 (29 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.398963730569948%\" valign=\"top\"\u003e\n \u003cp\u003e5 (31 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.347150259067358%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.362694300518134%\" valign=\"top\"\u003e\n \u003cp\u003e20 (29 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e11 (32 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.0880829015544045%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e29 (28 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e6 (67 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.7357512953367875%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.305699481865284%\" valign=\"top\"\u003e\n \u003cp\u003en.a.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.383419689119171%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.398963730569948%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.347150259067358%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.362694300518134%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.0880829015544045%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.844559585492227%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.7357512953367875%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003en.a. = not available\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3: Correlation analysis between CD66b tumor-associated neutrophil (TAN) densities and cell densities of other tumor-infiltrating inflammatory cells in different tumor locations.\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"743\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.604026845637584%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"15.167785234899329%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"10.201342281879194%\" valign=\"top\"\u003e\n \u003cp\u003eM1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.859060402684564%\" valign=\"top\"\u003e\n \u003cp\u003eM2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.590604026845638%\" valign=\"top\"\u003e\n \u003cp\u003eCD4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.12751677852349%\" valign=\"top\"\u003e\n \u003cp\u003eCD45RO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.993288590604028%\" valign=\"top\"\u003e\n \u003cp\u003eCD1a\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.456375838926174%\" valign=\"top\"\u003e\n \u003cp\u003eCD20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.604026845637584%\" rowspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eStromal CD66b+ TAN density in central tumor samples\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.167785234899329%\" valign=\"top\"\u003e\n \u003cp\u003eCorrelation coefficient\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.201342281879194%\" valign=\"top\"\u003e\n \u003cp\u003e-0.020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.859060402684564%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.370\u003csup\u003e**\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.590604026845638%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.475\u003csup\u003e**\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.12751677852349%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.240\u003csup\u003e*\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.993288590604028%\" valign=\"top\"\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.456375838926174%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.343\u003csup\u003e**\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.8568665377176%\" valign=\"top\"\u003e\n \u003cp\u003ep\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.700193423597678%\" valign=\"top\"\u003e\n \u003cp\u003e0.836\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.76595744680851%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.379110251450676%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.152804642166345%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.012\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.959381044487428%\" valign=\"top\"\u003e\n \u003cp\u003e0.956\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.18568665377176%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.8568665377176%\" valign=\"top\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.700193423597678%\" valign=\"top\"\u003e\n \u003cp\u003e107\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.76595744680851%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e107\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.379110251450676%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e108\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.152804642166345%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e108\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.959381044487428%\" valign=\"top\"\u003e\n \u003cp\u003e107\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.18568665377176%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e107\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.604026845637584%\" rowspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eIntraepithelial CD66b+ TAN density in central tumor samples\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.167785234899329%\" valign=\"top\"\u003e\n \u003cp\u003eCorrelation coefficient\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.201342281879194%\" valign=\"top\"\u003e\n \u003cp\u003e0.032\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.859060402684564%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.239\u003csup\u003e*\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.590604026845638%\" valign=\"top\"\u003e\n \u003cp\u003e0.106\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.12751677852349%\" valign=\"top\"\u003e\n \u003cp\u003e-0.067\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.993288590604028%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e-0.263\u003csup\u003e*\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.456375838926174%\" valign=\"top\"\u003e\n \u003cp\u003e0.086\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.8568665377176%\" valign=\"top\"\u003e\n \u003cp\u003ep\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.700193423597678%\" valign=\"top\"\u003e\n \u003cp\u003e0.748\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.76595744680851%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.015\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.379110251450676%\" valign=\"top\"\u003e\n \u003cp\u003e0.293\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.152804642166345%\" valign=\"top\"\u003e\n \u003cp\u003e0.506\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.959381044487428%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.012\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.18568665377176%\" valign=\"top\"\u003e\n \u003cp\u003e0.417\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.8568665377176%\" valign=\"top\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.700193423597678%\" valign=\"top\"\u003e\n \u003cp\u003e103\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.76595744680851%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e103\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.379110251450676%\" valign=\"top\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.152804642166345%\" valign=\"top\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.959381044487428%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e91\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.18568665377176%\" valign=\"top\"\u003e\n \u003cp\u003e91\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.604026845637584%\" rowspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eStromal CD66b+ TAN density in invasive front samples\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.167785234899329%\" valign=\"top\"\u003e\n \u003cp\u003eCorrelation coefficient\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.201342281879194%\" valign=\"top\"\u003e\n \u003cp\u003e-0.099\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.859060402684564%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.414\u003csup\u003e**\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.590604026845638%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.325\u003csup\u003e**\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.12751677852349%\" valign=\"top\"\u003e\n \u003cp\u003e0.038\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.993288590604028%\" valign=\"top\"\u003e\n \u003cp\u003e-0.055\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.456375838926174%\" valign=\"top\"\u003e\n \u003cp\u003e0.119\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.8568665377176%\" valign=\"top\"\u003e\n \u003cp\u003ep\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.700193423597678%\" valign=\"top\"\u003e\n \u003cp\u003e0.295\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.76595744680851%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.379110251450676%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.152804642166345%\" valign=\"top\"\u003e\n \u003cp\u003e0.682\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.959381044487428%\" valign=\"top\"\u003e\n \u003cp\u003e0.563\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.18568665377176%\" valign=\"top\"\u003e\n \u003cp\u003e0.207\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.8568665377176%\" valign=\"top\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.700193423597678%\" valign=\"top\"\u003e\n \u003cp\u003e115\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.76595744680851%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e115\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.379110251450676%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e116\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.152804642166345%\" valign=\"top\"\u003e\n \u003cp\u003e116\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.959381044487428%\" valign=\"top\"\u003e\n \u003cp\u003e114\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.18568665377176%\" valign=\"top\"\u003e\n \u003cp\u003e114\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.604026845637584%\" rowspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eIntraepithelial CD66b+ TAN density in invasive front samples\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.167785234899329%\" valign=\"top\"\u003e\n \u003cp\u003eCorrelation coefficient\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.201342281879194%\" valign=\"top\"\u003e\n \u003cp\u003e0.024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.859060402684564%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.325\u003csup\u003e**\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.590604026845638%\" valign=\"top\"\u003e\n \u003cp\u003e0.081\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.12751677852349%\" valign=\"top\"\u003e\n \u003cp\u003e-0.066\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.993288590604028%\" valign=\"top\"\u003e\n \u003cp\u003e0.052\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.456375838926174%\" valign=\"top\"\u003e\n \u003cp\u003e0.061\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.8568665377176%\" valign=\"top\"\u003e\n \u003cp\u003ep\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.700193423597678%\" valign=\"top\"\u003e\n \u003cp\u003e0.808\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.76595744680851%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.379110251450676%\" valign=\"top\"\u003e\n \u003cp\u003e0.425\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.152804642166345%\" valign=\"top\"\u003e\n \u003cp\u003e0.519\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.959381044487428%\" valign=\"top\"\u003e\n \u003cp\u003e0.623\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.18568665377176%\" valign=\"top\"\u003e\n \u003cp\u003e0.560\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.8568665377176%\" valign=\"top\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.700193423597678%\" valign=\"top\"\u003e\n \u003cp\u003e103\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.76595744680851%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e103\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.379110251450676%\" valign=\"top\"\u003e\n \u003cp\u003e98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.152804642166345%\" valign=\"top\"\u003e\n \u003cp\u003e98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.959381044487428%\" valign=\"top\"\u003e\n \u003cp\u003e93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.18568665377176%\" valign=\"top\"\u003e\n \u003cp\u003e93\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"8\" valign=\"top\"\u003e\n \u003cp\u003eCorrelation coefficient = Spearman\u0026apos;s \u003cem\u003e\u0026rho;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4: Univariate and multivariate analysis of disease-free survival according to Cox\u0026apos;s proportional hazards model.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"792\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"50.12626262626262%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"17.67676767676768%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eUnivariate analysis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.934343434343434%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"19.318181818181817%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eMultivariate analysis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.944444444444445%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50.12626262626262%\" valign=\"top\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.944444444444445%\" valign=\"top\"\u003e\n \u003cp\u003eHazard ratio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.732323232323232%\" valign=\"top\"\u003e\n \u003cp\u003e95% C.I.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.934343434343434%\" valign=\"top\"\u003e\n \u003cp\u003ep\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.595959595959595%\" valign=\"top\"\u003e\n \u003cp\u003eHazard ratio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.722222222222221%\" valign=\"top\"\u003e\n \u003cp\u003e95% C.I.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.944444444444445%\" valign=\"top\"\u003e\n \u003cp\u003ep\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50.12626262626262%\" valign=\"top\"\u003e\n \u003cp\u003eAge (yr) (\u0026lt;50 [n = 28] v. \u0026ge;50 [n = 116 ])\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.944444444444445%\" valign=\"top\"\u003e\n \u003cp\u003e0.96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.732323232323232%\" valign=\"top\"\u003e\n \u003cp\u003e0.32 - 2.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.934343434343434%\" valign=\"top\"\u003e\n \u003cp\u003e0.947\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.595959595959595%\" valign=\"top\"\u003e\n \u003cp\u003e---\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.722222222222221%\" valign=\"top\"\u003e\n \u003cp\u003e---\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.944444444444445%\" valign=\"top\"\u003e\n \u003cp\u003e---\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50.12626262626262%\" valign=\"top\"\u003e\n \u003cp\u003eStage (UICC I [n = 132] v. UICC II [n = 12 ])\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.944444444444445%\" valign=\"top\"\u003e\n \u003cp\u003e2.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.732323232323232%\" valign=\"top\"\u003e\n \u003cp\u003e0.59 - 6.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.934343434343434%\" valign=\"top\"\u003e\n \u003cp\u003e0.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.595959595959595%\" valign=\"top\"\u003e\n \u003cp\u003e---\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.722222222222221%\" valign=\"top\"\u003e\n \u003cp\u003e---\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.944444444444445%\" valign=\"top\"\u003e\n \u003cp\u003e---\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50.12626262626262%\" valign=\"top\"\u003e\n \u003cp\u003eTumor size (mm) (\u0026lt;20 [n = 134] v. \u0026ge;20 [n = 10 ])\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.944444444444445%\" valign=\"top\"\u003e\n \u003cp\u003e1.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.732323232323232%\" valign=\"top\"\u003e\n \u003cp\u003e0.33 - 6.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.934343434343434%\" valign=\"top\"\u003e\n \u003cp\u003e0.628\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.595959595959595%\" valign=\"top\"\u003e\n \u003cp\u003e---\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.722222222222221%\" valign=\"top\"\u003e\n \u003cp\u003e---\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.944444444444445%\" valign=\"top\"\u003e\n \u003cp\u003e---\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50.12626262626262%\" valign=\"top\"\u003e\n \u003cp\u003eHistological grading (G1 [n = 37] v. G2-3 [n = 104 ])\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.944444444444445%\" valign=\"top\"\u003e\n \u003cp\u003e6.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.732323232323232%\" valign=\"top\"\u003e\n \u003cp\u003e0.91 - 50.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.934343434343434%\" valign=\"top\"\u003e\n \u003cp\u003e0.062\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.595959595959595%\" valign=\"top\"\u003e\n \u003cp\u003e238079.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.722222222222221%\" valign=\"top\"\u003e\n \u003cp\u003e0 - \u0026gt;9999\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.944444444444445%\" valign=\"top\"\u003e\n \u003cp\u003e0.953\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50.12626262626262%\" valign=\"top\"\u003e\n \u003cp\u003eHistological typing (non-lobular [n = 122] v. lobular [n = 22 ])\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.944444444444445%\" valign=\"top\"\u003e\n \u003cp\u003e0.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.732323232323232%\" valign=\"top\"\u003e\n \u003cp\u003e0.24 - 2.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.934343434343434%\" valign=\"top\"\u003e\n \u003cp\u003e0.738\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.595959595959595%\" valign=\"top\"\u003e\n \u003cp\u003e---\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.722222222222221%\" valign=\"top\"\u003e\n \u003cp\u003e---\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.944444444444445%\" valign=\"top\"\u003e\n \u003cp\u003e---\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50.12626262626262%\" valign=\"top\"\u003e\n \u003cp\u003eDCIS (no [n = 76] v. yes [n = 56 ])\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.944444444444445%\" valign=\"top\"\u003e\n \u003cp\u003e0.68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.732323232323232%\" valign=\"top\"\u003e\n \u003cp\u003e0.26 - 1.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.934343434343434%\" valign=\"top\"\u003e\n \u003cp\u003e0.452\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.595959595959595%\" valign=\"top\"\u003e\n \u003cp\u003e---\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.722222222222221%\" valign=\"top\"\u003e\n \u003cp\u003e---\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.944444444444445%\" valign=\"top\"\u003e\n \u003cp\u003e---\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50.12626262626262%\" valign=\"top\"\u003e\n \u003cp\u003eKi67 (\u0026lt;20 [n = 109] v. \u0026ge;20 [n = 31 ])\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.944444444444445%\" valign=\"top\"\u003e\n \u003cp\u003e2.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.732323232323232%\" valign=\"top\"\u003e\n \u003cp\u003e0.91 - 5.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.934343434343434%\" valign=\"top\"\u003e\n \u003cp\u003e0.078\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.595959595959595%\" valign=\"top\"\u003e\n \u003cp\u003e1.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.722222222222221%\" valign=\"top\"\u003e\n \u003cp\u003e0.41 - 3.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.944444444444445%\" valign=\"top\"\u003e\n \u003cp\u003e0.712\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50.12626262626262%\" valign=\"top\"\u003e\n \u003cp\u003eHer2 status (negative [n = 132] v. positive [n = 7 ])\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.944444444444445%\" valign=\"top\"\u003e\n \u003cp\u003e0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.732323232323232%\" valign=\"top\"\u003e\n \u003cp\u003e0 - 269.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.934343434343434%\" valign=\"top\"\u003e\n \u003cp\u003e0.486\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.595959595959595%\" valign=\"top\"\u003e\n \u003cp\u003e---\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.722222222222221%\" valign=\"top\"\u003e\n \u003cp\u003e---\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.944444444444445%\" valign=\"top\"\u003e\n \u003cp\u003e---\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50.12626262626262%\" valign=\"top\"\u003e\n \u003cp\u003eLuminal (A [n = 96] v. B [n = 43 ])\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.944444444444445%\" valign=\"top\"\u003e\n \u003cp\u003e1.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.732323232323232%\" valign=\"top\"\u003e\n \u003cp\u003e0.80 - 4.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.934343434343434%\" valign=\"top\"\u003e\n \u003cp\u003e0.142\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.595959595959595%\" valign=\"top\"\u003e\n \u003cp\u003e---\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.722222222222221%\" valign=\"top\"\u003e\n \u003cp\u003e---\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.944444444444445%\" valign=\"top\"\u003e\n \u003cp\u003e---\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50.12626262626262%\" valign=\"top\"\u003e\n \u003cp\u003eHormone therapy (No [n = 14] v. Yes [n = 130 ])\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.944444444444445%\" valign=\"top\"\u003e\n \u003cp\u003e2.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.732323232323232%\" valign=\"top\"\u003e\n \u003cp\u003e0.27 - 15.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.934343434343434%\" valign=\"top\"\u003e\n \u003cp\u003e0.495\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.595959595959595%\" valign=\"top\"\u003e\n \u003cp\u003e---\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.722222222222221%\" valign=\"top\"\u003e\n \u003cp\u003e---\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.944444444444445%\" valign=\"top\"\u003e\n \u003cp\u003e---\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50.12626262626262%\" valign=\"top\"\u003e\n \u003cp\u003eChemotherapy (No [n = 134] v. Yes [n = 10 ])\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.944444444444445%\" valign=\"top\"\u003e\n \u003cp\u003e2.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.732323232323232%\" valign=\"top\"\u003e\n \u003cp\u003e0.70 - 8.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.934343434343434%\" valign=\"top\"\u003e\n \u003cp\u003e0.167\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.595959595959595%\" valign=\"top\"\u003e\n \u003cp\u003e---\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.722222222222221%\" valign=\"top\"\u003e\n \u003cp\u003e---\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.944444444444445%\" valign=\"top\"\u003e\n \u003cp\u003e---\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50.12626262626262%\" valign=\"top\"\u003e\n \u003cp\u003eStromal TAM polarization status (other [n = 78] v. M2-shifted [n = 44 ])\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.944444444444445%\" valign=\"top\"\u003e\n \u003cp\u003e3.53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.732323232323232%\" valign=\"top\"\u003e\n \u003cp\u003e1.39 - 8.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.934343434343434%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.008\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.595959595959595%\" valign=\"top\"\u003e\n \u003cp\u003e1.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.722222222222221%\" valign=\"top\"\u003e\n \u003cp\u003e0.56 - 4.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.944444444444445%\" valign=\"top\"\u003e\n \u003cp\u003e0.36\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50.12626262626262%\" valign=\"top\"\u003e\n \u003cp\u003eIntraepithelial TAM polarization status (other [n = 84] v. M2-shifted [n = 34 ])\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.944444444444445%\" valign=\"top\"\u003e\n \u003cp\u003e5.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.732323232323232%\" valign=\"top\"\u003e\n \u003cp\u003e1.96 - 14.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.934343434343434%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.595959595959595%\" valign=\"top\"\u003e\n \u003cp\u003e3.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.722222222222221%\" valign=\"top\"\u003e\n \u003cp\u003e1.07 - 11.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.944444444444445%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.038\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50.12626262626262%\" valign=\"top\"\u003e\n \u003cp\u003eStromal CD66b+ TIN density (low [n = 92] v. high [n = 16 ])\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.944444444444445%\" valign=\"top\"\u003e\n \u003cp\u003e5.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.732323232323232%\" valign=\"top\"\u003e\n \u003cp\u003e1.90 - 13.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.934343434343434%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.595959595959595%\" valign=\"top\"\u003e\n \u003cp\u003e1.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.722222222222221%\" valign=\"top\"\u003e\n \u003cp\u003e0.46 - 6.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.944444444444445%\" valign=\"top\"\u003e\n \u003cp\u003e0.44\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50.12626262626262%\" valign=\"top\"\u003e\n \u003cp\u003eIntraepithelial CD66b+ TIN density (low [n = 69] v. high [n = 38 ])\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.944444444444445%\" valign=\"top\"\u003e\n \u003cp\u003e2.98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.732323232323232%\" valign=\"top\"\u003e\n \u003cp\u003e1.09 - 8.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.934343434343434%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.033\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.595959595959595%\" valign=\"top\"\u003e\n \u003cp\u003e1.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.722222222222221%\" valign=\"top\"\u003e\n \u003cp\u003e0.56 - 5.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.944444444444445%\" valign=\"top\"\u003e\n \u003cp\u003e0.326\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"breast cancer, luminal, tumor-associated neutrophils, CD66b, tumor-associated macrophages","lastPublishedDoi":"10.21203/rs.3.rs-4012034/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4012034/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Tumor-associated neutrophils (TAN) are important modulators of the tumor microenvironment with opposing functions which can promote and inhibit tumor progression. The prognostic role of TANs in the luminal breast cancer subtype is unclear.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e A total of 144 patients were treated for early-stage hormone receptor positive breast cancer as part of an Accelerated Partial Breast Irradiation (APBI) phase II trial. Resection samples from multiple locations were processed into tissue microarrays and sections thereof immunohistochemically stained for CD66b+ neutrophils. CD66b+ neutrophil density was measured separately in the stromal and intraepithelial compartment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e High stromal and intraepithelial CD66b+ TAN density was a negative prognostic factor in central tumor samples. In addition, neutrophil density in adjacent normal breast tissue and lymph node samples also correlated with reduced disease-free survival. TAN density correlated with CD163+ M2-like tumor-associated macrophage (TAM) density, which we analyzed in a previous study. A combined analysis of TAM and TAN density revealed that TANs were only prognostically relevant in tumors with an elevated M1/M2 TAM ratio, while there was no impact on patient outcome in tumors with a low M1/M2 ratio.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e In conclusion, numerous CD66b+ neutrophils in tumor tissue, normal breast tissue and lymph nodes are a negative prognostic factor in early-stage luminal breast cancer. TAN recruitment might act as a compensatory mechanism of immunoevasion and disease progression in tumors which are unable to sufficiently attract and polarize TAMs.\u003c/p\u003e","manuscriptTitle":"Tumor-associated neutrophils are a negative prognostic factor in luminal breast cancers lacking immunosuppressive macrophage recruitment","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-07 19:56:31","doi":"10.21203/rs.3.rs-4012034/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"36b685c0-85c7-432f-ba7f-103a6af3e774","owner":[],"postedDate":"March 7th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-08-07T03:21:10+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-07 19:56:31","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4012034","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4012034","identity":"rs-4012034","version":["v1"]},"buildId":"cTy_lsJlmDsVRNrSptgXS","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}