The contribution of deleterious DPYD gene sequence variants to fluoropyrimidine toxicity in British cancer patients.
OBJECTIVE
The fluoropyrimidines have been extensively used for almost five decade worldwide for the treatment of solid cancers. However, severe toxicity is a major clinical problem and has been reported in association with deleterious sequence variants in dihydropyrimidine dehydrogenase (DPD) coding-gene (DPYD), causing DPD deficiency. Genetic DPD deficiency has previously been considered to be insignificant in the British population. The study aim was to assess the contribution of deleterious DPYD sequence variants to fluoropyrimidine toxicity amongst British cancer patients.


METHODS
Sequencing of the coding region of DPYD was undertaken in 47 patients (27 female, mean age 61 years), mainly with GI malignancy, experiencing grade 3 or 4 toxicity on fluoropyrimidines according to CTCAE criteria.


RESULTS
Myelotoxicity (37.5%) and diarrhoea (37.5%) were the most frequent toxicities followed by mucositis (19.6%), hand-foot syndrome (3.6%) and neurotoxicity (1.8%). 4 of 47 (8.5%) patients carried the 1905+1G>A splice site variant. All 4 cases were female and 3 of 4 suffered severe diarrhoea. A further five cases carried other sequence variants (2846A>T n = 4, 1679T>G n = 1). In total, 9 (19%) patients carried deficiency associated DPYD sequence variants.


CONCLUSIONS
Contrary to previous estimates for a UK population, genetic DPD deficiency accounts for around 19% of cases of severe fluoropyrimidine toxicity. The influence of DPD deficiency is such that toxicity can be avoided by prior testing and appropriate 5-FU dose/regimen alteration.
Department of Gastroenterology, Guy's and St Thomas' Hospital NHS Foundation Trust, College House, St Thomas' Hospital, London, UK.
Aathavan
A
Loganayagam
Monica
M
Arenas-Hernandez
Lynette
L
Fairbanks
Paul
P
Ross
Jeremy D
JD
Sanderson
Anthony M
AM
Marinaki
D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D000069287:Capecitabine; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives*; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects* / Q000031:analogs & derivatives*; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D012189:Retrospective Studies
D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000069287:Capecitabine; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil