1. IntroductionBreast cancer (BC) is the most commonly diagnosed malignant cancer in women [1], and bone is the most common distant metastatic site [2,3,4]. The bone scan (BS), a conventional and cost-effective modality for detecting the entire skeleton in one examination [5,6], is widely used in postoperative follow-up for surveillance of bone metastasis (BM) in BC patients presenting related symptoms after surgery. However, current guidelines do not recommend intensive BS screening, which is referred to BS screening in asymptomatic patients, without specific findings on clinical examination before a diagnosis of BM.The prognostic value of intensive postoperative BS remains unclear. Two well-designed randomized controlled trials, GIVIO (Interdisciplinary Group for Cancer Care Evaluation) trials [7], as well as Rosselli del Turco trials [8], and the Cochrane meta-analysis [9] demonstrated that intensive follow-up (imaging examinations including BS and laboratory tests) does not improve overall survival compared to clinical follow-up (physical examinations and annual mammography). Hence the American Society of Clinical Oncology (ASCO) [10], National Comprehensive Cancer Network (NCCN) [11] and European Society for Medical Oncology (ESMO) [12] do not recommend an intensive follow-up including BS.It is important to note that the two trials were conducted almost three decades ago when advanced postoperative screening methods and palliative therapeutic options were scarce. Moreover, oncologists at that time lacked an adequate understanding of the intrinsic biological characteristics of BC. Recently, new regimens of systemic chemotherapy [13,14] and endocrine therapy [15] have made considerable progress in increasing patients’ survival with far-advanced cancer. Anti-Her2 (human epidermal growth factor receptor 2) therapy increased the prognosis of patients with Her2-positive metastatic BC [16,17]. Bone-modifying agents, such as bisphosphonates [18] and denosumab [19], slowed down the progression of skeletal-related events, thus promoting the quality of life.

It is possible that recent improvements in diagnostics and treatments could promote earlier detection and effective treatment of BM, important for improving survival. Therefore, we conducted this multicenter real-world study to understand the prognostic factors of BC patients with BM, especially the prognostic impact of an intensive postoperative BS after initial diagnosis of BC.

4. Discussion

This multicenter real-world study showed an intensive postoperative BS improved survival for BC patients with BM. In the point of molecular subtypes of BC, palliative anti-Her2 therapy and endocrine therapy improved both OS and OSABM among patients with a Her2+ and ER+ BC, respectively. These results indicated that the intensive postoperative BS and phenotype-specific palliative systemic treatments were important for improving survival of patients with BM.

Currently, ASCO, NCCN and ESMO guidelines do not recommend an intensive postoperative BS for BC patients [10,11,12]. However, in clinical practice, there are substantial variations in adherence to guideline recommendations. Intensive follow-up is a widespread reality that costs 2.2–3.6 times more than follow-up suggested by guidelines [24]. In a large population-based retrospective longitudinal study (n = 11,219) of women in Canada, 8.7–14.6% of women underwent BS screening in each follow-up year, and about half of them had greater than ASCO guideline-recommended surveillance imaging for metastatic diseases [25]. In line with these results, Surveillance, Epidemiology, and End Results (SEER)-Medicare database showed that 13.3% of 37,967 patients underwent at least one BS screening in the first year of follow-up [26]. Similarly, in our study, 28.7% (304/1059) of patients received an intensive postoperative BS. There are several possible reasons for the overuse of intensive BS imaging. First, the patient-driven anxiety and the feeling of reassurance induced by intensive postoperative surveillance, including the BS. Stemmler et al. have examined 801 questionnaires of German women with a history of BC and reported that more than 47.8% of them needed an intensive schedule, which increased their feeling of security [27]. Second, patients with early or limited metastatic recurrence may be curable; thus, the monitoring of asymptomatic patients could result in better efficacy of BC treatment, at least in theory, when tumor burden is low [26]. Third, all the high-level evidence was conducted almost 30 years ago in an era of outdated technology and limited therapeutic options. Current evidence demonstrated that improvements in diagnostics and treatments could improve the survival of patients with metastatic BC, especially with more detailed subtype classification and corresponding efficient target therapies [13,14,15,17]. However, there are no current well-designed trials to verify this issue. To the best of our knowledge, this is the first study that observed the prognostic value of an intensive postoperative BS in patients with BC with BM.

In our study, an intensive postoperative BS resulted in an independent prognostic factor of OS and OSABM among patients with BC with BM. It was worth noticing that 85.4% (904/1059) of patients received palliative chemotherapy, and 66.1% (700/1059) received bone-modifying therapy. In addition, 75.5% (545/722) of ER+ patients received palliative endocrine therapy and 50% (94/188) of Her2+ patients received palliative anti-Her2 therapy. The strength of these treatments was much stronger than it was decades ago. Palliative endocrine therapy had been identified as an independent prognostic factor for OS as well as OSABM, and palliative anti-Her2 therapy also improved OS and OSABM of patients with Her2+ BC. For ER-Her2-patients, palliative systemic chemotherapy increased 5-year OS by 14.3% (57.7% vs. 43.4%) and 2-year OSABM by 18.7% (49.7% vs. 31.0%) compared with the patients who did not receive palliative chemotherapy. This evidence suggested that intensive detection and effective phenotype-specific systemic intervention for BM could be translated into a survival benefit.

In order to make intensive postoperative BSs more cost-effective, we selected high-risk patients based on stratified analysis. A higher tumor burden led to a higher risk of distant metastasis [28,29,30,31]. Our study showed that the patients at stage II-III progressed to BM more rapidly compared with those at stage I. It was worth nothing that an intensive postoperative BS particularly improved survival of patients at stage II. Consequently, it was rational to suggest patients with a heavy local tumor burden receive intensive postoperative BS screening. From an intrinsic biological point of view, early BC presents special metastatic behaviors [32,33], so postoperative monitoring strategies should vary accordingly. The ER-Her2-subtype, with a dramatically increased risk of distant relapse [34], accounted for 23.9% (253/1059) of patients in our study. An intensive postoperative BS improved OS as well as OSABM among ER-Her2-patients. Thus, we assumed that an intensive postoperative BS for ER-Her2-patients might be of significance. However, an intensive postoperative BS did not convert into a survival benefit in Her2+ patients. It is possible that this was due to limited Her2 status detection techniques and therapeutic options, even though early postoperative detection of BM was performed. In our study, 367 out of 1059 patients were diagnosed with BM before 2009, when Her2 status detection techniques were not commonly used in China, and trastuzumab was not widely implemented for relapse patients.It is also worth noting that for all eligible patients, 26.5% (281/1059) were diagnosed with BM only, 37.6% (398/1059) were BM with VM, 23.6% (250/1059) were BM followed by VM, and 12.3% (130/1059) were VM followed by BM. There is probably a certain percent of patients classified as BM with VM who developed BM first and then progressed to VM but were not detected when simple BM originated. Previous studies showed that 26% to 50% of patients with early BC developed bone metastasis as the first site of distant relapse [4]. Consequently, early detection and treatment of BM may prolong the interval to visceral metastasis. As predicted, according to interaction and univariate stratified subgroup analysis, an intensive postoperative BS could improve OS for patients with ‘’BM to VM”, thus supporting the idea that early detection and early treatment are effective.

This multicenter real-world study showed that an intensive postoperative BS should probably be recommended as a follow-up strategy for patients with BC with BM. The main limitation of the present study is the retrospective study design. When evaluating the prognostic value of an intensive postoperative BS, cost-effectiveness and quality of life were not included in the analyses. Future studies with a randomized design are warranted to get an explicit estimation.