Introduction: Breast cancer continues to be one of the most common malignancies in females, with mortality rates among the highest worldwide. Despite the availability of numerous clinical tools for managing breast cancer, recurrence, metastasis, and drug resistance remain significant barriers for clinical experts. Scientists consider these tumorigenic processes to be closely associated with breast cancer stem cells (BCSCs). While extensive research focuses on breast cancer cell lines in vitro, replicating the intricate dynamics of the internal tumor microenvironment remains a challenge. This microenvironment is influenced not only by biochemical factors but also by biomechanical cues, such as ECM stiffness and shear stress, which regulate cancer cell behavior through mechanotransduction pathways. Recognizing these limitations, our team has drawn upon years of cancer stem cell research to establish a practicable method. This method aims to facilitate a series of experiments exploring drug resistance mechanisms and to provide deeper insights into the role of BCSCs in tumorigenesis and progression in vivo. Materials and methods: 3-dimensional (3D) mammosphere culture method was established to enrich the breast cancer stem-like cells in vitro. Mammospheres forming assay was performed and mammosphere forming efficiency was calculated. Flow cytometry Analysis was used to detect the subpopulation of CD44+CD24−, meanwhile, the biomarkers of BCSCs were detected by western blot. All these indicates the success establishment of 3D cell culture method and the breast cancer stem-like cells are enriched and collected. Furtherly, western blots were performed to detect the conjectures of the BCSCs that the Notch signaling pathway and MAPK-ERK signaling have the crosstalk in breast cancer microenvironment and the positive feedback loops could be activated by the enriching of BCSCs. All these data were analyzed with GraphPad® Prism 9 software and Wilcoxon rank-sum test, nonlinear regression analysis, unpaired t tests were used. Results: MCF-7 breast cancer stem-like cells were observed as substantially distinct from native breast cell lines under 20x microscope and the mammosphere forming efficiency of MCF-7 breast cancer stem-like cells were higher than the native MCF-7 group. The subpopulation of CD44+CD24− was significantly increased in BCSC-like group and the EMT (Epithelial-Mesenchymal Transition) markers of BCSC which includes Nanog; Vimentin; OCT3/4; Slug and Sox2 were significantly increased. Lastly, Cyclin D3 and Hes1 which play important roles in the Notch signaling pathway and ERK protein were all significantly increased. Conclusion: The three-dimensional (3D) mammosphere culture method is a highly effective approach for collecting breast cancer stem cells (BCSCs) in vitro. Unlike traditional 2D cultures, this method replicates key physiological conditions of the tumor microenvironment (TME) and captures phenotypic heterogeneity. By promoting cell-cell and cell-ECM interactions, the 3D system mimics essential biomechanical cues, such as ECM stiffness and spatial gradients, which regulate BCSC behavior. This method reliably supports investigations into the molecular mechanisms of tumorigenesis. BCSCs enriched through this approach drive processes such as epithelial-mesenchymal transition (EMT) and activate signaling pathways like Notch and MAPK-ERK, which are closely linked to the TME and play critical roles in tumor progression and resistance. The 3D mammosphere culture method thus provides a robust tool for advancing our understanding of cancer biology and therapeutic development.

The randomized FIRE‐4.5 (AIO KRK0116) trial compared first‐line therapy with FOLFOXIRI (folinic acid, fluorouracil, oxaliplatin, and irinotecan) plus either cetuximab or bevacizumab in B‐Raf proto‐oncogene, serine/threonine kinase (BRAF) V600E‐mutant metastatic colorectal cancer (mCRC) patients. This study was accompanied by a prospective translational project analyzing cell‐free circulating tumor DNA (ctDNA) in plasma to test whether ctDNA analysis may help to guide clinical treatment decision making. FIRE‐4.5 included mCRC patients with BRAF V600E mutation detected by tissue‐based analyses. Liquid biopsies (LBs) were collected at baseline (pre‐treatment) and during therapy. Digital droplet PCR (ddPCR) technology was applied for determination of BRAF mutations and the in vitro diagnostics (IVD)‐certified ONCOBEAM RAS procedure for analysis of RAS mutations. The BRAF V600E variants in ctDNA were analyzable in 66 patients at start of the therapy, at baseline. No BRAF V600E mutations were detected in 26% (17/66) of patients and was associated with a significantly longer progression‐free survival (PFS: 13.2 vs 6.5 months; HR 0.47; P = 0.014) and overall survival (OS: 36.8 vs 13.2 months; HR 0.35; P = 0.02) as compared to ctDNA mutant patients. Patients with detectable BRAF mutations showed a clear superiority of FOLFOXIRI plus bevacizumab with regard to PFS (10.4 vs 5.7 months; HR 0.4; P = 0.009) and OS (16.6 vs 11.6 months; HR 0.5; P = 0.15), while this was not the case for BRAF wild‐type patients. Follow‐up LBs were obtained from 51 patients. Patients converting from BRAF V600E mutant to a BRAF V600 wild‐type status (36%, N = 18) had a superior PFS (8.6 vs 2.3 months; P = 0.0002) and OS (17.4 vs 5.1 months; P < 0.0001) compared to patients with stable or increased mutational allele frequency (12%, N = 6). Those patients also achieved a significantly greater disease control rate (89% vs 20%; P = 0.008). In conclusion, LB evaluating ctDNA is informative and may help to guide treatment in patients with BRAF V600E‐mutated mCRC.

IntroductionBreast cancer continues to be a major health concern and is currently the most commonly diagnosed cancer worldwide. Relapse, metastasis, and therapy resistance are major clinical issues that doctors need to address. We believe BYL-719, which is PI3 kinase p110а inhibitor, could also inhibit the breast cancer stem cell phenotype and epithelial-to-mesenchymal transition (EMT). In addition to the PI3K/AKT signaling pathway, BYL-719 can also inhibit essential cancer-related signaling pathways, all of which would ultimately act on the microenvironment of cancer stem cells, which is quite complicated and regulates the characteristics of tumors. These include the stemness and resistance of malignant tumors, plasticity of cancer stem cells, and anti-apoptotic features.Materials and methodsA three-dimensional (3D) mammosphere culture method was used in vitro to culture and collect breast cancer stem cells (BCSCs). MTT, clonogenic, and cell apoptosis assays were used to detect cell viability, self-renewal, and differentiation abilities. A sphere formation assay under 3D conditions was used to detect the mammophore inhibition rate of BYL-719. The subpopulation of CD44+CD24− was detected using flow cytometry analysis while EMT biomarkers and essential signaling pathways were detected using western blotting. All the data were analyzed using GraphPad Prism 9 software.ResultsBCSC-like cells were obtained by using the 3D cell culture method in vitro. We confirmed that BYL-719 could inhibit BCSC-like cell proliferation in 3D cultures and that the stemness characteristics of BCSC-like cells were inhibited. The PI3K/AKT/mTOR signaling pathway could be inhibited by BYL-719, and the Notch, JAK-STAT and MAPK/ERK signaling pathways which have crosstalk in the tumor microenvironment (TME) are also inhibited. By comparing eribulin-resistant breast cancer cell lines, we confirmed that BYL-719 could effectively overcome drug resistance.Summary/conclusionThe 3D cell culture is a novel and highly effective method for enriching BCSCs in vitro. Furthermore, the stemness and EMT of BCSCs were inhibited by BYL-719 by acting on various signaling pathways. Finally, we believe that drug resistance can be overcome by targeting the BCSCs. Conjugation of BYL-719 with other anti-neoplastic agents may be a promising treatment for this in clinic.

AbstractBackgroundMaintaining the ability to perform self‐care is a critical goal in patients with cancer. We assessed whether the patient‐reported ability to walk 4 m and wash oneself predict survival in patients with pre‐terminal cancer.MethodsWe performed a prospective observational study on 169 consecutive hospitalized patients with cancer (52% female, 64 ± 12 years) and an estimated 1–12 months prognosis at an academic, inpatient palliative care unit. Patients answered functional questions for ‘today’, ‘last week’, and ‘last month’, performed patient‐reported outcomes (PROs), and physical function assessments.ResultsNinety‐two (54%) patients reported the ability to independently walk 4 m and 100 (59%) to wash ‘today’. The median number of days patients reported the ability to walk 4 m and wash were 6 (IQR 0–7) and 7 (0–7) days (‘last week’); and 27 (5–30) and 26 (10–30) days (‘last month’). In the last week, 32% of patients were unable to walk 4 m on every day and 10% could walk on 1–3 days; 30% were unable to wash on every day and 10% could wash on 1–3 days. In the last months, 14% of patients were unable to walk 4 m on every day and 10% could only walk on 1–10 days; 12% were unable to wash on every day and 11% could wash on 1–10 days. In patients who could walk ‘today’ average 4 m gait speed was 0.78 ± 0.28 m/s. Patients who reported impaired walking and washing experienced more symptoms (dyspnoea, exertion, and oedema) and decreased physical function (higher Eastern Cooperative Oncology Group Performance Status, and lower Karnofsky Performance Status and hand‐grip strength [unable vs. able to walk ‘today’: 205 ± 87 vs. 252 ± 78 Newton, P = 0.001; unable vs. able to wash ‘today’: 204 ± 86 vs. 250 ± 80 Newton, P = 0.001]). During the 27 months of observation, 152 (90%) patients died (median survival 46 days). In multivariable Cox proportional hazards regression analyses, all tested parameters were independent predictors of survival: walking 4 m ‘today’ (HR 0.63, P = 0.015), ‘last week’ (per 1 day: HR 0.93, P = 0.011), ‘last month’ (per 1 day: HR 0.98, P = 0.012), 4 m gait speed (per 1 m/s: HR 0.45, P = 0.002), and washing ‘today’ (HR 0.67, P = 0.024), ‘last week (per 1 day HR 0.94, p=0.019), and ‘last month’ (per 1 day HR 0.99, P = 0.040). Patients unable to walk and wash experienced the shortest survival and most reduced functional status.ConclusionsIn patients with pre‐terminal cancer, the self‐reported ability to walk 4 m and wash were independent predictors of survival and associated with decreased functional status.

PURPOSE:BRAFV600E mutation is associated with a poor outcome in metastatic colorectal cancer (mCRC). This clinical trial investigated the efficacy of triplet chemotherapy (fluorouracil, folinic acid, oxaliplatin, and irinotecan) combined with either cetuximab or bevacizumab in patients with previously untreated BRAFV600E-mutant mCRC.PATIENTS AND METHODS:In this controlled, randomized, open-label phase II trial, 109 patients were randomly assigned, 107 of whom were included into the full analysis set (FAS). Patients were randomly assigned in a 2:1 ratio to receive either FOLFOXIRI plus cetuximab in the experimental arm (n = 72) or FOLFOXIRI plus bevacizumab in the control arm (n = 35). The primary end point was objective response rate (ORR) according to RECIST 1.1., evaluated in patients treated according to protocol (ATP population). Progression-free survival (PFS), overall survival (OS), toxicity, and feasibility were analyzed as secondary end points.RESULTS:Eighteen patients discontinued study treatment before the first tumor assessment, thus resulting in the ATP population of 89 patients. In these patients, ORR was 51% (30/59) in the cetuximab-based experimental arm and 67% (20/30) in the bevacizumab-based control arm (odds ratio, 1.93; 80% CI, 1.06 to 3.52; P = .92 [one-sided]). In the full analysis set, median PFS was significantly inferior in the experimental arm (6.7 months v 10.7 months; hazard ratio [HR], 1.89; P = .006). Median OS analyzed at an event rate of 64.5% showed a trend toward shorter survival in cetuximab-treated patients (12.9 months v 17.1 months; HR, 1.4; P = .20).CONCLUSION:To our knowledge, FIRE-4.5 is the first prospective and randomized study investigating first-line treatment of BRAFV600E-mutant mCRC. FOLFOXIRI plus cetuximab does not induce a higher ORR when compared with FOLFOXIRI plus bevacizumab in first-line treatment of BRAFV600E-mutant mCRC. Bevacizumab-based chemotherapy remains the preferable first-line treatment of patients with BRAFV600E-mutant mCRC.

Objectives: The novel long non-coding RNA (lncRNA) LINC01094 is often upregulated in renal cell carcinoma and glioma; however, its role in gastric cancer remains unclear. Here, we aim to demonstrate the relationship between LINC01094 and gastric cancer. Method: The gene expression (RNASeq) data of 375 patients with localized, locally advanced, and metastatic gastric cancer were extracted from The Cancer Genome Atlas. The Kruskal–Wallis test, Wilcoxon signed-rank test, and logistic regression were used to analyze the relationship between the clinicopathological characteristics and LINC01094 expression. Cox regression analysis and the Kaplan–Meier method were used to assess prognostic factors of gastric cancer. A nomogram based on Cox multivariate analysis was used to predict the impact of LINC01094 on gastric cancer prognosis. Gene set enrichment analysis (GSEA) was used to identify key LINC01094-associated signaling pathways. Fluorescence in situ hybridization (FISH) was performed to detect the location of LINC01094 in the tissue, and a competing endogenous (ce)RNA network was constructed to identify LINC01094-related genes. Spearman's rank correlation was used to elucidate the association between LINC01094 expression level and immune cell infiltration level. Result: LINC01094 expression was upregulated in gastric cancer tissues and strongly associated with overall survival using univariate Cox regression (hazard ratio [HR] = 1.476, 95% CI = 1.060-2.054, P = .021) and multivariate Cox regression analysis (HR = 1.535, 95% CI = 1.021-2.308, P = .039). The area under the receiver operating characteristic curve of LINC01094 was 0.910. GSEA showed a strong relationship between LINC01094 and the epithelial-mesenchymal transition pathway. RNA-FISH demonstrated that LINC01094 localized in the cytoplasm. It was closely related to the epithelial-mesenchymal transition (EMT) marker SNAI2, according to ceRNA ( R = 0.61, P < .001), and macrophage-related gene FCGR2A. Macrophages were also significantly positively correlated with LINC01094 expression ( R = 0.747, P < .001). Conclusion: High LINC01094 expression predicts poor prognosis in gastric cancer and is correlated with the epithelial-mesenchymal transition pathway and macrophage infiltration.

9511 Background: The liver is the most common site of metastases in patients (pts) with uveal melanoma (UM). Here, we present results from the prespecified first interim analysis of the SirTac trial, a prospective, single-center, randomized, investigator-initiated, open-label phase 2 study of Selective Internal Radiation Therapy with Yttrium-90-bearing resin microspheres; SIR-Spheres (SIRT) vs Transarterial Chemoembolization with Cisplatin and degradable starch microspheres; EmboCept S (DSM-TACE) in pts with liver-dominant metastatic UM. Methods: Pts with histologically confirmed, liver-dominant metastatic UM and ECOG PS 0-2 were enrolled and randomized 1:1 to SIRT or DSM-TACE. Randomization was stratified by lactate dehydrogenase (<2x vs ≥2x upper limit of normal) and pre-treatment with antiangiogenic agents. Extrahepatic metastases were allowed, if asymptomatic. Primary endpoint was progression-free survival (PFS). A total of 108 pts (54 per arm) were planned to be enrolled. Pts received TACE every 4-6 weeks until tumor devascularization or disease progression or intolerable toxicity was observed, and SIRT either as one whole-liver application or in two sequential sessions for each liver lobe. The primary objective of this prespecified analysis was to assess response by RECIST criteria v1.1 in the per-protocol (PP) population of the first 40 pts (20 pts in each arm). Results: Two patients had been treated with previous liver surgery, whereas all other patients had not received previous treatment for metastatic disease. There were no clinicopathological differences between the groups, except for a difference in age (median age SIRT arm 64 y vs 75 y in the TACE arm, p=0.018). All but 1 pt received treatment as randomized. This pt was excluded and replaced by the next TACE pt for this PP interim analysis. There were no differences in best overall response rates between the groups (no complete response, 1 partial response in both arms, stable disease in 19 (95%) and 17 (85%) pts in the SIRT and TACE arm, respectively, and 2 pts with progressive disease in the TACE arm). At a median follow-up of 13.9 mo from treatment start, median PFS in the PP population was 4.9 mo in the SIRT arm vs 2.2 mo in the TACE arm (p=0.037), with a higher median liver-PFS in the SIRT vs TACE arm (8.3 vs 2.2, p=0.026). Conclusions: In this planned interim analysis treatment in both arms was feasible with no differences in response. The explorativePFS analysis allows no conclusions on the final outcome after completion of the trial. The study continues recruitment. Clinical trial information: NCT02936388.

Aims: It is largely unknown whether cancer patients seen in routine care show ventricular arrhythmias in 24 h electrocardiograms (ECGs), and whether when they are detected they carry prognostic relevance. Methods and Results: We included 261 consecutive cancer patients that were referred to the department of cardiology for 24 h ECG examination and 35 healthy controls of similar age and sex in the analysis. To reduce selection bias, cancer patients with known left ventricular ejection fraction <45% were not included in the analysis. Non–sustained ventricular tachycardia (NSVT) episodes of either ≥3 and ≥4 beats duration were more frequent in cancer patients than controls (17% vs. 0%, p = 0.0008; 10% vs. 0%, p = 0.016). Premature ventricular contractions (PVCs)/24 h were not more frequent in cancer patients compared to controls (median (IQR), 26 (2–360) vs. 9 (1–43), p = 0.06; ≥20 PVCs 53% vs. 37%, p = 0.07). During follow-up, (up to 7.2 years, median 15 months) of the cancer patients, 158 (61%) died (1-/3-/5-year mortality rates: 45% [95%CI 39–51%], 66% [95%CI 59–73%], 73% [95%CI 64–82%]). Both non-sustained ventricular tachycardia of ≥4 beats and ≥20 PVCs/24 h independently predicted mortality in univariate and multivariate survival analyses, adjusted for all other univariate predictors of mortality as well as relevant clinical factors, including cancer stage and type, performance status (ECOG), prior potentially cardiotoxic anti-cancer drug therapy, coronary artery disease, potassium concentration, and haemoglobin (multivariate adjusted hazard ratios: NSVT ≥4 beats [HR 1.76, p = 0.022], ≥20 PVCs/24 h [HR 1.63, p < 0.0064]). Conclusions: NSVT ≥4 beats and ≥20 PVCs/day seen in routine 24 h ECGs of patients with cancer carry prognostic relevance.

Aims Many cancer patients die due to cardiovascular disease and sudden death, but data on ventricular arrhythmia prevalence and prognostic importance are not known. Methods and results Between 2005 and 2010, we prospectively enrolled 120 unselected patients with lung, colon, or pancreatic cancer due to one of three diagnoses: colorectal (n = 33), pancreatic (n = 54), or non-small cell lung cancer (n = 33). All were free of manifest cardiovascular disease. They were compared to 43 healthy controls similar in age and sex distribution. Each participant underwent 24 h electrocardiogram recording and cancer patients were followed for up to 12.5 years for survival (median 21 months). Ninety-six cancer patients (80%) died during follow-up [5-year survival: 27% (95% confidence interval 19-35%)]. Non-sustained ventricular tachycardia (NSVT) was more frequent in cancer patients vs. controls (8% vs. 0%, P = 0.021). The number of premature ventricular contractions (PVCs) over 24 h was not increased in cancer patients vs. controls (median 4 vs. 9, P = 0.2). In multivariable analysis, NSVT [hazard ratio (HR) 2.44, P = 0.047] and PVCs (per 100, HR 1.021, P = 0.047) were both significant predictors of mortality, independent of other univariable mortality predictors including tumour stage, cancer type, potassium concentration, prior surgery, prior cardiotoxic chemotherapy, and haemoglobin. In patients with colorectal and pancreatic cancer, >= 50 PVCs/24 h predicted mortality (HR 2.30, P = 0.0024), and was identified in 18% and 26% of patients, respectively. Conclusions Non-sustained ventricular tachycardia is more frequent in unselected patients with colorectal, pancreatic, and non-small cell lung cancer and together with PVCs predict long-term mortality. This raises the prospect of cardiovascular mortality being a target for future treatment interventions in selected cancers.

Combining sorafenib and eribulin mesylate may provide synergistic antitumor activities with limited overlapping toxicities. This phase 1b, open-label, dose-escalation study evaluated safety, pharmacokinetics, maximum tolerated dose/recommended phase 2 dose (MTD/RP2D), and preliminary efficacy of sorafenib plus standard-dose eribulin mesylate in patients with advanced, metastatic, or refractory tumors. Patients received sorafenib 200 mg twice daily (BID; n = 5), 600 mg/day (n = 8), and 400 mg BID (MTD; n = 27). Dose-limiting toxicities were increased alanine aminotransferase and acute coronary syndrome (both grade 3) in the 400-mg BID dose-escalation and expansion cohorts, respectively. No significant increase in mean QTcF duration was observed with eribulin plus sorafenib versus eribulin alone; there were no drug–drug interactions. Five patients achieved partial response; 16 achieved stable disease. The combination of sorafenib and eribulin mesylate presented no unexpected safety concerns and no significant impact on QT/QTc intervals or drug–drug interactions. Sorafenib 400 mg BID plus standard-dose eribulin is the RP2D.

BACKGROUND/AIMOne of the major problems in breast cancer treatment is pharmacoresistance. Therefore, exploration of treatment alternatives is of clinical relevance. The present work focused on tumor cell-inhibiting effects of a combination of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and all trans retinoic acid (ATRA) in breast cancer cells.MATERIALS AND METHODSBreast cancer cell lines (BT-20, BT-474, MDA-MB-231, MDA-MB-436, MDA-MB-453, MCF-7, SKBR3, T47D, ZR-75-1) and the mammary epithelial cell line MCF-10A were treated with TRAIL and ATRA alone and in combination. Cell viability was assessed via 3-(4,5)-dimethylthiahiazo(-z-yl)-3,5-di-phenytetrazoliumromide (MTT) assay, the potential of cell colony formation via clonogenic assay, cell death induction via cell-cycle analysis by fluorescence-activated cell sorting (FACS), terminal deoxynucleotidyltransferase-mediated UTP nick end labeling (TUNEL) assay and Cell death detection ELISAPLUS, expression of apoptosis and TRAIL pathway proteins via western blot and cell surface expression of TRAIL receptor 1 (DR4) via FACS analysis.RESULTSTRAIL and ATRA evoked synergistic inhibition of breast cancer cell viability based on cytostatic and cytotoxic mechanisms. This correlated with augmented fragmentation of nuclear DNA, up-regulation of TRAIL receptor, down-regulation of cyclin D1 and enhancement of caspase activity. MCF-10A cells were merely slightly susceptible to TRAIL and ATRA.CONCLUSIONThe cytostatic and cytotoxic effects of the combination of TRAIL and ATRA are tumor cell-selective.

Chemokines are guiding cues for directional trafficking of mesenchymal stem cells (MSC) upon injury and local chemokine delivery at injury sites is an up-to-date strategy to potentiate and prolong recruitment of MSC. In this study we present the chemokine CCL25, also referred to as thymus-expressed chemokine, to mobilize human MSC along positive but not along negative gradients. We hence proceeded to design a biodegradable and injectable release device for CCL25 on the basis of poly(lactic-co-glycolic acid) (PLGA). The conducted studies had the objective to optimize PLGA microparticle fabrication by varying selected formulation parameters, such as polymer type, microparticle size and interior phase composition. We found that microparticles of D-v,D-50 similar to 75 mu m and fabricated using end-capped polymers, BSA as carrier protein and vortex mixing to produce the primary emulsion yielded high chemokine loading and delayed CCL25 release. To determine bioactivity, we investigated CCL25 released during the microparticle erosion phase and showed that deacidification of the release medium was required to induce significant MSC mobilization. The designed PLGA microparticles represent an effective and convenient off-the-shelf delivery tool for the delayed release of CCL25. However, continuative in vivo proof-of-concept studies are required to demonstrate enhanced recruitment of MSC and/or therapeutical effects in response to CCL25 release microparticles. Statement of Significance With the discovery of chemokines, particularly CXCL12, as stimulators of stem cell migration, the development of devices that release CXCL12 has proceeded quickly in the last few years. In this manuscript we introduce CCL25 as chemokine to induce mobilization of human MSC. This study proceeds to demonstrate how selection of key formulation parameters of CCL25 loading into PLGA microparticles exerts considerable influence on CCL25 release. This is important for a broad range of efforts in in situ tissue engineering where the candidate chemokine and the delivery device need to be selected carefully. The use of such a cell-free CCL25 release device may provide a new therapeutic option in regenerative medicine. (C) 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Background: Metastatic uveal melanoma (mUM) is a rare disease with poor prognosis, hardly responding to systemic treatment. As the liver is the most common and prognostic relevant metastatic site, liver-directed therapies have come into focus. Methods: A retrospective analysis was carried out in patients who were treated at our center between 2008 and 2017 receiving chemotherapy (1000 mg/m2 gemcitabine + 3500 mg/m2 treosulfan (GeT) on days 1 + 8, 4-week cycles) or transarterial chemoembolization (TACE, EmboCept® S microspheres + 50 mg cisplatin, every 4-6 weeks) as 1st-line therapy for mUM. Results: 287 patients were treated for mUM in the time period, 93 received TACE and 82 GeT as 1st-line therapy. Patient characteristics differed in the metastatic pattern: patients receiving GeT having a significant higher rate of non-liver dominant metastatic disease compared to the TACE group (p < 0.001), whereas there was no difference in age, sex, DFI, laboratory values and percentage of liver involvement. Median overall survival (OS) in the GeT group was 11.3 vs. 8.4 months in the TACE group (p = 0.089), with a median progression-free survival (PFS) of 2.7 and 2.8 months respectively (ns). Overall response rate for GeT was 6.8% and disease control rate was 41.1%, for TACE 10.2% and 47.7% respectively (both ns). Age, sex, baseline laboratory values, PFS and percentage of liver involvement were significantly associated with OS in univariate analysis. Multivariate Cox regression analysis identified male sex, elevated bilirubin, GGT, ALP, percentage of liver involvement >50% and PFS ≤2.7 months as significant independent prognostic factors for shorter survival. The metastatic pattern and the type of treatment did not show to be significant prognostic factors. Conclusions: Liver-directed therapies can improve response rates compared to systemic therapies and should be preferred in patients with liver-dominant metastatic pattern. However, PFS and OS remain poor and not significantly different between intrahepatic and systemic therapies. Further research should focus on developing new therapies based on a better understanding of the biology of these tumors. Legal entity responsible for the study: Charité Comprehensive Cancer Center, Charité - University Medicine Berlin. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.