Page 92 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 4
ref. 11 – CAP/FU, comb Rosmarin D et al. Genetic markers of toxicity from capecitabine and
other fluorouracil- based regimens: investigation in the QUASAR2 study, systematic review, and meta- analysis.
J Clin Oncol 2014;32:1031 -9. PubMed PMID: 24590654.
Level of evidence score: 4
gene act. 0-1,5: CTC-AE 4
- The gene variants *2A, *13 and c.2846A>T together predicted 5-FU grade ≥ 3 toxicity with a sensitivity of 5.3%, specificity of 99.4%, positive predictive value of 81.8% and negative predictive value of 68%. The low sensitivity and negative predictive value might be attributed to the combination chemotherapy, which may add to the 5-FU toxicity.
NOTE: Genotyping was for 25 gene variants of which only 4 (*2A, *13, c.2846A>T and 274G>C) were found in this population from the USA.
After colorectal cancer excision, 927 patients received adjuvant therapy with capecitabine 1250 mg/m2 twice daily on days 1-14 of a 3-week cycle either as monotherapy (n = 436) or in combination with bevacizumab (n = 491). Grade III-V toxicity comprised hand-foot syndrome (n = 206), diarrhoea (n = 97) and neutropenia (n = 19).
Variant c.2846A>T:
- Associated with grade III-V toxicity (OR = 9.35; 95% CI: 2.01-43.4) (S)
- No association with grade III-V diarrhoea and grade III-V hand-foot syndrome (NS).
Given the allele frequency found, this is apparently based on 5 defect alleles.
Variants *2A, 496A>G, c.1236G>A:
- No association with grade III-V toxicity, grade III-V diarrhoea and grade III-V hand-foot syndrome (NS). Given the allele frequency found, this is apparently based on 4 defect alleles for *2A, 83 for 496A>G and 18 for c.1236G>A.
Variant c.2846A>T and/or *2A:
- Associated with grade III-V toxicity (OR = 5.51; 95% CI: 1.95-15.5) (S)
- No association with grade III-V diarrhoea and grade III-V hand-foot syndrome (NS)
- Both patients who died were carriers of *2A or c.2846A>T
Meta-analysis of 6 studies during which Caucasian patients received capecitabine or 5-FU-based therapy. Of these 6 studies, the study covered in the paragraph above and Schwab, 2008, were also included separately in this risk analysis.
Variant *2A:
- No association with grade III-V toxicity for capecitabine (2 studies, n = 1035) (NS)
- No significant association with grade III-V toxicity for 5-FU infusion, but there was a trend (2 studies, n =
Authors’ conclusion: “Global capecitabine toxicity (grades 0/1/2 v grades 3/4/5) was associated with the rare, functional DPYD alleles c.2846A>T>A and *2A (combined odds ratio, 5.51).”
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