The effect of distant metastases sites on survival in de novo stage-IV breast cancer: A SEER database analysis

Abstract

To investigate the effect of distant metastases sites on survival in patients with de novo stage-IV breast cancer. From 2010 to 2013, patients with a diagnosis of de novo stage-IV breast cancer were identified using the Surveillance, Epidemiology, and End Results database. Univariate and multivariate Cox regression analyses were performed to analyze the effect of distant metastases sites on breast cancer–specific survival and overall survival. A total of 7575 patients were identified. The most common metastatic sites were bone, followed by lung, liver, and brain. Patients with hormone receptor+/human epidermal growth factor receptor 2− and hormone receptor+/human epidermal growth factor receptor 2+ status were more prone to bone metastases. Lung and brain metastases were common in hormone receptor−/human epidermal growth factor receptor 2+ and hormone receptor−/human epidermal growth factor receptor 2− subtypes, and patients with hormone receptor+/ human epidermal growth factor receptor 2+ and hormone receptor−/human epidermal growth factor receptor 2+ subtypes were more prone to liver metastases. Patients with liver and brain metastases had unfavorable prognosis for breast cancer–specific survival and overall survival, whereas bone and lung metastases had no effect on patient survival in multivariate analyses. The hormone receptor−/human epidermal growth factor receptor 2− subtype conferred a significantly poorer outcome in terms of breast cancer–specific survival and overall survival. hormone receptor+/human epidermal growth factor receptor 2+ disease was associated with the best prognosis in terms of breast cancer–specific survival and overall survival. Patients with liver and brain metastases were more likely to experience poor prognosis for breast cancer–specific survival and overall survival by various breast cancer subtypes. Distant metastases sites have differential impact on clinical outcomes in stage-IV breast cancer. Follow-up screening for brain and liver metastases might be effective in improving breast cancer–specific survival and overall survival.

Introduction

Breast cancer is the most common malignancy in women, with approximately 1.7 million new cases of breast cancer occurring worldwide each year.¹ The incidence of breast cancer has increased dramatically over the past three decades, but with progress in early diagnosis and comprehensive treatment, breast cancer mortality has gradually declined in recent years.² With developments in imaging quality, the early detection of breast cancer has gradually increased but approximately 2.4%–6% of patients are still being diagnosed as de novo stage-IV breast cancer at the time of initial diagnosis.^3–5 The survival of de novo metastatic disease has improved with more prevalent use of novel oncology drug treatments such as endocrine therapy and monoclonal antibodies.^6–8 Retrospective studies have also shown that local treatment, including surgery and radiotherapy, can improve survival in stage-IV breast cancer patients.^9–13

In patients diagnosed with advanced breast cancer during follow-up, the most common metastatic sites were bone, followed by lung, liver, and brain. Furthermore, the survival of patients with various metastatic sites is variable. Patients with bone and lung metastases have better survival, while those with liver and brain metastases tend to have the poorest survival.^14,15 The pattern of site-specific metastases is similar in patients with de novo stage-IV breast cancer.^16,17 However, due to the limited number of patients and differences in treatment strategies, the effect of distant metastases sites on survival in patients with de novo stage-IV breast cancer remains controversial.^18–20 Breast cancer subtype (BCS) is based on the status of hormone receptor (HR), human epidermal growth factor receptor 2 (HER2), and Ki-67 and is an important factor in how breast cancer is treated. In this study, we investigated whether survival of de novo stage-IV breast cancer patients was affected by distant metastases sites and whether this effect was influenced by BCS in the systemic therapy era.

Materials and methods

Patients

From 2010 to 2013, patients diagnosed with stage-IV breast cancer at initial diagnosis were identified using the Surveillance, Epidemiology, and End Results (SEER) database.²¹ Patients with the following inclusion criteria were included in the analysis: (1) breast cancer as the primary cancer diagnosis; (2) distant metastasis sites including bone, lung, liver, and brain metastases; and (3) the status of estrogen receptor (ER), progesterone receptor (PR), and HER2 being available. Informed consent is not required for SEER database data. This study was approved by the Ethics Committee of Xiamen Cancer Hospital, the First Affiliated Hospital of Xiamen University, and Sun Yat-sen University Cancer Center (Approval No. 2016J01635).

Clinicopathological features

The following demographic and clinicopathological factors were assessed: year of diagnosis, age, race, tumor size, nodal stage, tumor grade, local surgery, HR status, HER2 status, and marital status. From 2010, distant metastasis sites recorded in SEER included bone, lung, liver, and brain metastases. The subtypes of BCS were defined as HR+/HER2−, HR+/HER2+, HR−/HER2+ and HR−/HER2−. The primary endpoints of this study were breast cancer–specific survival (BCSS) and overall survival (OS).

Statistical analysis

Statistical analyses were performed using SPSS software, version 18.0 (SPSS, Chicago, IL, USA). The χ² tests and Fisher’s exact probability tests were used to analyze the differences between the qualitative data. Survival curves depending on the period of diagnosis were calculated according to the Kaplan–Meier method. The log-rank test was used to assess significant differences for BCSS and OS. Significant and independent risk factors for BCSS and OS were identified by Cox proportional hazard models. A p value <0.05 was considered to be statistically significant in all analyses.

Results

Patient demographics and clinicopathological characteristics

A total of 7575 patients were identified, and the median age was 60 years (range = 19–103 years). The demographics and clinicopathological characteristics of patients are shown in Table 1. The number of patients diagnosed with stage-IV breast cancer increased gradually from 2010 to 2013. In this cohort, 75.5% of patients were ethnically White and 70.1% of patients were node positive. A total of 2449 (32.3%) patients received local surgery. There were 4622 (61.0%) patients with HR+/HER2− disease, 1273 (16.8%) with HR+/HER2+ disease, 663 (8.8%) with HR−/HER2+ disease, and 1017 (13.4%) had the HR−/HER2− subtype. A total of 1384 (29.9%), 429 (33.7%), 230 (34.7%), and 406 (39.9%) patients with HR+/HER2−, HR+/HER2+, HR−/HER2+, and HR−/HER2− subtypes received local surgery, respectively.

Table 1.

Patient characteristics.

Characteristics	n (%)
Age (years)
Median (range)	60 (19–103)
Year of diagnosis
2010	1691
2011	1879
2012	1905
2013	2100
Ethnicity
White	5716
Black	1277
Other and unknown	582
Grade
Well differentiated	477
Moderately differentiated	2666
Poorly/undifferentiated	3129
Unknown	1303
Tumor size (cm)
≤2	1039
2–5	2959
>5	2233
Unknown	1344
Nodal stage
Node negative	1657
Node positive	5309
Unknown	609
Breast cancer subtype
HR+/HER2−	4622
HR+/HER2+	1273
HR−/HER2+	663
HR−/HER2−	1017
Surgery
No	5126
Yes	2449
Marital status
Single	3892
Married	3279
Unknown	404

HR: hormone receptor; HER2: human epidermal growth factor receptor 2.

Distribution of distant metastases sites

The distributions of distant metastases sites are shown in Table 2. The most common metastatic sites were bone, followed by lung, liver, and brain. A total of 4843 (63.9%), 2004 (26.5%), 623 (8.2%), and 105 (1.4%) patients had one, two, three, and four metastatic sites, respectively. In patients with single metastatic site, a total of 1215 (37.2%), 364 (44.3%), 287 (43.9%), and 36 (34.3%) patients with bone, lung, liver, and brain metastases received local surgery, respectively. There were 449 (22.4%), 91 (14.6%), and 7 (6.7%) patients with two, three, and four metastatic sites received local surgery, respectively.

Table 2.

The distribution of distant metastases sites.

Specific site of distant metastasis	n
Bone alone	3262
Lung alone	822
Liver alone	654
Brain alone	105
Bone + Liver	729
Bone + Lung	846
Liver + Lung	198
Bone + Brain	158
Brain + Liver	24
Brain + Lung	49
Bone + Lung + Liver	450
Bone + Brain + Liver	58
Brain + Liver + Lung	21
Bone + Brain + Lung	94
Bone + Brain + Liver + Lung	105

Patients with HR+/HER2− and HR+/HER2+ disease were more prone to bone metastases. Lung and brain metastases were common in HR−/HER2+ and HR−/HER2− subtypes, and patients with HR+/HER2+ and HR−/HER2+ subtypes were more prone to liver metastases (Table 3).

Table 3.

The relationship between breast cancer subtypes and metastatic sites.

Specific site of distant metastasis	HR+/HER2−	HR+/HER2+	HR−/HER2+	HR−/HER2−	p
Bone only
No	653 (21.3)	301 (40.2)	251 (65.5)	376 (58.5)	<0.001
Yes	2415 (78.7)	448 (59.8)	132 (34.5)	267 (41.5)
Lung only
No	2704 (88.1)	623 (83.2)	276 (72.1)	418 (65.0)	<0.001
Yes	364 (11.9)	126 (16.8)	107 (27.9)	225 (35.0)
Liver only
No	2816 (91.8)	587 (78.4)	253 (66.1)	533 (82.9)	<0.001
Yes	252 (8.2)	162 (21.6)	130 (33.9)	110 (17.1)
Brain only
No	3031 (98.8)	736 (98.3)	369 (96.3)	602 (93.6)	<0.001
Yes	37 (1.2)	13 (1.7)	14 (3.7)	41 (6.4)
Bone
No	759 (16.4)	354 (27.8)	296 (44.6)	464 (45.6)	<0.001
Yes	3863 (83.6)	919 (72.2)	367 (55.4)	553 (54.4)
Lung
No	3208 (69.4)	858 (67.4)	394 (59.4)	530 (52.1)	<0.001
Yes	1414 (30.6)	415 (32.6)	269 (40.6)	487 (47.9)
Liver
No	3588 (77.6)	751 (59.0)	327 (49.3)	670 (65.9)	<0.001
Yes	1034 (22.4)	522 (41.0)	336 (50.7)	347 (34.1)
Brain
No	4336 (93.8)	1167 (91.7)	582 (87.8)	876 (86.1)	<0.001
Yes	286 (6.2)	106 (8.3)	81 (12.2)	141 (13.9)

HR: hormone receptor; HER2: human epidermal growth factor receptor 2.

Effect of distant metastases sites on survival

In the univariate analyses (Table S1), patients with bone-only metastases were associated with longer BCSS and OS, whereas lung, liver, and brain metastases at diagnosis of metastatic disease were associated with a poorer BCSS and OS. Patients with HR+/HER2+ disease had the best BCSS and OS by univariate analyses.

In the multivariate Cox analyses, patients with liver (BCSS, hazard ratio (HaR) = 1.57, 95% confidence interval (CI) = 1.42–1.74, p < 0.001; OS, HaR = 1.535, 95% CI = 1.40–1.69, p < 0.001) and brain metastases (BCSS, HaR = 1.74, 95% CI = 1.515–2.00, p < 0.001; OS, HaR = 1.73, 95% CI = 1.53–1.98, p < 0.001) were significantly more likely to have an unfavorable prognosis for BCSS and OS, whereas patients with bone-only and lung metastases did not experience poor survival prognosis (Table 4).

Table 4.

Multivariate Cox regression analysis of prognostic factors influencing survival.

Characteristic	BCSS			OS
	HaR	95% CI	p	HaR	95% CI	p
Age (years)	1.024	1.021–1.027	<0.001	1.026	1.023–1.029	<0.001
Year of diagnosis (continuous variable)
Ethnicity
White	1			1
Black	1.193	1.079–1.317	0.001	1.240	1.130–1.361	<0.001
Other and unknown	0.963	0.826–1.123	0.633	0.965	0.834–1.115	0.900
Grade
Well differentiated	1			1
Moderately differentiated	1.399	1.143–1.711	0.001	1.284	1.072–1.538	0.007
Poorly/undifferentiated	1.894	1.546–2.321	<0.001	1.713	1.428–2.055	<0.001
Tumor size (cm)
≤2	1			1
2–5	1.044	0.918–1.187	0.511	1.026	0.911–1.154	0.677
>5	1.182	1.037–1.347	0.012	1.151	1.018–1.300	0.024
Nodal stage
Node negative	–			1
Node positive	–	–	–	0.882	0.807–0.964	0.006
Breast cancer subtype
HR+/HER2−	1			1
HR+/HER2+	0.801	0.711–0.902	<0.001	0.802	0.717–0.897	<0.001
HR−/HER2+	1.059	0.916–1.224	0.441	1.109	0.969–1.269	0.134
HR−/HER2−	2.544	2.289–2.827	<0.001	2.535	2.296–2.800	<0.001
Surgery
No	1			1
Yes	0.532	0.484–0.585	<0.001	0.537	0.491–0.574	<0.001
Marital status
Single	1			1
Married	0.791	0.728–0.860	<0.001	0.783	0.725–0.847	<0.001
The sites of distant metastases
Bone only—yes versus no	0.915	0.748–1.120	0.389	0.900	0.745–1.088	0.277
Lung—yes versus no	0.953	0.794–1.144	0.606	0.976	0.822–1.160	0.786
Liver—yes versus no	1.570	1.421–1.736	<0.001	1.535	1.396–1.687	<0.001
Brain—yes versus no	1.741	1.515–2.001	<0.001	1.728	1.526–1.981	<0.001
The number of distant metastases (n)
1	1			1
2	1.254	1.140–1.380	<0.001	1.220	1.115–1.335	<0.001
3	1.512	1.301–1.758	<0.001	1.491	1.293–1.718	<0.001
4	1.016	0.736–1.403	0.922	1.063	0.788–1.433	0.688

HR: hormone receptor; HER2: human epidermal growth factor receptor 2; BCSS: breast cancer–specific survival; OS: overall survival; HaR: hazard ratio; CI: confidence interval.

Figure 1.

Kaplan–Meier estimates for (a) breast cancer–specific survival and (b) overall survival depending on the sites of distant metastases for de novo stage-IV breast cancer.

[Figure omitted. See PDF]

Regression analysis was conducted to evaluate the prognostic value of BCS (the HR+/HER2− subtype was used as a reference; Table 4). The HR−/HER2− subtype was associated with a significantly poorer outcome in terms of BCSS and OS, HR+/HER2+ disease was associated with the best prognosis in terms of BCSS and OS, whereas there was no significant difference in survival between patients with HR+/HER2− and HR−/HER2+ disease (Figure 2).

Figure 2.

Kaplan–Meier estimates for (a) breast cancer–specific survival and (b) overall survival depending on the breast cancer subtypes for de novo stage-IV breast cancer.

[Figure omitted. See PDF]

The effect of distant metastases sites on survival by various BCS was analyzed. In the univariate analyses, the sites of distant metastases had prognostic effect by various BCS, except in the HR−/HER2− subtype with lung metastases. Using multivariate analyses, liver and brain metastases were adverse prognostic factors for BCSS and OS in HR+/HER2−, HR+/HER2+, and HR−/HER2− subtypes. However, patients with bone-only and lung metastases experienced similar survival. In patients with the HR−/HER2+ subtype, lung, liver, and brain metastases were unfavorably associated with BCSS and OS, whereas bone-only metastasis was not associated with survival (Table S2).

Discussion

In this study, we investigated the characteristics of distant metastasis of de novo stage-IV breast cancer and the effect of different metastatic sites on the survival of patients. Our study suggests that patients with different BCS have different metastatic patterns, while the site of distant metastasis is a prognostic factor for stage-IV breast cancer.

Currently, the recommended definition for BCS refers primarily to ER, PR, HER2, and Ki-67 status.²² Since the SEER database did not record patient Ki-67 status, we used ER, PR, and HER2 to establish the BCS. It has been found that BCS not only predicts the survival and treatment of patients,^23–25 but different BCS may also be associated with organ-specific metastases. In our previous study of patients who had developed metastatic breast cancer (MBC) during their follow-up, patients with HER2-positive subtype (HR+/HER2+ and HR−/HER2+) experienced significant liver metastasis. Furthermore, those patients with luminal tumors (HR+/HER2− and HR+/HER2+) were more likely to be affected by bone metastasis, and patients with the HR−/HER2− subtype were more likely to experience lung and brain metastases.²⁶ Our results are similar to other studies.^27–30 In this study, we found that patients with HR+/HER2− and HR+/HER2+ disease were more likely to have bone metastases, while distant metastatic stage was confirmed during the initial diagnosis of breast cancer. Furthermore, patients with HR−/HER2+ and HR−/HER2− disease were more likely to experience lung metastasis and brain metastasis, while liver metastases were common in those with HER2+ expression. These studies suggest that BCS may be characterized by typical patterns of metastatic spread, which supports the hypothesis that breast cancer is a systemic disease with heterogeneous characteristics.

Bone metastasis has been reported as the most common metastatic site of de novo stage-IV breast cancer, followed by lung, liver, and brain,^16,17 which was similar to our study. Patients with stage-IV breast cancer represent a heterogeneous group whose prognosis and outcome may be dependent on the sites of distant metastases. Previous studies have found that brain and liver metastatic sites were found to be independent, unfavorable prognostic factors in patients who had developed MBC during their follow-up.^14,15 However, the prognostic value of distant metastases sites in de novo stage-IV breast cancer remains controversial. In a study by Gerratana et al.,¹⁸ including 31% of patients with de novo disease, results showed that liver metastasis was an independent prognostic factor for OS, while bone-only, lung, and brain metastases had no effect on survival. However, due to the limited number of patients with brain metastases (n = 23), potential bias was introduced into that study.¹⁸ Studies by Neuman et al.¹⁹ found that bone metastases and visceral metastases were prognostic factors affecting survival, but not refined the patients with visceral metastases, which may have exerted potential impact on outcomes. In the study by Ording et al., there were 870 de novo patients (of 3518 patients), and patients with brain-only and liver-only metastases had an increased risk of mortality compared to patients who only had bone metastasis. Patients with lung-only metastasis experienced similar mortality rates as patients with bone-only metastasis.²⁰ In this study, we employed a population-based database to analyze the prognostic effect of distant metastases sites in de novo stage-IV breast cancer. Our results showed that bone-only and lung metastases in patients had no effect on BCSS and OS, whereas patients with liver and brain metastases experienced the highest rate of mortality. These studies suggest that distant metastases sites have a differential impact on clinical outcomes. These fundamental, cohort-based observations may assist physicians in evaluating the survival potential of patients with de novo stage-IV breast cancer.

Although the SEER database did not document detailed treatment of patients, we enrolled patients after 2010; therefore, this study still conforms to the era of modern systematic therapy. In a contemporary treatment model, 5-year survival in HR-positive patients could reach 50%,¹⁹ while the median OS of HER2-positive advanced breast cancer patients receiving trastuzumab-based therapy has exceeded 3 years.³¹ Our study also found that survival in those with HR+/HER2+ disease was significantly better than survival in those with HR+/HER− and HR−/HER2+ disease, while those with HR−/HER2− disease had the poorest survival prospects. Our results are consistent with previous studies.^16,32 Advances in chemotherapy, endocrine, and targeted therapy could result in improved survival in many patients with de novo stage-IV breast cancer.

In our study, bone metastases in different BCS did not affect survival, and lung metastasis was only of prognostic value in patients with the HR−/HER2+ subtype, whereas poor prognosis for liver metastases and brain metastases was unaffected by BCS. Bone metastases did not affect patient survival, which was associated with HR+/HER2− and HR+/HER2+ subtypes in the majority of patients with bone metastases. These patients may be able to better tolerate endocrine therapy and targeted therapy; in addition, radiotherapy and local surgery have also been shown to provide better control for bone and lung metastases.^33–35 Although, patients HER2+ subtype were more prone to liver metastases, which may benefit from combined HER2 targeted therapy. However, liver metastases may be regarded as a sign of systemic tumor spread, which is amenable to targeted therapy or systemic chemotherapy.³⁶ One reason for the poor survival of breast cancer patients with brain metastases may be the difficulty of drug entry into the blood–brain barrier. Therefore, it is necessary to re-evaluate stage-IV breast cancer patients according to the anatomic site of distant metastases and assess the criteria used to define the progression of disease.

It is important to describe some of the limitations in this study. First, retrospective studies are inherently biased. Second, the SEER database only included four specific sites of distant metastases at the initial diagnosis, and we could not obtain further details concerning the time of secondary metastasis. In addition, there was a lack of details concerning chemotherapy, endocrine therapy, targeted therapy, and specific treatment of metastatic organs in the SEER database.

In conclusion, our population-based study suggests that distant metastases sites have differential impact on clinical outcomes in de novo stage-IV breast cancer. We advocate follow-up screening during aftercare for brain and liver metastases, as this might be effective.

S.-G.W., H.L., and L.-Y.T. have contributed equally to this work. The authenticity of this article has been validated by uploading the key raw data onto the Research Data Deposit (RDD) public platform (www.researchdata.org.cn), with the approval RDD number as RDDA2017000172.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by grants from the Sci-Tech Office of Guangdong Province (Nos 2013B021800157 and 2013B021800458) and the Natural Science Foundation of Fujian Province (No. 2016J01635).