Third Line Eribulin for Triple-negative Metastatic Breast Ductal Carcinoma Resulting in Extended Progression-free Survival of 57 Months

Ding

2023

Tohoku J. Exp. Med.

Apatinib is a tyrosine kinase inhibitor (TKI) that targets vascular endothelial growth factor receptor 2 (VEGFR2) as an effective antiangiogenic agent. The current study intended to explore the treatment efficacy and safety profile of third-line apatinib plus chemotherapy in metastatic triple-negative breast cancer (mTNBC) patients. This multicenter, retrospective, cohort study analyzed 97 mTNBC patients who underwent third-line apatinib plus single-agent chemotherapy (N=45) or single-agent chemotherapy (N=52). The objective response rate (44.4% versus 19.2%, P=0.007) and disease control rate (77.8% versus 48.1%, P=0.003) were higher in the apatinib plus chemotherapy group than in the chemotherapy group. The apatinib plus chemotherapy group had a longer median progression-free survival (PFS) (6.9 (95%CI: 5.2-8.6) versus 4.3 (95%CI: 3.2-5.4) months, P=0.008) and overall survival (OS) (11.6 (95%CI: 9.3-13.9) versus 9.0 (95%CI: 7.3-10.7) months, P=0.012) than the chemotherapy group.Further adjustment of multivariate Cox's regression analysis verified that apatinib plus chemotherapy (versus chemotherapy) resulted in a longer PFS (P=0.003) and OS (P=0.010). There was no difference in adverse events between the two groups, except that hypertension was higher in the apatinib plus chemotherapy group than in the chemotherapy group (P=0.018); meanwhile, the grade 3-4 adverse events in the apatinib plus chemotherapy group included hypertension (13.3%), neutropenia (8.9%), nausea and vomiting (4.4%), fatigue (4.4%), leukopenia (4.4%), thrombocytopenia (2.2%), and hand-foot syndrome (2.2%). Third-line apatinib plus chemotherapy may achieve a more satisfying survival benefit and no obvious safety concerns in mTNBC A c c e p t e d M a n u s c r i p t 3 patients compared with mono-chemotherapy. However, more large-scale, randomized studies are warranted for further validation.

Section: Discussionmentioning

confidence: 48%

Efficacy and Safety of Third-Line Apatinib plus Chemotherapy in Metastatic Triple-Negative Breast Cancer Patients: A Multicenter, Retrospective, Cohort Study

Ding

2023

Tohoku J. Exp. Med.

“…Eribulin is used for the treatment of advanced breast cancer, including TNBC [ 41 , 42 ]. Since STING expression is heterogenous in TNBC cancer cells and tumors [ 6 , 43 ], this prompted the hypothesis that eribulin could augment the IFNβ response initiated by STING agonists in TNBC cells with a functional STING pathway.…”

Section: Resultsmentioning

confidence: 99%

The Microtubule Destabilizer Eribulin Synergizes with STING Agonists to Promote Antitumor Efficacy in Triple-Negative Breast Cancer Models

Takahashi‐Ruiz

Fermaintt

Wilkinson

et al. 2022

Cancers

Eribulin is a microtubule destabilizer used in the treatment of triple-negative breast cancer (TNBC). Eribulin and other microtubule targeted drugs, such as the taxanes, have shared antimitotic effects, but differ in their mechanism of microtubule disruption, leading to diverse effects on cellular signaling and trafficking. Herein, we demonstrate that eribulin is unique from paclitaxel in its ability to enhance expression of the immunogenic cytokine interferon beta (IFNβ) in combination with STING agonists in both immune cells and TNBC models, including profound synergism with ADU-S100 and E7766, which are currently undergoing clinical trials. The mechanism by which eribulin enhances STING signaling is downstream of microtubule disruption and independent of the eribulin-dependent release of mitochondrial DNA. Eribulin did not override the requirement of ER exit for STING activation and did not inhibit subsequent STING degradation; however, eribulin significantly enhanced IRF3 phosphorylation and IFNβ production downstream of the RNA sensing pathway that converges on this transcription factor. Additionally, we found that eribulin enhanced the population of activated CD4+ T-cells in vivo when combined with either a STING agonist or tumor, demonstrating the ability to function as an immune adjuvant. We further interrogated the combination of eribulin with ADU-S100 in the MMTV-PyVT spontaneous murine mammary tumor model where we observed significant antitumor efficacy with combination treatment. Together, our findings demonstrate that microtubule targeted chemotherapeutics have distinct immunological effects and that eribulin’s ability to enhance innate immune sensing pathways supports its use in combination with immunotherapies, such as STING agonists, for the more effective treatment of TNBC and other malignancies.

“…In addition, eribulin inhibits tumor progression or metastasis by reducing hypoxia [ 25 ], reversing epithelial–mesenchymal transition [ 26 ], suppressing migration and invasion [ 26 ], and preventing tumor vasculature remodeling [ 25 ]. Eribulin has been used to treat advanced or metastatic breast cancer, including TNBC [ 27 , 28 , 29 ], and has been used to overcome chemotherapy resistance. Eribulin produced regression of cisplatin-resistant tumors in a patient-derived xenograft model of triple-negative matrix-producing breast carcinoma [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

Identification of Kinase Targets for Enhancing the Antitumor Activity of Eribulin in Triple-Negative Breast Cell Lines

et al. 2023

Background: Triple-negative breast cancer (TNBC) is the most aggressive molecular subtype of breast cancer, and current treatments are only partially effective in disease control. More effective combination approaches are needed to improve the survival of TNBC patients. Eribulin mesylate, a non-taxane microtubule dynamics inhibitor, is approved by the U.S. Food and Drug Administration to treat metastatic breast cancer after at least two previous chemotherapeutic regimens. However, eribulin as a single agent has limited therapeutic efficacy against TNBC. Methods: High-throughput kinome library RNAi screening, Ingenuity Pathway Analysis, and STRING analysis were performed to identify target kinases for combination with eribulin. The identified combinations were validated using in vivo and ex vivo proliferation assays. Results: We identified 135 potential kinase targets whose inhibition enhanced the antiproliferation effect of eribulin in TNBC cells, with the PI3K/Akt/mTOR and the MAPK/JNK pathways emerging as the top candidates. Indeed, copanlisib (pan-class I PI3K inhibitor), everolimus (mTOR inhibitor), trametinib (MEK inhibitor), and JNK-IN-8 (pan-JNK inhibitor) produced strong synergistic antiproliferative effects when combined with eribulin, and the PI3K and mTOR inhibitors had the most potent effects in vitro. Conclusions: Our data suggest a new strategy of combining eribulin with PI3K or mTOR inhibitors to treat TNBC.