Bone metastases at initial diagnosed breast cancer — A retrospective study based on SEER database

Background To explore the features of incidence proportions and survivals of breast cancer patients with bone metastasis when first diagnosed. Methods Data were extracted from the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute. Stratifications were made according to molecular subtype, age, sex, race and other factors. We performed multivariable logistic and Cox regression analysis to detect predictors of occurrence of bone metastasis at first diagnosis and factors related to all-cause mortality. Results We identified 310789 patients with breast cancer within the study period. Approximately 3.6% patients were diagnosed as bone metastasis within the entire cohort and 50.5% of the metastasis cohort. The highest incidence was from the cohorts of HR+/HER2+ (5.0% of the entire cohort). N3, metastases to brain, lung and liver were associated with higher possibility of developing bone metastases. For survival, HR+/HER2+ experience the longest survival time (41 months) and triple-negative patients had the shortest survival period (10 months). lymph node status other than N0 and distal metastasis to brain, lung and liver as possible factors which were associated with higher all-cause mortality. We recommend routine bone screen at first diagnosis within high risk patients.


Abstract Background
To explore the features of incidence proportions and long-term survivals of breast cancer patients with bone metastasis when first diagnosed.

Methods
Data were extracted from the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute. Stratifications were made according to molecular subtype, age, sex, race and other factors. We performed multivariable logistic and Cox regression analysis to detect predictors of occurrence of bone metastasis at first diagnosis and factors related to all-cause mortality.

Results
We identified 310789 patients with breast cancer within the study period. Approximately 3.6% patients were diagnosed as bone metastasis within the entire cohort and 50.5% of the metastasis cohort. The highest incidence was from the cohorts of HR+/HER2+ (5.0% of the entire cohort). N3, metastases to brain, lung and liver were associated with higher possibility of developing bone metastases. For survival, HR+/HER2+ experience the longest survival time (41 months) and triplenegative patients had the shortest survival period (10 months). lymph node status other than N0 and distal metastasis to brain, lung and liver as possible factors which were associated with higher allcause mortality.

Conclusions
We recommend routine bone screen at first diagnosis within high risk patients.

Background
Breast cancer is one of the most common malignancy in female and nearly 12% of diagnosed breast cancer is metastatic (1)(2)(3). Bone metastases is a common site for metastases among breast cancer patients and counts for approximately 70% of disease specific death according to previous study (4)(5)(6). However, population-based study of robust estimates relating to the incidence of bone metastases at diagnosis of breast cancer is lacking, partly due to the International Classification of Diseases (ICD) coding system did not label out metastases subtype of cancer patients. In previous autopsy studies, 74% of patients were found to have bone metastases, part of these patients was not clinically apparent prior to death (7).Because of lacking existed evidence, there is no recommendation for routine assessment or continued reassessment of bone metastases (8,9). Thus, most patients with bone metastases are diagnosed by symptoms which usually necessitating interventions to prevent further adverse events (10). Studies of population-based for prognosis among patients with newly diagnosed bone metastases are currently lacking .Hence, the present study used the Surveillance, Epidemiology, and End Results(SEER) database to investigate the incidence proportion of bone metastases in breast cancer as main goal. The second aim of this study is to estimate survival data and find sociodemographic and clinical predictors relevant to poorer survival.

Methods
Data of cancer incidence, treatment and survival of nearly 30% of the US population from 20 cancer registries was included in the SEER database. We downloaded the data from 2010 to 2014 through SEER stat. We extracted data of patients of invasive breast cancer with confirmed bone metastases at initial diagnosed. Further screening was conducted to exclude bone metastases by autopsy or death certificate as well as patients without complete follow-up records. We studied the data by stratifying breast cancer by molecular subtype; hormone receptor-positive human epidermal growth factor receptor-2 negative (HR +/HER2-), HR+/HER2+, HR-/HER2+ and triple-negative breast cancer (TNBC).
Calculation was made among exact number and incidence proportions after stratification by age, race and gender. Two kinds of incidence proportion were calculated, bone metastases divided by total breast cancer as the first and bone metastases divided by all metastases as the second. Multivariable logistic regression was performed to investigate the relevant influential factors of presence of bone metastases if there were available from SEER. By using Kaplan-Meier method, survival estimates were conducted. To identify covariates associated with mortality, multivariable Cox regression was performed. All data was obtained using SEER*Stat Software version 8.3.4 (https://seer.cancer.gov/seerstat/). Statistical analyses were performed by SPSS statistical software version 21. All P values were two-sided, and P≤0.05 was considered significant.

Discussion
In this study, we describe that the incidence of identified bone metastases among patients with newly diagnosed breast cancer and characterize the subsequent survival of such patients. We found that patients with HR+/HER2+ has the highest incidence proportion of bone metastases while triplenegative sub-types the lowest. Moreover, the effect of black race, insurance status and marital status on bone metastases rate is not obvious. Patients in the bone metastases cohort were likely diagnosed as a result of kinetic system symptoms given that guidelines for breast cancer patients do not recommend screening imaging of the bone. So, the true incidence of breast cancer with bone metastasesis is likely underestimated by the results in the study. We also found that HR+/HER2+ experience the longest survival time (41 months) and triple-negative patients had the shortest survival period (10 months) among patients with bone metastases at diagnose. The development of bone metastases is multifactorial. Metastases through blood is very common in distant metastases in breast cancer. It increases the risk of cancer metastases that breast cancer transfers through the abundant blood flow of vertebral-venous plexus to bone (11) . Otherwise, bone is suggested to be a large repository of growth-stimulating factors including fibroblast growth factors, platelet-derived growth factors, and bone morphogenetic proteins. These factors could promote tumor growth and provide a basic ground for tumor metastases (12,13). It is reported that skeletal metastases often occur in HR+/HER2-patients with breast cancer when it recurrences. As is shown in our research, the HR+/HER2+ patients has the highest incidence proportion of bone metastases. Previous reports showed that dissemination of breast cancer cells took place long before the detection of breast cancer metastases. Under many circumstances, these cells die during dissemination. Unfortunately, parts of these cancer cell might survive and exist in a dormant state in bone marrow (14,15). And the dormant cells with HR+ could be reactivated by steroid hormone. As a result, they subsequently develop metastases in bone as they can hijack normal biological processes concerning bone remodeling (16). We found the outcome of bone metastases patients was better than those with other organ like the brain, liver, or lung metastases and HR+/HER2+patients experienced the longest survival time (41 months). HR+ patients with breast cancer are sensitive to targeted therapy, endocrine therapy can remit the tumor and improve the survival of patients. HER2+ patients are sensitive to anti-HER2 therapy ( 17,18). Thus, that is probably why patients with HR+, HER2+ status have better outcome. Breast cancer patients are closely associated with bone metastases (19).
Previous research found that 62.5% of patients with initial metastases breast cancer were diagnosed with bone metastases (20)

Availability of data and material
The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests
The study no grant Conflicts of interest All authors declared they have no potential conflicts of interest.

Funding
The study was not funded by any fund

Authors' contributions
The article was mainly written by Zheng Wang and Xiaoli Tang and they contributed equally to the study. Qi Zhang, Xiaoqing Wu, Meiyuan Yang and Zhixiang Jin helped with date analyzing and paper editing. The whole study was instructed by Daorong Wang. Survival analysis among patients with initial bone metastases stratified by subtype Survival metastatic bone and brain Survival metastatic bone and liver