Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5FU). Genetic variations in DPD have emerged as predictive risk factors for severe fluoropyrimidine toxicity. Here, we report novel and rare genetic variants underlying DPD deficiency in 9 cancer patients presenting with severe fluoropyrimidine-associated toxicity. All patients possessed a strongly reduced DPD activity, ranging from 9 to 53% of controls. Analysis of the DPD gene (DPYD) showed the presence of 21 variable sites including 4 novel and 4 very rare aberrations: 3 missense mutations, 2 splice-site mutations, 1 intronic mutation, a deletion of 21 nucleotides and a genomic amplification of exons 9-12. Two novel/rare variants (c.2843T>C, c.321+1G>A) were present in multiple, unrelated patients. Functional analysis of recombinantly-expressed DPD mutants carrying the p.I948T and p.G284V mutation showed residual DPD activities of 30% and 0.5%, respectively. Analysis of a DPD homology model indicated that the p.I948T and p.G284V mutations may affect electron transfer and the binding of FAD, respectively. cDNA analysis showed that the c.321+1G>A mutation in DPYD leads to skipping of exon 4 immediately upstream of the mutated splice-donor site in the process of DPD pre-mRNA splicing. A lethal toxicity in two DPD patients suggests that fluoropyrimidines combined with other therapies such as radiotherapy might be particularly toxic for DPD deficient patients. Our study advocates a more comprehensive genotyping approach combined with phenotyping strategies for upfront screening for DPD deficiency to ensure the safe administration of fluoropyrimidines.
ObjectiveTo investigate treatment choices and outcomes in women with ovarian cancer, comparing elderly (≥75 years) and younger patients (<75 years).MethodsA single-center retrospective analysis of patients diagnosed with ovarian cancer between 2010 and 2015. The initial treatment plan and course of treatment were extracted from medical files.ResultsOf 128 included patients, 34% were aged ≥75 years. The initial treatment plan consisted of the combination of cytoreductive surgery and platinum-based doublet chemotherapy (ie, standard treatment) in only 10% of the elderly patients with an indication for this treatment. 5% of these patients completed this treatment without adaptations (compared with 85% and 48%, respectively, in younger patients). 38% of the elderly patients with an indication for cytoreductive surgery and chemotherapy received best supportive care only. Patient preference was an important reason to withhold standard treatment. Surgery- and chemotherapy-related complications and hospital admissions did not differ between groups. Median survival was lower in the elderly (p=0.002) and in patients receiving best supportive care (p<0.001).ConclusionsElderly patients were less frequently treated in accordance with the treatment guideline. To select those older patients who may benefit from (adapted) treatment is challenging. Future studies should evaluate determinants associated with treatment completion to improve outcomes in this vulnerable population.
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