Two DPYD Variants Join List of Variants Predictive of Fluoropyrimidine Toxicity


Key Points

  • DPYD variants c.1679T>G and c.1236G>A/HapB3 were associated with an increased risk of severe fluoropyrimidine-associated toxicity, according to a systematic review and meta-analysis.
  • Both variants were associated with an increased risk of gastrointestinal and hematologic toxicity.

In a systematic review and meta-analysis reported in The Lancet Oncology, Meulendijks et al found that the DPYD variants c.1679T>G and c.1236G>A/HapB3 were predictive of severe fluoropyrimidine-associated toxicity, with the variant c.1601G>A not achieving a significant relationship. DPYD*2A and c.2846A>T are established predictors of worse toxicity.

Study Details

The study involved data from 7,365 patients from 8 studies assessing associations between DPYD c.1679T>G, c.1236G>A/HapB3, and c.1601G>A and grade ≥3 fluoropyrimidine-associated toxicity in patients receiving fluorouracil, capecitabine, or tegafur/uracil as single agents, in combination with other drugs, or with radiotherapy.

Association With Toxicity

In multivariate analysis, DPYD c.1679T>G (adjusted relative risk [RR] = 4.40, P < .0001) and c.1236G>A/HapB3 (adjusted RR = 1.59, P < .0001) were significantly associated with severe fluoropyrimidine-related toxicity. An association with c.1601G>A did not achieve significance (adjusted RR = 1.52, P = .15). Both c.1679T>G and c.1236G>A/HapB3 were associated with gastrointestinal toxicity (adjusted RR = 5.72, P = .015, and 2.04, P < .0001) and hematologic toxicity (adjusted RR = 9.76, P = .00014, and 2.07, P = .013), and neither variant was associated with a significantly increased risk of hand-foot syndrome.

The established risk factors DPYD*2A (adjusted RR = 2.85, P < .0001) and c.2846A>T (adjusted RR = 3.02, P < .0001) were both associated with severe fluoropyrimidine-associated toxicity.

The investigators concluded: “DPYD variants c.1679T>G and c.1236G>A/HapB3 are clinically relevant predictors of fluoropyrimidine-associated toxicity. Upfront screening for these variants, in addition to the established variants DPYD*2A and c.2846A>T, is recommended to improve the safety of patients with cancer treated with fluoropyrimidines.”

Jan H. Schellens, MD, of the Netherlands Cancer Institute, Amsterdam, is the corresponding author of The Lancet Oncology article.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.