DPYD polymorphisms c.496A>G, c.2194G>A and c.85T>C and risk of severe adverse drug reactions in patients treated with fluoropyrimidine‐based protocols

Abstract

Aims Cancer patients with reduced dihydropyrimidine dehydrogenase (DPD) activity are at increased risk of severe fluoropyrimidine (FP)‐related adverse events (AE). Guidelines recommend FP dosing adjusted to genotype‐predicted DPD activity based on four DPYD variants (rs3918290, rs55886062, rs67376798 and rs56038477). We evaluated the relationship between three further DPYD polymorphisms: c.496A>G (rs2297595), *6 c.2194G>A (rs1801160) and *9A c.85T>C (rs1801265) and the risk of severe AEs. Methods Consecutive FP‐treated adult patients were genotyped for “standard” and tested DPYD variants, and for UGT1A1*28 if irinotecan was included, and were monitored for the occurrence of grade ≥3 (National Cancer Institute Common Terminology Criteria) vs. grade 0–2 AEs. For each of the tested polymorphisms, variant allele carriers were matched to respective wild type controls (optimal full matching combined with exact matching, in respect to: age, sex, type of cancer, type of FP, DPYD activity score, use of irinotecan/UGT1A1, adjuvant therapy, radiotherapy, biological therapy and genotype on the remaining two tested polymorphisms). Results Of the 503 included patients (82.3% colorectal cancer), 283 (56.3%) developed grade ≥3 AEs, mostly diarrhoea and neutropenia. Odds of grade ≥3 AEs were higher in c.496A>G variant carriers (n = 127) than in controls (n = 376) [OR = 5.20 (95% CI 1.88–14.3), Bayesian OR = 5.24 (95% CrI 3.06–9.12)]. Odds tended to be higher in c.2194G>A variant carriers (n = 58) than in controls (n = 432) [OR = 1.88 (0.95–3.73), Bayesian OR = 1.90 (1.03–3.56)]. c.85T>C did not appear associated with grade ≥3 AEs (206 variant carriers vs. 284 controls). Conclusion DPYD c.496A>G and possibly c.2194G>A variants might need to be considered for inclusion in the DPYD genotyping panel.

Influence of Single-Nucleotide Polymorphisms on Clinical Outcomes of Capecitabine-Based Chemotherapy in Colorectal Cancer Patients: A Systematic Review

“…This review included five studies that reported contradictory results regarding the association of various SNPs in the DPYD gene with capecitabine toxicity [ 21 , 23 , 25 , 26 , 28 , 31 ]. These results agree with studies conducted in patients with other cancers or treated with other FPs [ 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ]. A meta-analysis of six studies in 6119 European ancestry (international) patients with solid neoplasms (gastrointestinal, breast, pancreas, bile duct, among others) treated with FPs reported that the DPYD rs1801160 SNP was associated with an increased risk of toxicity, indicating that this SNP should be included in clinical practice [ 45 ].…”

“…In turn, a study in 503 CRC patients of European ancestry (Croatia) treated with FPs reported that patients carrying the DPYD rs1801160 and rs2297595 SNPs showed, respectively, a tendency towards and a significant association with severe adverse events. This study also mentioned that the inclusion of these SNPs in clinical practice should be considered [ 46 ]. Similar findings are reported by a study in 508 patients of European ancestry (Italy) with CRC (stages II–III) treated with FP.…”

“…Two recent studies in patients with gastrointestinal neoplasms ( n = 80 and 93), of Jordanian (Jordan) and Latin American (Chile) origin, reported a significant association between the DPYD rs1801265 SNP and adverse events during FP therapy [ 49 , 50 ]. However, two other studies conducted in patients with gastrointestinal neoplasms ( n = 503 and 113), of European and African American origin (Croatia, USA), found no significant association between this SNP and FP severe toxicity [ 46 , 51 ]. The differences in these findings may be due to several factors, such as sample size and ethnicity of the population being investigated.…”

Discrepancies between dihydropyrimidine dehydrogenase phenotyping and genotyping: What are the explanatory factors?

“…46 However, this relatively common allele (frequency from 1.4% to 6.7% depending on the study population) 43,47 was shown to be associated with normal DPD activity both in silico 24,48 and in vivo. 47 These contradictory data for this variant, as well as for other variants that we identified, [30][31][32][49][50][51][52] highlight the fact that further studies are required to elucidate the impact of these rare variants and their combination 53 on DPD activity and the risk of fluoropyrimidine-induced toxicity. In addition, we identified a new variant never previously described (c.2011T>C) in one patient.…”

Advanced statistics identification of participant and treatment predictors associated with severe adverse effects induced by fluoropyrimidine-based chemotherapy

“…This has the potential to reduce IL-6 signaling and hence, participants with WT alleles would be expected to have decreased probability of experiencing constipation, not an increased probability as observed. In addition, although there have been no reports associating the DPYD SNP and constipation, it has been recently linked to other adverse effects, including abdominal pain, oral mucositis and diarrhea [ 30 ]. Finally, the association between participants with WT alleles of the BDNF rs6265 SNP and higher BDNF secretion [ 31 ] having decreased probability of constipation aligns with the role that BDNF plays in GI motility.…”