Table 3. Multivariable Cox regression analysis for biomarkers signature score improvements upon clinical parameters.

Predictors	Test set (n=282, events=122)		Internal validation 9999 bootstrap samples		External validation (n=135, events=80)
	HR (95% CI)	P-value	HR (95% CI)	P-value	HR (95% CI)	P-value
Baseline model based on demographics and clinical parameters
Age	1.01 (0.99, 1.02)	0.46	1.01 (0.99, 1.02)	0.48	0.99 (0.97, 1.01)	0.26
Gender	1.15 (0.74, 1.77)	0.53	1.14 (0.75, 1.83)	0.54	1.21 (0.75, 1.96)	0.43
Histopathological grade	1.50 (1.11, 2.02)	0.007	1.50 (1.12, 2.00)	0.006	1.14 (0.76, 1.71)	0.53
Nodal status	2.56 (1.56, 4.21)	<0.001	2.61 (1.57, 4.71)	<0.001	4.99 (1.96, 12.7)	<0.001
Tumor stage	1.47 (0.90, 2.41)	0.13	1.50 (0.92, 2.62)	0.15	2.97 (1.49, 5.91)	0.002
Clinical stage	0.77 (0.36, 1.66)	0.51	0.77 (0.33, 1.90)	0.56	0.23 (0.08, 0.70)	0.009
Discriminatory value	c-statistics=0.62		c-statistics=0.60a		c-statistics=0.61a
Improved model using biomarker signature score
Biomarker signature score	1.10 (1.07, 1.13)	<0.001	1.10 (1.07, 1.13)	<0.001	1.08 (1.02, 1.15)	0.009
Age	1.00 (0.99, 1.01)	0.97	1.00 (0.99, 1.01)	0.97	0.99 (0.97, 1.01)	0.19
Gender	1.12 (0.73, 1.74)	0.60	1.11 (0.73, 1.75)	0.60	1.29 (0.80, 2.09)	0.29
Histopathological grade	1.33 (0.98, 1.79)	0.06	1.32 (1.00, 1.77)	0.05	1.11 (0.74, 1.67)	0.61
Nodal status	2.29 (1.41, 3.71)	<0.001	2.37 (1.45, 4.29)	0.03	4.77 (1.87, 12.2)	0.001
Tumor stage	1.52 (0.92, 2.50)	0.10	1.54 (0.91, 2.72)	0.14	3.05 (1.53, 6.06)	0.001
Clinical stage	0.79 (0.37, 1.68)	0.53	0.76 (0.30, 1.91)	0.61	0.27 (0.09, 0.80)	0.02
Discriminatory value	c-statistics=0.71		c-statistics=0.70a		c-statistics=0.64a

Abbreviations: CI, confidence interval; HR, hazard ratio.

^aOptimism-corrected index.