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 first 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 patient6.
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 significantly affected the prognosis of patients (Figure 1) compared to the non-surgical group (c2 = 146.023, P < 0.001), benefitting most for 70 month (Figure 2) (c2 = 157.117, P < 0.001). For another ,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). Although the treatment of breast cancer is surgery-based comprehensive treatment,the survival benefit from primary surgery may be related to the following conditions: 1. Surgery can remove the primary tumor site, get rid of the primary tumor cell and tumor stem cells, and reduce the possibility of peripheral release and spread of circulating tumor cells24-26; 2. Primary surgery can play an important role at local control of on patients: Tumor ulcer, infection and other aspects ,which improving patients' physical and psychological quality of life; 3. Primary surgery can reduce the burden of tumor and improve the curative effect of tumor chemotherapy22,27;4.Resection of the primary tumor can reduce the immune suppression of the tumor on the body, activate CD4 and CD8 T lymphocytes, and stimulate the immune response of the body to tumor cells12,28,29
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 benefit in advanced breast cancer5,16-18. However, in recent years, many retrospective studies7-15 had shown that resection of the primary site of advanced breast cancer could bring survival benefits, 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 results23 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 first-line therapy,the reason was that the patients treated with surgery were more likely to have larger tumors, the higher tumor burden16. 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 benefit 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 benefit was associated with ER positive and HER2/neu-negative disease, age under 55, and bone metastases only18.
Different primary tumor surgery methods took different survival benefit,which might be associated with baseline of patients undergoing surgery. For further analysis,we found that there was statistical significance 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 confirmed the fact that the prognosis was better in patients with simple bone metastasis from breast cancer with a lower tumor burden. Studies7,30,31 showed that there was no significant survival benefit 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 prognosis7. In addition, in the data analysis of breast cancer with bone metastasis, Her-2 overexpression was statistically significant 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 therapy32,33.
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 treatment34-36, 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 results37.
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.