Original ResearchIdentification of microRNA biomarkers for response of advanced soft tissue sarcomas to eribulin: Translational results of the EORTC 62052 trial
Introduction
Eribulin mesylate (Halaven®, Eisai Inc) is a synthetic analog of halichondrin B, a natural polyether macrolide occurring in marine sponges such as Halichondria spec [1], [2]. In vitro studies demonstrated that eribulin potently inhibits cell proliferation at sub to low nM range concentrations in a variety of cancer cell lines [3], [4]. In murine xenograft models of multiple cancer types including breast cancer, glioblastoma, leiomyosarcoma, fibrosarcoma and others, eribulin treatment caused tumour regression and increased survival [4], [5], [6]. Both eribulin and halichondrin B were found to interact with microtubules, leading to the formation of aberrant mitotic spindles that fail the metaphase/anaphase checkpoints, causing a mitotic arrest and eventually apoptosis [3], [4], [7], [8]. Eribulin displayed some unique properties not seen in most other microtubule binding agents, such as Vinca alkaloids or taxanes. First, the mitotic arrest by eribulin was found to be irreversible [8], and second, eribulin acted as a microtubule dynamics inhibitor through high affinity binding to each of the 13 β-tubulin subunits at the plus end of each microtubule filament [9]. The binding of eribulin caused a strong inhibition of microtubule growth but had no effect on microtubule shortening [10]. In addition to its antimitotic properties, eribulin affected the epithelial–mesenchymal transition of breast cancer cells, switching back from mesenchymal to epithelial states, thereby decreasing migration and invasiveness [11]. Furthermore, eribulin exhibited inhibitory effects on the Wnt/β-catenin pathway [12] and was involved in vascular remodeling in human breast cancer models [13].
Eribulin, either as single agent or in combination with other anticancer drugs, has been tested in several clinical trials [14]. Eribulin is approved by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) as treatment for metastatic breast cancer patients who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease; prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting [15]. In a prospective trial, performed by the European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group (EORTC STBSG), the activity and safety of eribulin was studied in patients with STS [16]. In this non-randomised, multicenter phase II trial (EORTC 62052) eribulin mesylate was administered at a dose of 1.4 mg/m2 on days 1 and 8 every 3 weeks, in four independent groups: leiomyosarcomas, adipocytic sarcomas, synovial sarcomas and other STS. The primary end-point of the study was the progression-free survival (PFS) rate at 12 weeks using RECIST 1.0. The percentage of patients progression-free at 12 weeks was 47% in adipocytic sarcoma, 32% in leiomyosarcoma, 21% in synovial sarcoma and 19% in other sarcomas [16] meeting the prespecified criterion for further testing in the adipocytic and leiomyosarcoma cohorts. Based on these findings, eribulin was then explored in a large randomised phase III trial (NCT01327885), which compared eribulin with dacarbazine in adipocytic sarcoma (liposarcoma) and leiomyosarcoma patients after failure of two or more lines of conventional chemotherapy for advanced disease. This trial documented an overall survival (OS) benefit of STS patients favouring eribulin [17], eventually resulting in approval of the FDA and the EMA for the treatment of patients with unresectable or metastatic liposarcoma who have received a prior anthracycline-containing regimen.
In this exploratory study, we aimed to identify potential microRNA (miRNA) biomarkers in STS that predict responsiveness to eribulin to more accurately determine which STS patients would benefit from the treatment with eribulin. The miRNA expression profiles of tumours derived from STS patients who were enrolled in the EORTC 62052 phase II clinical trial were determined and correlated with the response to eribulin.
Section snippets
Patients
From 65 patients, involved in the EORTC 62052 phase II clinical study [16], and consenting to the translational research, archived formalin-fixed paraffin-embedded (FFPE) tumour tissue was collected from either the primary tumour or a metastatic lesion. The series included 21 leiomyosarcomas, 14 adipocytic sarcomas, 9 synovial sarcomas and 21 other sarcoma histotypes (see Supplemental Table S1 for a further specification of the latter group). The tumour samples were collected prior to starting
MicroRNA expression identifies different sarcoma subtypes
In order to identify miRNAs present in STS samples that are associated with response to eribulin, we determined the miRNA expression profiles of a series of FFPE tumour samples. Patient and tumour characteristics are listed in Table 1. Unsupervised clustering was used to classify samples based on similarity in miRNA expression without prior knowledge of sample identity. Fig. 1 depicts the unsupervised clustering tree of all 65 STS samples, based on the expression of 196 of 756 miRNAs found to
Discussion
In this study, we identified miRNAs of which the expression levels in STS correlated with response to eribulin as defined by the absence of progression at week 12 of the systemic treatment. The expression of 26 miRNAs, including well-known miRNA clusters, was found to differ significantly between responders and non-responders. Our results are a first indication that a biomarker signature associated with outcome to eribulin treatment in advanced STS patients may be defined.
A closer look at the
Role of the funding source
The study sponsor was not involved in the study design, in the collection of samples and data, in the analysis and interpretation of data, in the writing of the report; and in the decision to submit the paper for publication.
Conflict of interest statement
PS has received consultancy and speaker honoraria from EISAI. The remaining authors declare no conflict of interest.
Funding
The EORTC 62052 clinical trial and translational research were supported by Eisai Limited, Hatfield, UK and coordinated by the EORTC.
Acknowledgements
The EORTC 62052 clinical trial and translational research were supported by Eisai Limited, Hatfield, UK and coordinated by EORTC. The authors express their gratitude to Xander den Dekker for his expert help with the miRNA profiling and to Jasmien Wellens for her excellent technical support. The authors thank the European Organization for Research and Treatment of Cancer for permission to use the data from EORTC study 62052 for this research. The contents of this publication and methods used are
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2022, Surgical Oncology Clinics of North AmericaCitation Excerpt :Using molecular profiling approaches within prospective studies therefore establishes comprehensive and high-quality datasets, which can then be interrogated for biomarkers. For example, miRNA analysis of tumor samples from patients in the EORTC 62052 phase 2 trial assessing eribulin in STS revealed that miR-106a, miR-17, and miR-34a levels differ between responders and nonresponders,23 thereby highlighting a potential method of patient stratification for eribulin treatment. However, there are also challenges associated with prospective studies.
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2022, Journal of Orthopaedic ScienceCitation Excerpt :However, the response to eribulin differs even with the same histological subtypes of sarcomas. As a biomarker to predict the efficacy of eribulin, the expression level of micro-ribonucleic acids in the tumor tissues was associated with the prognosis in patients with advanced STS [12]. Systemic inflammatory response has been reported to be associated with the outcomes of both early-stage and advanced-stage cancers [13,14].
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2018, Cancer Treatment ReviewsCitation Excerpt :A more in-depth understanding of the full spectrum of the anti-tumor activity of eribulin may help improve the selection of patients who are most likely to benefit from this therapy. Recently, a microRNA biomarker signature for eribulin response was identified in a group of patients with advanced STS [69]. In this exploratory substudy of patients from a phase 2 sarcoma trial with eribulin (EORTC trial 62052 [70]), the pattern of microRNA expression was significantly different between patients who responded to eribulin (defined as absence of progression at week 12) and nonresponders.
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2018, Advances in Clinical ChemistryCitation Excerpt :In a large multicenter study investigating the effect of adding bevacizumab to standard chemotherapy in patients diagnosed with epithelial ovarian cancer, low levels of hsa-miR-200b, hsa-miR-1274A (tRNALys5), and hsa-miR-141 were significantly associated with better survival, and the level of hsa-miR-200c seemed predictive of effect of treatment with bevacizumab [37]. In a phase II clinical trial investigating the effects of eribulin in the treatment of metastatic soft tissue sarcoma, 26 specific miRNAs were predictive of response out of the 756 miRNA assessed in paraffin-embedded sections [38]. In their phase II study, Gagez and colleagues found that hsa-miR-125b and hsa-miR-532-3p predicted the efficiency of rituximab-mediated lymphodepletion in chronic lymphocytic leukemia patients [39].
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2018, European Journal of CancerCitation Excerpt :Increasing insight into the biology of the different STS subtypes will hopefully lead to the identification of predictive markers beyond conventional histology. For example, in the context of a phase II trial, a subset of miRNAs, regardless of underlying histology, was revealed that might identify patients benefiting from eribulin [30]. Likewise, studies are investigating whether programmed cell death ligand-1 (PD-L1) expression, mutational load or composition of immune infiltrates can be used to predict outcome to anti-PD(L)1-antibodies [24,31].
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These authors contributed equally.