Modified FOLFIRINOX (mFOLFIRINOX) is a standard treatment in advanced pancreatic cancer (aPC). Because of the presence of either loss-of-function mutations in DPYD (c.1679T>G, IVS14 + 1G>A, c.2194G>A, c.2846A>T) or UGT1A1*28 variant associated with reduced UGT1A1 expression, deficiency of DPD and UGT may result in drug accumulation and severe toxicities caused by fluoropyrimidines and irinotecan, respectively.
The present study analyzes the association between DPYD and UGT variants and adverse drug reactions (ADRs) in aPC patients (pts) treated with mFOLFIRINOX. Blood samples were collected from 104 pts, and analyses of DPYD c.1679T>G, IVS14 + 1G>A, c.2194G>A, c.2846A>T and UGT1A1*28 were performed by automatic sequencing. Statistical analysis was performed by chi-square, Mann-Whitney and Spearman's rho tests on SPSS v.23s.
None of the pts was carrier of the c.1679G and c.2846T alleles. Only one IVS14 + 1GA was found and 8 pts had c.2194GA genotype. ADRs grade (G) ≥3 were neutropenia (42.3%), diarrhea (7.7%) and stomatitis (7.7%). The statistical analysis of the IVS14 + 1GA has not been performed due to the extremely low frequency of the mutant allele (0.96%), however IVS14 + 1GA patient experienced G4 hematological and gastrointestinal ADRs after the first cycle. We observed a trend toward significant association between c.2194GA genotype and the risk of thrombocytopenia (p = 0.080) and hand-foot syndrome (HFS) (p = 0.096). The UGT1A1*28 allele was found in 56 (54.4%) pts (*1/*28, n = 38; *28/*28, n = 18) and it was correlated with the risk of developing thrombocytopenia (p = 0.006) and neutropenia (p = 0.044). Moreover, this risk increased as the number of *28 alleles increased (*28/*28 > *1/*28 > *1/*1, p = 0.003). No significant correlation with diarrhea was found.
Our data confirm that DPYD IVS14 + 1A is associated with life-threatening toxicities and that the c.2194A allele could be possibly associated with thrombocytopenia and HFS, but validation in larger cohorts is needed. UGT1A1*28 allele is associated with a higher risk of G3/4 thrombocytopenia and neutropenia, and should be implemented in routine practice to personalize treatment in aPC.
Clinical trial identification
Legal entity responsible for the study
University of Pisa
All authors have declared no conflicts of interest.