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      Eribulin in pretreated metastatic breast cancer patients: results of the TROTTER trial—a multicenter retrospective study of eribulin in real life

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          Abstract

          This retrospective multicenter analysis was aimed to evaluate clinical activity and tolerability of eribulin in pretreated metastatic breast cancer patients in clinical practice. Patients treated with eribulin from January 2012 to July 2013 were enrolled in the observational study from 10 italian hospitals. Tumor and toxicity evaluation were performed according to Agenzia Italiana Farmaco. One-hundred and thirteen patients were included in the study. Median age 62 years old. 71.7 % of the patients had visceral involvement and the majority had a burden of disease involving two or more organs with a median number of 2 (1–6). The median number of previous chemotherapy regimens for advanced disease was 3 (1–10). Median number of eribulin cycles was 4 (1–27). Overall response rate was 24 % (95 % CI 16.0–31.8). Clinical benefit rate, was 35.4 % (95 % CI 26.6–44.2). At a median follow-up of 29.6 months (8.3–41.9) the median progression free survival was 3.3 months (0.6–26.7; 95 % CI 2.4–4.2), and the median overall survival 11.6 months (0.6–33.3; 95 % CI 8.7–14.5). No correlation was recorded between subtypes in terms of ORR and CBR. Toxicity was manageable. Main common grade 3–4 toxicities were neutropenia (19.4 %), febrile neutropenia (0.9 %), asthenia (3.5 %), abnormal liver function test (1.8 %), stomatitis (0.9 %). Our results confirm that treatment with eribulin is feasible and safe in real-world patients.

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          The primary antimitotic mechanism of action of the synthetic halichondrin E7389 is suppression of microtubule growth.

          E7389, which is in phase I and II clinical trials, is a synthetic macrocyclic ketone analogue of the marine sponge natural product halichondrin B. Whereas its mechanism of action has not been fully elucidated, its main target seems to be tubulin and/or the microtubules responsible for the construction and proper function of the mitotic spindle. Like most microtubule-targeted antitumor drugs, it inhibits tumor cell proliferation in association with G(2)-M arrest. It binds to tubulin and inhibits microtubule polymerization. We examined the mechanism of action of E7389 with purified microtubules and in living cells and found that, unlike antimitotic drugs including vinblastine and paclitaxel that suppress both the shortening and growth phases of microtubule dynamic instability, E7389 seems to work by an end-poisoning mechanism that results predominantly in inhibition of microtubule growth, but not shortening, in association with sequestration of tubulin into aggregates. In living MCF7 cells at the concentration that half-maximally blocked cell proliferation and mitosis (1 nmol/L), E7389 did not affect the shortening events of microtubule dynamic instability nor the catastrophe or rescue frequencies, but it significantly suppressed the rate and extent of microtubule growth. Vinblastine, but not E7389, inhibited the dilution-induced microtubule disassembly rate. The results suggest that, at its lowest effective concentrations, E7389 may suppress mitosis by directly binding to microtubule ends as unliganded E7389 or by competition of E7389-induced tubulin aggregates with unliganded soluble tubulin for addition to growing microtubule ends. The result is formation of abnormal mitotic spindles that cannot pass the metaphase/anaphase checkpoint.
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            In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B.

            Halichondrin B is a highly potent anticancer agent originally found in marine sponges. Although scarcity of the natural product has hampered efforts to develop halichondrin B as a new anticancer drug, the existence of a complete synthetic route has allowed synthesis of structurally simpler analogues that retain the remarkable potency of the parent compound. In this study, we show that two macrocyclic ketone analogues of halichondrir B, ER-076349 and ER-086526, have sub-nM growth inhibitory activities in vitro against numerous human cancer cell lines as well as marked in vivo activities at 0.1-1 mg/kg against four human xenografts: MDA-MB-435 breast cancer, COLO 205 colon cancer, LOX melanoma, and NIH: OVCAR-3 ovarian cancer. ER-076349 and ER-086526 induce G2-M cell cycle arrest and disruption of mitotic spindles, consistent with the tubulin-based antimitotic mechanism of halichondrin B. This is supported further by direct binding of the biotinylated analogue ER-040798 to tubulin and inhibition of tubulin polymerization in vitro by ER-076349 and ER-086526. Retention of the extraordinary in vitro and in vivo activity off halichondrin B in structurally simplified, fully synthetic analogues establishes the feasibility of developing halichondrin B-based agents as highly effective, novel anticancer drugs.
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              Induction of morphological and biochemical apoptosis following prolonged mitotic blockage by halichondrin B macrocyclic ketone analog E7389.

              E7389, a macrocyclic ketone analog of the marine natural product halichondrin B, currently is undergoing clinical trials for cancer. This fully synthetic agent exerts its highly potent in vitro and in vivo anticancer effects via tubulin-based antimitotic mechanisms, which are similar or identical to those of parental halichondrin B. In an attempt to understand the impressive potency of E7389 in animal models of human cancer, its ability to induce apoptosis following prolonged mitotic blockage was evaluated. Treatment of U937 human histiocytic lymphoma cells with E7389 led to time-dependent collection of cells in the G2-M phase of the cell cycle, beginning as early as 2 h and becoming maximal by 12 h. Increased numbers of hypodiploid events were seen beginning at 12 h, suggesting initiation of apoptosis after prolonged E7389-induced mitotic blockage. The identity of hypodiploid events as apoptotic cells under these conditions was confirmed by two additional morphologic criteria: green to orange/yellow shifts on acridine orange/ethidium bromide staining, and cell surface annexin V binding as assessed by flow cytometry. Several biochemical correlates of apoptosis also were seen following E7389 treatment, including phosphorylation of the antiapoptotic protein Bcl-2, cytochrome c release from mitochondria, proteolytic activation of caspase-3 and -9, and cleavage of the caspase-3 substrate poly(ADP-ribose) polymerase (PARP). In LNCaP human prostate cancer cells, treatment with E7389 also led to generation of hypodiploid cells, activation of caspase-3 and -9, and appearance of cleaved PARP, indicating that E7389 can activate cellular apoptosis pathways under anchorage-independent and -dependent cell culture conditions. These results show that prolonged mitotic blockage by E7389 can lead to apoptotic cell death of human cancer cells in vitro and can provide a mechanistic basis for the significant in vivo anticancer efficacy of E7389.
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                Author and article information

                Contributors
                +390171616350 , ornella.garrone@gmail.com
                filippo.montemurro@ircc.it
                c.saggia@inwind.it
                nicla.laverde@fbf.milano.it
                anna.vandone@libero.it
                airoldim@yahoo.com
                deconciliis@asl.at.it
                arly.donadio@alice.it
                lucio.f@ospedale.cuneo.it
                antonella.polimeni477@gmail.com
                moletti@aslal.it
                alicegiacobino@hotmail.com
                mcmerlano@gmail.com
                Journal
                Springerplus
                Springerplus
                SpringerPlus
                Springer International Publishing (Cham )
                2193-1801
                21 January 2016
                21 January 2016
                2016
                : 5
                : 59
                Affiliations
                [ ]Medical Oncology, A.O. Ospedale di Insegnamento S. Croce e Carle, V. M. Coppino, 26, 12100 Cuneo, Italy
                [ ]Investigative Clinical Oncology, Fondazione del Piemonte per l’Oncologia, Candiolo Cancer Institute (IRCCS), Strada Provinciale 142, 10060 Candiolo, Turin, Italy
                [ ]Medical Oncology, A.O.U. Maggiore della Carità, C. G. Mazzini, 28, 28100 Novara, Italy
                [ ]Department of Oncology, A.O. Fatebenefratelli & Oftalmico, C. di Porta Nuova, 25, 20121 Milan, Italy
                [ ]Department of Medical Oncology 2, A.O.U. Città della Salute e della Scienza, C. Bramante, 88, 10126 Turin, Italy
                [ ]Medical Oncology, Ospedale Cardinal Massaia, C. D. Alighieri, 201, 14100 Asti, Italy
                [ ]Breast Unit, A.O.U. Città della Salute e della Scienza, C. Bramante, 88, 10126 Turin, Italy
                [ ]Radiotherapy Oncology, A.O. Ospedale di Insegnamento S. Croce e Carle, V. M. Coppino, 26, 12100 Cuneo, Italy
                [ ]Medical Oncology, Ospedale Ivrea, Piazza Credenza, 2, 10015 Ivrea, Italy
                [ ]Medical Oncology, Ospedale S. Spirito, V. G. Giolitti, 2, 15033 Casale Monferrato, Italy
                [ ]Department of Oncology, Ospedale degli Infermi, V. Ponderanesi, 2, 13875 Ponderano, Italy
                Article
                1700
                10.1186/s40064-016-1700-0
                4720621
                26835238
                e092adbe-db6e-4878-9f89-5c459a1337ad
                © Garrone et al. 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 2 January 2016
                : 8 January 2016
                Categories
                Research
                Custom metadata
                © The Author(s) 2016

                Uncategorized
                metastatic breast cancer,eribulin,real life,toxicity
                Uncategorized
                metastatic breast cancer, eribulin, real life, toxicity

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