Annamaria Ruzzo et al., Dihydropyrimidine dehydrogenase pharmaco- genetics for predicting fluoropyrimidine-related toxicity in the randomised, phase III adjuvant TOSCA trial in high-risk colon cancer patients. British Journal of Cancer

A Ruzzo1,23, F Graziano2,23, Fabio Galli3, Francesca Galli3, E Rulli3, S Lonardi4, M Ronzoni5, B Massidda6, V Zagonel4, N Pella7, C Mucciarini8, R Labianca9, M T Ionta6, I Bagaloni1, E Veltri10, P Sozzi11, S Barni12, V Ricci5, L Foltran13, M Nicolini14, E Biondi15, A Bramati16, D Turci17, S Lazzarelli18, C Verusio19, F Bergamo4, A Sobrero20, L Frontini21, M Menghi22 and M Magnani1

1Department of Biomolecular Sciences, Università degli Studi di Urbino ‘Carlo Bo’, Urbino 61032, Italy
2Azienda Ospedaliera ‘Ospedali Riuniti Marche Nord’, Department of Oncology, Pesaro 61122, Italy
3Laboratory of Methodology for Clinical Research, Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche ‘Mario Negri’, Milano 20156, Italy
4IOV- IRCCS, Padova 35128, Italy
5Ospedale San Raffaele, Department of Oncology, Milano 20132, Italy
6Azienda Ospedaliera Universitaria di Cagliari, P.O. Monserrato, Monserrato 09042, Italy
7Azienda Ospedaliera S. Maria della Misericordia, Department of Oncology, Udine 33010, Italy
8Ospedale ‘B. Ramazzini’, Department of Oncology, Carpi 41012, Italy
9Ospedale Papa Giovanni XXIII, Department of Oncology, Bergamo 24127, Italy
10Ospedale di Gaeta (ASL Latina), Department of Oncology, Gaeta 04024, Italy
11Ospedale degli Infermi di Biella, Department of Oncology, Biella 13875, Italy
12Ospedale ‘Treviglio-Caravaggio’, Department of Oncology, Treviglio 24047, Italy
13Azienda Ospedaliera Santa Maria degli Angeli, Department of Oncology, Pordenone 33170, Italy
14Azienda Ospedaliera Ospedale ‘Cervesi’, Department of Oncology, Cattolica 47841, Italy
15Ospedale ‘F, Renzetti’, Department of Oncology, Lanciano 66034, Italy
16Azienda Ospedaliera Fatebenefratelli, Department of Oncology, Milano 20121, Italy
17AUSL Ospedale di Ravenna, Department of Oncology, Ravenna 48121, Italy
18Azienda Ospedaliera di Cremona, Department of Oncology, Cremona 26100, Italy
19Ospedale di Saronno, Department of Oncology, Saronno 21047, Italy
20Azienda Ospedaliera ‘Ospedale San Martino’, Department of Oncology, Genova 16132, Italy
21Fondazione GISCAD, Parabiago 20015, Italy
22Diatech Pharmacogenetics, Jesi 60035, Italy
23These authors contributed equally to this work.

background: Dihydropyrimidine dehydrogenase (DPD) catabolises ~85% of the administered dose of fluoropyrimidines. Functional DPYD gene variants cause reduced/abrogated DPD activity. DPYD variants analysis may help for defining individual patients’ risk of fluoropyrimidine-related severe toxicity.

methods: The TOSCA Italian randomised trial enrolled colon cancer patients for 3 or 6 months of either FOLFOX-4 or XELOX adjuvant chemotherapy. In an ancillary pharmacogenetic study, 10 DPYD variants (*2A rs3918290 G>A, *13 rs55886062 T>G, rs67376798 A>T, *4 rs1801158 G>A, *5 rs1801159 A>G, *6 rs1801160 G>A, *9A rs1801265 T>C, rs2297595 A>G, rs17376848 T>C, and rs75017182 C>G), were retrospectively tested for associations with greater than or equal tograde 3 fluoropyrimidine-related adverse events (FAEs). An association analysis and a time-to-toxicity (TTT) analysis were planned. To adjust for multiple testing, the Benjamini and Hochberg’s False Discovery Rate (FDR) procedure was used.

results: FAEs occurred in 194 out of 508 assessable patients (38.2%). In the association analysis, FAEs occurred more frequently in *6 rs1801160 A allele carriers (FDR=0.0083). At multivariate TTT analysis, significant associations were found for *6 rs1801160 A allele carriers (FDR<0.0001), *2A rs3918290 A allele carriers (FDR<0.0001), and rs2297595 GG genotype carriers (FDR=0.0014). Neutropenia was the most common FAEs (28.5%). *6 rs1801160 (FDR<0.0001), and *2A rs3918290 (FDR=0.0004) variant alleles were significantly associated with time to neutropenia.

conclusions: This study adds evidence on the role of DPYD pharmacogenetics for safety of patients undergoing fluoropyrimidine-based chemotherapy.

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