1753P - Universal DPYD genotyping in patients with gastrointestinal malignancies: Real-world data from a single institution in Italy

Background

In up to 30% of gastrointestinal (GI) malignancies, fluoropyrimidines (FP) are associated with severe adverse drug reactions (ADRs). Dihydropyrimidine dehydrogenase (DPYD), is a polymorphic gene involved in FP catabolism. The identification of deleterious variants associated with increased toxicity is recommended before treatment initiation [c.1905+1G>A (*2A); c.1679T>G (*13); c.1129-5923C>G (*IVS10); c.2846A>T (*949) or during treatment in case of ADR [c.2194G>A (*6)]. The estimated prevalence of DPYD deficient genotypes in the European population is <8%. This study aimed to determine the prevalence and implication of systematic DPYD testing in an unselected population with GI tumours.

Methods

The germline DPYD test was conducted on a consecutive series of 1000 pts diagnosed with GI malignancies at our Department between June 2020 and December 2022, candidates for FP for colorectal (CRC 69%), gastroesophageal (GEC 15%), biliopancreatic (BPC 12%), other GI tumours (4%) or double GI malignancy (<1%).

Results

Overall, 819 pts (82%) were DPYD wild type (WT) and 181 (18%) had a deleterious DPYD variant. Among DPYD mutated pts, 134 had CRC (74%), 23 GEC (13%), 17 BPC (9%), 5 other GI tumours (2%) and 1 had CRC and GEC (1%). 184 deleterious variants were observed in 181 pts, the most prevalent was DPYD *6 (N=146 15%) (Table). In 4 pts *6 coexisted with other variants, requiring dose personalization. Of 133 pts enrolled in interventional trials including FP treatment, 24 (18%) reported a deleterious variant: 2A N=1, IVS10 N=2, *6 N=21.

Table: 1753P

^a recommended dose based on SIF and CPIC guidelines *4 patients presented a double heterozygosis DPYD6 and *2A (N=1), FP dose <50% DPYD6 and c*949 (N=1), FP dose <50% DPYD6 and *IVS10 (N=2), FP dose 50%FP= fluoropyrimidines, WT=wild type

Conclusions

Our large cohort of GI pts revealed a higher prevalence of deleterious DPYD variants compared to previous reports. DPYD*6 was the most frequent genotype and, at a low rate, occurred with other variants requiring major dose adjustments. To prevent severe ADR and to adequately report toxicity and changes in pts' quality of life, our data suggest that DPYD assessment should be mandatory and included in all FP-based clinical trials.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale.

Funding

Has not received any funding.

Disclosure

C. Cardone: Financial Interests, Personal and Institutional, Advisory Board: Bayer. All other authors have declared no conflicts of interest.