Nowadays, breast cancer is the most commonly diagnosed cancer in women worldwide. The incidence rate has risen rapidly over the past few decades, with an annual growth rate of about 6.1% [12, 13] . It is estimated that in 2019 approximately over 150,000 women have stage IV breast cancer in the United States. In addition, about 6% of female breast cancer patients have distant metastasis at the time of diagnosis [1, 14]. Stage IV breast cancer is defined by metastasis from the breast and axilla to distant sites, most commonly the bone[1]. Traditionally, stage IV breast cancer is considered an incurable disease and the goal of treatment is to prolong life and reduce or prevent symptoms[15].Previous knowledge has shown that the mainstay of treatment is systemic therapy, which includes chemotherapy, endocrine therapy, and targeted drugs, and so on. While surgery is reserved for symptomatic tumors bleeding or ulceration. Advances in systemic treatment have significantly improved the control of metastases and prolonged survival in IV breast cancer patients. In this context, the role of mastectomy in survival has therefore become a question worth considering. Earlier studies had indicated that the growth of distant metastases could be stimulated by advanced local surgery[16]. Researchers pointed out that primary tumors can represent a source of antiangiogenic factors and growth factor inhibitors, suggesting that it can inhibit the growth of distant metastases. Surgical resection reduced angiostatin secretion and also stimulated the release of growth factors, which might promoted tumor growth[17-19] In 2015, a randomized controlled trial on the effect of surgery for de novo stage IV breast cancer in India suggested that local surgery did not significantly improve overall survival [9]. Similarly, the initial reports from prospective studies by Badwe[20] et al and Soran [21] et al also failed to demonstrate a survival benefit among IV breast cancer patients who underwent surgical resection. However, these findings were criticized for a disproportionate inclusion of patients with advanced metastatic disease, insufficient systemic therapy regimens, and treatment sequences that did not match contemporary practices[22].
Although other series reported similar results, the effectiveness of mastectomy in IV breast cancer remains uncertain. It has been suggested that that although surgical resection of the primary tumor may cause transient increase in tumor burden, it substantially reduced overall tumor burden and improved survival by restoring immune responsiveness and enhancing sensitivity to chemotherapy[23, 24]. In recent years, some observational studies have shown that 35%-60% of breast cancer patients with stage IV received surgical resection and this treatment was associated with a survival advantage [4, 15, 25, 26]. Similarly, survival advantage with surgery for the intact breast primary in stage IV breast cancer has also been demonstrated in several studies. In 2012, Petrelli et al. [27] reported that the first meta-analysis compared survival outcomes in patients with stage IV breast cancer who received PTR or no PTR. They analyzed 15 observational studies and found that PTR provided survival benefits for stage IV breast cancer patients (HR=0.69; 95% CI: 0.63-0.77; P < 0.001). A completed trial (NCT00557986) in Turkey showed that surgery did not achieve a survival benefit after 3 years of follow-up, but after 5 years follow-up, patients with surgery achieved a better survival, especially in patients with bone metastases alone. The same result was also shown in another report. Rapiti et al [28] reported that complete surgical excision of the primary tumor led to a 40% reduction in the risk of death from breast cancer and was most pronounced for women with bone-only metastatic disease can benefit from initial surgical treatment. The question of management of the primary tumor in women with de novo stage IV breast cancer has caused us great concern, particularly in patients with bone-only metastases. It is undeniable that these retrospective studies may have limitations, including the inability to control selective bias. To explore the potential impact of surgery on the survival of patients with bone metastases, we selected a total of 1180 breast cancer patients histologically confirmed AJCC M1 breast cancer with bone metastases in National Cancer Institute’s SEER database, which was diagnosed between January 2010 and December 2011. In this large, nationally representative study of more than 1180 breast cancer patients, we analyzed the data and confirmed that patients who underwent palliative mastectomy showed better survival than individuals who did not undergo mastectomy. On multivariate Cox regression analysis to control for the effect of known covariates including age at diagnosis, race, pathological grade, molecular subtype, and chemotherapy type, palliative mastectomy for de novo stage IV breast cancer remained an independent factor associated with better survival. Although a survival advantage of fewer prognostic factors, such as T stage, has not yet been clearly demonstrated in our study. Comprehensive local therapy, including surgery for the intact breast primary, may improve locoregional control outcomes for IV breast cancer, particularly in IBC [6]. In contrast, chemotherapy was significantly related to better OS (HR=0.704, 95%CI (0.570-0.870), P<0.0001) and CSS (HR=0.730, 95%CI (0.585-0.911), P=0.005) for all IV breast cancer patients (Table 2, Table 3). This result is in agreement with other reports. In Soran et al.'s MF07-01 trial, among the 274 patients that could be evaluated, the results showed that OS was significantly longer in the patients who received surgery followed by chemotherapy [29]. Consequently, primary tumor mastectomy may improve survival of patients with stage IV breast cancer when used in conjunction with chemotherapy.
Through subgroup analysis, we found that primary tumor removal was significant associated with improvement in survival in most subgroups. Therefore, surgical management for the primary tumor could be considered more actively in patients with stage IV breast cancer. In addition, the availability of chemotherapy and adjuvant therapy for the treatment of IV breast cancer is already commonly used and showed significant OS and CSS. Therefore, patients with metastatic breast cancer will develop a durable long-term response and improved survival outcome with coordinated multidisciplinary therapy[15]. Joint efforts from surgeons, pathologists, oncologists and radiologists have been made to better personalized approach to patient management on an individualized basis.
Limitation and strength
We would like to acknowledge some certain limitations of this study. Undoubtedly, a relevant selection bias cannot be excluded since younger and healthier patients with less comorbidity and metastases have a higher propensity of being operated on, whereas the older, sicker patients with multiple metastases are less likely to undergo surgery. Nevertheless, the advantage of the present analysis of the SEER database is the high power of a large cohort and the potential to mirror outcomes in the daily clinical routine.
These results of the present study shed light on the role of surgery and potential benefit in solitary bone metastases of breast cancer. We hope that the ongoing trials will help to clarify the effects of palliative mastectomy of patients with metastatic breast cancer.