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

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, 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

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.

Keywords: Breast cancer; Eribulin; Neurotoxicity; Peripheral neuropathy; Polymorphisms.

Conflict of interest statement

NLV Eisai, MSD, Roche, Novartis, Astrazeneca, GSK, Pfizer, Gentili, Celgene. GD no competing interests. OG Eisai, MSD, Pierre Fabre, Seagen, Gilead, Novartis. DS Astrazeneca, Novartis, LILT, University of Trieste, Lilly, Pfizer, Roche, Istituto Gentili. AF Astrazeneca, Celgene, Dompè, Eisai, Lilly, Novartis, Pfizer, Roche, Pierre, Fabre. MC no competing interests. DGG Astrazeneca, Novartis, LILT, University of Trieste, Lilly, Pfizer, Roche, Novartis, Istituto Gentili. MN no competing interests. EP no competing interests. EF no competing interests. EC no competing interests. GS no competing interests. IM Eli Lilly, Novartis, Istituto Gentili, Roche, Pfizer, Ipsen, and Pierre Fabre.. ASB no competing interests. LC Astrazeneca, Pfizer, Ipsen, Celgene. EC no competing interests. ER no competing interests. ER no competing interests. LL no competing interests. FG no competing interests. AB Astellas, Jansenn, GSK. AM Sophosbiotech, Janssen. AC Novartis. PV Eisai, Roche, Pfizer, Novartis, Istituto Gentili. VT no competing interests. GF no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Study flow chart
Fig. 2
Fig. 2
A Overall population OS; B Overall population DOT; C OS based on biological subtypes; D DOT based on biological subtypes
Fig. 3
Fig. 3
Cumulative incidence of severe toxicities (A) and any grade toxicity (B)

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