Abstract P5-14-01: Eribulin tolerability and correlation between neuropathy and a set of polymorphisms in metastatic breast cancer patients. Results from the PAINTER (Polymorphism And Incidence of Toxicity in ERibulin treatment) study
Authors: La Verde Nicla , Damia Giovanna , Garrone Ornella , D'Onofrio Loretta , Fabi Alessandra , Ciccarese Mariangela , Generali Daniele , Nunzi Martina , Poletto Elena , Pedrazzoli Paolo , Cretella Elisabetta , Scandurra Giuseppa , Meattini Icro , Bertolini Alessandro S , Cavanna Luigi , Romagnoli Emanuela , Legramandi Lorenzo , Guffanti Federica , Rulli Eliana , Moretti Anna , Bocci Barbara , Farina Gabriella 
Published: March 2020

Abstract
BACKGROUND: Metastatic breast cancer (MBC) is an incurable disease and its treatment focuses mainly on prolonging patients (pts) survival and improving their quality of life. As a consequence, management of treatment related adverse events (AE) is very important. Eribulin (E) is a microtubule inhibitor that has shown to increase overall survival in pre-treated MBC pts. Its most common AEs are asthenia, neutropenia and peripheral neuropathy (N).
PATIENTS AND METHODS: PAINTER (Clinical trial registration: NCT 0286403) is a multicenter, interventional, single-arm, phase IV study, aimed at surveying the tolerability of E (dose 1.4 mg/m2 day 1, 8 every 21 days) in an unselected MBC pts population pre-treated with taxanes and antracyclines. The secondary objective was to investigate the relationship between specific polymorphisms and incidence and severity of peripheral N. Toxicity (T) was reported according to the NCI CTCAE v4.0. Genomic DNA was isolated from whole blood samples (Maxwell whole blood DNA kit-Promega). 15 SNPs (Single Nucleotide Polymorphisms) were genotyped by Taqman specific assays. For SNPs analysis, we selected pts with available genomic data and who started E treatment N was evaluated by medical examination.
RESULTS: From May 2014 to June 2018, 180 pts were enrolled from 20 Italian centres and 170 were evaluable. Pts and tumors characteristics were as follows: median age 60 years, ductal carcinoma 76.3%, visceral disease 68.8%, luminal type 64.7%, Her2 positive 18.3%, triple negative 17%, median previous treatment lines for MBC 5, median years from first diagnosis 6.1. Pts received E for 4.5 median cycles (Q1-Q3: 3.0-7.0; min-max: 1-23); 48.8% of pts experienced dose reduction, due to neutropenia (23.9%) and liver injury (12%) and 5.2% of pts discontinued E for T or for pts refusal. Previous neuropathy was reported in 15.9% of pts. Table 1 shows the incidence of expected AEs. N (all grades) during E treatment was reported in 33.9% of patients (G2-G3-G4: 15%). The risk of N occurrence in the first 5 cycles was 32.5% (for any grade N) and 13.2% (for severe N). Other G1-G4 toxicities were: dermatological in 8.6% pts, liver injury in 13.6%, pulmonary in 13.6%. Interestingly, 40.7% of pts reported pain, especially osteo-muscular, abdominal and at tumor site. Ten serious AEs were reported and only two were E related. 159 pts were evaluable for the analysis of polymorphism. Among the selected SNPs, the allelic variant T of the polymorphism rs2233335 in NDRG1 gene (Fisher test p &lt;0.001) and the allelic variant C of the polymorphism rs7214723 in CAMKK1 gene, showed a higher and statistically significant N occurrence (Fisher test p=0.04).
CONCLUSIONS: PAINTER study offers a wide spectrum of information about E tolerability. Asthenia, neuropathy and neutropenia were the most common T, but few pts experienced severe AEs. Schedule and dosage modifications were common, as expected in pre-treated pts, but T rarely led to treatment discontinuation. Importantly, we found for first time that the SNPs rs2233335 (G/T and T/T) in NDRG1 gene and rs7214723 (CC and CT) in CAMKK1 gene were associated with E induced N. These data on pharmacogenetic testing, if validated, could allow a tailored treatment with E.
Table 1. Incidence of expected AEsAEsG1G2G3G4Severe T (G3+G4) N=170n (%)n (%)n (%)n (%)% [%95%CI]Neuropathy 31 (18.2)20 (11.8)5 (2.9)0 (0.0)14.7 [9.75 - 20.9] #Neutropenia 15 (8.8)11 (6.5)16 (9.4)10 (5.9)15.3 [10.2 - 21.6]Constipation 16 (9.4)8 (4.7)1 (0.6)0 (0.0)0.6 [0.02 - 3.23]Alopecia 25 (14.7)13 (7.6)N.A.*N.A.*7.6 [4.13 - 12.7]Asthenia 38 (22.4)38 (22.4)10 (5.9)0 (0.0)5.9 [2.86 - 10.6]Nausea 19 (11.2)6 (3.5)0 (0.0)0 (0.0)0.0#: G2 for neuropathy and alopecia were considered as severe T *N.A.: Not applicable
Citation Format: Nicla La Verde, Giovanna Damia, Ornella Garrone, Loretta D'Onofrio, Alessandra Fabi, Mariangela Ciccarese, Daniele Generali, Martina Nunzi, Elena Poletto, Paolo Pedrazzoli, Elisabetta Cretella, Giuseppa Scandurra, Icro Meattini, Alessandro S Bertolini, Luigi Cavanna, Emanuela Romagnoli, Lorenzo Legramandi, Federica Guffanti, Eliana Rulli, Anna Moretti, Barbara Bocci, Gabriella Farina. Eribulin tolerability and correlation between neuropathy and a set of polymorphisms in metastatic breast cancer patients. Results from the PAINTER (Polymorphism And Incidence of Toxicity in ERibulin treatment) study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-14-01.