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 Ruzzo^1,23, F Graziano^2,23, 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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