Impact of Surgery on Survival in Breast Cancer with Bone Metastases: a SEER database retrospective analysis

Purpose It was controversial to operate on the primary site of breast cancer with simple bone metastasis (cid:0) we found that the surgery could improve survival in patients with breast cancer with bone metastases via a SEER database retrospective analysis. Method Totolly 2917 cases of breast cancer with bone metastasis, rst diagnosed between 2010 and 2015 in the National Cancer Institute surveillance, Epidemiology, and Results Database (SEER).We assessed the effect of different surgical procedures on survival and prognosis by the correlation statistics. Results Compared with the non-surgical group , the prognosis of patients on the primary tumor surgical group shows the statistical signicance (c2 = 146.023, P < 0.001), the survival benet of the breast-conserving group was the highest for 70 months(c2=157.117,P<0.001). Compared with the non-surgery group, the median OS of primary surgery group was: HR=0.525, 95%CI=0.467-0.590,P<0.001. In the breast-conserving group, the median operative OS: HR=0.394, 95%CI=0.325-0.478,P<0.001. Conclusion: This study showed that primary surgery could improve the prognosis and overall survival of women with advanced breast cancer with bone metastasis alone. Under the condition of low tumor burden, breast conserving surgery was a better choice.


Introduction
Breast cancer is the most common malignant tumor threating women's health,there are over 270,000 new cases diagnosid yearly and approximately 42,000 raleted deaths, ranking rst in morbidity and second in mortality in the world 1 . Although with the improvement of people's health awareness and the development of medical technology, the screening and treatment of early breast cancer have been signi cantly improved, about 5% of patients still appear distant bone metastasis at the rst diagnosis, and the incidence of bone metastasis is as high as 70% in advanced metastatic breast cancer 2,3 .
Currently, for breast cancer with bone metastasis, the treatment principle is to relieve pain, restore function and improve the quality of life,increase the survival time,mainly comprehensive therapy including in Radiation and chemotherapy 4-6 . There is growing evidence indicating that the active primary site surgery is associated with survival bene ts in many retrospective studies [7][8][9][10][11][12][13][14][15] although prospective studies produced a small number of positive results [16][17][18] . the selective bias current guidelines do not recommend routine screening of bone metastases in patients with localized breast cancer only if directed by signs or symptoms.There is no de nite result whether the operation on the primary site of breast cancer with bone metastasis bene ts or not until now.
As for this, we used the Surveillance, Epidemiology, and End Results (SEER) database to investigate the effect of surgical operation on the prognosis of the patients with breast cancer with bone metastases from 2010 to 2015.

Data
We obtained data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database , which consists of 18 population-based cancer registries. The SEER program of the National Cancer Institute collects and publishes cancer incidence and survival data encompassing approximately 28% of the United States population. In this study,we used SEER*Stat Version 8.3.6 (http://www.seer.cancer.gov/seerstat) from the National Cancer Institute to survey eligible patients.

Patients
We collected breast cancer patients with bone metastases between 2010 and 2015 based on the 7th edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual 19

Patient characteristics
A total of 2917 patients with breast cancer with simple bone metastasis were included in this study according to the inclusion criteria and exclusion criteria.Patient and tumor characteristics are listed in table 1. Among them, there were 1245 cases (42.7%, 1235/2917) in the primary surgery group and 1672 cases (57.3%, 1672/2917) in the non-surgery group. The clinicopathological parameters in surgical group with statistical signi cance were: marital status, age, histological grade, T stage, N stage, ER, molecular subtype, radiotherapy and chemotherapy compared with the non-surgical group. Compared with the nonoperative patients, the proportion of young patients undergoing surgery was higher (c2 =21.613, P<0.001). Compared with unmarried patients, married patients had a higher surgical rate (46.8%vs38.8%). With the higher of tissue grade, the higher of T stage and N stage of tumor, the more proportion of the operation rate (P<0.001), and the more ratio of radiotherapy and chemotherapy of surgical patients signi cantly (P<0.001). Compared with ER positive, ER+/HER2-and ER+/HER2+ patients, ER negative, TNBC, and HER2-enriched breast cancer patients had higher surgical rates (P<0.001 and P=0.009). There were no signi cant differences in race, Ethnic origin,behavior, laterality, HER2 and PR expression between surgical patients and non-surgical patients.
3.2 Univariate analysis and multivariate analysis on the prognosis of breast cancer with bone metastasis 2917 cases of clinical pathology and prognosis of breast cancer with bone metastases of single factor analysis in the result analysis(table2), the clinicopathological parameters in uencing the prognosis of patients were race, histologic grade, marital status, age, histology, T stage, tumor radiotherapy and chemotherapy, ER, PR, and HER2, subtypes, primary tumors surgery and surgical procedure (P < 0.05), and had no relevant to ethnic origin, laterality, and N staging (P > 0.05). According to the results of single factor analysis ,primary site surgical group signi cantly affected the prognosis of patients ( Figure 1) compared to the non-surgical group (c2 = 146.023, P < 0.001); In the surgery group, the survival time of the breast-conserving group ( Figure 2) bene tted most for 70 month (c2 = 157.117, P < 0.001). With the higher histological grading, higher T stage , the more the median survival time decreased (P<0.001). Compared with the black,the white and others got a longer survival time (c2 = 35.071, P < 0.001); The expression of ER, PR, and HER2, histology of invasive ductal carcinoma, married patients,younger age, radiotherapy, and chemotherapy were all protective factors for breast cancer with bone metastasis (P<0.001). Single factor analysis results showed in the molecular subtype analysis, her2-positive breast cancer had the best prognosis, with the median survival time up to 73 months, while three-negative breast cancer had the worst prognosis, with the median survival time of 13 months, the difference was statistically signi cant(c2=242.199,P<0.001). COX multivariate regression analysis was performed on the pathological parameters signi cant by univariate analysis (table3). The results showed that the clinicopathological parameters with statistical signi cance were race, age, marital status, histological grade, histology, chemotherapy, ER, PR, HER2, molecular subtype, T stage, primary surgery and surgical mode. The results of univariate analysis were consistent with the above factors except the slight change of radiotherapy factors.

Comparison of baseline data among 1245 patients with different surgical modes
To further analyze the difference in survival analysis between different surgical methods, we used chisquare test to further analyze the baseline data of 1245 patients with different surgical methods. According to the analysis of table 4 results, there were statistically signi cant differences in T staging, N staging, radiotherapy and chemotherapy (P<0.05) in baseline data of 1245 patients, with no signi cant differences in other variables.In the breast-conserving group, the proportion of T and N stages, radiotherapy and chemotherapy was higher: the clinical stages of breast-conserving patients were lower, the tumor burden was lower, and the treatment was more active.

Discussion
As is known to all, advanced breast cancer refers to a tumor that has metastasized to other organs of the body. Generally, it cannot be cured and has a poor prognosis. Therefore, it is the therapeutic goal to improve the overall survival and the quality of life of patients, and systemic treatment is the rst choice. The intervention guideline of local surgery for breast cancer is to relieve symptoms, remove tumor rupture, bleeding, fungal infection and cancer pain without affecting the life of the patient 6 .
In our study, the pathology of breast cancer patients with bone metastasis was mostly LuminalA type (ER+/HER2-) (72.5%),which had good prognosis for the reason of the stable endocrine therapy and low proliferative index. According to the results of single factor analysis ,primary site surgical group signi cantly affected the prognosis of patients (  12,28,29 In the past related studies about advanced invasive carcinoma 20-22 ,a phenomenon had been observed in gastric cancer, ovarian cancer, colon cancer that the reduction in tumor burden and an increase in overall survival were associated, but it was controversial that surgery did not take a survival bene t in advanced breast cancer 5,[16][17][18] . However, in recent years, many retrospective studies 7-15 had shown that resection of the primary site of advanced breast cancer could bring survival bene ts, which were most obvious in young patients with positive estrogen receptor, low tumor burden, negative human epidermal growth factor receptor, and simple bone metastasis. Why were the conclusions of retrospective studies inconsistent with those of prospective studies, We analyzed the three prospective clinical studies.Firstly, the Translational Breast Cancer Research Consortium 013 (TBCRC-013 study) was a prospective multi-institutional registry trial which aimed to evaluate the role of surgery in stage IV breast cancer.Patients diagnosed with stage IV breast cancer at presentation (group A, n=112) or stage IV within 3 months of diagnosis (group B, n=16) were enrolled.Early results 23 from this study showed that surgery was associated with improved survival on multivariate analysis (HR 0.28, 95% CI 0.10-0.74, P = 0.01); In addition, 3-year overall survival results were demonstrated no difference in survival by the use of surgery among patients who responded to rstline therapy,the reason was that the patients treated with surgery were more likely to have larger tumors, the higher tumor burden 16 . Secondly, the prospective clinical trial was initiated at Tata Memorial Centre in India enrolling 350 patients to receive locoregional treatment (n=173) or no locoregional treatment (n=177). The result indicated the surgery could not take survival bene t because of unreasonable systemic therapy that they did not uniformly include taxanes, and most patients (92%) with HER2-positive breast cancer did not receive trastuzumab therapy;In addition, in the baseline data of the operation group, it had more of metastases number (75% vs25%),the less of the bone metastases (29%) 17 .At last, the MF07-01 trial conducted by the Turkish Federation seemed to produce positive result. Although there was no difference in survival at 36 months, overall survival was improved for the surgery group at 41.6% as compared to 24.4% in the no surgery group at 5 years. (46 versus 37 months, P = 0.005). Subgroup analysis showed that the survival bene t was associated with ER positive and HER2/neu-negative disease, age under 55, and bone metastases only 18 .
Different primary tumor surgery methods took different survival bene t,which might be associated with baseline of patients undergoing surgery. For further analysis,we found that there was statistical signi cance on the baseline of the BCS group,Mastectomy group and Radicial Mastectomy group( Table  4) in terms of T stage, N stage, chemotherapy, radiation therapy; There were lower tumor load , T stage, N stage levels and higher proportion of chemotherapy, radiation therapy in the BCS group, which further con rmed the fact that the prognosis was better in patients with simple bone metastasis from breast cancer with a lower tumor burden. Studies 7,30,31 showed that there was no signi cant survival bene t in further expanding the scope of surgery and lymph node dissection.Axillary lymph node status was not correlated with prognosis and was not an independent factor affecting prognosis, which was consistent with the results of multi-factor analysis in our study, but surgical margin status was correlated with patient prognosis 7 . In addition, in the data analysis of breast cancer with bone metastasis, Her-2 overexpression was statistically signi cant in univariate and multivariate analyses (P<0.05), and Her2 overexpression is a protective factor affecting breast cancer bone metastasis, which might be related to anti-Her-2 targeted therapy 32,33 .
Although positive results are obtained obviously, limitations of the study should be acknowledged.Firstly, we are lack of the whole information about systemic treatment,such as endocrine therapy, HER2-targeted therapy, or chemotherapy, which may lead to some bias in the survival analysis. Also,the short of data in the SEER database on events associated with bone metastasis as well as related systematic treatment 34-36 , has implications for the conclusions..Another potential issue is the possibility of incomplete or inaccurate claim entry as well as variability in coding practices among physicians. It is important to note that the tumor burden of patients selected for surgery is relatively low,which is also part of the surgical bias and has a certain impact on the results 37 .
To sum up, this study shows that primary surgery can improve the prognosis and overall survival of women with advanced breast cancer with simple bone metastasis. Under the premise of low tumor burden and comprehensive treatment, breast conserving surgery is a better choice. Although the application of primary surgery in advanced patients is controversial, the comprehensive treatment, systemic evaluation, and surgical timing, surgical mode selection of breast cancer for patients with simple bone metastasis from breast cancer need to be supported by prospective research data.