Page 30 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 2
the Food and Drug Administration (FDA)49 and European Medicines Agency (EMA) after retrospective analyses of three studies (CRYSTAL trial, OPUS trial and CA225025).50-52 Also hormone receptor status for hormone therapy in breast cancer has never been proven in a prospective randomised study.
Table 1. Toxicity associations of DPYD variants
Group
Terrazzino
et al.
20139
Rosmarin
et al.
20148
Meulendijks
et al.
201530
Rosmarin
et al.
20154
Rosmarin
et al.
20154
DPYD variant
DPYD*2A (rs3918290)
c.2846A>T (rs67376798)
DPYD*2A (rs3918290)
c.2846A>T (rs67376798)
DPYD*2A (rs3918290) c.2846A>T (rs67376798)
DPYD*2A (rs3918290) c.2846A>T (rs67376798) DPYD*13 (rs55886062)
c.1236G>A/HapB3 (rs56038477)
rs12132152 (AF: 0.03) rs12022243 (AF: 0.22)
rs76387818 rs7548189
Association with 5-FU and/or capecitabine grade ≥3 toxicity
(OR/*RR [95% CI], p-value)
Overall toxicity (5.42 [2.79–10.52], p<0.001) Diarrhoea (5.54 [2.31–13.29], p<0.001) Haematological toxicity (15.77 [6.36–39.06], p<0.001) Mucositis (7.48 [3.03–18.47], p<0.001)
Overall toxicity (8.18 [2.65–25.25], p<0.001) Diarrhoea (6.04 [1.77–20.66], p=0.004)
Overall toxicity (6.71 [1.66-27.1], p=0.0075) (5-FU in.) Diarrhoea (7.71 [1.61–36.9], p=0.011) (5-FU in.) Mucositis/stomatitis (7.15 [1.75–29.1], p=0.0061) (5-FU bo.)
Neutropenia (12.90 [3.13–53.3], p=0.00040) (5-FU bo.)
Overall toxicity (9.35 [2.01–43.4], p=0.0043) (cap) Diarrhoea (3.14 [0.82–11.9], p=0.093) (cap) Hand-foot syndrome (1.31 [0.35–4.96], p=0.69) (cap)
Overall toxicity (5.51 [1.95–15.51], p=0.0013) (cap)
Overall toxicity (*2.85 [1.75–4.62], p<0.0001)
Overall toxicity (*3.02 [2.22–4.10], p<0.0001)
Overall toxicity (*4.40 [2.08–9.30], p<0.0001) Gastrointestinal toxicity (*5.72 [1.40–23.33], p=0.015) Haematological toxicity (*9.76 [3.03–31.48], p=0.00014)
Overall toxicity (*1.59 [1.29–1.97], p<0.0001) Gastrointestinal toxicity (*2.04 [1.49–2.78], p<0.0001) Haematological toxicity (*2.07 [1.17–3.68], p=0.013)
Overall toxicity (3.83 [3.26–4.40], p=4.31*10–6) (cap) Hand-foot syndrome (6.12 [5.48–6.76], p=3.29*10–8) (cap) Diarrhoea (0.44 [0–1.32], p=0.065) (cap)
Overall toxicity (1.69 [1.45–1.94], p=2.55*10–5) (cap) Hand-foot syndrome (1.43 [1.16–1.7], p=0.0096) (cap) Diarrhoea (1.79 [1.54–2.05], p=9.86*10–6) (cap)
Overall toxicity (4.05 [3.47–4.62], p=2.11*10–6) (cap) Hand-foot syndrome (6.44 [5.79–7.09], p=1.75*10–8) (cap) Diarrhoea (0.44 [0–1.33], p=0.071) (cap)
Overall toxicity (1.67 [1.43–1.91], p=3.79*10–5) (cap) Hand-foot syndrome (1.42 [1.15–1.69], p=0.011) (cap) Diarrhoea (1.21 [0.84–1.58], p=0.0015) (cap)
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