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Background/aim: Eribulin, a non-taxane microtubule inhibitor, improves the tumor immune microenvironment via vascular remodeling. Systemic peripheral immune markers such as absolute lymphocyte count (ALC) and neutrophil-to-lymphocyte ratio (NLR) have been reported as prognostic factors of patients treated with eribulin. However, the usefulness of the longitudinal changes of these blood parameters during eribulin treatment remains unknown., Patients and Methods: A total of 97 patients with locally advanced or metastatic breast cancer treated with eribulin were recruited. ALC and NLR values were collected at each cycle of treatment. The correlation between ALC and NLR and prognosis and antitumor effects was retrospectively evaluated., Results: Progression-free and overall survival for patients with a base line ALC ≥1,500/μl was significantly better than that for those with a lower ALC (p=0.049 and p=0.004, respectively). The mean ALC in the non-progressive disease (PD) group increased, while that in the PD group slightly decreased over time. A low ALC at the last cycle was significantly correlated with PD (p=0.030). Of the 64 patients with PD, 47 were classified as having progression due to a pre-existing lesion (PPL), and 17 patients were classified as having progression due to new metastasis (PNM). The mean ALC for the PPL group slightly increased during eribulin treatment, while that for the PNM group decreased., Conclusion: Eribulin treatment may have improved the immune status in eribulin responders. Monitoring ALC values may be useful for early assessment of response to therapy., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: We investigated the usefulness of dynamic changes in absolute lymphocyte count (ALC) and neutrophil-to-lymphocyte ratio (NLR) during eribulin therapy as predictive markers for survival benefit including post-progression survival (PPS)., Patients and Methods: We retrospectively investigated 94 advanced breast cancer (ABC) patients who underwent eribulin therapy between July 2011 and June 2020., Results: The multivariate analysis showed that high baseline ALC and low NLR were independent predictive markers for overall survival (OS) (p=0.007 and p=0.011, respectively) and PPS (p=0.005 and p=0.007, respectively). Dynamic changes in ALC were also associated with OS and PPS (p=0.015, and p=0.026, respectively) and were an independent predictive marker for PPS (p=0.021)., Conclusion: Baseline ALC and NLR and dynamic changes in ALC during eribulin therapy were significantly associated with survival benefit including PPS for patients with ABC., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Eribulin is widely used for the treatment of breast cancer and soft-tissue sarcoma (STS). Previous studies identified the pre-treatment absolute lymphocyte count, baseline neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein concentration as potential prognostic markers in patients with breast cancer treated with eribulin. However, prognostic factors for eribulin treatment in patients with STS have not been identified., Patients and Methods: This was a retrospective analysis of data collected prospectively from 53 patients who were treated with eribulin for recurrent or metastatic STS between March 2016 and August 2019. Univariate and multivariate analyses were performed to determine the predictive factors of durable clinical benefit, progression-free survival, and overall survival., Results: L-Sarcoma histology [hazard ratio (HR)=28.20, 95% confidence intervaI (CI)=1.67-476.00; p=0.021] and pre-treatment NLR <3.0 (HR=9.96, 95% CI=1.28-77.7; p=0.028) were independent factors predictive of durable clinical benefit. In addition, pre-treatment NLR <3.0 (HR=0.34, 95% CI=0.16-0.74; p=0.0059) and male sex (HR=0.23, 95% CI=0.10-0.52; p<0.001) were independent factors predictive of better progression-free survival., Conclusion: This retrospective study found that baseline NLR predicts the efficacy of eribulin for STS., (Copyright© 2021, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: The prognostic nutritional index (PNI) and neutrophil-to-lymphocyte ratio (NLR) are prognostic markers for operable breast cancer. However, their importance in patients with metastatic breast cancer (MBC) remains unclear. This study aimed to evaluate these parameters as prognostic markers in MBC patients treated with eribulin., Patients and Methods: A total of 60 patients with MBC treated with eribulin were included., Results: Although high PNI and low NLR were correlated with better progression-free survival (PFS) and overall survival (OS), PNI had stronger impact as prognostic marker than NLR (PNI: HR=0.35, p=0.0008 for PFS and HR=0.27, p=0.0068 for OS; NLR: HR=0.71, p=0.081 for PFS and HR=0.63, p=0.14 for OS). Multivariate analysis demonstrated that PNI was an independent predictor of PFS (HR=0.30, p=0.0009)., Conclusion: PNI could be a more reliable prognostic marker for MBC patients treated with eribulin than NLR., (Copyright© 2021, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: There is no established standard chemotherapy after administration of the combination endocrine plus CDK4/6 inhibitor therapy for luminal-type breast cancer. We used patient-derived xenograft (PDX) models to determine the antitumor activity of eribulin and capecitabine after endocrine therapy plus CDK4/6 inhibitor., Materials and Methods: We examined the antitumor activity of fulvestrant, palbociclib, eribulin, and capecitabine in 4 luminal-type breast cancer PDX models (OD-BRE-0188, -0438, -0450, -0745). In OD-BRE-0438, we determined the antitumor activity of chemotherapy after fulvestrant-palbociclib treatment. We also performed immunohistochemical analysis to explore the effects of treatment on E-cadherin in tumor tissues., Results: Fulvestrant, fulvestrant-palbociclib and chemotherapy had antitumor activity in the 4 PDX models. In OD-BRE-0438 (the most resistant to fulvestrant-palbociclib), eribulin had superior antitumor activity to capecitabine after fulvestrant plus palbociclib. Only eribulin tended to increase E-cadherin expression., Conclusion: Eribulin had superior antitumor activity to capecitabine after fulvestrant-palbociclib in the OD-BRE-0438 model., (Copyright © 2020 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: We investigated the efficacy of neutrophil-to-lymphocyte ratio (NLR), absolute lymphocyte count (ALC), and C-reactive protein (CRP) in predicting overall survival of metastatic breast cancer patients treated with eribulin., Patients and Methods: Overall, 74 patients treated with eribulin were enrolled and their baseline levels of NLR, ALC, and CRP retrieved. Cutoff values of NLR, ALC, and CRP were set at 3.0, 1500/μl, and 0.3 mg/dl, respectively. Overall survival (OS) was compared according to marker levels., Results: The OS of NLR-low, ALC-high, and CRP-low groups at baseline was significantly longer than that of NLR-high, ALC-low, and CRP-high groups (p=0.0027, p=0.0013, and p=0.0164, respectively). The combination of ALC and CRP was significantly associated with OS by multivariate analysis (p=0.048)., Conclusion: Baseline levels of NLR, ALC, and CRP were significantly associated with OS in patients treated with eribulin. The combination of ALC and CRP improved the predictive efficacy compared to individual markers., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: In addition to its cytocidal effects as a microtubule dynamics inhibitor, eribulin mesylate (eribulin) regulates the tumour microenvironment. We examined the clinical significance of tumour infiltrating lymphocytes (TILs) and transforming growth factor-β (TGF-β), which are local markers of host immunity, and of the neutrophil-lymphocyte ratio (NLR) and absolute lymphocyte count (ALC), which are systemic markers., Patients and Methods: We administered eribulin chemotherapy to 106 patients with locally advanced or metastatic breast cancer. Of these, 21 had their lesions resected., Results: The response to eribulin was significantly associated with ALC (p=0.007). The expression of pSmad2 (an indicator of activation of TGF-β downstream signaling) was significantly decreased before and after eribulin chemotherapy (p<0.001). Moreover, a baseline ALC ≥ 1,500 /μl was observed in a significantly high number of patients with pSmad2 negative conversion (p<0.001)., Conclusion: Eribulin improved the tumour immune microenvironment by decreasing TGF-β expression. This demonstrated that local change can be evaluated based on ALC., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Matrix-producing breast carcinoma (MPBC) is a rare and usually aggressive triple-negative breast cancer (TNBC). In the present report, we determined the drug sensitivity for a triple-negative MPBC using a patient-derived orthotopic xenograft (PDOX) model., Materials and Methods: The PDOX model was established in the left 2 nd mammary by surgical orthotopic implantation (SOI). MPBC PDOX models were randomized into 4 groups (6 mice per group) when the tumor volume became 80 mm 3 : G1, control group; G2, cisplatinum group [intraperitoneal (i.p.) injection, weekly, for 2 weeks]; G3, paclitaxel group (i.p., weekly, for 2 weeks); G4, eribulin group [intravenous (i.v.) injection, weekly, for 2 weeks]. All mice were sacrificed on day 15. Tumor volume and body weight were measured one time per week., Results: The MPBC PDOX model was resistant to cisplatinum (p=0.800). Paclitaxel suppressed tumor growth compared to the control group (p=0.009). However, only eribulin regressed the tumor (p=0.001)., Conclusion: Eribulin has clinical potential for triple-negative MPBC patients., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Several proteins involved in immune regulation and the relationship among these, the tumor microenvironment, and clinical outcomes of eribulin treatment were evaluated in advanced or metastatic breast cancer patients., Patients and Methods: This retrospective cohort study comprised 52 eribulin-treated locally advanced or metastatic breast cancer patients. Cancer tissue samples were obtained before and after treatment in 10 patients. Immunohistochemistry was performed to determine programmed death (PD)-1, CD8, and forkhead box P3 (FOXP3) expression by stromal tumor-infiltrating lymphocytes, and PD-ligand (L1) and PD-L2 expression by cancer cells., Results: Of the 10 patients, 5 were responders (partial response) and 5 were non-responders (stable disease, 2; progressive disease, 3) to eribulin. PD-1, PD-L2, and FOXP3 expression became negative in 5 patients, PD-L1 expression became negative in 6 patients, and CD8 expression became positive in 3 patients after treatment. The response to eribulin was significantly associated with PD-L1 and FOXP3 negative conversion (p=0.024 and 0.004, respectively). The change in E-cadherin expression (positive or negative) was also correlated with the changes in PD-L1 and FOXP3 (p=0.024 and 0.004, respectively). Kaplan-Meier analysis with log-rank tests revealed that progression-free survival and time-to-treatment failure were significantly longer in patients with PD-L1 and FOXP3 negative conversion (p=0.012 and 0.001; p=0.049 and 0.018, respectively)., Conclusion: The efficacy of eribulin may be attributed to its biological effects on the immune system (reduction of PD-L1 and FOXP3 expression) through epithelial-mesenchymal transition suppression, and vascular remodeling and improvement of the tumor microenvironment., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Eribulin mesylate (eribulin) is currently used for the treatment of locally advanced or metastatic breast cancer (MBC). It is a cytotoxic agent with unique mechanisms that suppress the epithelial-mesenchymal transition (EMT) of cancer cells and promote tumor vascular remodeling. In this study, we investigated the expression of markers for EMT and hypoxia in sets of clinical specimens collected before and after eribulin treatment to verify its unique mechanisms., Patients and Methods: The expression of markers for EMT and cellular hypoxia [E-cadherin, N-cadherin, vimentin, and carbonic anhydrase 9 (CA9)] was examined immunohistochemically in MBC tissues collected from 20 patients before and after chemotherapy with either eribulin (n=10) or paclitaxel (n=10)., Results: An increase of E-cadherin and decrease of CA9 expression were observed in MBC tissues from patients with objective clinical responses to eribulin treatment. Patients with E-cadherin-positive conversion and CA9-negative conversion had significantly higher response rates (p=0.004 and p=0.024, respectively) and prolonged time to treatment failure (p=0.018 and p=0.038, respectively) than patients without changes in marker expression., Conclusion: Expression of EMT and hypoxia markers in clinical samples from patients with MBC was suppressed by eribulin treatment. The results provide additional clinical data on improved survival of patients treated with eribulin and the mechanism of response., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: One reason of poor survival rate of patients with pancreatic cancer is the development of chemoresistance. The aim of the present study was to investigate the effects of eribulin mesylate in gemcitabine-refractory advanced pancreatic cancer cell lines., Materials and Methods: Three human pancreatic cancer cell lines (AsPC-1, Panc-1, and SUIT-2) and human pancreatic endoderm (hPE) cells were used to evaluate the antitumor effects of gemcitabine and eribulin mesylate. Cell viability after treatment of cells with different concentrations of gemcitabine and eribulin mesylate was evaluated using water-soluble tetrazolium salts (WST) assays; cytotoxic effects were evaluated on the basis of morphological changes to cells., Results: Gemcitabine had no effect on cell viability of AsPC-1 nor Panc-1 cells, whereas gemcitabine reduced cell viability of SUIT-2 cells in a dose-dependent manner. Eribulin mesylate significantly reduced cell viability of both AsPC-1 and Panc-1 cells (p<0.001 and p=0.002, respectively), but had no effect on hPE cells. Microscopic examination of AsPC-1 and Panc-1 cells after treatment with eribulin mesylate revealed morphological changes that included cell shrinkage, membrane blebbing, and fragmentation of the cells after drug exposure, and these were concentration-dependent effects., Conclusion: The findings of the present study suggest that eribulin mesylate may be a promising potential anticancer drug for gemcitabine-refractory advanced pancreatic cancer., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Eribulin mesilate (eribulin), a first-in-class halichondrin B-based microtubule dynamics inhibitor, has been shown to promote vascular remodeling and reversal of epithelial-mesenchymal transition (EMT) apart from its antimitotic activity in breast cancer models., Materials and Methods: Anti-proliferative activity of eribulin was examined in vitro and in vivo in several human soft tissue sarcoma (STS) cell lines. To assess tumor blood perfusion and phenotypic changes, eribulin was investigated in a leiomyosarcoma xenograft and in vitro in liposarcoma and leiomyosarcoma cell lines., Results: Eribulin showed anti-proliferative activity in vitro against all six cell lines investigated, with 50% inhibitory concentration values of around 1 nmol/l, as well as significant antitumor activity against four xenografts in vivo. In addition, eribulin significantly enhanced tumor blood perfusion in xenografts and induced morphological changes and up-regulation of differentiation marker genes., Conclusion: In pre-clinical models, eribulin showed anti-proliferative activity against a variety of histopathological subtypes of STS. Eribulin might also cause tumor vasculature remodeling to enhance tumor blood perfusion and induce tumor cell differentiation., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)