Table 4. Association of variant combinations and/or DPD phenotype with capecitabine-related toxicity (maximum toxicity grade considering hematotoxicity, digestive and neurotoxicity).
| Tested biomarkers |
Patients at risk |
Grade 3–4 toxicity |
Grade 4 toxicity |
||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| / N total | Sens. |
Spe. |
PPV |
NPV |
RR (95%CI) |
N event | p # |
Sens. |
Spe. |
PPV |
NPV |
RR (95%CI) |
N event |
p # |
|
| Three consensual variants (*2A, I560S, D949V)* |
2.9% (7/242) |
16.7% | 99.1% | 71.4% | 89.4% | 6.71 (3.69–12.2) |
12.4% (30) | <0.001 | 20% | 97.5% | 14.3% | 98.3% | 8.39 (1.07–65.7) |
2.1% (5) |
0.14 |
| Seven in vitro deleterious variants** |
4.6% (11/241) |
26.7% | 98.6% | 72.7% | 90.4% | 7.60 (4.44–13.0) |
12.4% (30) | <0.001 | 60% | 96.6% | 27.3% | 99.1% | 31.36 (5.8–168.9) |
2.1% (5) | 0.001 |
| Eleven in silico deleterious variants*** |
6.2% (15/241) |
26.7% | 96.7% | 53.3% | 90.3% | 5.48 (2.95–10.16) |
12.4% (30) | <0.001 | 60% | 94.9% | 20.0% | 99.1% | 22.6 (4.08–125.1) |
2.1% (5) | 0.002 |
| U >16 ng/ml |
9% (18/203) ## |
12.5% | 91.6% | 16.7% | 88.6% | 1.47 (0.48–4.45) |
11.8% (24) | 0.45 | 66.7% | 92% | 11.1% | 99.5% | 20.56 (1.96–215.8) |
1.5% (3) | 0.021 |
| Combined U>16 ng/ml and/or consensual variants* |
10.3% (21/203) |
20.8% | 91.1% | 23.8% | 89.6% | 2.28 (0.95–5.47) |
11.8% (24) | 0.082 | 66.7% | 90.5% | 9.5% | 99.5% | 17.33 (1.64–183.1) |
1.5% (3) | 0.029 |
| Combined U>16 ng/ml and/or in vitro deleterious variants** | 10.9% (22/202) |
25.0% | 91.0% | 27.3% | 90.0% | 2.73 (1.21–6.14) |
11.9% (24) | 0.030 | 66.7% | 89.9% | 9.1% | 99.4% | 16.36 (1.55–173.2) |
1.5% (3) | 0.032 |
* The number of patients developing grade 3–4 toxicity among patients carrying DPYD variants was 2/3 for variant *2A, 1/1 for variant *13, 2/3 for variant D949V, 1/1 for variant F100L, 0/1 for variant D342G, 1/1 for variant S492L, 1/1 for variant R592W. All these variants were mutually exclusive.
** In vitro deleterious variants were *2A, I560S, D949V, F100L, D342G, S492L R592W (See Table 3 for details and literature references).
*** In silico deleterious variants were *2A, I560S, D949V, A26T, T65M, F100L, D342G, G366G, S492L, R592W, R696H (see Table 3 for details).
# p value of the Fisher Exact test.
## on this subset of 203 patients, association between either the presence of one variant among the 3 or 7 deleterious DPYD variants and grade 3–4 toxicity was confirmed (p = 0.002 and 0.001, respectively) but association with grade 4 toxicity was not.
Sens means sensibility (% of patients positive for the tested biomarker among those experiencing toxicity), Spe means specificity (% of patients negative for the tested biomarker among those without toxicity), PPV means positive predictive value (% of patients experiencing toxicity among those positive for the tested biomarker), NPV means negative predictive value (% of patients without toxicity among those negative for the tested biomarker), RR means relative risk (ratio of the toxicity risk in patients positive for the tested biomarker to that in patients negative for the tested biomarker), NS means not significant.