Page 285 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Compound heterozygous DPYD variant allele carriers
available pharmacogenetic dosing guidelines.19,20 For example, patient 1 carried DPYD*2A and c.1236G>A in trans. The gene activity values range from inactive (0) to fully active (1). DPYD*2A and c.1236G>A/HapB3 have values of 0 and 0.5, respectively. As this patient carries the variants in trans, each allele contains one variant and no fully functional allele remains. Therefore, the cumulated gene activity score (GAS) is 0.5. The GAS can be used to determine dose recommendations according to the genotype, as was previously described.12 The GAS ranges from 0 to 2, and a score of 0.5 corresponds to a dose recommendation of 25%. The DPD enzyme activity of patient 1 was 0.9 nmol/(mg*h). This was divided by the mean of the reference value (9.9), which results in a theoretical DPD activity of 9%. For each patient for whom phasing details were known, the GAS was determined and compared to the theoretical DPD activity. Dose recommendations according to the GAS (genotype) and theoretical DPD activity (phenotype) were divergent in almost all cases, as shown in Table 2.
Table 1. Characteristics of patient cases
Shown per patient are primary tumor, treatment, capecitabine dose, executed assays (genotype, dihydropyrimidine dehydrogenase (DPD) enzyme activity, and additional assays) information. Additional assays are droplet digital PCR, PacBio sequencing (Menlo Park, CA, USA), or an in-house developed technique. For the executed assays it is shown whether these were executed prior to treatment (P) or retrospectively (R).
Patient # Primary Treatment Tumor
Capecitabine dose Executed assays
1 BC 2 BC
3 CRC 4 BC 5 CRC 6 CRC 7 CRC
CAP CAP
CAP+OX
CAP
CAP+RT
CAP+OX
CAP+OX+ BEV
1,000 mg/m2/bid
800 mg bid (50%)
900 mg bid (50%)a 1,500 mg bid
800 mg bid (50%) 1,000 mg/m2/bid 1,000 mg/m2/bid
Genotyping (R), DPD activity (R), in-house technique (R), droplet digital PCR (R)
Genotyping (P), DPD activity (R), in-house technique(R)
Genotyping (P), DPD activity (P), PacBio (R) Genotyping (R), DPD activity (Rb)
Genotyping (P+Rc), DPD activity (Rd), PacBio (R) Genotyping (R), DPD activity (R)
Genotyping (R), DPD activity (R)
11
a Increased to 70% in the second cycle;
b During hospital admission;
c DPYD*2A was prospectively identified, c.2846A>T d During treatment.
Abbreviations: BC: breast cancer; CRC: colorectal oxaliplatin; BEV: bevacizumab; bid: bis in die/twice
was retrospectively identified;
cancer; CAP: capecitabine; RT: radiotherapy; OX: a day.
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