Eribulin in the Management of Advanced Breast Cancer: Implications of Current Research Findings

Kok, Victor C.

doi:10.4137/bcbcr.s32787

Cited by 5 publications

(7 citation statements)

References 36 publications

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“…Thus, synergistic growth inhibition was found with eribulin in both the cell lines investigated. Eribulin is an inhibitor of microtubule dynamics and is approved by the U.S. Food and Drug Administration for the treatment of unresectable or metastatic liposarcomas that are no longer responding to anthracycline‐based chemotherapy and for patients with metastatic breast cancer who have received at least two prior chemotherapy regimens for late‐stage disease . In contrast to our findings with eribulin, additive inhibitory effects were observed when PRIMA‐1 MET was combined with docetaxel or carboplatin.…”

Section: Discussioncontrasting

confidence: 78%

Mutant p53: a novel target for the treatment of patients with triple‐negative breast cancer?

Synnott

Murray

McGowan

et al. 2016

Intl Journal of Cancer

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The identification and validation of a targeted therapy for patients with triple-negative breast cancer (TNBC) is currently one of the most urgent needs in breast cancer therapeutics. One of the key reasons for the failure to develop a new therapy for this subgroup of breast cancer patients has been the difficulty in identifying a highly prevalent, targetable molecular alteration in these tumors. Recently however, the p53 gene was found to be mutated in approximately 80% of basal/TNBC, raising the possibility that targeting the mutant p53 protein product might be a new approach for the treatment of this form of breast cancer. In this study, we investigated the anti-cancer activity of PRIMA-1 and PRIMA-1 MET (APR-246), two compounds which were previously reported to reactivate mutant p53 and convert it to a form with wild-type (WT) properties. Using a panel of 18 breast cancer cell lines and 2 immortalized breast cell lines, inhibition of proliferation by PRIMA-1 and PRIMA-1 MET was found to be cell-line dependent, but independent of cell line molecular subtype. Although response was independent of molecular subtype, p53 mutated cell lines were significantly more sensitive to PRIMA-1 MET than p53 WT cells (p 5 0.029). Furthermore, response (measured as IC 50 value) correlated significantly with p53 protein level as measured by ELISA (p 5 0.0089, r520.57, n 5 19). In addition to inhibiting cell proliferation, PRIMA-1 MET induced apoptosis and inhibited migration in a p53 mutant-dependent manner. Based on our data, we conclude that targeting mutant p53 with PRIMA-1 MET is a potential new approach for treating p53-mutated breast cancer, including the subgroup with triple-negative (TN) disease.

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Section: Discussioncontrasting

confidence: 78%

Mutant p53: a novel target for the treatment of patients with triple‐negative breast cancer?

Synnott

Murray

McGowan

et al. 2016

Intl Journal of Cancer

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“…However, therapies dedicated to metastatic breast cancer (MBC) have been dramatically improved in the last decade with the approval of human epidermal growth factor receptor 2 (HER2) inhibitors [ 3 - 6 ], mammalian target of rapamycin inhibitors [ 7 ], CDK4/6 inhibitors [ 8 - 10 ], and new chemotherapy agents [ 11 ]. One of these molecules, eribulin mesylate (EM) is approved by the Food and Drug Administration (FDA), the European Medicine Agency (EMA), and Asian regulatory authorities [ 12 ] since the results of a randomized phase III trial showing that EM improved overall survival (OS) versus treatments of physician choice after anthracyclines and taxane failure [ 13 ]. Another trial comparing EM to capecitabine in patients previously treated with taxanes and anthracyclines failed to show superiority, even though a trend in better progression-free survival (PFS) was suggested in triple-negative (TN) and HER2-negative subgroups [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Safety Results and Analysis of Eribulin Efficacy according to Previous Microtubules-Inhibitors Sensitivity in the French Prospective Expanded Access Program for Heavily Pre-treated Metastatic Breast Cancer

Sabatier

Dièras²,

Pivot

et al. 2018

Cancer Res Treat

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PurposeEribulin is approved for advanced breast cancers refractory to anthracyclines and taxanes. Efficacy according to sensitivity to previous therapies has been poorly explored.Materials and MethodsSafety data were collected prospectively and we retrospectively collected efficacy data from the five French centres that participated in the Eribulin E7389-G000-398 expanded access program. Our main objectives were exploration of safety and analysis of eribulin efficacy (progression-free survival [PFS] and overall survival [OS]) according to sensitivity to the last microtubule-inhibiting agent administered.ResultsMedian eribulin treatment duration was 3.3 months for the 250 patients included in this prospective single-arm study. Two hundreds and thirty-nine patients (95.6%) experienced an adverse event (AE) related to treatment including 129 (51.6%) with grade ≥ 3 AEs. The most frequently observed toxicities were cytopenias (59.6% of included patients), gastro-intestinal disorders (59.2%), and asthenia (56.4%). The most frequent grade 3-4 AE was neutropenia (37.2% with 4.8% febrile neutropenia). Median PFS and OS were 4.6 and 11.8 months, respectively. Patients classified as responders to the last microtubule-inhibiting therapy had a longer OS (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.51 to 0.94; p=0.017), and tended to display a better PFS (HR, 0.78; 95% CI, 0.58 to 1.04; p=0.086). OS improvement was still significant in multivariate analysis (adjusted HR, 0.53; 95% CI, 0.35 to 0.79; p=0.002).ConclusionThis work based on a prospective study suggests that identification of patients likely to be more sensitive to eribulin could be based on their previous response to microtubules inhibitors.

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“…In this study, the most common AE of ≥grade 3 was neutropenia, which is a common haematologic toxicity observed in patients treated with eribulin [ 7 , 8 , 18 ], whereas the incidence of neutropenia is lower with capecitabine-based chemotherapy compared with capecitabine-free chemotherapy [ 20 ]. The frequency of grade 3/4 neutropenia was 100% in our study as opposed to 66.7% in a previous study [ 16 ].…”

Section: Discussionmentioning

confidence: 99%

“…It binds at microtubule ends to a single site on tubulin to suppress dynamic instability, unlike taxanes. Eribulin has received U.S. Food and Drug Administration and European Medicines Agency approval for the treatment of locally advanced or MBC refractory to both anthracyclines and taxanes [ 6 ]; additionally, it gained approval in Japan in May 2010 [ 7 ]. Eribulin showed a significant and clinically meaningful improvement in overall survival (OS) compared to treatment of physician’s choice in patients with heavily pretreated MBC in a phase III study [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…To date, docetaxel plus capecitabine [ 12 ] and gemcitabine plus paclitaxel [ 13 ] have demonstrated superior survival benefit in patients with MBC. Currently, eribulin-based combinations are being actively studied and attracting attention from oncologists engaged in particularly difficult-to-treat settings such as triple-negative breast cancer (TNBC) [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

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Phase I dose-finding study of eribulin and capecitabine for metastatic breast cancer: JBCRG-18 cape study

et al. 2017

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BackgroundEribulin is a nontaxane microtubule inhibitor with activity in patients with metastatic breast cancer (MBC). We conducted a phase I dose-finding study of eribulin and capecitabine in patients with MBC pretreated with anthracycline and taxane.MethodsWomen with MBC aged ≤70 years were enrolled. A 3 + 3 dose escalation design was used: level 0 dosing, eribulin (1.4 mg/m2 intravenously on days 1 and 8) plus capecitabine [825 mg/m2 orally twice daily (BID)]; 2-weeks-on, 1-week-off in a 21-day cycle. If there were no dose-limiting toxicities (DLTs), level 1 capecitabine dose was 1000 mg/m2 BID. The primary objective was to determine maximum tolerated dose, DLTs, and recommended dose (RD). Secondary objectives included pharmacokinetics, safety, and best overall response rate.ResultsNine women with MBC were enrolled; six at level 0, three at level 1. One patient had grade 4 DLTs at level 0 (serum creatinine 7.65 mg/dL and uric acid 13.4 mg/dL), considered associated with study drugs. Level 1 dosing was taken as the RD. Neutropenia was the most common ≥grade 3 toxicity. Pharmacokinetic parameters of eribulin were not influenced by co-administration of capecitabine. Of three patients in level 1, one achieved partial response and one had prolonged stable disease.ConclusionEribulin with capecitabine in the level 1 dosing schedule was associated with manageable toxicities and promising clinical activity. This combination is recommended for phase II investigation.Electronic supplementary materialThe online version of this article (doi:10.1007/s12282-017-0798-4) contains supplementary material, which is available to authorized users.

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Eribulin in the Management of Advanced Breast Cancer: Implications of Current Research Findings

Cited by 5 publications

References 36 publications

Mutant p53: a novel target for the treatment of patients with triple‐negative breast cancer?

Mutant p53: a novel target for the treatment of patients with triple‐negative breast cancer?

Safety Results and Analysis of Eribulin Efficacy according to Previous Microtubules-Inhibitors Sensitivity in the French Prospective Expanded Access Program for Heavily Pre-treated Metastatic Breast Cancer

Phase I dose-finding study of eribulin and capecitabine for metastatic breast cancer: JBCRG-18 cape study

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