Page 196 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 7
At the Netherlands Cancer Institute (NKI), Amsterdam, the Netherlands, a prospective clinical trial was executed in which patients were prospectively genotyped for DPYD*2A followed by dose reductions of ≥50% in DPYD*2A carriers (NCT00838370).19 The trial was approved by the institutional review board (IRB) of all participating institutes, and all DPYD*2A carriers provided written informed consent before study registration. The patients were retrospectively genotyped for the three other variants (DPYD*13, c.2846A>T, c.1236G>A). A total of 497 patients received CRT and were selected for the present study. Two patients had missing genotypes and were excluded. Radiation dose in Gray (Gy) and fractions (Fr) given to the patient could be collected retrospectively for 425 patients.
At Leiden University Medical Center (LUMC), Leiden, the Netherlands, a retrospective database was created for the purpose of this study. The study was reviewed and approved by the IRB. All patients scheduled to start fluoropyrimidine-based CRT between April 2013 and September 2017 were evaluated. In total, 253 patients started therapy. In April 2013, only DPYD*2A was genotyped; DPYD*13 and c.2846A>T were added to the genotyping panel in October, and c.1236G>A was added in May 2014. Some patients were prospectively genotyped for DPYD*2A alone (N=20) or DPYD*2A, DPYD*13 and c.2846A>T (N=35). Missing genotypes were determined retrospectively. Thirteen patients could not be genotyped and were excluded. Data were collected from the electronic patient files. Ten percent of the data was checked by an independent data manager. Ten percent of toxicity data was checked by an oncologist and radiation oncologist. Limited discrepancies were discussed and similar errors were searched and corrected.
At CRO-Aviano National Cancer Institute, Northern Italy, 207 patients were enrolled in a study from December 1993 to April 2016. All procedures were reviewed and approved by the IRB and patients signed written informed consent for research purposes. Ninety-five patients were included in the present study of whom additional chemotherapy treatment details could be collected. Sixteen patients were prospectively tested for DPYD*2A, DPYD*13 and c.2846A>T, and 79 patients were tested after start of treatment. Missing genotypes of c.1236G>A were determined retrospectively. Two patients had incomplete genotype data and were excluded.
Groups
All included patients in the combined database were grouped into wild-types receiving standard fluoropyrimidine dosages in CRT, DPYD variant allele carriers receiving standard fluoropyrimidine dosages in CRT or DPYD variant allele carriers receiving upfront reduced fluoropyrimidine dosages in CRT. DPYD variant allele carriers are heterozygous or homozygous for a DPYD variant (DPYD*2A, DPYD*13, c.2846A>T or c.1236G>A). Initial dose reductions (25 or 50%) were applied corresponding to pharmacogenetic guidelines.16,17
Toxicity
Treatment-related toxicity data were scored prospectively according to the National Cancer Institute common terminology criteria for adverse events (CTC-AE) v3.020 for the NKI and CRO databases, and retrospectively using CTC-AE v4.0321 for the LUMC database. It was not possible to determine missing toxicities retrospectively. In CRT a continuous regimen
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