Table 4. Cox proportional hazard models of DRFS for (Z)-endoxifen plasma levels, MR DM-Tam/(Z)-endoxifen or CYP2D6 activity score/phenotype.
Quantitative analyses | Categorical analyses | |||||||
---|---|---|---|---|---|---|---|---|
|
HR (per unit)a |
95% CI |
Wald P |
|
Factor |
HR |
95% CI |
Wald P |
(Z)-Endoxifen (nM) | (Z)-Endoxifen (nM) | >35 | 1 (Reference) | |||||
Unadjusted | 0.989 | 0.973–1.004 | 0.142 | 24.7–35 | 1.61 | 0.76–3.38 | 0.210 | |
Adjusted | 0.992 | 0.977–1.007 | 0.291 | 14.15–24.7 | 1.45 | 0.69–3.06 | 0.329 | |
<14.15 | 1.94 | 0.96–3.93 | 0.064 | |||||
Nodal status | Negative | 1 (Reference) | ||||||
Positive | 2.09 | 1.11–3.92 | 0.022 | |||||
Chemotherapy | No | 1 (Reference) | 0.243 | |||||
Yes | 1.65 | 0.71–3.83 | ||||||
MR DM-Tam/(Z)-Endoxifen | MR DM-Tam/(Z)-Endoxifen | <31 | 1 (Reference) | |||||
Unadjusted | 1.008 | 1.001–1.015 | 0.025 | 31–115 | 1.43 | 0.86–2.37 | 0.167 | |
Adjusted | 1.007 | 1.000–1.014 | 0.036 | >115 | 3.82 | 1.47–9.89 | 0.006 | |
Nodal status | Negative | 1 (Reference) | ||||||
Positive | 2.09 | 1.12–3.89 | 0.021 | |||||
Chemotherapy | No | 1 (Reference) | ||||||
Yes | 1.62 | 0.70–3.74 | 0.260 | |||||
CYP2D6 activity score | CYP2D6 phenotype class | EM/UM | 1 (Reference) | |||||
Unadjusted | 0.611 | 0.425–0.88 | 0.008 | hetEM/IM | 1.55 | 0.88–2.72 | 0.132 | |
Adjusted | 0.623 | 0.429–0.905 | 0.013 | PM | 1.98 | 0.82–4.79 | 0.128 | |
Nodal status | Negative | 1 (Reference) | ||||||
Positive | 2.15 | 1.14–4.04 | 0.018 | |||||
Chemotherapy | No | 1 (Reference) | ||||||
Yes | 1.60 | 0.69–3.73 | 0.277 |
Abbreviations: CI, confidence interval; DRFS, distant recurrence-free survival; HR, hazard ratio; MR DM-Tam/(Z)-endoxifen, metabolic ratio N-desmethyltamoxifen/(Z)-endoxifen; TAM, tamoxifen.
Node status was binary coded with factor levels negative vs positive; chemotherapy was binary coded with levels no (no chemotherapy given) and yes (chemotherapy given); CYP2D6 and tamoxifen metabolite predictor variables were coded categorically. Models were corrected for nodal status and chemotherapy and stratified for ethnicity.
For univariate analysis, HR refers to an increase by one unit (1 nM) of steady-state endoxifen plasma concentration, increase of the dimensionless MR DM-Tam/(Z)-endoxifen ranging between 8 (highest) and 176 (lowest) endoxifen formation rates and an increase by one unit of CYP2D6 phenotype score ranging from 0 (PM) to 3 (UM).