Serum uracil predicts fluoropyrimidine-associated toxicity
Pretreatment uracil concentration appears to be a useful phenotypic marker for identifying patients at high risk of fluoropyrimidine-associated toxicity, demonstrating high sensitivity and positive predictive value (PPV), according to a study.
In a cohort of 550 cancer patients (median age 58 years; 58 percent female) treated with fluoropyrimidine-based chemotherapy during a previous prospective multicentre trial, higher serum uracil concentration prior to treatment initiation was strongly associated with severe and fatal drug-related toxicity. Serum uracil concentrations were measured using a validated liquid chromatography–tandem mass spectrometry method. [Br J Cancer 2017;116:1415–1424]
Compared with patients who had low pretreatment uracil concentration (<13 ng ml–1), those with pretreatment concentrations in the upper percentiles were at significantly increased risk of global severe toxicity (grade ≥3)—the primary study endpoint—with the risk increasing proportionally as serum uracil concentrations increased. The odds ratios (ORs) were 8.2 (95 percent CI, 2.55 to 26.1; p=0.0004) among patients with 13.9 to 16 ng ml–1 pretreatment uracil concentrations and 5.3 (1.53 to 18.7; p=0.0087) among those with >16 ng ml–1.
High pretreatment uracil concentrations (>16 ng ml–1) also showed a strong association with fatal treatment-related toxicity (OR, 44.8; p=0.001), severe gastrointestinal toxicity (OR, 33.7; p<0.0001) and toxicity-related hospitalization (OR, 16.9; p<0.0001).
“Sensitivity to identify patients at risk of early severe toxicity was three times higher for phenotyping [uracil concentration cutoff of ≥13.9 ml–1] than for genotyping of the established DPYD variants c.2846A4T, c.1679T4G, and c.1129-5923C4G (18 vs 6 percent),” the authors noted. [Lancet Oncol 2015;16:1639–1650]
Similarly, the PPV was found to be higher for phenotyping vs genotyping of the established DPYD variants (35 vs 13 percent). Diagnostic accuracy did not further improve with combined genotyping and phenotyping compared to phenotyping alone.
“Our results suggest that pretreatment serum uracil concentration can potentially improve an upfront test to identify patients with dihydropyrimidine dehydrogenase (DPD) deficiency who are at high risk of severe and potentially fatal toxicity,” the authors said.
“DPD converts its endogenous substrate uracil (U) into dihydrouracil (DHU), and the pretreatment ratio of serum concentrations of DHU to U – the DHU/U ratio – has been investigated as a phenotypic measure of systemic DPD activity,” the authors said.
In the present study, uracil was shown to be superior to the DHU/U ratio as a predictor of severe fluoropyrimidine-associated toxicity in patients and correlated better with peripheral blood mononuclear cells DPD activity in healthy volunteers.
The authors warned that the findings should be interpreted while keeping in mind that patients with the DPYD*2A mutation were excluded from the analysis.
Still, while calculations of diagnostic accuracy could therefore be affected as a result, it is expected that this will only affect sensitivity and PPV to a minor extent in view of the low frequency of DPYD*2A, they said.