title: Clinical validity of a DPYD-based pharmacogenetic test to predict severe toxicity to fluoropyrimidines.
abstract: Pre-therapeutic DPYD pharmacogenetic test to prevent fluoropyrimidines (FL)-related toxicities is not yet common practice in medical oncology. We aimed at investigating the clinical validity of DPYD genetic analysis in a large series of oncological patients. Six hundred three cancer patients, treated with FL, have been retrospectively tested for eight DPYD polymorphisms (DPYD-rs3918290, DPYD-rs55886062, DPYD-rs67376798, DPYD-rs2297595, DPYD-rs1801160, DPYD-rs1801158, DPYD-rs1801159, DPYD-rs17376848) for association with Grade ≥3 toxicity, developed within the first three cycles of therapy. DPYD-rs3918290 and DPYD-rs67376798 were associated to Grade ≥3 toxicity after bootstrap validation and Bonferroni correction (p = 0.003, p = 0.048). DPYD-rs55886062 was not significant likely due to its low allelic frequency, nonetheless one out of two heterozygous patients (compound heterozygous with DPYD-rs3918290) died from toxicity after one cycle. Test specificity for the analysis of DPYD-rs3918290, DPYD-rs55886062 and DPYD-rs67376798 was assessed to 99%. Among the seven patients carrying one variant DPYD-rs3918290, DPYD-rs55886062 or DPYD-rs67376798 allele, not developing Grade ≥3 toxicity, 57% needed a FL dose or schedule modification for moderate chronic toxicity. No other DPYD polymorphism was associated with Grade ≥3 toxicity. Our data demonstrate the clinical validity and specificity of the DPYD-rs3918290, DPYD-rs55886062, DPYD-rs67376798 genotyping test to prevent FL-related Grade ≥3 toxicity and to preserve treatment compliance, and support its introduction in the clinical practice.
authors.affiliation: Experimental and Clinical Pharmacology, Centro Di Riferimento Oncologico-National Cancer Institute, 2-33081, Aviano, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Toffoli
authors.affiliation: Experimental and Clinical Pharmacology, Centro Di Riferimento Oncologico-National Cancer Institute, 2-33081, Aviano, Italy.
authors.forename: Luciana
authors.initials: L
authors.lastname: Giodini
authors.affiliation: Medical Oncology Unit B, Centro Di Riferimento Oncologico-National Cancer Institute, 2-33081, Aviano, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Buonadonna
authors.affiliation: Medical Oncology Unit A, Centro Di Riferimento Oncologico-National Cancer Institute, 2-33081, Aviano, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Berretta
authors.affiliation: Department of Radiation Oncology, Centro Di Riferimento Oncologico-National Cancer Institute, 2-33081, Aviano, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: De Paoli
authors.affiliation: Medical Oncology Unit B, Centro Di Riferimento Oncologico-National Cancer Institute, 2-33081, Aviano, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Scalone
authors.affiliation: Medical Oncology Unit B, Centro Di Riferimento Oncologico-National Cancer Institute, 2-33081, Aviano, Italy.
authors.forename: Gianmaria
authors.initials: G
authors.lastname: Miolo
authors.affiliation: Section of Internal Medicine, Department of Experimental and Clinical Medicine, University of Florence, 6-50139, Florence, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Mini
authors.affiliation: Section of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, 6-50139, Florence, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Nobili
authors.affiliation: Medical Oncology Unit 1, Istituto Oncologico Veneto- IRCCS, 64-35128, Padua, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Lonardi
authors.affiliation: Medical Oncology Unit, University Hospital, 15-33100, Udine, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Pella
authors.affiliation: Oncology Unit, "Azienda Ospedaliera Santa Maria degli Angeli", Pordenone, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Lo Re
authors.affiliation: Experimental and Clinical Pharmacology, Centro Di Riferimento Oncologico-National Cancer Institute, 2-33081, Aviano, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Montico
authors.affiliation: Experimental and Clinical Pharmacology, Centro Di Riferimento Oncologico-National Cancer Institute, 2-33081, Aviano, Italy.
authors.forename: Rossana
authors.initials: R
authors.lastname: Roncato
authors.affiliation: Experimental and Clinical Pharmacology, Centro Di Riferimento Oncologico-National Cancer Institute, 2-33081, Aviano, Italy.
authors.forename: Eva
authors.initials: E
authors.lastname: Dreussi
authors.affiliation: Experimental and Clinical Pharmacology, Centro Di Riferimento Oncologico-National Cancer Institute, 2-33081, Aviano, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Gagno
authors.affiliation: Experimental and Clinical Pharmacology, Centro Di Riferimento Oncologico-National Cancer Institute, 2-33081, Aviano, Italy.
authors.forename: Erika
authors.initials: E
authors.lastname: Cecchin
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000627:therapeutic use; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects* / Q000627:therapeutic use; D005820:Genetic Testing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: D000964:Antimetabolites, Antineoplastic; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil
keywords: cancer; chemotherapy; dihydropyrimidine dehydrogenase; fluoropyrimidines; pharmacogenetics; polymorphism; toxicity