Young age is an independent adverse prognostic factor in early stage breast cancer: a population-based study

Figures & data

Table 1 Patient characteristics of the study population

	Age <35 N=6,668	(%)	35≤ Age < 60 (N=143,920)	(%)	P
Race					<0.001
White	4,798	72.0	110,989	77.1
Black	1,034	15.5	16,621	11.5
Other	787	11.8	15,482	10.8
Unknown	49	0.7	828	0.6
Laterality					0.826
Left	3,380	50.7	72,755	50.6
Right	3,288	49.3	71,165	49.4
Tumor size					<0.001
T1	2,868	43.0	89,891	62.5
T2	3,123	46.8	47,612	33.1
T3	677	10.2	6,417	4.5
Lymph nodes					<0.001
N0	3,464	51.9	93,168	64.7
N1	2,272	34.1	37,741	26.2
N2	605	9.1	9,144	6.4
N3	327	4.9	3,867	2.7
Stage					<0.001
I	1,864	28.0	68,346	47.5
IIA	2,229	33.4	41,180	28.6
IIB	1,367	20.5	18,834	13.1
IIIA	881	13.2	11,693	8.1
IIIC	327	4.9	3,867	2.7
Grade					<0.001
I	331	5.0	25,579	17.8
II	2,007	30.1	56,273	39.1
III	4,243	63.6	60,868	42.3
IV	87	1.3	1,200	0.8
ER					<0.001
Positive	4,102	61.5	106,576	74.1
Negative	2,346	35.2	32,925	22.9
Borderline	15	0.2	235	0.2
Unknown	205	3.1	4,184	2.9
PR					<0.001
Positive	3,545	53.2	93,262	64.8
Negative	2,863	42.9	45,103	31.3
Borderline	28	0.4	556	0.4
Unknown	232	3.5	4,999	3.5
HER2					<0.001
Positive	742	11.1	11,305	7.9
Negative	2099	31.5	49,319	34.3
Borderline	55	0.8	1,302	0.9
Unknown	3,772	56.6	81,994	57.0
Subtype					<0.001
HER2+/ER−	194	2.9	3,316	2.3
HER2+/ER+	546	8.2	7,973	5.5
HER2−/ER+	1,460	21.9	41,035	28.5
Triple negative	639	9.6	8,238	5.7
Other	3,829	57.4	83,358	57.9

Abbreviations: ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2.

Figure 1 Kaplan–Meier curves of BCSS and OS based on age for all patients in the younger group (15–35 years) vs older group (35–60 years).

Abbreviations: BCSS, breast cancer-specific survival; OS, overall survival.

Table 2 Univariate and multivariate Cox proportional hazard model of BCSS

Variables	Univariate analysis				Multivariate analysis
	HR	(95% CI)		P-value	HR	(95% CI)		P-value
Age (years)
35–60	Ref				Ref
15–35	1.923	1.779	2.078	<0.001	1.200	1.110	1.297	<0.001
Race
White	Ref				Ref
Black	2.087	1.981	2.199	<0.001	1.448	1.374	1.527	<0.001
Other	0.887	0.822	0.958	0.002	0.865	0.800	0.934	<0.001
Unknown	0.361	0.214	0.610	<0.001	0.377	0.223	0.636	<0.001
Laterality
Left	Ref
Right	0.970	0.931	1.012	0.160
Tumor size
T1	Ref				Ref
T2	3.758	3.582	3.942	<0.001	2.005	1.906	2.108	<0.001
T3	7.974	7.457	8.526	<0.001	2.994	2.788	3.215	<0.001
Lymph nodes
N0	Ref				Ref
N1	2.643	2.512	2.782	<0.001	2.101	1.994	2.213	<0.001
N2	5.733	5.392	6.095	<0.001	3.686	3.458	3.928	<0.001
N3	11.516	10.767	12.317	<0.001	6.432	5.996	6.900	<0.001
Grade
I	Ref				Ref
II	4.584	3.959	5.307	<0.001	2.896	2.499	3.356	<0.001
III	13.035	11.308	15.026	<0.001	4.669	4.033	5.406	<0.001
IV	11.571	9.351	14.319	<0.001	4.427	3.568	5.494	<0.001
ER
Positive	Ref				Ref
Negative	3.075	2.946	3.210	<0.001	1.401	1.313	1.496	<0.001
Borderline	2.276	1.579	3.279	<0.001	1.191	0.816	1.736	0.365
Unknown	1.654	1.490	1.837	<0.001	1.281	0.966	1.700	0.085
PR
Positive	Ref				Ref
Negative	3.066	2.933	3.205	<0.001	1.579	1.478	1.687	<0.001
Borderline	2.589	2.046	3.275	<0.001	1.832	1.436	2.336	<0.001
Unknown	1.727	1.561	1.911	<0.001	1.256	0.959	1.644	0.098
HER2
Positive	Ref				Ref
Negative	1.426	1.217	1.670	<0.001	2.236	1.909	2.620	<0.001
Borderline	1.356	0.911	2.020	0.134	2.034	1.365	3.029	<0.001
Unknown	1.648	1.419	1.915	<0.001	2.156	1.856	2.505	<0.001

Notes: Multivariate analysis includes age, race, tumor size, lymph nodes, grade, ER status, PR status, and HER2 status. The P-values are derived from Wald test.

Abbreviations: BCSS, breast cancer-specific survival; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2.

Table 3 Univariate and multivariate Cox proportional hazard model of OS

Variables	Univariate analysis				Multivariate analysis
	HR	(95% CI)		P-value	HR	(95% CI)		P-value
Age (years)
35–60	Ref				Ref
15–35	1.684	1.564	1.812	<0.001	1.111	1.032	1.196	0.005
Race
White	Ref				Ref
Black	2.072	1.977	2.171	<0.001	1.510	1.440	1.584	<0.001
Other	0.892	0.832	0.955	0.001	0.873	0.815	0.936	<0.001
Unknown	0.374	0.236	0.594	<0.001	0.388	0.244	0.616	<0.001
Laterality
Left	Ref
Right	0.976	0.940	1.014	0.209
Tumor size
T1	Ref				Ref
T2	3.081	2.956	3.211	<0.001	1.819	1.741	1.901	<0.001
T3	6.217	5.849	6.608	<0.001	2.678	2.509	2.858	<0.001
Lymph nodes
N0	Ref				Ref
N1	2.255	2.157	2.358	<0.001	1.853	1.770	1.940	<0.001
N2	4.583	4.335	4.844	<0.001	3.118	2.943	3.304	<0.001
N3	8.921	8.383	9.492	<0.001	5.373	5.035	5.734	<0.001
Grade
I	Ref				Ref
II	2.398	2.182	2.635	<0.001	1.628	1.480	1.791	<0.001
III	5.818	5.319	6.364	<0.001	2.388	2.172	2.626	<0.001
IV	5.270	4.444	6.251	<0.001	2.287	1.923	2.720	<0.001
ER
Positive	Ref				Ref
Negative	2.653	2.552	2.757	<0.001	1.365	1.286	1.448	<0.001
Borderline	1.988	1.419	2.786	<0.001	1.150	0.812	1.628	0.432
Unknown	1.619	1.478	1.773	<0.001	1.338	1.045	1.713	0.021
PR
Positive	Ref				Ref
Negative	2.601	2.501	2.705	<0.001	1.462	1.378	1.551	<0.001
Borderline	2.224	1.792	2.760	<0.001	1.670	1.337	2.087	<0.001
Unknown	1.650	1.511	1.801	<0.001	1.177	0.929	1.490	0.177
HER2
Positive	Ref				Ref
Negative	1.381	1.202	1.588	<0.001	2.025	1.761	2.328	<0.001
Borderline	1.387	0.980	1.962	0.065	1.956	1.382	2.768	<0.001
Unknown	1.553	1.361	1.771	<0.001	1.949	1.708	2.224	<0.001

Notes: Multivariate analysis includes age, race, tumor size, lymph nodes, grade, ER status, PR status, and HER2 status. The P-values are derived from Wald test.

Abbreviations: OS, overall survival; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2.

Figure 2 Kaplan–Meier curves of BCSS and OS of 1:1 matched groups based on age for all patients in the younger group (15–35 years) vs older group (35–60 years).

Abbreviations: BCSS, breast cancer-specific survival; OS, overall survival.

Figure 3 Subgroup analyses of BCSS based on lymph node status (N0, N1, N2, N3). The HR was calculated by multivariate Cox proportional hazard model adjusted for age, race, tumor size, grade, ER status, PR status, and HER2 status (Wald test).

Abbreviations: BCSS, breast cancer-specific survival; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2.

Figure 4 Subgroup analyses of OS based on lymph node status (N0, N1, N2, N3). The HR was calculated by multivariate Cox proportional hazard model adjusted for age, race, tumor size, grade, ER status, PR status, and HER2 status (Wald test).

Abbreviations: OS, overall survival; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2.

Figure 5 Subgroup analyses of BCSS and OS based on ER status (positive). The HR was calculated by multivariate Cox proportional hazard model adjusted for age, race, tumor size, lymph nodes, grade, PR status, and HER2 status (Wald test).

Abbreviations: BCSS, breast cancer-specific survival; OS, overall survival; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2.

Figure 6 Subgroup analyses of BCSS and OS based on ER status (negative). The HR was calculated by multivariate Cox proportional hazard model adjusted for age, race, tumor size, lymph nodes, grade, PR status, and HER2 status (Wald test).

Abbreviations: BCSS, breast cancer-specific survival; OS, overall survival; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2.

Figure 7 Cubic spline curve of the relationship between age and HR (BCSS and OS). Age was treated as a dummy variable categorized in two-year strata. Cox proportional hazard model (Wald test) was utilized to calculate the HR of each age group compared with the group (≥58 and <60) (reference).

Table S1 Baseline characteristics of the younger and older patients in a 1:1 matched group

	Age<35 N=6668	(%)	35≤Age<60 N=6668	(%)	P
Race					0.664
White	4798	72.0	4815	72.2
Black	1034	15.5	1019	15.3
Other	787	11.8	796	11.9
Unknown	49	0.7	38	0.6
Tumor size					0.972
T1	2868	43.0	2880	43.2
T2	3123	46.8	3117	46.7
T3	677	10.2	671	10.1
Lymph nodes					0.994
N0	3464	51.9	3459	51.9
N1	2272	34.1	2270	34.0
N2	605	9.1	605	9.1
N3	327	4.9	334	5.0
Grade					0.958
I	331	5.0	327	4.9
II	2007	30.1	1991	29.9
III	4243	63.6	4268	64.0
IV	87	1.3	82	1.2
ER					0.609
Positive	4102	61.5	4112	61.7
Negative	2346	35.2	2353	35.3
Borderline	15	0.2	9	0.1
Unknown	205	3.1	194	2.9
PR					0.135
Positive	3545	53.2	3539	53.1
Negative	2863	42.9	2900	43.5
Borderline	28	0.4	14	0.2
Unknown	232	3.5	215	3.2
HER2					0.855
Positive	742	11.1	725	10.9
Negative	2099	31.5	2120	31.8
Borderline	55	0.8	48	0.7
Unknown	3772	56.6	3775	56.6
Diagnosis year					1.000
2003	522	7.8	522	7.8
2004	528	7.9	534	8.0
2005	505	7.6	505	7.6
2006	539	8.1	538	8.1
2007	541	8.1	542	8.1
2008	549	8.2	550	8.2
2009	535	8.0	535	8.0
2010	560	8.4	564	8.5
2011	590	8.8	586	8.8
2012	621	9.3	620	9.3
2013	574	8.6	569	8.5
2014	604	9.1	603	9.0

Abbreviations: ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2.

Table S2 Imputed multivariate Cox proportional hazard model of BCSS and OS

Variables	BCSS				OS
	HR	(95% CI)		P-value	HR	(95% CI)		P-value
Age (years)
35–60	Ref					ref
15–35	1.214	1.120	1.316	<0.001	1.123	1.041	1.211	0.003
Race
White	Ref					Ref
Black	1.423	1.346	1.505	<0.001	1.489	1.417	1.564	<0.001
Other	0.884	0.816	0.959	0.003	0.890	0.829	0.955	0.001
Tumor size
T1	Ref					ref
T2	1.985	1.886	2.090	<0.001	1.803	1.724	1.886	<0.001
T3	2.987	2.776	3.214	<0.001	2.672	2.499	2.856	<0.001
Lymph nodes
N0	Ref					ref
N1	2.107	1.998	2.222	<0.001	1.858	1.773	1.947	<0.001
N2	3.744	3.509	3.996	<0.001	3.159	2.978	3.351	<0.001
N3	6.620	6.134	7.145	<0.001	5.504	5.128	5.907	<0.001
Grade
I	Ref					ref
II	3.045	2.630	3.535	<0.001	1.704	1.549	1.876	<0.001
III	5.147	4.439	5.969	<0.001	2.606	2.366	2.871	<0.001
IV	5.004	4.026	6.219	<0.001	2.552	2.141	3.042	<0.001
ER
Positive	Ref					ref
Negative	1.367	1.273	1.468	<0.001	1.335	1.247	1.429	<0.001
Borderline	1.116	0.778	1.601	0.543	1.094	0.769	1.555	0.606
PR
Positive	Ref					ref
Negative	1.666	1.556	1.783	<0.001	1.529	1.434	1.631	<0.001
Borderline	1.877	1.441	2.446	<0.001	1.727	1.363	2.189	<0.001
HER2
Positive	Ref					ref
Negative	2.228	1.924	2.581	<0.001	1.997	1.825	2.185	<0.001
Borderline	1.845	1.468	2.319	<0.001	1.867	1.565	2.226	<0.001

Notes: Multivariate analysis includes age, race, tumor size, lymph nodes, grade, ER status, PR status, and HER2 status. The P-values are derived from Wald test.

Abbreviations: BCSS, breast cancer-specific survival; OS, overall survival; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2.