Polymorphisms within the DPYD gene are present in 7% of Europeans but account for 23% of life-threatening toxicity from fluoropyrimidine (FP) chemotherapy. Four DPYD variants have an adjusted relative risk for toxicity of 1.59 - 4.4. Upfront genotyping is safe and cost effective but not mandated by ESMO guidelines. To reduce the risk of life-threatening toxicity we implemented prospective DPYD testing as standard practice.
Consecutive colorectal cancer (CRC) patients in a UK cancer centre due to receive FP chemotherapy were genotyped by real time PCR for known clinically relevant DPYD mutations: c.1905+G>A 2*, c.2846A>T, c.1679T>G and c.1605 G>A and from March 2017, c.1236G>A/HapB. We followed published recommendations for dose reduction or alternative drug. Demographics, dose, toxicity and survival data were collected.Table: 560P
|DPYD Heterozygote mutations (No homozygote or compound heterozygote mutations)||Adjusted RR||No. (%)||Mean 1st dose %||Any grade 3/4 toxicity No. (%)||Grade 3/4 diarrhoea No. (%)|
|c.1236G.A/ HapB3||1.59||7 (3%)||76%||1||0|
|c.1601G>A||1.52 (Non significant)||11(5)%||80%||4||2|
|Any heterozygote mutation||23 (10%)||80%||7 (30%)||3 (13%)|
|Wildtype||1||207 (90%)||93%||42 (20%)||20 (10%)|
|Total 58% adjuvant 27% neoadjuvant 24% palliative||230 (100%)||92%||49 (21%)||23 (10%)|
Between 1/1/16-31/12/2017, 230 patients were tested. 72% had capecitabine, 24% 5-fluorouracil, and 4% raltitrexed combinations. After dose reduction or alternative therapy, grade 3/4 diarrhoea was similar in wildtype and mutations (10 vs 13%) and any toxicity admissions were not significantly different (p = 0.284). There were no treatment deaths.
To our knowledge, we are the only UK centre to implement prospective DPYD testing in routine clinical practice for CRC patients. In published data of unselected CRC patients the G3/4 GI toxicity is 15%, but if 2* variant is present this increases to 73%. In the latter population, genotype guided dosing reduces the risk to 28%. Our rate for all variants was 10% but limited by small numbers. Pharmacokinetics in another study showed adequate 5FU exposure with a 50% dose reduction, alleviating underdosing concerns. The growing evidence supports prospective DPYD testing. We have shown it is practical and may mitigate serious toxicities.
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