Breast cancer (BC) is the leading cause of female mortality worldwide. Approximately 290560 new cases were diagnosed, and 43780 deaths in the United States alone in 2022 (1). Despite great advances in the systemic treatment of BC over recent years, largely attributable to the rise of endocrine therapy, anti-HER2 therapy, CDK4/6 inhibitor, and mTOR inhibitor (2), tumor progression and distant metastasis (DM) remain the major obstacles for the long-term survival of BC patients (3). Approximately 3.5–6% of newly diagnosed BC cases have synchronous metastasis, with bone being the most common site (4, 5). Approximately three-quarters of stage IV BC patients have bone metastases (BM). BC patients with BM usually experience a poor prognosis, with a three-year survival of 25% and a five-year survival rate of 13% (6).

Generally, BC presented with BM is considered a virtually incurable disease, with therapeutic goals primarily focusing on symptom relief and quality of life (7). Whether these patients should undergo surgical intervention for primary lesions remains controversial. The conventional view believed that locoregional surgery for BC patients with metastatic disease reduced only the local tumor burden without preventing the disease’s progression. It would also expose the patients to surgical risks and post-operative complications (8–10). Recent reports suggest that the surgical resection of primary tumors improves survival in BC patients with BM. A large cohort retrospective study designed by Huang et al. revealed that BC patients with BM who underwent local surgery had better survival outcomes than those who did not (median survival: 50 months versus 31 months, p < 0.001) (11). Another study demonstrated that local surgery positively impacted survival in BC patients with BM (12). However, this work was limited to investigating the significance of surgery for BC patients with only BM. The disparity of surgical benefits among different patterns of synchronous extraskeletal metastases, such as the lung, brain, and liver, in BC patients with BM at initial diagnosis has not been thoroughly studied. Individual patient characteristics and differences in disease progression make it unclear whether primary tumor resection should be recommended for all BC patients with synchronous BM.

Surgeons are frequently challenged in their daily practice to make reasonable judgments about the suitability of BC patients with synchronous BM for locoregional surgery based on the understanding of the vast amount of high-dimensional and heterogeneous data combined with their knowledge of clinical experience to inform their clinical decisions. Poor medical decisions may not provide the best treatment options, affecting patient safety and increasing healthcare costs (13). A nomogram, which has been developed for various malignancies, can provide visualized probability estimates tailored to each individual as an easy-to-use and integrated prediction model (14, 15). To date, no such model exists to estimate the probability of local surgical benefit in BC patients with BM and thus to guide rational medical decisions for surgical treatment in this population. Hence, we used a population-based database to address the clinical needs and thoroughly explore the role of local surgery in BC patients with BM. We propose a novel prediction model that accurately identifies patients who could benefit from surgical resection of primary lesions.

BC is one of the most prevalent malignancies worldwide, and tumor invasion and distant metastases are the leading causes of mortality in BC patients (16). Bone is the most frequently involved site in patients with metastatic BC, with approximately 65–75% of deceased BC patients carrying evidence of BM (17). To date, anti-tumor systemic therapy and bone-targeted drugs have been used to slow bone resorption and reduce the risk of bone-related events in BC patients with BM. Surgical resection of the primary lesion is not usually the preferred treatment option for these patients (18). However, recent retrospective studies have demonstrated that locoregional surgery has a significant survival advantage in BC patients with BM (11, 12, 19). The opinions from the 5th International Consensus Conference on Advanced Breast Cancer suggested that performing breast surgery in a select group of patients with metastatic BC may help improve quality of life and potentially prolong survival time. Continuing locoregional surgery has the potential to eliminate BC stem cells, decrease the tumor burden in vivo, improve the efficacy of systemic chemotherapy, and reduce the likelihood of primary tumor cells spreading to distant organs and forming new metastases (20, 21). In contrast, several researchers disagreed; previous studies concluded that surgical intervention on primary tumors did not improve the survival outcome of patients with metastatic BC, including bone metastases (8, 22). These slightly contradictory findings indicate that not all BC patients with BM could extend their survival with additional local surgery, creating a dilemma for surgeons. Nevertheless, existing guidelines fail to specify which BC patients with BM were suitable for surgical resection of the primary tumor. It remains an open question to determine which BC patients with BM would benefit from this procedure.

To address this concern, we systematically investigated the impact of local surgery on survival in BC patients with BM using the research data extracted from a population-based database. We developed a novel prediction model specifically for this population to quantify the probability of surgical benefit individually. Consistent with previous reports (11, 12, 23), our study revealed the potential of surgical resection of the primary tumor in managing BC patients with BM, suggesting local surgery could be a reasonable option in multimodality treatment to improve prognosis. Furthermore, the well-validated prediction model was expected to accurately stratify BC patients with BM according to their predicted potential to benefit from local surgery. The surgeons can more accurately identify the optimal surgical candidates with the assistance of this newly proposed nomogram, possibly allowing aggressive surgical treatment of the primary lesion to be more judiciously administered in BC patients with BM. Our analysis also suggested that local surgery did not improve survival in BC patients with BM estimated by our model as not benefiting from this surgical procedure ( Figure 8 ). This group of patients may suffer from severe complications following invasive surgical procedures (24).

This study indicated that the probability of benefiting from local surgery for BC patients with BM was associated with six independent indicators, including race, T stage, breast subtype, liver metastasis, brain metastasis, and radiotherapy, among which the breast subtype illustrated the strongest correlation with the potential of surgical benefit. A large cohort study implemented by Tan and colleagues (25) suggested that patients with hormone receptor-positive (HR-positive) were more likely to benefit from surgical treatment of primary lesions than their counterparts with hormone receptor-negative (HR-negative). They examined 10,441 eligible metastatic BC patients from 2004 to 2008. They divided them into four groups: the primary and metastatic resection group (R0 group), the primary resection-only group, the metastatic resection-only group, and the non-surgery group. The median survival for these patients in four groups was 66, 52, 38, and 28 months, respectively (p < 0.05). In contrast, no statistically significant difference in survival was observed among the four surgical treatment groups in patients with HR-negative. Similarly, Neuman HB et al. reported a trend toward improved survival with primary tumor resection. It was noted most strongly in patients with ER/PR positive and/or HER2 positive disease. According to our model, patients with HR-/HER2- are least likely to benefit from surgical resection of the primary tumor. Additionally, we performed subgroup analyses to explore the heterogeneity in the treatment effect of local surgery. The results demonstrated that triple-negative breast cancer (TNBC) was the only subtype that may not benefit from surgery. TNBC is a highly aggressive subtype of BC characterized by extensive visceral metastases and frequent early postoperative recurrences (26, 27). TNBC patients with BM have a 40% lower five-year survival rate than non-TNBC patients (28). This suggests that effective systemic therapy may be even more significant for highly aggressive TNBC patients with BM. Besides, the status of liver metastasis and brain metastasis were also independently related to the surgical benefit in BC patients with BM. Previous studies have revealed that the prognosis of BC patients with BM may vary with the metastatic pattern (18, 29, 30). Two meta-analyses reported that patients with fewer metastases could benefit more substantially from local surgery (31, 32). Additionally, patients with brain and liver metastases were more severely ill than those with bone and lung metastases (33, 34). Likewise, our study suggested that in the case of the metastatic pattern of bone, liver, and brain metastases as well as bone, liver, lung, and brain metastases, surgery failed to provide survival benefit in these two subgroups. This suggests that BC patients with BM presenting with liver or brain metastases at initial presentation will have a poor prognosis, and their survival time will become limited, echoing the fact that the status of brain and liver metastases is closely relevant to whether patients can benefit from surgery at the primary site.

Notably, differences in sociodemographic factors and differentially expressed genes between white person and the African America patients may contribute to their differential survival benefit from locoregional surgery (35, 36). Meanwhile, the higher T stage usually represented more aggressive biological behavior and larger tumor size, which also were generally accompanied by abundant neovascularization; in such situations, extrusion during surgery would tremendously increase the risk of hematogenous metastases (37). Moreover, radiotherapy (RT) was considered a powerful adjunct therapy on perioperatively tumor control in BC patients with BM. A recent systematic review on treating BC patients with BM suggested that RT could decrease the local tumor burden in more radiosensitive subtypes and reduce the risk of local recurrence after surgery (38). Local control rates were higher in patients who received both local surgery and RT, indicating that RT improved quality of life and enhanced the survival benefit of local surgery (39, 40). Although patients treated with concomitant RT can better benefit from local surgery, the toxicity of radiotherapy also deserves attention. Chest radiation therapy may cause serious heart complications, such as premature coronary artery disease, valvular heart disease, pericarditis, arrhythmias, and restrictive/constrictive cardiomyopathy with heart failure (41). The newly proposed prediction model incorporating the above-mentioned independent predictors promises to be a useful tool for individualized quantification of the probability of benefiting from surgical resection of primary lesions in BC patients with BM and assisting in identifying optimal candidates for this procedure in clinical practice.

Nevertheless, this study still had several potential limitations. First, the study was retrospective and may have been subjected to selection bias related to the study design. Second, the SEER database lacked specific information about systemic treatments such as HER2 targeted therapy, endocrine therapy, and immunotherapy, so it is unclear whether locoregional surgery combined with these therapies could result in additional survival benefits. Besides, the SEER database failed to record some important information, including patient’s general condition and if they suffered complications, which may bias the choice of surgical treatment for the patients. Finally, further validation of our data is required in large-scale prospective studies.

In this study, we thoroughly investigated the effect of local surgery on survival in BC patients with BM. We discovered that patients in specific groups could gain the survival benefit from this procedure. Additionally, a novel prediction model was proposed to quantify the probability of surgical benefit, allowing further selection of BC patients with BM suitable for surgical resection of primary tumors.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

We received permission to access the research data file in the SEER program from the National Cancer Institute, US (reference number 15685-Nov2020). Approval was waived by the ethics committee of China-Japan Union Hospital of Jilin University, as SEER data is publicly available and de-identified.

YT: Conceptualization, Data curation, Formal Analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. SX: Data curation, Methodology, Software, Writing – original draft. LJ: Formal Analysis, Project administration, Visualization, Writing – original draft. CZ: Data curation, Methodology, Writing – original draft. DZ: Conceptualization, Supervision, Writing – review & editing.