Abstract 453P
Background
Dihydropyrimidine dehydrogenase (DPYD) is an important enzyme in the metabolism of fluoropyrimidines. Genetic variations in the DPYD gene are associated with severe fluoropyrimidine toxicity and up front dose reductions are indicated. The UK National Health Service (NHS) now recommends DPYD genetic testing for all patients considered for fluoropyrimidine chemotherapy. We conducted a retrospective study to evaluate routine DPYD mutation testing on fluoropyrimidine associated toxicity in a cohort of GI cancer patients in a high-volume tertiary centre.
Methods
Patients with GI cancers at the Royal Marsden were tested for DPYD mutations (c.1905+1G>A, c.2846A>T, c.1679T>G, c.1236G>A, c.1601G>A) prior to commencing fluoropyrimidines alone or in combination with other cytotoxics and/or radiotherapy. Patients with a DPYD heterozygous mutation received an initial dose reduction of 25-50%. DPYD homozygous carriers did not receive fluoropyrimidines. Patients who had previously received fluoropyrimidines were excluded. Toxicity by CTCAE v4.03 criteria was compared between DPYD heterozygous mutation and wild type carriers.
Results
Between 1st December 2018 and 31st July 2019, 393 patients commencing a capecitabine (63.6%) or 5-FU (36.4%) containing regimen were included in the study. Of the 371 patients who were tested 33 (8.8%) were heterozygous DPYD variant carriers and 338 (91.2%) were DPYD wild type. The most prevalent mutations were c.1601G>A (n=16) and c.1236G>A (n=9). Mean relative dose intensity for the first dose was 54.2% (range 37.5-75%) for DPYD heterozygous carriers and 93.2% (42.9-100%) for DPYD wild-type carriers. Overall grade ≥3 toxicity was similar in DPYD variant carriers (12.1%) as compared with wild type carriers (25.7%; Exact Fisher P=0.0924).
Conclusions
Our study demonstrates successful routine DPYD mutation testing prior to the initiation of fluoropyrimidine chemotherapy with high uptake. In this real world setting, the frequency of genotypic variants is in keeping with published data. In patients with DPYD heterozygous mutations, severe toxicity appears to be mitigated by upfront dose reductions of 25-50% as compared to historical controls.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Royal Marsden NHS Foundation Trust.
Funding
Has not received any funding.
Disclosure
D.K.W. Lau: Financial Interests, Institutional, Research Grant: Merck/AGITG. F. Arouri: Financial Interests, Personal, Full or part-time Employment: Roche; Pierre Fabre. S. Rao: Financial Interests, Personal, Advisory Board: Bayer; Roche; Financial Interests, Personal, Funding, Travel, Accommodations, Expenses: Incyte; Bayer. I. Chau: Financial Interests, Personal, Advisory Board: Astellas; AstraZeneca; Bayer; Boehringer Ingelheim; Incyte; Merck-Serono; MSD; Eli Lilly; Pierre Fabre; Roche; Bristol Meyers Squibb; Financial Interests, Personal, Invited Speaker: Eisai; Eli Lilly; OncXerna; Financial Interests, Personal, Other, DMC chairman: Five Prime Therapeutics; Financial Interests, Institutional, Principal Investigator: Cilag-Janssen; Eli Lilly. D. Cunningham: Financial Interests, Institutional, Research Grant: MedImmune/AstraZeneca; Clovis; Eli Lilly; 4SC; Bayer; Celgene; NIHR EME; Roche; Financial Interests, Institutional, Research Grant, IMP only: Leap; Financial Interests, Personal, Advisory Board: Ovibio. N. Starling: Financial Interests, Institutional, Research Grant: AstraZeneca; Bristol Meyers Squibb; Pfizer; Financial Interests, Personal, Funding, Travel/accomodation: AstraZeneca; Bristol Meyers Squibb; Eli Lilly; Merck; Roche; MSD; Financial Interests, Personal, Advisory Board: Pfizer; AstraZeneca; Servier; MSD; Financial Interests, Personal, Funding, Honoraria: Merck Serono; Pierre Fabre; GSK; Amgen; Eli Lilly; MSD; Servier. All other authors have declared no conflicts of interest.