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Fluorouracil Toxicity and DPYD

Fluorouracil Toxicity and DPYD

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5-Fluorouracil (5FU) is a fluorinated pyrimidine analogue commonly used in combination chemotherapy regimens for patients with breast, colorectal, lung, and other malignancies. Dihydropyrimidine dehydrogenase (DPD), an enzyme encoded by the DPYD gene, is the rate-limiting step in pyrimidine catabolism and deactivates more than 80% of standard doses of 5FU and the oral 5FU prodrug capecitabine.

True deficiency of DPD affects approximately 5% of the overall population. In these patients, the lack of enzymatic activity increases the half-life of the drug, resulting in excess drug accumulation and toxicity. [1] In addition, 3% to 5% of the population has a partial DPD deficiency due to sequence variations in DPYD gene, which potentially limits their ability to fully metabolize the drug, thereby resulting in toxicity. [2, 3, 4, 5]

The IVS14+1G>A mutation in intron 14 coupled with exon 14 deletion (known as DPYD*2A) is the most well known variant resulting in partial DPD deficiency and 5FU toxicity. [1] Other recognized variants associated with toxicity include 496A>G in exon 6; 2846A>T in exon 22; [6, 7] and T1679G (DPYD*13) in exon 13, [8] although multiple other mutations have been detected in individual families and via full gene sequences.

Patients with DPD deficiency who are treated with 5FU or capecitabine are at significantly increased risk of developing severe (grade III/IV) and potentially fatal neutropenia, mucositis, diarrhea. [2, 6, 7, 9, 10] As noted in their respective product labels, both 5FU and capecitabine are therefore contraindicated in patients with known DPD deficiency.

By contrast, the clinical effects of DPYD variants and partial DPD deficiency are unclear. Different series have demonstrated increased toxicity to varying degrees, [6, 7] but mutations in DPYD have, for the most part, been unable to account for the magnitude of toxicity seen in the general population. Some groups have begun to evaluate the contribution of mutations in other candidate genes, [7] but the effects of these and other genetic and nongenetic factors will remain unknown until there is clear elucidation of all of the pathways involved in 5FU/capecitabine metabolism. [11]

Based on what is known to date about the role of DPD in 5FU/capecitabine metabolism, patients with known DPD deficiency and/or a family history of known mutations should avoid therapy with 5FU/capecitabine. [12] For the general population, because true DPD deficiency is rare and because the clinical implications of partial deficiency are still unclear, screening for mutations prior to initiating therapy is not warranted. [2, 11] In addition, even if a partial deficiency is detected, there are no guidelines on how to tailor therapy to minimize toxicity, so the clinical utility of testing for DPYD variants remains unclear. [13, 14, 15]

Until such time that guidelines are available, patients with known or suspected partial DPD deficiency who might be at greater risk for fluorouracil toxicity can be managed per the dose modification guidelines outlined in the capecitabine product label. In this rare situation, alternative non-5FU containing treatment regimens (if available) may also be considered.

In December 2015, the FDA approved uridine triacetate (Vistogard), a pyrimidine analog, for emergency treatment following a fluorouracil or capecitabine overdose in patients with early-onset, severe or life-threatening toxicity affecting the heart or central nervous system, as well as after early onset, unusually severe adverse reactions (GI toxicity and/or neutropenia) within 96 hours after fluorouracil or capecitabine administration. Following oral administration, uridine triacetate is deacetylated by nonspecific esterases, yielding uridine in the circulation, which competitively inhibits cell damage and cell death caused by fluorouracil. In 2 trials, of those who were treated with uridine triacetate for overdose, 97% were still alive at 30 days. Of those treated with uridine triacetate for early-onset, severe or life-threatening toxicity, 89% were alive at 30 days. [16]

Enzymatic activity in patients with suspected DPD deficiency can be determined via RNA extracted from peripheral blood mononuclear cells and measurement of DPD mRNA copy number. High-throughput genetic analysis using denaturing high performance liquid chromatography (DHPLC) can be used if the patient is severely neutropenic. [17]

Testing for DPD deficiency and the IVS14+1G>A DPYD variant (DPYD*2A) is available; testing for other variants is not currently available.

The following companies currently offer testing for DPYD mutations:

EntroGen (http://www.entrogen.com)

Myriad (http://www.myriadtests.com)

LabCorp (http://www.labcorp.com)

Molecular Diagnostics Laboratories (http://www.mdl-labs.com)

Lee A, Ezzeldin H, Fourie J, Diasio R. Dihydropyrimidine dehydrogenase deficiency: impact of pharmacogenetics on 5-fluorouracil therapy. Clin Adv Hematol Oncol. 2004 Aug. 2(8):527-32. [Medline].

Gross E, Busse B, Riemenschneider M, Neubauer S, Seck K, Klein HG, et al. Strong association of a common dihydropyrimidine dehydrogenase gene polymorphism with fluoropyrimidine-related toxicity in cancer patients. PLoS One. 2008. 3(12):e4003. [Medline]. [Full Text].

Amstutz U, Froehlich TK, Largiadèr CR. Dihydropyrimidine dehydrogenase gene as a major predictor of severe 5-fluorouracil toxicity. Pharmacogenomics. 2011 Sep. 12(9):1321-36. [Medline].

Kim SR, Park CH, Park S, Park JO, Lee J, Lee SY. Genetic polymorphisms associated with 5-Fluorouracil-induced neurotoxicity. Chemotherapy. 2010. 56(4):313-7. [Medline].

Rumiato E, Boldrin E, Amadori A, Saggioro D. DMET™ (Drug-Metabolizing Enzymes and Transporters) microarray analysis of colorectal cancer patients with severe 5-fluorouracil-induced toxicity. Cancer Chemother Pharmacol. 2013 Aug. 72(2):483-8. [Medline].

van Kuilenburg AB, Haasjes J, Richel DJ, et al. Clinical implications of dihydropyrimidine dehydrogenase (DPD) deficiency in patients with severe 5-fluorouracil-associated toxicity: identification of new mutations in the DPD gene. Clin Cancer Res. 2000. 4705-4712.

Schwab M, Zanger UM, Marx C, Schaeffeler E, Klein K, Dippon J, et al. Role of genetic and nongenetic factors for fluorouracil treatment-related severe toxicity: a prospective clinical trial by the German 5-FU Toxicity Study Group. J Clin Oncol. 2008 May 1. 26(13):2131-8. [Medline].

Johnson MR, Wang K, Diasio RB. Profound dihydropyrimidine dehydrogenase deficiency resulting from a novel compound heterozygote genotype. Clin Cancer Res. 2002 Mar. 8(3):768-74. [Medline].

Diasio RB, Johnson MR. Dihydropyrimidine dehydrogenase: its role in 5-fluorouracil clinical toxicity and tumor resistance. Clin Cancer Res. 1999 Oct. 5(10):2672-3. [Medline].

Deenen MJ, Tol J, Burylo AM, Doodeman VD, de Boer A, Vincent A, et al. Relationship between single nucleotide polymorphisms and haplotypes in DPYD and toxicity and efficacy of capecitabine in advanced colorectal cancer. Clin Cancer Res. 2011 May 15. 17(10):3455-68. [Medline].

Ezzeldin HH, Diasio RB. Predicting fluorouracil toxicity: can we finally do it?. J Clin Oncol. 2008 May 1. 26(13):2080-2. [Medline].

Saif MW. Dihydropyrimidine dehydrogenase gene (DPYD) polymorphism among Caucasian and non-Caucasian patients with 5-FU- and capecitabine-related toxicity using full sequencing of DPYD. Cancer Genomics Proteomics. 2013 Mar-Apr. 10(2):89-92. [Medline].

Jennings BA, Loke YK, Skinner J, Keane M, Chu GS, Turner R, et al. Evaluating predictive pharmacogenetic signatures of adverse events in colorectal cancer patients treated with fluoropyrimidines. PLoS One. 2013 Oct 22. 8(10):e78053. [Medline]. [Full Text].

Offer SM, Lee AM, Mattison LK, Fossum C, Wegner NJ, Diasio RB. A DPYD variant (Y186C) in individuals of african ancestry is associated with reduced DPD enzyme activity. Clin Pharmacol Ther. 2013 Jul. 94(1):158-66. [Medline]. [Full Text].

Loganayagam A, Arenas Hernandez M, Corrigan A, Fairbanks L, Lewis CM, Harper P, et al. Pharmacogenetic variants in the DPYD, TYMS, CDA and MTHFR genes are clinically significant predictors of fluoropyrimidine toxicity. Br J Cancer. 2013 Jun 25. 108(12):2505-15. [Medline]. [Full Text].

Vistogard (uridine triacetate) [package insert]. Gaithersburg, MD: Wellstat Therapeutics. December, 2015. Available at [Full Text].

Saif MW, Ezzeldin H, Vance K, Sellers S, Diasio RB. DPYD*2A mutation: the most common mutation associated with DPD deficiency. Cancer Chemother Pharmacol. 2007 Sep. 60(4):503-7. [Medline].

Fazia Mir, MD Fellow, Department of Gastroenterology, University of Missouri-Columbia School of Medicine

Fazia Mir, MD is a member of the following medical societies: American College of Physicians

Disclosure: Nothing to disclose.

Shamudheen Rafiyath, MD Hematologist/Oncologist, Arizona Oncology

Shamudheen Rafiyath, MD is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Karl S Roth, MD Retired Professor and Chair, Department of Pediatrics, Creighton University School of Medicine

Karl S Roth, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American College of Nutrition, American Pediatric Society, American Society for Nutrition, American Society of Nephrology, Association of American Medical Colleges, Medical Society of Virginia, New York Academy of Sciences, Sigma Xi, Society for Pediatric Research, Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Maurie Markman, MD Senior Vice President for Clinical Affairs and National Director for Medical Oncology, Cancer Treatment Centers of America

Maurie Markman, MD is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Clinical Oncology, and American Society of Hematology

Disclosure: Genentech Consulting fee Consulting; Cellgene Consulting fee Consulting; Hana Pharmaceuticals Consulting fee Consulting; Boehringer Ingelheim Consulting fee Consulting; Morphotech Consulting fee Consulting; Amgen Consulting fee Consulting

Fluorouracil Toxicity and DPYD

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