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Breast Cancer Research
Published in: Breast Cancer Research 1/2022

Open Access 01-12-2022 | Breast Cancer | Research

Tolerability of Eribulin and correlation between polymorphisms and neuropathy in an unselected population of female patients with metastatic breast cancer: results of the multicenter, single arm, phase IV PAINTER study

Authors: Nicla La Verde, Giovanna Damia, Ornella Garrone, Daniele Santini, Alessandra Fabi, Mariangela Ciccarese, Daniele Giulio Generali, Martina Nunzi, Elena Poletto, Elisa Ferraris, Elisabetta Cretella, Giuseppa Scandurra, Icro Meattini, Alessandro Stefano Bertolini, Luigi Cavanna, Elena Collovà, Emanuela Romagnoli, Eliana Rulli, Lorenzo Legramandi, Federica Guffanti, Annalisa Bramati, Anna Moretti, Alessandra Cassano, Patrizia Vici, Valter Torri, Gabriella Farina, PAINTER investigators

Published in: Breast Cancer Research | Issue 1/2022

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Abstract

Background

Metastatic breast cancer (MBC) is an incurable disease and its treatment focuses on prolonging patients’ (pts) overall survival (OS) and improving their quality of life. Eribulin is a microtubule inhibitor that increases OS in pre-treated MBC pts. The most common adverse events (AEs) are asthenia, neutropenia and peripheral neuropathy (PN).

Methods

PAINTER is a single arm, phase IV study, aimed at evaluating the tolerability of eribulin in MBC pts. Secondary objectives were the description of treatment efficacy and safety, the assessment of the incidence and severity of PN and its association with genetic polymorphisms. Genomic DNA was isolated from blood samples and 15 Single Nucleotide Polymorphisms (SNPs) were genotyped by Taqman specific assays. The association between PN and SNPs were evaluated by Fisher exact test.

Results

Starting from May 2014 until June 2018 180 pts were enrolled in this study by 20 Italian centers. 170 of these pts could be evaluated for efficacy and toxicity and 159 for polymorphisms analysis. The median age of pts was 60 years old and the biological subtypes were luminal type (64.7%), Her2 positive (18.3%) and triple negative (17%). Pts were pretreated with a median of 5 lines for MBC. The median follow up of this study was 15.4 months with a median number of 4.5 cycles administered (minimum–maximum 1–23). The median overall survival was 12 months. 48.8% of pts experienced a dose reduction, mainly for neutropenia (23.9%) and liver toxicity (12%). 65 pts (38.2%) reported at least one severe toxicity. Neutropenia and neurotoxicity were the most frequent severe AEs (15.3% and 14.7%, respectively); other reported toxicities were osteo-muscular, abdominal or tumor site pain (19.4%), liver toxicity (6.6%), pulmonary toxicity (6.5%) and dermatological toxicity (3.6%). Among the 15 evaluated SNPs, an association with PN was found for rs2233335 and rs7214723.

Conclusions

Eribulin is a well-tolerated treatment option in MBC. Schedule and dosage modifications were common, but toxicity rarely led to treatment discontinuation. SNPs rs2233335 (G/T and T/T) in the NDRG1 gene and rs7214723 (CC and CT) in the CAMKK1 gene were associated with PN. These findings, if validated, could allow a tailored treatment with eribulin in cancer patients.
Trial registration: ClinicalTrials.gov ID: NCT02864030.
Appendix
Available only for authorised users
Literature
1.
2.
Cardoso F, Costa A, Senkus E, Aapro M, Andre F, Barrios CH, Bergh J, Bhattacharyya G, Biganzoli L, Cardoso MJ, et al. 3rd ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 3). Ann Oncol. 2017;28(1):16–33.CrossRefPubMed
3.
4.
Tripathy D, Im SA, Colleoni M, et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol. 2018;19(7):904–15.CrossRefPubMed
5.
O’Shaughnessy J, Kaklamani V, Kalinsky K. Perspectives on the mechanism of action and clinical application of eribulin for metastatic breast cancer. Future Oncol. 2019;15(14):1641–53.CrossRefPubMed
6.
Jordan MA, Kamath K, Manna T, Okouneva T, Miller HP, Davis C, Littlefield BA, Wilson L. The primary antimitotic mechanism of action of the synthetic halichondrin E7389 is suppression of microtubule growth. Mol Cancer Ther. 2005;4(7):1086–95.CrossRefPubMed
7.
Okouneva T, Azarenko O, Wilson L, Littlefield BA, Jordan MA. Inhibition of centromere dynamics by eribulin (E7389) during mitotic metaphase. Mol Cancer Ther. 2008;7(7):2003–11.CrossRefPubMedPubMedCentral
8.
Smith JA, Wilson L, Azarenko O, Zhu X, Lewis BM, Littlefield BA, Jordan MA. Eribulin binds at microtubule ends to a single site on tubulin to suppress dynamic instability. Biochemistry. 2010;49(6):1331–7.CrossRefPubMed
9.
Cortes J, Schoffski P, Littlefield BA. Multiple modes of action of eribulin mesylate: Emerging data and clinical implications. Cancer Treat Rev. 2018;70:190–8.CrossRefPubMed
10.
Cortes J, O’Shaughnessy J, Loesch D, Blum JL, Vahdat LT, Petrakova K, Chollet P, Manikas A, Dieras V, Delozier T, et al. Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet. 2011;377(9769):914–23.CrossRefPubMed
11.
Kaufman PA, Awada A, Twelves C, Yelle L, Perez EA, Velikova G, Olivo MS, He Y, Dutcus CE, Cortes J. Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2015;33(6):594–601.CrossRefPubMedPubMedCentral
12.
Twelves C, Cortes J, Vahdat L, Olivo M, He Y, Kaufman PA, Awada A. Efficacy of eribulin in women with metastatic breast cancer: a pooled analysis of two phase 3 studies. Breast Cancer Res Treat. 2014;148(3):553–61. Erratum in: Breast Cancer Res Treat. 2015;149(1):313.
13.
Peng L, Hong Y, Ye X, Shi P, Zhang J, Wang Y, Zhao Q. Incidence and relative risk of peripheral neuropathy in cancer patients treated with eribulin: a meta-analysis. Oncotarget. 2017;8(67):112076–84.CrossRefPubMedPubMedCentral
14.
Cavaletti G, Alberti P, Marmiroli P. Chemotherapy-induced peripheral neurotoxicity in the era of pharmacogenomics. Lancet Oncol. 2011;12(12):1151–61.CrossRefPubMed
15.
Islam B, Lustberg M, Staff NP, Kolb N, Alberti P, Argyriou AA. Vinca alkaloids, thalidomide and eribulin-induced peripheral neurotoxicity: From pathogenesis to treatment. J Peripher Nerv Syst. 2019;24(Suppl 2):S63–73.PubMed
16.
Frederiks GN, Lam SW, Guchelaar HJ, Boven E. Genetic polymorphisms and paclitaxel- or docetaxel-induced toxicities. Syst Rev Cancer Treat Rev. 2015;41:935–50.CrossRef
17.
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of the binomial. Biometrika. 1934;26:404–13.CrossRef
18.
Machin D Campbell MJ Prognostic factors studies, In Design of studies for medical research, John Wiley & Sons 2005, New York, 227–245
19.
Swain SM, Arezzo JC. Neuropathy associated with microtubule inhibitors: diagnosis, incidence, and management. Clin Adv Hematol Oncol. 2008;6(6):455–67.PubMed
20.
Baldwin RM, Owzar K, Zembutsu H, Chhibber A, Kubo M, Jiang C, Watson D, Eclov RJ, Mefford J, McLeod HL, Friedman PN, Hudis CA, Winer EP, Jorgenson EM, Witte JS, Shulman LN, Nakamura Y, Ratain MJ, Kroetz DL. A genome-wide association study identifies novel loci for paclitaxel-induced sensory peripheral neuropathy in Calgb 40101. Clin Cancer Res. 2012;18(18):5099–109.CrossRefPubMedPubMedCentral
21.
Sucheston LE, Zhao H, Yao S, Zirpoli G, Liu S, Barlow WE, Moore HC, Thomas Budd G, Hershman DL, Davis W, Ciupak GL, Stewart JA, Isaacs C, Hobday TJ, Salim M, Hortobagyi GN, Gralow JR, Livingston RB, Albain KS, Hayes DF. Ambrosone CB genetic predictors of taxane-induced neurotoxicity in a swog phase iii intergroup adjuvant breast cancer treatment trial (S0221). Breast Cancer Res Treat. 2011;130(3):993–1002.CrossRefPubMedPubMedCentral
22.
Mir O, Alexandre J, Tran A, Durand IP, Pons G, Treluyer MJ, Goldwasser F. Relationship between Gstp1 Ile(105)val polymorphism and docetaxel-induced peripheral neuropathy: clinical evidence of a role of oxidative stress in taxane toxicity. Ann Oncol. 2009;20(4):736–40.CrossRefPubMed
23.
Sissung TM, Mross K, Steinberg SM, Behringer D, Figg WD, Sparreboom A, Mielke S. Association of ABCB1 genotypes with paclitaxel-mediated peripheral neuropathy and neutropenia. Eur J Cancer. 2006;42(17):2893–6.CrossRefPubMedPubMedCentral
24.
Hasmats J, Kupershmidt I, Rodríguez-Antona C, Su QJ, Khan MS, Jara C, Mielgo X, Lundeberg J, Green H. Identification of candidate SNPS for drug induced toxicity from differentially expressed genes in associated tissues. Gene. 2012;506(1):62–8.CrossRefPubMed
25.
Johnson DC, Corthals SL, Walker BA, Ross FM, Gregory WM, Dickens NJ, Lokhorst HM, Goldschmidt H, Davies FE, Durie BG, Van Ness B, Child JA, Sonneveld P. Morgan GJ genetic factors underlying the risk of thalidomide-related neuropathy in patients with multiple myeloma. J Clin Oncol. 2011;29(7):797–804.CrossRefPubMed
26.
La Verde N, Collovà E, Blasi L, Pinotti G, Palumbo R, Bonotto M, Garrone O, Brunello A, Rimanti A, Bareggi C, Zaniboni A, Frassoldati A, Foglietta J, Berardi R, Moretti A, Farina G, Porcu L, Barni S. Overall survival in metastatic breast cancer patients in the third millennium: results of the COSMO study. Clin Breast Cancer. 2020 9:S1526–8209(20)30272-X.
27.
Im SA, Lu YS, Bardia A, et al. Overall survival with ribociclib plus endocrine therapy in breast cancer. N Engl J Med. 2019;381(4):307–16.CrossRefPubMed
28.
Bardia A, Hurvitz SA, Tolaney SM, Loirat D, Punie K, Oliveira M, Brufsky A, Sardesai SD, Kalinsky K, Zelnak AB, Weaver R, Traina T, Dalenc F, Aftimos P, Lynce F, Diab S, Cortés J, O'Shaughnessy J, Diéras V, Ferrario C, Schmid P, Carey LA, Gianni L, Piccart MJ, Loibl S, Goldenberg DM, Hong Q, Olivo MS, Itri LM, Rugo HS; Ascent Clinical Trial Investigators. Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med. 2021 Apr 22;384(16):1529–1541.
29.
Garrone O, Montemurro F, Saggia C, La Verde N, Vandone AM, Airoldi M, De Conciliis E, Donadio M, Lucio F, Polimeni MA, et al. Eribulin in pretreated metastatic breast cancer patients: results of the TROTTER trial-a multicenter retrospective study of eribulin in real life. Springerplus. 2016;5:59.CrossRefPubMedPubMedCentral
30.
Pedersini R, Vassalli L, Claps M, Tulla A, Rodella F, Grisanti S, Amoroso V, Roca E, Simoncini EL, Berruti A. Eribulin in heavily pretreated metastatic breast cancer patients in the real world: a retrospective study. Oncology. 2018;94(Suppl 1):10–5.CrossRefPubMed
31.
Fabi A, Moscetti L, Ciccarese M, Caramanti M, Salesi N, La Verde N, Russillo M, Generali D, Scandurra G, Vari S, Pacetti U, Cognetti F, Giannarelli D. Eribulin in heavily pretreated metastatic breast cancer patients and clinical/biological feature correlations: impact on the practice. Future Oncol. 2015;11(3):431–8.CrossRefPubMed
32.
Jacot W, Heudel PE, Fraisse J, Gourgou S, Guiu S, Dalenc F, Pistilli B, Campone M, Levy C, Debled M, et al. Real-life activity of eribulin mesylate among metastatic breast cancer patients in the multicenter national observational ESME program. Int J Cancer. 2019;145(12):3359–69.CrossRefPubMed
33.
Perez-Garcia JM, Cortes J. The safety of eribulin for the treatment of metastatic breast cancer. Expert Opin Drug Saf. 2019;18(5):347–55.CrossRefPubMed
34.
Adamo V, Ricciardi GRR, Giuffrida D, Scandurra G, Russo A, Blasi L, Spadaro P, Iacono C, Soto Parra HJ, Savarino A, Ferraú F, Zerilli F, Verderame F, Butera A, Santangelo C, Franchina V, Caruso M. Eribulin mesylate use as third-line therapy in patients with metastatic breast cancer (VESPRY): a prospective, multicentre, observational study. Ther Adv Med Oncol. 2019;19(11):1758835919895755.
35.
Gamucci T, Michelotti A, Pizzuti L, Mentuccia L, Landucci E, Sperduti I, Di Lauro L, Fabi A, Tonini G, Sini V, Salesi N, Ferrarini I, Vaccaro A, Pavese I, Veltri E, Moscetti L, Marchetti P, Vici P. Eribulin mesylate in pretreated breast cancer patients: a multicenter retrospective observational study. J Cancer. 2014;5(5):320–7.CrossRefPubMedPubMedCentral
36.
Altinoz MA, Ozpinar A, Alturfan EE, Elmaci I. Vinorelbine's anti-tumor actions may depend on the mitotic apoptosis, autophagy and inflammation: hypotheses with implications for chemo-immunotherapy of advanced
37.
Tsurutani J, Sakata Y, Matsuoka T. Chemotherapy-induced peripheral neuropathy in breast cancer patients treated with eribulin: interim data from a post-marketing observational study. Breast Cancer. 2019;26(2):235–43.CrossRefPubMed
38.
39.
Fukuda Y, Li Y, Segal RA. A mechanistic understanding of axon degeneration in chemotherapy-induced peripheral neuropathy. Front Neurosci. 2017;31(11):481.CrossRef
40.
Park SB, Kwok JB, Loy CT, Friedlander ML, Lin CS, Krishnan AV, Lewis CR, Kiernan MC. Paclitaxel-induced neuropathy: potential association of MAPT and GSK3B genotypes. BMC Cancer. 2014;22(14):993.CrossRef
41.
Johnson DC, Corthals SL, Walker BA, Ross FM, Gregory WM, Dickens NJ, Lokhorst HM, Goldschmidt H, Davies FE, Durie BG, Van Ness B, Child JA, Sonneveld P, Morgan GJ. Genetic factors underlying the risk of thalidomide-related neuropathy in patients with multiple myeloma. J Clin Oncol. 2011 Mar 1;29(7):797–804.CrossRefPubMed
42.
Sundar R, Jeyasekharan AD, Pang B, Soong RC, Kumarakulasinghe NB, Ow SG, Ho J, Lim JS, Tan DS, Wilder-Smith EP, Bandla A, Tan SS, Asuncion BR, Fazreen Z, Hoppe MM, Putti TC, Poh LM, Goh BC, Lee SC. Low levels of NDRG1 in nerve tissue are predictive of severe paclitaxel-induced neuropathy. PLoS ONE. 2016 Oct 7;11(10): e0164319.CrossRefPubMedPubMedCentral
43.
Ciruelos E, Apellániz-Ruiz M, Cantos B, Martinez-Jáñez N, Bueno-Muiño C, Echarri MJ, Enrech S, Guerra JA, Manso L, Pascual T, Dominguez C, Gonzalo JF, Sanz JL, Rodriguez-Antona C, Sepúlveda JM. A pilot, phase ii, randomized, open-label clinical trial comparing the neurotoxicity of three dose regimens of nab-paclitaxel to that of solvent-based paclitaxel as the first-line treatment for patients with human epidermal growth factor receptor type 2-negative metastatic breast cancer. Oncologist. 2019;24(11):e1024–33.CrossRefPubMedPubMedCentral
44.
Kolyadina IV - 10 years of success achieved by eribulin while treating HER2-negative mBC: from randomized studies to routine practice -Kolyadina IV- Journal: Tumors of female reproductive system, 2021; 17(3): 59–68
45.
Ahsan T, Urmi NJ, Sajib AA. Heterogeneity in the distribution of 159 drug-response related SNPs in world populations and their genetic relatedness. PLoS One. 2020 Jan 23;15(1)
Metadata
Title
Tolerability of Eribulin and correlation between polymorphisms and neuropathy in an unselected population of female patients with metastatic breast cancer: results of the multicenter, single arm, phase IV PAINTER study
Authors
Nicla La Verde
Giovanna Damia
Ornella Garrone
Daniele Santini
Alessandra Fabi
Mariangela Ciccarese
Daniele Giulio Generali
Martina Nunzi
Elena Poletto
Elisa Ferraris
Elisabetta Cretella
Giuseppa Scandurra
Icro Meattini
Alessandro Stefano Bertolini
Luigi Cavanna
Elena Collovà
Emanuela Romagnoli
Eliana Rulli
Lorenzo Legramandi
Federica Guffanti
Annalisa Bramati
Anna Moretti
Alessandra Cassano
Patrizia Vici
Valter Torri
Gabriella Farina
PAINTER investigators
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2022
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-022-01560-w

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