Patterns of distant metastases in patients with triple‐negative breast cancer—A population‐based study

This study provided systematic insights into the patterns of triple‐negative breast cancer (TNBC) distant metastases (DM) and investigated the related elements for the prognosis prediction of TNBC patients based on a large sample. We reviewed eligible patients with TNBC from the SEER database between 2010 and 2015. We also analyzed differences in baseline characteristics among patients with diverse modes of metastasis. Meanwhile, we calculated proportional mortality ratio and expression of proportional trends in different patients. Subsequently, KM analysis was employed to investigate the survival outcomes. Finally, the predictive and prognostic factors of DM were identified. In this study, we included 24 822 TNBC patients, including 1026 DM patients and 23 796 non‐DM patients. At the time of initial diagnosis, 4.1% of patients had DM, and 36.9% had multiple metastases. According to the study, the most common sites of metastasis in DM patients were bone (251 cases) and lung (244 cases), while the least common organ of metastasis was brain (37 cases). Age, grade, T, N, and marital status were deemed as risk elements of DM. T stage, insurance status, marital status, surgery treatment, chemotherapy, number of metastatic sites, and metastatic sites also significantly affected the diagnosis of DM. Our study showed that the most common site of metastasis in TNBC patients with DM was bone and the least common site was brain. Different modes of metastasis have different survival and prognostic characteristics. Thus, our research may have important implications for the clinical practice of TNBC patients in the future.

between different countries, BC remains the leading cause of death among women aged 20-50 years. 3 BC is a heterogeneous disease. In view of the genetic, epigenetic, and transcriptomicss alterations, the histologic and biological characteristics of BC are diverse; 95% of BC is adenocarcinoma, which starts as a local disease. 4 Invasive/metastatic BC can be divided into nonspecific type cancer (60%-75%) and special type (20%-25%). 5 In terms of biological characteristics, three types of molecular biomarkers (estrogen receptor [ER], progesterone receptor [PR], and HER2) are detected by molecular biological methods for the molecular type of BC, [6][7][8] including Luminal A, Luminal B, human epidermal receptor 2 positive (HER2+) type, and triple-negative BC (TNBC). 9,10 The incidence of TNBC in BC is approximately 10-15%, but it is one of the most aggressive subtypes. 11 TNBC distant metastasis (DM) refers to the metastasis of BC outside the ipsilateral breast, chest wall, and regional lymph nodes, which is the major cause of death (COD) of BC; 6-10% of cases have metastasis at the time of diagnosis, and nearly 30% will relapse or metastasize. 12 About 25% of TNBC patients still have local recurrence and DM after active treatment.
There are many metastases of BC such as brain, lung, liver, and so forth. 13,14 At present, there are few effective methods for the treatment of metastatic TNBC, resulting in poor prognosis of patients with metastatic TNBC. Therefore, it is urgent to further investigate the predictive and prognostic factors of DM in TNBC. [15][16][17][18][19] However, the shortcomings of previous studies are mostly single-center studies with small sample size and incomplete long-term follow-up information.
Therefore, we used SEER database to establish prognostic models for TNBC patients with different metastasis modes to further explore the risk factors affecting distant metastasis of tumor.

| Database
We employed the "SEER*Stat 8.3.8" software (Version 8.3.6; NCI) to download the data from the SEER registry. The SEER database contains detailed information on cancer patients in the United States.
In our study, we signed the data agreement and used the 10 977-Nov2019 database. In addition, the Institutional Review Board allowed us to use this public database appropriately.

| Patient identification
The TNBC patients with positive pathology were retrospectively extracted from SEER 18 registry. All patients were diagnosed between 2010 and 2015, as DM data were collected from 2010. Inclusion criteria: For further analyses, age at diagnosis was divided into <45, 45-69, and ≥ 70 years old, the race was classified into White, Black, and Other. Furthermore, the pathological grade was divided into four levels: high, moderately, poorly, and undifferentiated. Median household income was calculated to define high-and low-level household income.

| Identification of prognostic characteristics
KM curves were used to explore the overall survival of DM or the metastatic site in TNBC patients. We analyzed COD in different groups of patients who died during long-term follow-up. Uni-and multivariable cox analyses were constructed to explore the risk factors of DM in TNBC patients. Finally, COX analyses were developed to find prognostic factors of OS and CSS.

| Statistical analysis
In our study, data were mainly presented by n (%). Chi-square test was used for comparison between categorical variables. The fundamental analyses were completed based on SPSS 23.0 software (SPSS Inc) and R software (Version 3.4.1). All analytical processes were twosided, and p < .05 was deemed to have statistical significance.   The most common sites of metastasis in DM patients were bone (24.46%) and lung (23.78%), while the least common organ of metastasis was brain (3.61%). In addition, we found that nearly 36.94% of patients had two or more metastases ( 30.6% vs. 36.9%, p = .037). However, no statistically significant differences were found in comparison with other variables. Finally, the patients were divided into four groups (simple brain, simple bone, simple liver, and simple lung), and the comparison between groups is shown in Table S1. Compared with other sites, patients with lung metastasis had a later stage of disease, while patients with brain metastasis underwent radiotherapy more frequently ( p = .021, p < .001).

| Proportional death rate
The results of subgroup analyses are shown in Figure 3.  more pronounced as the number of metastatic sites increased ( Figure 2B). It is worth noting that DM in the brain caused all deaths ( Figure 2C).

| Survival results
As shown in Figure 3A  shown to be associated with long-term survival in BC. 24 Another study from the SEER database found that race, age, grade, molecular subtype, surgery, brain and liver metastases were independently associated with BC-specific survival. 25 However, there remained several limitations in our study that should not be ignored. First, we were unable to obtain more information from SEER database, including lymphatic or vascular invasion, the sequence and specific arrangement of multiple metastases and even molecular biomarkers. Second, the database lacked some important clinical information, including LDH, hemoglobin, neutrophil count, platelet count, and so on. If we include these, we can improve the comprehensiveness of analyzing and concluding.
Furthermore, limitations include a lack of information on rare subtypes of TNBC that may alter treatment, such as metaplasia, adenoid cystic, and acrosine subtypes. Finally, the primary population for this study was American, and the applicability of the results to other populations is questionable.