The retrospective cohort study demonstrated that LRT was associated with a significant benefit with respect to OS with a 53% relative difference in the risk of death as compared STA in women with dnMBC. Subgroup analyses also demonstrated improved outcomes in patients who had received surgery in these patients, with a median OS of 42 months (HR, 0.48), compared with no-surgery. Herein, we found that LRT, the combinations of surgery with radiation therapy used in this patient population have shown a consistent and meaningful prolongation of survival over STA. The Kaplan–Meier curve for OS showed separation between the two groups beginning at approximately 10 months, and the separation widened over time. This OS benefit was generally consistent across patient subgroups, including those who received surgical resection of the primary tumor. In this study, the greatest benefits were seen among both patients who had surgery with negative margins and patients undergone SAC or SDC, with an average survival of 56 months, regardless of the site of their metastatic disease. Exploratory analyses also demonstrated consistent treatment effects across specified subgroups. Our findings show that LRT in patients with dnMBC had a positive impact on OS. This work will support and add evidence to the critical concepts in the treatment of women with dnMBC.
With respect to the survival effects of LRT in patients with dnMBC, retrospective studies have shown the potential survival benefits [8, 15, 39–45], while prospective studies have revealed mixed results [29]. Currently, three published prospective studies have assessed the impact of LRT in dnMBC. A randomized controlled trial by Badwe et al. [35] found no difference in OS based on LRT; another study by Soran et al. [36] randomized 274 dnMBC patients to either LRT or SAT, in whom survival was similar at 36 months, but actually higher in LRT group vs STA group at 60 months; the ABCSG-28 POSYTIVE trial by Fitzal F et al.[37] stopped early owing to poor recruitment and no definite conclusion was reached. In addition, a prospective registry study of 127 patients noted no improvement in OS for those having resection of their intact primary disease. To date, prospective trials failed to provide a definitive answer to the question of optimal utility of surgery in this patient population [46]. Despite these trials have been criticized due to systemic therapy protocols which differ from standard modern treatments, as well as broad inclusion and exclusion criteria, they continue to provide important data. By contrast, multiple retrospective studies and large meta-analysis have revealed the potential survival benefits with LRT in patients with dnMBC. A recent meta-analysis by Ritika Gera et al., of 216066 patients found all forms of LRT resulted in a significant 31.8% reduction in mortality and surgical resection resulted in a significant 36.2% reduction in mortality. Ritika Gera therefore concluded that LRT of the primary tumour seems to improve overall survival in dnMBC [21]. Another study by Seo et al. showed that LRT might be an important option for dnMBC patients [47]. Our findings are in accordance with these reports analyzing the impact of LRT on survival.
The latest research from the NCDB (2003–2012) demonstrated that among women alive 1 year after a diagnosis of metastatic breast cancer, surgical resection of the primary tumor was associated with improved survival, regardless of treatment sequence [8]. Another recent study based on the SEER database (2010–2015) proposed a survival advantage with surgical intervention (median OS, 43 months for surgery vs. 27 months for non-surgery) [45]. Similarly, in our study, the median OS of the two groups was 42 months vs. 22 months, respectively.
Most retrospective studies focused on the survival outcomes of surgical treatment after systemic chemotherapy. For example, a recent research by Whitney O. Lane et al. from NCDB showed that the greatest survival benefit was seen in women treated with systemic therapy followed by surgery; median OS was 52.8 months compared to 37.5 months for those undergoing STA [8]. However, no studies discussed the survival of receiving surgical treatment at three different time periods (SAC, SDC and SBC) in dnMBC patients. One of major strength of this study, we analyzed the survival outcomes of SBC, SDC and SAC, rather than that of SAC alone.
In the present study, despite defferent timings of surgery that included SAC, SDC and SBC, patients underwent resection of the primary tumor not only failed to increase the risk of death, but instead showed an improvement in OS compared to nonsurgical treatment during the follow-up period. Moreover, our study found a significant OS difference between patients in whom the three surgical options were SAC, SDC and SBC. Compared with SBC, both SAC and SDC have a survival advantage in these three different options (p = 0.013). The authors speculated that patients with SAC or SDC may have an opportunity to receive preoperative or concurrent chemotherapy with surgery, and thus respond well to complete local remission of the tumor, leading to prolonged survival.
We also found that surgery with negative margin had a positive impact on OS for surgical patients. In our study, OS was significantly improved in patients with negative margins versus patients with positive margins, with a median OS of 56 months versus 16 months (p < .0001), respectively. The results of this study show that the surgical removal of primary tumor in these patients does not impair survival but actually improves prognosis if done with negative surgical margins. It has been suggested that the total tumor burden plays a central role in survival and that the removal of the primary tumour reduces the tumour burden, thereby increasing response to systemic therapy [44, 48]. Another factor is that the primary tumour is that the main source of new clonal lines of cancer cells, which are implicated in the emergence of resistance to therapy and the appearance of more aggressive disease phenotypes [49]. Consistent with this hypothesis, recent studies found a strong correlation between the level of circulating tumor cells and prognosis of metastatic breast cancer [50, 51]. Surgery would disrupt this process.
As an alternative to surgery, the survival impact of radiotherapy were also analyzed in the present study. The results were received for radiotherapy on survival with a p value of 0.053 calculated by log-rank statistics (47 months versus 37 months). Obviously, our findings are not consistent with the conclusions of contemporaneous cohorts from the literature [4, 52–55]. Current trial showed that those patients who received radiation did not improve their survival, possibly because of the small sample and size limited number of events.
Some limitations in the interpretation of our findings should be acknowledged. This study’s retrospective nature inevitably leads to certain limitations, such as potential selection bias, and the reliance on various clinicians’ documentation of indications for treatments. For patients, the choice of treatment is usually at the clinicians’ discretion. Moreover, the study includes a limited number of patients and it is not possible to derive definitive conclusions regarding survival outcomes, especially relative to LRT. Despite these limitations, our study has several strengths. We tried to address some controversial and important issues in a field where limited data are available. First, few studies have compared the survival outcomes of dnMBC patients undergoing surgery at three different intervals between systemic chemotherapy and surgery. To the best of our knowledge, this is the first study that assessed the survival outcomes of these patients with a particular focus on the three different intervals associated with use of surgery, and concluded that SAC and SDC benefited significantly. Furthermore, whether surgical margins corresponding to the three surgical procedures have an impact on patient survival has not been previously studied. In the present study, we found a significant survival difference between patients in whom the surgical margins were negative and positive. The results showed that patient who had SAC or SDC, with negative surgical margins, were expected to have better survival. However, due to the above limitations, in our study, more researches should be conducted to confirm the hypothesis.