3.1 Patient characteristics
We identified 398 patients with breast cancer who developed distant metastasis and who met the inclusion criteria. The mean age at the time of initial treatment was 47.6 ± 11.0 years. Almost half of the patients had stage III breast cancer initially (45.8%), and two-thirds of the patients underwent mastectomy (68.6%). The clinical characteristics of the included patients are listed in Table 1. The interval between the detection of metastatic lesions and the date of previous imaging studies for the particular organ for each individual patient is shown in Figure 1. The median interval between the previous imaging study and the detection of metastasis was 10.5 ± 9.8 months. Our patients were classified into two groups: the intensive screening group (ISG, n = 199) and the less-intensive screening group (LSG, n = 199), with median intervals of 4.5 ± 1.6 and 16.4 ± 11.0 months, respectively. The ISG had a significantly higher incidence of neoadjuvant chemotherapy, postoperative radiotherapy, stage III disease, and previous history of locoregional recurrence, and was more likely to be diagnosed in more recent years (Table 1).
3.2 Survival outcomes and screening intensity
The distant-metastasis free survival of the 398 patients with breast cancer according to the frequency of imaging studies is shown in Figure 2a. The distant-metastasis free survival of the two groups was not significantly different, but the patients in the ISG had a shorter time to distant metastasis especially in the early phase of follow-up (log rank p = 0.083, Breslow p = 0.002). The LSG had a significantly higher overall survival (log rank p = 0.046, Breslow p = 0.015, Figure 2b). However, after adjusting for other prognostic factors, multivariate Cox regression analysis revealed no significant difference in overall survival between the two groups (hazard ratio [HR] = 1.21, 95% confidence interval [CI]: 0.95–1.54; p = 0.124; Table 2). The initial N stage, hormone receptor status, Ki-67 expression level, history of previous locoregional recurrence, presence of symptoms at the diagnosis of distant metastasis, and metastatic site remained independent factors predicting overall survival.
We further examined the association between the screening intensity for distant metastasis and survival considering different subtypes of breast cancer. As shown in Figure 2c-2f, the screening intensity did not affect the survival outcomes considering HR+/HER2-, HR+/HER2+, and HR-/HER2- subtypes. However, the LSG group had significantly better overall survival than the ISG group did when the tumors were HR-/HER2+. Nevertheless, the prognostic importance of screening intensity did not remain significant after adjusting for other prognostic factors (HR = 1.47, 95% CI: 0.80–2.73; p = 0.217, see Additional file 1).
3.3 Sites of metastasis, presence of symptoms, and effects of screening intensity
Among the 398 patients with distant metastasis, 220 developed distant metastasis in a single organ: 100 patients had bone metastasis, 85 had lung metastasis, and 35 had liver metastasis. The remaining 178 patients developed metastases in multiple organs. The intensity of screening did not affect the overall survival of patients who developed metastasis in the bones, liver, or multiple organs. However, the overall survival of patients whose first site of metastasis was the lungs was significantly low (Figure 3). The screening intensity remained an independent prognostic factor of overall survival in patients with lung metastasis after adjusting for other prognostic factors (HR = 2.10, 95% CI: 1.06–4.17; p = 0.034, see Additional file 2).
As the presence of symptoms at the time of diagnosis might lead to the performance of imaging studies earlier than the pre-scheduled dates, patients who develop symptomatic, rapidly progressing distant metastasis are more likely to have a shorter time interval between the previous imaging studies and the diagnosis of distant metastasis. To overcome this issue, we identified 225 patients whose distant metastases were asymptomatic and who were diagnosed using screening imaging studies. As shown in Figure 4, we observed similar associations between the screening intensity and the survival outcomes of patients with asymptomatic distant metastasis. Patients in the LSG had significantly higher overall survival when the patients had HR-/HER2+ tumors and when the first site of metastasis was the lungs (Figure 4d and 4h). In addition, among these 225 asymptomatic patients, the screening intensity was significantly associated with the overall survival of patients with HR-/HER2- tumors (Figure 4e).