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, DPYDrs1801159, 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 5 0.003, p 5 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, DPYDrs55886062, DPYD-rs67376798 genotyping test to prevent FL-related Grade 3 toxicity and to preserve treatment compliance, and support its introduction in the clinical practice.The identification of the genetic bases of inter-individual variability in terms of response or toxicity to pharmacological treatments is a key point in the field of personalized therapy. Specifically, in the oncological setting the high variability observed in the tumor response to treatment and in the severity of toxicity emphasizes the importance of improving the knowledge on the clinical validity of the pharmacogenetic tests.Fluoropyrimidines (FL) are listed among the drugs with pharmacogenetic warnings. 1 Despite the acknowledged efficacy of these drugs in the treatment of different solid tumors, 2 the FL treatment remains challenging as a result of a considerable inter-patient variability in terms of efficacy and toxicity. 3,4 The pharmacogenetic research, aimed at defining predictive markers of FL response, mainly focused on the dihydropyrimidine dehydrogenase (DPD), which is the first and rate-limiting enzyme of FL catabolic pathway. Up to date, 160 single nucleotide polymorphisms (SNPs) that alter the DPD aminoacids sequence have been identified within the gene (DPYD) codifying for this enzyme 5,6 and many clinical studies have been trying to investigate their association with FL-related severe toxicities. 3,[7][8][9][10][11] Recently the discussion in the scientific community about the clinical effectiveness of pharmacogenetics has given rise to the publication of drug dosing guidelines with indications and recommendations about drug...

Cost Evaluation of Irinotecan‐Related Toxicities Associated With the UGT1A1*28 Patient Genotype

“…To avoid the confounding effect of other patient genotypes associated with toxicity, seven heterozygous patients for dihydropyrimidine dehydrogenase (DPYD) alleles increasing the risk of 5-fluorouracil toxicity 13 were excluded from the present analysis. Among these seven patients, one grade 4 toxicity, two grade 3 toxicities, two grade 2 toxicities requiring treatment interruption/delay were reported, while two patients did not develop any toxicity.…”

“…FOLFIRI was the standard of care for first‐line treatment of mCRC at the time of the study, and it is still a standard backbone chemotherapy for patients with mCRC. UGT1A1*28 (rs8175347) and variants conferring DPD deficiency (rs67376798, rs3918290, rs55886062 in DPYD ) were previously genotyped . According to the FOLFIRI regimen, the irinotecan dose was 180 mg/m 2 intravenously for 2 h on day 1 + 5‐fluorouracil 400 mg/m 2 bolus followed by 5‐fluorouracil 600 mg/m 2 continuous infusion during 22 h on days 1 and 2 + LV 200 mg/m 2 on days 1 and 2 every 2 weeks.…”

“…UGT1A1*28 (rs8175347) and variants conferring DPD deficiency (rs67376798, rs3918290, rs55886062 in DPYD) were previously genotyped. 6,13 According to the FOLFIRI regimen, the irinotecan dose was 180 mg/m 2 intravenously for 2 h on day 1 1 5fluorouracil 400 mg/m 2 bolus followed by 5-fluorouracil 600 mg/m 2 continuous infusion during 22 h on days 1 and 2 1 LV 200 mg/m 2 on days 1 and 2 every 2 weeks. A complete FOLFIRI cycle takes 28 days.…”

Pharmacogenomics, biomarker network and allele frequencies in colorectal cancer

“…Inactivation of 5-FU depends on dihydropyrimidine dehydrogenase (DPYD) activity 61 . The deficient activity of DPYD leads to prolonged 5-FU plasma half-life, causing a severe hematological toxicity 62 .…”

Fluoropyrimidine-Associated Toxicity in Two Gastrointestinal Cancer Patients: Potential Role of Common DPYD Polymorphisms

“…As rightly underlined by Deenen and Meulendijks [6], screening for DPYD variants may not eliminate all fluoropyrimidine-associated toxicities; however, the evidence regarding the clinical utility of DPYD genotype-guided dosing of fluoropyrimidines is such that it should be considered in international clinical practice guidelines. Until now, pretherapeutic DPYD pharmacogenetic testing to prevent fluoropyrimidine-related toxicities has not been a very common practice in medical oncology; however, the evidence of the clinical validity and specificity of the DPYD *2A, DPYD *13, and DPYD rs67376798 genotyping test to prevent fluoropryrimidine-related toxicity and to preserve treatment compliance could change the habits in medical oncology [7,8]. The more common deep intronic variant c.1129- 5923C>G has been significantly linked to severe 5-FU toxicity [9,10].…”