Incidence and prognostic factors of patients with synchronous liver metastases upon initial diagnosis of breast cancer: a population-based study

Figures & data

Table 1 Clinicopathological characteristics of patients with liver metastases according to breast cancer subtype

Patient characteristics	Breast cancer subtype										Total		P-value
	HR+/HER2−		HR+/HER2+		HR−/HER2		Triple-negative		Unknown
	N	%	N	%	N	%	N	%	N	%	N	%
All patients	1,257	38.9	670	20.5	460	14	432	13.2	438	13.4	3,276	100
Age at diagnosis, years
18–40	124	9.7	99	14.8	64	13.9	45	10.4	17	3.9	349	10.7	<0.001*
41–60	571	44.7	332	49.6	231	50.2	208	48.1	195	44.5	1,537	46.9
61–80	478	37.5	202	30.1	142	30.9	153	35.4	173	39.5	1,148	35
>80	103	8.1	37	5.5	23	5	26	6	53	12.1	242	7.4
Year of diagnosis
2010	210	16.5	102	15.2	68	14.8	75	17.4	111	25.3	566	17.3	<0.001*
2011	256	20.1	119	17.8	89	19.3	84	19.4	100	22.8	648	19.8
2012	251	19.7	158	23.6	83	18	78	18.1	69	15.8	639	19.5
2013	295	23.1	126	18.8	99	21.5	104	24.1	85	19.4	709	21.6
2014	264	20.7	165	24.6	121	26.3	91	21.1	73	16.7	714	21.8
Sex
Male	5	0.4	6	0.9	1	0.2	1	0.2	7	1.6	20	0.6	0.025*
Female	1,271	99.6	664	99.1	459	99.8	431	99.8	431	98.4	3,256	99.4
Race
White	950	74.5	495	73.9	336	73	300	69.4	323	73.7	2,404	73.4	0.052
Black	220	17.2	119	17.8	78	17	106	24.5	81	18.5	604	18.4
Asian/Pacific Islander	89	7	50	7.5	42	9.1	25	5.8	32	7.3	238	7.3
American India/Alaska	10	0.8	6	0.9	2	0.4	1	0.2	2	0.5	21	0.6
Unknown	7	0.5	0	0	2	0.4	0	0	0	0	9	0.3
Histology
IDC	881	69	551	82.2	373	81.1	347	80.3	199	45.4	2,351	71.8	<0.001*
ILC	148	11.6	22	3.3	2	0.4	11	2.5	25	5.7	208	6.3
Othersa	247	19.4	97	14.5	85	18.5	74	17.1	214	48.9	717	21.9
Pathological grade
I	87	6.8	12	1.8	1	0.2	3	0.7	11	2.5	114	3.5	<0.001*
II	461	36.1	207	30.9	114	24.8	66	15.3	70	16	918	28
III/IV	462	36.2	356	53.1	272	59.1	304	70.4	118	26.9	1,512	46.2
Unknown	266	20.8	95	14.2	73	15.9	59	13.7	239	54.6	732	22.3
Surgery
No surgery	1,015	79.5	491	73.3	337	73.3	286	66.2	388	88.6	2,517	76.8	<0.001*
BCS	81	6.3	52	7.8	33	7.2	51	11.8	12	2.7	229	7
Mastectomy	174	13.6	122	18.2	84	18.3	92	21.3	30	6.8	502	15.3
Unknown	6	0.5	5	0.7	6	1.3	3	0.7	8	1.8	28	0.9
Number of extrahepatic metastatic sites to lung, bone, and brain
0	282	22.1	191	28.5	159	34.6	129	29.9	90	20.5	851	26	<0.001*
1	536	42	276	41.2	161	35	179	41.4	169	38.6	1,321	40.3
2	319	25	146	21.8	82	17.8	77	17.8	104	23.7	728	22.2
All 3	56	4.4	20	3	25	5.4	27	6.3	17	3.9	145	4.4
Unknown	83	6.5	37	5.5	33	7.2	20	4.6	58	13.2	231	7.1
Marital status
Unmarriedb	651	51	331	49.4	226	49.1	223	51.6	233	53.2	1,664	50.8	0.366
Married	540	42.3	295	44	211	45.9	183	42.4	168	38.4	1,397	42.6
Unknown	85	6.7	44	6.6	23	5	26	6	37	8.4	215	6.6
Insurance status
Uninsured	56	4.4	40	6	18	3.9	28	6.5	27	6.2	169	5.2	0.046*
Insured	1,196	93.7	616	91.9	435	94.6	393	91	393	89.7	3,033	92.6
Unknown	24	1.9	14	2.1	7	1.5	11	2.5	18	4.1	74	2.3

Notes:

a Including other histology of invasive breast cancer except IDC and ILC;

b including divorced, separated, single (never married), and widowed; + denotes positive; – denotes negative;

* denotes a statistically significant P-value.

Abbreviations: BCS, breast conserving surgery; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; IDC, infiltrating ductal carcinoma; ILC, infiltrating lobular carcinoma.

Table 2 Incidence and median OS of patients with liver metastases at initial diagnosis of breast cancer stratified by breast cancer subtype

Breast cancer subtype	Number of patients			Incidence of liver metastases, %		Survival among patients with liver metastases, medium (IQR), months
	With breast cancer	With metastatic disease	With liver metastases	Among entire population	Among metastatic subgroup
HR+/HER2−	151,039	6,202	1,276	0.8	20.6	21.0 (7.0–43.0)
HR+/HER2+	22,834	1,786	670	2.9	37.5	36.0 (14.0–NR)
HR− /HER2+	9,964	989	460	4.6	46.5	29.0 (9.0–48.0)
Triple-negative	24,463	1,524	432	1.8	28.4	9.0 (4.0–17.0)
Unknown	16,149	1,496	438	2.7	29.3	13.0 (3.0–29.0)
All subtypes	224,449	11,997	3,276	1.5	27.3	20.0 (6.0–45.0)

Notes: + denotes positive; – denotes negative.

Abbreviations: HER2, human epidermal growth factor receptor 2; HR, hormone receptor; IQR, interquartile range; NR, not reached; OS, overall survival.

Table 3 Multivariate logistic regression for the presence of liver metastases at initial diagnosis of breast cancer

Variables	Among entire population		Among metastatic subgroup
	OR (95% CI)	P-value	OR (95% CI)	P-value
Age at diagnose, years
18–40	1 (reference)		1 (reference)
41–60	0.798 (0.696–0.916)	0.001*	0.842 (0.723–0.980)	0.026*
61–80	0.596 (0.517–0.687)	<0.001*	0.617 (0.528–0.721)	<0.001*
>80	0.556 (0.458–0.675)	<0.001*	0.554 (0.451–0.682)	<0.001*
Sex
Male	1 (reference)		1 (reference)
Female	2.250 (1.381–3.666)	0.001*	2.526 (1.546–4.128)	<0.001*
Race
White	1 (reference)		1 (reference)
Black	1.131 (1.015–1.259)	0.025*	1.018 (0.909–1.141)	0.754
Asian/Pacific Islander	0.891 (0.764–1.038)	0.137	0.915 (0.774–1.082)	0.299
American India/Alaska	0.927 (0.566–1.518)	0.763	0.993 (0.579–1.702)	0.978
Unknown	0.484 (0.247–0.949)	0.035*	0.485 (0.229–1.025)	0.058
Histology
IDC	1 (reference)		1 (reference)
ILC	0.958 (0.815–1.127)	0.608	0.780 (0.658–0.924)	0.004*
Othersa	1.008 (0.907–1.121)	0.877	0.886 (0.791–0.992)	0.035*
Pathological grade
I	1 (reference)		1 (reference)
II	2.013 (1.641–2.468)	<0.001*	1.243 (0.993–1.555)	0.057
III/IV	2.757 (2.245–3.385)	<0.001*	1.431 (1.144–1.792)	0.002*
Unknown	3.344 (2.692–4.153)	<0.001*	1.465 (1.162–1.847)	0.001*
Number of extrahepatic metastatic sites to lung, bone, and brain
0	1 (reference)		1 (reference)
1	47.726 (43.418–52.462)	<0.001*	0.418 (0.375–0.466)	<0.001*
2	107.212 (95.302–120.611)	<0.001*	0.920 (0.809–1.046)	0.203
All 3	220.416 (169.800–286.122)	<0.001*	1.936 (1.490–2.516)	<0.001*
Unknown	152.389 (125.913–184.432)	<0.001*	1.966 (1.593–2.426)	<0.001*
Breast cancer subtype
HRa/HER2−	1 (reference)		1 (reference)
HRa/HER2+	2.353 (2.106–2.630)	<0.001*	2.066 (1.833–2.330)	<0.001*
HR-/HER2	3.746 (3.271–4.290)	<0.001*	2.698 (2.327–3.129)	<0.001*
Triple-negative	1.483 (1.303–1.688)	<0.001*	1.287 (1.122–1.477)	<0.001*
Unknown	1.673 (1.467–1.908)	<0.001*	1.550 (1.350–1.780)	<0.001*
Marital status
Unmarriedb	1 (reference)		1 (reference)
Married	0.887 (0.815–0.965)	0.005*	0.986 (0.901–1.080)	0.767
Unknown	1.134 (0.957–1.345)	0.147	1.195 (0.995–1.435)	0.056
Insurance status
Uninsured	1 (reference)		1 (reference)
Insured	0.878 (0.724–1.063)	0.183	1.044 (0.857–1.271)	0.670
Unknown	0.870 (0.623–1.213)	0.411	1.027 (0.725–1.455)	0.882

Notes:

a Including other histology of invasive breast cancer except IDC and ILC;

b including divorced, separated, single (never married), and widowed; + denotes positive; – denotes negative;

* denotes a statistically significant P-value.

Abbreviations: HER2, human epidermal growth factor receptor 2; HR, hormone receptor; IDC, infiltrating ductal carcinoma; ILC, infiltrating lobular carcinoma.

Figure 1 Kaplan–Meier curves for OS among patients with liver metastases upon initial diagnosis of breast cancer.

Notes: (A) OS. (B) OS stratified by the breast cancer subtype. (C) OS stratified by the extent of extrahepatic metastatic diseases.

Abbreviations: HER2, human epidermal growth factor receptor 2; HR, hormone receptor; + denotes positive; - denotes negative; OS: overall survival.

Figure 2 Kaplan–Meier curves for overall survival among patients with liver metastases according to individual metastases.

Notes: (A) Patients with only liver metastases vs those with liver and other metastases. (B) Patients with bone metastases vs those without bone metastases. (C) Patients with lung metastases vs those without lung metastases. (D) Patients with brain metastases vs those without brain metastases.

Table 4 Median OS of breast cancer patients stratified by extent of extrahepatic metastatic disease

Breast cancer subtype	Type of extrahepatic metastasis	OS, median (IQR), months
		Extrahepatic metastatic disease only	Liver and extrahepatic metastatic disease	P-value
HR+/HER2−	Bone	40.0 (21.0–NR)	23.0 (9.0–39.0)	<0.001*
	Lung	44.0 (14.0–57.0)	24.0 (7.0–33.0)	<0.001*
	Brain	12.0 (4.0–36.0)	6.0 (1.0–18.0)	0.125
	2 of 3	29.0 (12.0–55.0)	15.0 (6.0–34.0)	<0.001*
	All 3	17.0 (6.0–37.0)	13.0 (2.0–52.0)	0.791
HR+/HER2+	Bone	49.0 (27.0–NR)	35.0 (16.0–NR)	0.001*
	Lung	55.0 (22.0–NR)	26.0 (4.0–NR)	0.004*
	Brain	30.0 (13.0–NR)	NR	0.267
	2 of 3	42.0 (21.0–NR)	24.0 (6.0–NR)	<0.001*
	All 3	17.0 (5.0–NR)	8.0 (2.0–NR)	0.580
HR−/HER2+	Bone	NR (22.0–NR)	30.0 (11.0–45.0)	0.001*
	Lung	24.0 (11.0–NR)	25.0 (8.0–48.0)	0.605
	Brain	14.0 (8.0–38.0)	6.0 (4.0–6.0)	0.005*
	2 of 3	17.0 (6.0–NR)	24.0 (4.0–36.0)	0.613
	All 3	5.0 (3.0–9.0)	6.0 (3.0–16.0)	0.815
Triple-negative	Bone	14.0 (6.0–34.0)	7.0 (4.0–14.0)	<0.001*
	Lung	14.0 (6.0–26.0)	11.0 (5.0–18.0)	0.023*
	Brain	8.0 (3.0–19.0)	14.0 (3.0–22.0)	0.934
	2 of 3	9.0 (4.0–19.0)	7.0 (2.0–11.0)	0.064
	All 3	5.0 (3.0–18.0)	6.0 (1.0–12.0)	0.855
Unknown	Bone	24.0 (9.0–NR)	15.0 (5.0–29.0)	0.001*
	Lung	19.0 (4.0–50.0)	16.0 (4.0–26.0)	0.247
	Brain	10.0 (5.0–20.0)	1.0 (1.0–1.0)	<0.001*
	2 of 3	14.0 (3.0–39.0)	12.0 (2.0–28.0)	0.133
	All 3	13.0 (1.0–44.0)	2.0 (1.0–2.0)	0.059
All subtypes	Bone	38.0 (18.0–NR)	22.0 (8.0–43.0)	<0.001*
	Lung	25.0 (11.0–NR)	15.0 (5.0–31.0)	<0.001*
	Brain	13.0 (4.0–34.0)	6.0 (3.0–22.0)	0.261
	2 of 3	24.0 (9.0–NR)	15.0 (5.0–34.0)	<0.001*
	All 3	9.0 (4.0–34.0)	7.0 (2.0–22.0)	0.117

Notes: + denotes positive; – denotes negative;

* denotes a statistically significant P-value.

Abbreviations: HER2, human epidermal growth factor receptor 2; HR, hormone receptor; IQR, interquartile range; NR, not reached; OS, overall survival.

Table 5 Cox regression of OS and BCSS among patients with liver metastasis

	OS				BCSS
	Univariate analysis		Multivariate analysis		Univariate analysis		Multivariate analysis
Variable	Hazard ratio (95% CI)	P-value	Hazard ratio (95% CI)	P-value	Hazard ratio (95% CI)	P-value	Hazard ratio (95% CI)	P-value
Age at diagnose, years
18–40	1 (reference)		1 (reference)		1 (reference)		1 (reference)
41–60	1.523 (1.251–1.855)	<0.001*	1.445 (1.185–1.762)	<0.001*	1.548 (1.265–1.895)	<0.001*	1.464 (1.194–1.794)	<0.001*
61–80	2.327 (1.907–2.839)	<0.001*	2.113 (1.726–2.586)	<0.001*	2.285 (1.862–2.803)	<0.001*	2.059 (1.673–2.535)	<0.001*
>80	4.406 (3.453–5.621)	<0.001*	4.180 (3.248–5.379)	<0.001*	4.150 (3.221–5.347)	<0.001*	3.891 (2.994–5.058)	<0.001*
Sex
Male	1 (reference)		1 (reference)		1 (reference)		1 (reference)
Female	1.037 (0.517–2.077)	0.919	1.193 (0.589–2.417)	0.623	0.978 (0.488–1.959)	0.949	1.117 (0.552–2.264)	0.758
Race
White	1 (reference)		1 (reference)		1 (reference)		1 (reference)
Black	1.104 (0.970–1.256)	0.134	1.108 (0.970–1.267)	0.132	1.080 (0.945–1.235)	0.257	1.077 (0.938–1.236)	0.293
Asian/Pacific Islander	0.985 (0.805–1.207)	0.887	1.074 (0.876–1.317)	0.491	0.905 (0.729–1.123)	0.363	0.979 (0.788–1.217)	0.850
American India/Alaska	0.985 (0.528–1.836)	0.962	1.104 (0.590–2.068)	0.757	1.046 (0.561–1.950)	0.887	1.157 (0.617–2.167)	0.650
Unknown	0.537 (0.173–1.669)	0.283	0.577 (0.184–1.814)	0.347	0.565 (0.182–1.754)	0.323	0.596 (0.189–1.874)	0.376
Histology
IDC	1 (reference)		1 (reference)		1 (reference)		1 (reference)
ILC	1.138 (0.929–1.394)	0.212	1.089 (0.878–1.351)	0.438	1.147 (0.932–1.412)	0.196	1.106 (0.887–1.380)	0.371
Othersa	1.344 (1.191–1.518)	<0.001*	1.163 (1.014–1.333)	0.031*	1.328 (1.172–1.506)	<0.001*	1.136 (0.986–1.308)	0.077
Pathological grade
I	1 (reference)		1 (reference)		1 (reference)		1 (reference)
II	1.083 (0.809–1.449)	0.592	1.186 (0.879–1.601)	0.265	1.094 (0.808–1.482)	0.562	1.191 (0.872–1.627)	0.272
III/IV	1.302 (0.981–1.730)	0.068	1.517 (1.125–2.046)	0.006*	1.333 (0.992–1.791)	0.056	1.533 (1.124–2.093)	0.007*
Unknown	1.468 (1.093–1.971)	0.011*	1.294 (0.949–1.763)	0.103*	1.508 (1.110–2.049)	0.009*	1.318 (0.955–1.817)	0.093
Surgery
No surgery	1 (reference)		1 (reference)		1 (reference)		1 (reference)
BCS	0.678 (0.557–0.825)	<0.001*	0.750 (0.613–0.918)	0.005*	0.685 (0.560–0.838)	<0.001*	0.759 (0.617–0.934)	0.009*
Mastectomy	0.601 (0.521–0.692)	<0.001*	0.648 (0.558–0.752)	<0.001*	0.589 (0.509–0.683)	<0.001*	0.637 (0.546–0.744)	<0.001*
Unknown	0.291 (0.121–0.700)	0.006*	0.350 (0.144–0.852)	0.021*	0.308 (0.128–0.741)	0.009*	0.357 (0.147–0.869)	0.023*
Number of extrahepatic metastatic sites to lung, bone, and brain
0	1 (reference)		1 (reference)		1 (reference)		1 (reference)
1	1.424 (1.248–1.625)	<0.001*	1.250 (1.092–1.431)	0.001*	1.465 (1.278–1.680)	<0.001*	1.295 (1.126–1.489)	<0.001*
2	1.734 (1.496–2.009)	<0.001*	1.605 (1.379–1.868)	<0.001*	1.753 (1.504–2.043)	<0.001*	1.633 (1.394–1.911)	<0.001*
All 3	2.622 (2.062–3.335)	<0.001*	2.254 (1.762–2.882)	<0.001*	2.747 (2.148–3.513)	<0.001*	2.361 (1.836–3.037)	<0.001*
Unknown	1.816 (1.469–2.245)	<0.001*	1.580 (1.272–1.963)	<0.001*	1.939 (1.563–2.405)	<0.001*	1.701 (1.364–2.120)	<0.001*
Breast cancer subtype
HRa/HER2−	1 (reference)		1 (reference)		1 (reference)		1 (reference)
HRa/HER2+	0.609 (0.523–0.708)	<0.001*	0.666 (0.571–0.778)	<0.001*	0.626 (0.536–0.731)	<0.001*	0.682 (0.582–0.800)	<0.001*
HR−/HER2a	0.808 (0.686–0.953)	0.011*	0.909 (0.767–1.077)	0.270	0.824 (0.696–0.977)	0.026*	0.924 (0.776–1.100)	0.374
Triple-negative	2.067 (1.798–2.376)	<0.001*	2.283 (1.968–2.649)	<0.001*	2.123 (1.839–2.451)	<0.001*	2.346 (2.013–2.735)	<0.001*
Unknown	1.488 (1.268–1.745)	<0.001*	1.336 (1.130–1.580)	0.001*	1.548 (1.315–1.823)	<0.001*	1.395 (1.175–1.656)	<0.001*
Marital status
Unmarriedb	1 (reference)		1 (reference)		1 (reference)		1 (reference)
Married	0.769 (0.693–0.853)	<0.001*	0.863 (0.775–0.962)	0.008*	0.778 (0.699–0.866)	<0.001*	0.865 (0.773–0.967)	0.011*
Unknown	0.918 (0.743–1.136)	0.433	0.891 (0.717–1.107)	0.297	0.929 (0.747–1.156)	0.511	0.895 (0.715–1.119)	0.330
Insurance status
Uninsured	1 (reference)		1 (reference)		1 (reference)		1 (reference)
Insured	0.734 (0.578–0.932)	0.011*	0.741 (0.580–0.947)	0.017*	0.745 (0.582–0.954)	0.020*	0.765 (0.594–0.986)	0.038*
Unknown	0.807 (0.534–1.220)	0.309	0.744 (0.487–1.135)	0.169	0.846 (0.554–1.290)	0.437	0.787 (0.511–1.213)	0.278

Notes:

a Including other histology of invasive breast cancer except IDC and ILC;

b including divorced, separated, single (never married), and widowed; + denotes positive; – denotes negative;

* denotes a statistically significant P-value.

Abbreviations: BCS, breast conserving surgery; BCSS, breast cancer-specific survival; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; IDC, infiltrating ductal carcinoma; ILC, infiltrating lobular carcinoma; OS; overall survival.