Owing to exceptional heterogeneity in the outcome of invasive breast cancer it is essential to develop highly accurate prognostic tools for effective therapeutic management. Based on this pressing need, we aimed to improve breast cancer prognosis by exploring the prognostic value of tumor histology image analysis. Patient group (n=78) selection was based on invasive breast cancer diagnosis without systemic treatment with a median follow-up of 147 months. Gray-level co-occurrence matrix texture analysis was performed retrospectively on primary tumor tissue section digital images stained either nonspecifically with hematoxylin and eosin or specifically with a pan-cytokeratin antibody cocktail for epithelial malignant cells. Univariate analysis revealed stronger association with metastasis risk by texture analysis when compared with clinicopathological parameters. The combination of individual clinicopathological and texture variables into composite scores resulted in further powerful enhancement of prognostic performance, with an accuracy of up to 90%, discrimination efficiency by the area under the curve [95% confidence interval (CI)] of 0.94 (0.87-0.99) and hazard ratio (95% CI) of 20.1 (7.5-109.4). Internal validation was successfully performed by bootstrap and split-sample cross-validation, suggesting that the models are generalizable. Whereas further validation is needed on an external set of patients, this preliminary study indicates the potential use of primary breast tumor histology texture as a highly accurate, simple, and cost-effective prognostic indicator of distant metastasis risk.

The critical prognostic importance of the grayscale texture is revealed.

The only way to perceive the real clinical course of disease and the prognostic significance of potential biomarkers is follow-up of patients who did not receive any kind of adjuvant therapy. Many studies have confirmed high levels of interleukin 8 (IL8) in HER2-enriched and basal-like (ER-) primary breast tumours, but less is known about the significance of IL8 in hormone-dependent breast cancer. The aim of this study was to evaluate the prognostic significance of IL8 and clinicopathological parameters in hormone-dependent breast cancer, and to examine possible associations between them that might imply possible biological dependence. The study included 91 early-stage breast cancer patients with detectable levels of hormone receptors (ER>0, PR>0). None of the patients received adjuvant therapy according to valid protocol at that time. HER2 status was determined on paraffin-embedded tumour tissue sections by CISH. IL8 levels were determined by ELISA in cytosol tumour extracts of 65 patients with long-term follow-up (144 months). Nonparametric statistical tests were used for data analyses. Patients with low IL8 levels (M<88.8 pg/mg) had significantly longer relapse-free survival (RFS) compared to patients with high IL8 levels (M≥88.82 pg/mg) (Log rank test, p=0.002). Patients with ERhighIL8low phenotype had significantly longer RFS compared to those with ERhighIL8high and ERlowIL8high phenotypes (p=0.04 and p=0.02, respectively); patients with PRlowIL8low phenotype had significantly longer RFS compared to those with PRlowIL8high and PRhighIL8high phenotypes (p=0.003 and p=0.02, respectively); patients with HER2-IL8low phenotype had significantly longer RFS compared to those with HER2-IL8high and HER2+IL8high phenotypes (p=0.01 and p=0.02, respectively). Our results indicate significant contribution of IL8 on survival of hormone-dependent early-stage breast cancer patients and association with established parameters such as ER/PR and HER2.

We evaluated urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) prognostic value in postmenopausal, node-negative breast cancer patients bearing tumors with estrogen receptor (ER)/progesterone receptor (PR) expression, treated with locoregional therapy alone, within an early follow-up. We focused our analysis on tumors of histological grade II in order to improve its prognostic value and, consequently, to improve a decision-making process. The cytosol extracts of 73 tumor samples were used for assessing several biomarkers. ER and PR levels were measured by classical biochemical method. Cathepsin D was assayed by a radiometric immunoassay while both uPA and PAI-1 level determinations were performed by enzyme-linked immunosorbent assays. HER-2 gene amplification was determined by chromogenic in situ hybridization (CISH) in primary tumor tissue. Patients bearing tumors smaller than or equal to 2 cm (pT1) or those with low PAI-1 levels (PAI-1 < 6.35 pg/mg) showed favorable outcome compared to patients bearing tumors greater than 2 cm (pT2,3) or those with high PAI-1 levels, respectively. Analyses of 4 phenotypes, defined by tumor size and PAI-1 status, revealed that patients bearing either pT1 tumors, irrespective of PAI-1 levels, or pT2,3 tumors with low PAI-1 levels, had similar disease-free interval probabilities and showed favorable outcome compared to those bearing pT2,3 tumors with high PAI-1 levels. Our findings suggest that tumor size and PAI-1, used in combination as phenotypes are not only prognostic but might also be predictive in node-negative, postmenopausal breast cancer patients bearing histological grade II tumors with ER/PR expression, during an early follow-up period.

Higher concentrations of IL-8, uPA, PAI-1 and MMP2, as is MMP9 and VEGF, confirmed aggressive phenotype and poor prognosis in different subgroups.

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To cite this article: Todorović-Raković N, Radulovic M, Vujasinović T, Milovanović J, Nikolić-Vukosavljević D. The prognostic time dependence of intra-tumoural IFN␥ mRNA and protein in patients with breast cancer followed for 14 years after surgery and radiotherapy, without subsequent systemic therapy. Eur. Cytokine Netw. 2017; 28(4): 151-6 ABSTRACT. There is increasing evidence for the importance of immunity in breast cancer. IFN␥ is expected to have a prognostic value based on its major role in innate and specific cell-mediated immunity. In this retrospective study, based on the 14-year follow-up of 73 patients with breast cancer after surgery and radiotherapy but no subsequent systemic therapy, we investigated the prognostic time dependence of intra-tumoural IFN␥ mRNA and protein levels. Over the entire 14 years of follow-up, neither IFN␥ mRNA nor protein was significantly associated with metastasis outcome by AUC and Cox regression criteria. However, evaluation of the shorter periods has revealed a prognostic significance in the late follow-up period of 7-14 years for IFN␥ mRNA and protein with the maximal respective AUCs of 0.72 and 0.73 and hazard ratios of 6.1 and 5.2, respectively. Interestingly, the opposite prognostic association was discovered for IFN␥ mRNA and protein in the first 7 years of follow-up, possibly due to the negative correlation of IFN␥ protein and mRNA. Moreover, the prognostic association of IFN␥ mRNA has shifted from marking the favourable outcome in the first 7 years to poor outcome thereafter. This study contributes to clarification of the previously inconsistent prognostic performance of IFN␥ by providing the first prognostic evaluation with long follow-up, time-dependence assessment and absence of any chemotherapy influence.

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