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Triple-negative breast cancer (TNBC) is traditionally treated with systemic chemotherapy, often resulting in significant off-target toxicity. In this study, we assess the efficacy of intraductal chemotherapeutic delivery, aimed at reducing systemic side effects. Using an in situ TNBC model, created by intraductal injection of 4T1-luc cells, we identified day 3 post-tumor implantation as an optimal early intervention point. Echocardiographic analysis confirmed that intraductal administration of eribulin (ERI) or doxorubicin (DOX) did not cause cardiac dysfunction or apoptosis. Our results demonstrate that intraductal delivery of ERI and DOX significantly enhances anti-tumor and anti-metastatic effects. Mechanistically, ERI followed by DOX increased intratumoral perfusion, improved drug concentration, reversed epithelial-mesenchymal transition, and inhibited tumor cell invasion and metastasis. Additionally, this approach triggered immunogenic cell death and activated a systemic anti-tumor immune response. These findings underscore the potential of intraductal chemotherapy as a safe, highly effective approach, offering a preclinical foundation for minimally invasive TNBC therapies.

A subgroup analysis of a randomized study demonstrated that patients with advanced or metastatic liposarcoma treated with eribulin had longer overall survival and progression-free survival compared to those treated with dacarbazine, suggesting eribulin as a therapeutic option for advanced liposarcoma. Therefore, this study aims to evaluate the cost-effectiveness of eribulin versus dacarbazine in the treatment of advanced liposarcoma. We established a 10-year Markov model to compare the cost-effectiveness of eribulin and dacarbazine regimens. Clinical data were sourced from a subgroup analysis of a multicenter, randomized, open-label phase 3 trials. Quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were computed. The total cost of the dacarbazine scheme was $10,895.558, with a QALY of 0.533. In contrast, the total cost of the eribulin scheme was $16,961.891, with a QALY of 0.698. The ICER between the eribulin and dacarbazine schemes was $36,736.467, which is below the willingness-to-pay (WTP) threshold in China ($37,877.469). From the perspective of the Chinese healthcare system, eribulin is cost-effective compared to dacarbazine at the WTP threshold.

Our understanding of neoadjuvant treatment with microtubule inhibitors (MTIs) for triple negative breast cancer (TNBC) remains limited. To advance our understanding of the role of breast cancer driver genes' mutational status with pathological complete response (pCR; ypT0/isypN0) prediction and to identify distinct gene sets for MTIs like eribulin and paclitaxel, we carried out targeted genomic (n = 50) and whole transcriptomic profiling (n = 64) of TNBC tumor samples from the Japan Breast Cancer Research Group 22 (JBCRG‐22) clinical trial. Lower PIK3CA, PTEN, and HRAS mutations were found in homologous recombination deficiency (HRD)‐high (HRD score ≥ 42) tumors with higher pCR rates. When HRD‐high tumors were stratified by tumor BRCA mutation status, the pCR rates in BRCA2‐mutated tumors were higher (83% vs. 36%). Transcriptomic profiling of TP53‐positive tumors identified downregulation of FGFR2 (false discovery rate p value = 2.07e‐7), which was also the only common gene between HRD‐high and ‐low tumors with pCR/quasi‐pCR treated with paclitaxel and eribulin combined with carboplatin, respectively. Differential enrichment analysis of the HRD‐high group posttreatment tumors revealed significant correlation (p = 0.006) of the glycan degradation pathway. FGFR2 expression and the differentially enriched pathways play a role in the response and resistance to MTIs containing carboplatin treatment in TNBC patients. Our study hypothesizes FGFR2's potential role in response to microtubule inhibitors containing neoadjuvant chemotherapy in TP53 mutated and microtubule genes in homologous recombination deficiency‐high triple negative breast cancer tumors.

BackgroundBiomarkers for predicting response to the immunotherapy and chemotherapy combination in breast cancer patients are not established. In this study, we report exploratory genomic and transcriptomic analyses of pretreatment tumor tissues from patients enrolled in phase II clinical trial of a combination of eribulin and nivolumab for HER-2-negative metastatic breast cancer (MBC) (KORNELIA trial, NCT04061863).MethodsWe analyzed associations between tumor molecular profiles based on genomic (n = 76) and transcriptomic data (n = 58) and therapeutic efficacy. Patients who achieved progression-free survival (PFS) ≥ 6 months were defined as PFS6-responders and PFS6-nonresponders otherwise.FindingsAnalyses on tumor mutation burden (TMB) showed a tendency toward a favorable effect on efficacy, while several analyses related to homologous recombination deficiency (HRD) indicated a potentially negative impact on efficacy. Patients harboring TP53 mutations showed significantly poor PFS6 rate and PFS, which correlated with the enrichment of cell cycle-related signatures in PFS6-nonresponders. High antigen presentation gene set enrichment scores (≥ median) were significantly associated with longer PFS. Naïve B-cell and plasma cell proportions were considerably higher in long responders (≥ 18 months).InterpretationGenomic features including TMB, HRD, and TP53 mutations and transcriptomic features related to immune cell profiles and cell cycle may distinguish responders. Our findings provide insights for further exploring the combination regimen and its biomarkers in these tumors.

Purpose Although changes in circulating tumour DNA (ctDNA) in breast cancer are well described, the kinetics of their fluctuations has not been described over short timescales. We investigated ctDNA dynamics during alternating cycles of chemotherapy and hormonal treatment in pre-treated patients with oestrogen receptor-positive metastatic breast cancer. Methods Patients received alternating, 9-week cycles of eribulin and aromatase inhibitors (AIs). The clinical primary endpoint, progression-free survival (PFS), was monitored at 3, 6 and 9 months; secondary endpoints, clinical benefit rate (CBR), safety and tolerability profiles, were also assessed. Importantly, ctDNA fluctuations were monitored using the Oncomine™ Breast cfDNA assay to test whether biomarkers may change rapidly between chemotherapy and aromatase inhibitor (AI) treatment in the setting of advanced breast cancer, potentially reflecting disease dynamics. Results The median PFS was 202 days (95% CI: 135-undefined) and 235 days (95% CI: 235-undefined) at 6 and 9 months, respectively, with a 50% CBR at both 6 and 9 months. Dynamic changes in ctDNA were observed in short timescales between chemotherapy and AI treatment and support the clinical benefit (CB) seen in individual patients and, critically, appear informative of acquired resistance in real time. Conclusion Changes in ctDNA can occur rapidly and reflect changes in patients’ clinical tumour responses (NCT02681523).

Background Pre-clinical data suggests a potential synergistic effect of eribulin and platinum. However, clinical data on the combination for metastatic breast cancer (mBC) is lacking. We evaluated the efficacy and safety of eribulin plus carboplatin (ErCb) in patients with mBC. Patients and methods This multicenter, real-world cohort study included patients with pre-treated metastatic triple negative breast cancer (TNBC) or endocrine-refractory hormone receptor (HR) positive, HER2-negative mBC who received ErCb. Eribulin (1.4 mg/m2) and carboplatin (target AUC = 2) were administered intravenously on day 1 and 8 of 21-day cycle. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were evaluated. Results From March 2022 to December 2023, a cohort of 37 patients were recruited to the study. Among them, 22 patients have TNBC and 15 have HR + HER2 − mBC. Of the 22 patients with TNBC, 8 had an initial diagnosis of the HR + HER2 − subtype. The median treatment was 6 cycles (range, 2 − 8 cycles). In the full cohort, TNBC, and HR + HER2 − subgroup, the ORR were 51.4%, 54.5% and 46.7%, the DCR were 81.1%, 81.8% and 80%, and the median PFS were 5 months, 5 months, and 5.2 months, respectively. The median OS was 12.7 months in the entire cohort and 12.8 months in TNBC subgroup. The most common grade 3/4 hematological AEs were neutropenia (37.8%), leukopenia (35.1%), febrile neutropenia (10.8%), thrombocytopenia (5.4%), and anemia (2.7%). No grade 3/4 non-hematological AEs were observed. Conclusion ErCb demonstrated favorable efficacy and tolerability in patients with heavily pre-treated mBC, especially TNBC. The findings of the current study warrant further investigation of the application of this combination in earlier lines of mBC treatment.

Background The PI3K/AKT pathway is frequently altered in advanced triple-negative breast cancer (aTNBC), representing a promising target. Ipatasertib, a pan-AKT inhibitor, has shown activity with taxane-based chemotherapy and acceptable safety. This study evaluated the safety and efficacy of ipatasertib with non-taxane chemotherapy for aTNBC. Methods The PATHFINDER trial was a multicenter, open-label, non-comparative, phase IIa study with a safety run-in phase. Eligible patients had TNBC pretreated in the advanced setting with one or two chemotherapy regimens, including a taxane, and no prior exposure to PI3K/mTOR/AKT inhibitors. Patients received 21-day cycles of ipatasertib combined with capecitabine (arm A), eribulin (arm B), or carboplatin plus gemcitabine (arm C). The safety run-in phase determined feasibility and phase IIa doses. The primary endpoint was the incidence of treatment-emergent adverse events (TEAEs). Key secondary endpoints included progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). The analysis was exploratory without formal hypothesis testing. Results A total of 54 patients were assigned to arms A ( N  = 22), B ( N  = 25), and C ( N  = 7). Arm C was discontinued due to toxicity during the safety run-in phase. At data cut-off (November 2023), the overall median follow-up was 12.1 (range: 0.2–35.6) months. Common TEAEs in arm A were diarrhea (59.1%, 0.0% G ≥ 3), fatigue (36.4%, 0.0% G ≥ 3), and nausea (36.4%, 0.0% G ≥ 3); in arm B neutropenia (52.0%; 32.0% G ≥ 3), diarrhea (52.0%, 4.0% G3) and stomatitis (44.0%; 8.0% G3); and in arm C thrombocytopenia (85.7%, 85.7%G ≥ 3), anemia (85.7%, 57.1% G ≥ 3), neutropenia (71.4%, 71.4% G ≥ 3). No treatment-related deaths occurred. Median PFS was 2.7 (95%CI, 1.5–4.1) and 3.8 (95%CI, 1.5–9.6) months; median OS was 15.5 (95%CI, 11.8–19.3) and 11.5 (95%CI, 8.8–25.1) months; and ORR was 9.1% and 36.0% for arms A and B, respectively. No significant differences in efficacy were observed by PIK3CA mutational status. Conclusions Ipatasertib combined with capecitabine or eribulin showed acceptable safety but was not tolerable with carboplatin plus gemcitabine. The addition of ipatasertib to capecitabine or eribulin shows a potential efficacy signal in this patient population, compared to historical monotherapy data of these treatments. Identifying biomarkers to predict response to AKT inhibitors in TNBC is crucial. Trial registration www.clinicaltrials.gov , NCT04464174. Registered 09 July 2020.

Background Trastuzumab (Tmab), pertuzumab (Pmab), and taxane has been a standard first-line treatment for recurrent or metastatic human epidermal growth factor (HER2)-positive breast cancer (HER2 + mBC) but has some safety issues due to taxane-induced toxicities. This has led to ongoing efforts to seek less toxic alternatives to taxanes that are equally effective when used in combination with Tmab plus Pmab. This study aims to show the non-inferiority of eribulin, a non-taxane microtubule inhibitor, against taxane, as a partner for dual HER2 blockade. Methods/design This multicenter, randomized, open-label, parallel-group, phase III study will involve a total of 480 Japanese women with HER2 + mBC who meet the following requirements: (1) age 20–70 years; (2) no prior cytotoxic chemotherapy (excluding trastuzumab-emtansine) for mBC; (3) ≥ 6 months after prior neoadjuvant or adjuvant cytotoxic chemotherapy; (4) presence of any radiologically evaluable lesion; (5) left ventricular ejection fraction ≥ 50%; (6) Eastern Cooperative Oncology Group performance status score of 0 or 1; (7) adequate organ function; and (8) life expectancy of at least 6 months. They will be randomized 1:1 to receive eribulin (1.4 mg/m 2 on days 1 and 8) or taxane (docetaxel 75 mg/m 2 on day 1 or paclitaxel 80 mg/m 2 on days 1, 8, and 15) in combination with Tmab (8 mg/kg then 6 mg/kg) plus Pmab (840 mg then 420 mg) on day 1 of each 21-day cycle. The treatment will be continued until disease progression or unmanageable toxicity. The primary endpoint is progression-free survival as per investigator according to RECIST v1.1 criteria. Key secondary endpoints include objective response rate, overall survival, quality of life and safety. Non-inferiority will be tested with two margins of 1.33 and 1.25 in a stepwise manner. If non-inferiority is shown with a margin of 1.25, superiority will then be tested. Discussion If this study shows the non-inferiority, or even superiority, of Tmab, Pmab, and eribulin against the existing taxane-containing regimen, this new regimen may become a standard first- or second-line treatment option for HER2 + mBC in Japan. Trial registration ClinicalTrials.gov , ID: NCT03264547 . Registered on 28 June 2017.

PurposeEribulin is a unique anti-cancer drug which can improve overall survival (OS) of patients with metastatic breast cancer (MBC), probably by modulating the tumor immune microenvironment. The aim of this study was to investigate the clinical significance of serum levels of immune-related and inflammatory cytokines in patients treated with eribulin. Furthermore, we investigated the association between cytokines and immune cells, such as myeloid-derived suppressor cells (MDSCs) and cytotoxic and regulatory T cells, to explore how these cytokines might affect the immune microenvironment.MethodsSixty-eight patients with MBC treated with eribulin were recruited for this retrospective study. The relationship of cytokines, including interleukin (IL)-6, to progression-free survival and OS was examined. CD4+ and CD8+ lymphocyte, MDSCs and regulatory T cell levels were determined in the blood by flow cytometry analysis.ResultsIn our cohort, patients with high IL-6 at baseline had shorter progression-free survival and OS compared with those with low IL-6 (p = 0.0017 and p = 0.0012, respectively). Univariable and multivariable analyses revealed that baseline IL-6 was an independent prognostic factor for OS (p = 0.0058). Importantly, CD8+ lymphocytes were significantly lower and MDSCs were significantly higher in patients with high IL-6, compared to those with low IL-6.ConclusionBaseline IL-6 is an important prognostic factor in patients with MBC treated with eribulin. Our results show that high IL-6 is associated with higher levels of MDSCs which suppress anti-tumor immunity, such as CD8+ cells. It appears that eribulin is not particularly effective in patients with high IL-6 due to a poor tumor immune microenvironment.