title: Upfront Genotyping of DPYD*2A to Individualize Fluoropyrimidine Therapy: A Safety and Cost Analysis.
abstract: OBJECTIVE
  Fluoropyrimidines are frequently prescribed anticancer drugs. A polymorphism in the fluoropyrimidine metabolizing enzyme dihydropyrimidine dehydrogenase (DPD; ie, DPYD*2A) is strongly associated with fluoropyrimidine-induced severe and life-threatening toxicity. This study determined the feasibility, safety, and cost of DPYD*2A genotype-guided dosing.
  
  
  METHODS
  Patients intended to be treated with fluoropyrimidine-based chemotherapy were prospectively genotyped for DPYD*2A before start of therapy. Variant allele carriers received an initial dose reduction of ≥ 50% followed by dose titration based on tolerance. Toxicity was the primary end point and was compared with historical controls (ie, DPYD*2A variant allele carriers receiving standard dose described in literature) and with DPYD*2A wild-type patients treated with the standard dose in this study. Secondary end points included a model-based cost analysis, as well as pharmacokinetic and DPD enzyme activity analyses.
  
  
  RESULTS
  A total of 2,038 patients were prospectively screened for DPYD*2A, of whom 22 (1.1%) were heterozygous polymorphic. DPYD*2A variant allele carriers were treated with a median dose-intensity of 48% (range, 17% to 91%). The risk of grade ≥ 3 toxicity was thereby significantly reduced from 73% (95% CI, 58% to 85%) in historical controls (n = 48) to 28% (95% CI, 10% to 53%) by genotype-guided dosing (P < .001); drug-induced death was reduced from 10% to 0%. Adequate treatment of genotype-guided dosing was further demonstrated by a similar incidence of grade ≥ 3 toxicity compared with wild-type patients receiving the standard dose (23%; P = .64) and by similar systemic fluorouracil (active drug) exposure. Furthermore, average total treatment cost per patient was lower for screening (€2,772 [$3,767]) than for nonscreening (€2,817 [$3,828]), outweighing screening costs.
  
  
  CONCLUSIONS
  DPYD*2A is strongly associated with fluoropyrimidine-induced severe and life-threatening toxicity. DPYD*2A genotype-guided dosing results in adequate systemic drug exposure and significantly improves safety of fluoropyrimidine therapy for the individual patient. On a population level, upfront genotyping seemed cost saving.
authors.affiliation: Maarten J. Deenen, Didier Meulendijks, Annemieke Cats, Marjolein K. Sechterberger, Henk Boot, Hilde Rosing, Jos H. Beijnen, and Jan H.M. Schellens, Netherlands Cancer Institute; Paul H. Smits and Marcel Soesan, Slotervaart Hospital, Amsterdam; Johan L. Severens, Erasmus University Medical Center, Rotterdam; Caroline M.P.W. Mandigers, Canisius Wilhelmina Hospital, Nijmegen; and Jos H. Beijnen and Jan H.M. Schellens, Utrecht University, Utrecht, the Netherlands.
authors.forename: Maarten J
authors.initials: MJ
authors.lastname: Deenen
authors.affiliation: Maarten J. Deenen, Didier Meulendijks, Annemieke Cats, Marjolein K. Sechterberger, Henk Boot, Hilde Rosing, Jos H. Beijnen, and Jan H.M. Schellens, Netherlands Cancer Institute; Paul H. Smits and Marcel Soesan, Slotervaart Hospital, Amsterdam; Johan L. Severens, Erasmus University Medical Center, Rotterdam; Caroline M.P.W. Mandigers, Canisius Wilhelmina Hospital, Nijmegen; and Jos H. Beijnen and Jan H.M. Schellens, Utrecht University, Utrecht, the Netherlands.
authors.forename: Didier
authors.initials: D
authors.lastname: Meulendijks
authors.affiliation: Maarten J. Deenen, Didier Meulendijks, Annemieke Cats, Marjolein K. Sechterberger, Henk Boot, Hilde Rosing, Jos H. Beijnen, and Jan H.M. Schellens, Netherlands Cancer Institute; Paul H. Smits and Marcel Soesan, Slotervaart Hospital, Amsterdam; Johan L. Severens, Erasmus University Medical Center, Rotterdam; Caroline M.P.W. Mandigers, Canisius Wilhelmina Hospital, Nijmegen; and Jos H. Beijnen and Jan H.M. Schellens, Utrecht University, Utrecht, the Netherlands.
authors.forename: Annemieke
authors.initials: A
authors.lastname: Cats
authors.affiliation: Maarten J. Deenen, Didier Meulendijks, Annemieke Cats, Marjolein K. Sechterberger, Henk Boot, Hilde Rosing, Jos H. Beijnen, and Jan H.M. Schellens, Netherlands Cancer Institute; Paul H. Smits and Marcel Soesan, Slotervaart Hospital, Amsterdam; Johan L. Severens, Erasmus University Medical Center, Rotterdam; Caroline M.P.W. Mandigers, Canisius Wilhelmina Hospital, Nijmegen; and Jos H. Beijnen and Jan H.M. Schellens, Utrecht University, Utrecht, the Netherlands.
authors.forename: Marjolein K
authors.initials: MK
authors.lastname: Sechterberger
authors.affiliation: Maarten J. Deenen, Didier Meulendijks, Annemieke Cats, Marjolein K. Sechterberger, Henk Boot, Hilde Rosing, Jos H. Beijnen, and Jan H.M. Schellens, Netherlands Cancer Institute; Paul H. Smits and Marcel Soesan, Slotervaart Hospital, Amsterdam; Johan L. Severens, Erasmus University Medical Center, Rotterdam; Caroline M.P.W. Mandigers, Canisius Wilhelmina Hospital, Nijmegen; and Jos H. Beijnen and Jan H.M. Schellens, Utrecht University, Utrecht, the Netherlands.
authors.forename: Johan L
authors.initials: JL
authors.lastname: Severens
authors.affiliation: Maarten J. Deenen, Didier Meulendijks, Annemieke Cats, Marjolein K. Sechterberger, Henk Boot, Hilde Rosing, Jos H. Beijnen, and Jan H.M. Schellens, Netherlands Cancer Institute; Paul H. Smits and Marcel Soesan, Slotervaart Hospital, Amsterdam; Johan L. Severens, Erasmus University Medical Center, Rotterdam; Caroline M.P.W. Mandigers, Canisius Wilhelmina Hospital, Nijmegen; and Jos H. Beijnen and Jan H.M. Schellens, Utrecht University, Utrecht, the Netherlands.
authors.forename: Henk
authors.initials: H
authors.lastname: Boot
authors.affiliation: Maarten J. Deenen, Didier Meulendijks, Annemieke Cats, Marjolein K. Sechterberger, Henk Boot, Hilde Rosing, Jos H. Beijnen, and Jan H.M. Schellens, Netherlands Cancer Institute; Paul H. Smits and Marcel Soesan, Slotervaart Hospital, Amsterdam; Johan L. Severens, Erasmus University Medical Center, Rotterdam; Caroline M.P.W. Mandigers, Canisius Wilhelmina Hospital, Nijmegen; and Jos H. Beijnen and Jan H.M. Schellens, Utrecht University, Utrecht, the Netherlands.
authors.forename: Paul H
authors.initials: PH
authors.lastname: Smits
authors.affiliation: Maarten J. Deenen, Didier Meulendijks, Annemieke Cats, Marjolein K. Sechterberger, Henk Boot, Hilde Rosing, Jos H. Beijnen, and Jan H.M. Schellens, Netherlands Cancer Institute; Paul H. Smits and Marcel Soesan, Slotervaart Hospital, Amsterdam; Johan L. Severens, Erasmus University Medical Center, Rotterdam; Caroline M.P.W. Mandigers, Canisius Wilhelmina Hospital, Nijmegen; and Jos H. Beijnen and Jan H.M. Schellens, Utrecht University, Utrecht, the Netherlands.
authors.forename: Hilde
authors.initials: H
authors.lastname: Rosing
authors.affiliation: Maarten J. Deenen, Didier Meulendijks, Annemieke Cats, Marjolein K. Sechterberger, Henk Boot, Hilde Rosing, Jos H. Beijnen, and Jan H.M. Schellens, Netherlands Cancer Institute; Paul H. Smits and Marcel Soesan, Slotervaart Hospital, Amsterdam; Johan L. Severens, Erasmus University Medical Center, Rotterdam; Caroline M.P.W. Mandigers, Canisius Wilhelmina Hospital, Nijmegen; and Jos H. Beijnen and Jan H.M. Schellens, Utrecht University, Utrecht, the Netherlands.
authors.forename: Caroline M P W
authors.initials: CM
authors.lastname: Mandigers
authors.affiliation: Maarten J. Deenen, Didier Meulendijks, Annemieke Cats, Marjolein K. Sechterberger, Henk Boot, Hilde Rosing, Jos H. Beijnen, and Jan H.M. Schellens, Netherlands Cancer Institute; Paul H. Smits and Marcel Soesan, Slotervaart Hospital, Amsterdam; Johan L. Severens, Erasmus University Medical Center, Rotterdam; Caroline M.P.W. Mandigers, Canisius Wilhelmina Hospital, Nijmegen; and Jos H. Beijnen and Jan H.M. Schellens, Utrecht University, Utrecht, the Netherlands.
authors.forename: Marcel
authors.initials: M
authors.lastname: Soesan
authors.affiliation: Maarten J. Deenen, Didier Meulendijks, Annemieke Cats, Marjolein K. Sechterberger, Henk Boot, Hilde Rosing, Jos H. Beijnen, and Jan H.M. Schellens, Netherlands Cancer Institute; Paul H. Smits and Marcel Soesan, Slotervaart Hospital, Amsterdam; Johan L. Severens, Erasmus University Medical Center, Rotterdam; Caroline M.P.W. Mandigers, Canisius Wilhelmina Hospital, Nijmegen; and Jos H. Beijnen and Jan H.M. Schellens, Utrecht University, Utrecht, the Netherlands.
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.affiliation: Maarten J. Deenen, Didier Meulendijks, Annemieke Cats, Marjolein K. Sechterberger, Henk Boot, Hilde Rosing, Jos H. Beijnen, and Jan H.M. Schellens, Netherlands Cancer Institute; Paul H. Smits and Marcel Soesan, Slotervaart Hospital, Amsterdam; Johan L. Severens, Erasmus University Medical Center, Rotterdam; Caroline M.P.W. Mandigers, Canisius Wilhelmina Hospital, Nijmegen; and Jos H. Beijnen and Jan H.M. Schellens, Utrecht University, Utrecht, the Netherlands. j.schellens@nki.nl.
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D003365:Costs and Cost Analysis; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics*; D005260:Female; D005820:Genetic Testing; D060005:Genotyping Techniques / Q000191:economics / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D057285:Precision Medicine / Q000191:economics / Q000379:methods*; D011446:Prospective Studies; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects; D055815:Young Adult
chemical_list: D011743:Pyrimidines; D042943:Dihydrouracil Dehydrogenase (NADP)