Baseline characteristics
In the First Affiliated Hospital of Chongqing Medical University between January 2012 and November 2018, 6,453 patients were diagnosed with BC. A total of 126 patients diagnosed as BBC were recruited and 59 patients were diagnosed as SBBC, of which 16 patients received NAC treatment, and 67 patients were diagnosed as MBBC. Figure 1 shows the flow chart of reasons for exclusion. The disease characteristics of SBBC and MBBC are shown in Table 1. Because of missing data on one side of MBBC, significant statistical differences could be seen between SBBC and MBBC. Thus, to eliminate this bias, and according to the result of statistical research, we used the frequency of the indicator instead of the missing data (original data is provided in Supplementary table 1). It is clear in the table 1 that patients with SBBC more often had an early clinical stage (stage I and II at diagnosis) on the right side (P = 0.007), low histological grade on the left side (P = 0.021), and higher HER2 expression on the left side (P = 0.017) than patients with MBBC. A significantly higher expression of hormone receptor (HR) was evident in patients with SBBC compared with patients with MBBC. This led to the conclusion that more luminal subtypes, especially luminal A, are found in patients with SBBC, and more triple-negative subtypes are found in patients with MBBC. Considering the time interval of the two sides and drug resistance, patients with MBBC usually received two regimens of chemotherapy.
Survival state in all patients and separately in patients with SBBC and MBBC
At the end of follow-up, 101 patients had survived. The differences in the patients and disease characteristics between the survival and non-survival groups are given in Table 2. Interestingly, some obvious differences were identified in these two groups. For the survival group, statistically different characteristics included a smaller tumor size (left P = 0.074; right P = 0.022), negative sentinel lymph node (left P = 0.000; right P = 0.000) of both sides, an earlier clinical stage at diagnosis (left P = 0.038; right P = 0.028), and lower expressions of ER (left P = 0.037; right P = 0.079) and PR (left P = 0.059; right P = 0.047). On the contrary, in the non-survival group, higher expression of ER and PR, larger tumor size, and positive sentinel lymph nodes and axillary lymph nodes could be seen. These data showed that higher expression of ER and PR, larger tumor size, and positive sentinel lymph nodes and axillary lymph nodes were associated with survival.
The logistic regression of all characteristics indicated that sentinel lymph node (left odds ratio [OR] = 12.102; 95% confidence interval [CI]: 2.24–65.31; P = 0.004; right OR = 22.969; 95% CI: 4.39–120.16; P = 0.000), axillary lymph node (left OR = 2.916; 95% CI: 1.16–7.32; P = 0.023; right OR = 15.671; 95% CI: 3.32–74.01; P = 0.001), PR of right (OR = 2.361; 95% CI: 1.08–5.17; P = 0.032) and molecular subtype of the right side (OR = 4.932; 95% CI: 1.71–14.23; P = 0.003) might relate to the survival state (Table 3). The analysis and results above were for all the patients with BBC.
Furthermore, the Cox survival analysis of all characteristics in SBBC showed that the statistically different characteristics were concentrated on the left side tumor of the breast (Table 4). The left-side characteristics, including tumor size (HR = 2.941; 95% CI :1.41–6.15; P = 0.004), axillary lymph node (HR = 2.222; 95% CI: 0.95–5.18; P = 0.064), clinical stage (HR = 1.566; 95% CI: 1.06–2.31; P = 0.023), tumor type (HR = 3.815; 95% CI: 1.62–8.99; P = 0.002), histological grade (HR = 1.881; 95% CI: 1.14–3.11; P = 0.014), and molecular subtype (HR = 1.952; 95% CI: 1.19–3.20; P = 0.008), all influenced survival. This result indicated that the tumor in the left side of breast might have a more profound effect on survival state than the right side. To exclude whether differences in the characteristics of the two sides contributed to this result, the characteristics between the two sides were compared, but identified no difference (Table 5). The multivariate analysis of overall survival time of patients with SBBC showed that the only factor that affected survival was left-side tumor type (HR = 4.532; 95% CI: 1.77–11.61; P = 0.002; Supplementary table 2). The Cox survival analysis of all characteristics for patients with MBBC showed that the only factors involved in survival were age (HR = 0.105; 95% CI: 0.013–0.819; P = 0.032) and Ki67 of the right side (HR = 2.186; 95% CI: 1.04–4.60; P = 0.040). A multivariate analysis of patients with MBBC, however, showed that age (HR = 0.101; 95% CI: 0.01–0.79; P = 0.029) was the only characteristic that affected survival time (Supplementary table 3 and 4).
Changes of characteristics after NAC in SBBC
In patients with SBBC, 16 received NAC treatment, and only 10 patients survived during the follow-up time. Because changes in the characteristics of the tumor after NAC predict a different prognosis in patients with UBC [10-13], characteristics through core needle biopsy and surgical tissue section were collected (Supplementary table 5 and 6). The changes in characteristics were compared before and after NAC between the survival group and non-survival group (Table 6) and also recorded the response to NAC (Table 7). However, no statistical difference was found.
The Kaplan-Meier survival estimate was used to analyze changes in factors affecting prognosis in patients with SBBC who received NAC. Results showed that a decrease in tumor size (survival time left and right: 53.50±10.35, P = 0.887), clinical stage (survival time left: 72.33±10.65, P = 0.159, survival time right: 54.20±11.42, P = 0.918), Ki67 (survival time left: 51.57±9.22, P = 0.530, survival time right: 57.25±12.21, P = 0.924), and P53 (due to the limited number of patients, the conclusions can only be draw for survival time of the right in the SPSS software; the survival time of right: 59.14±7.27, P = 0.079) may indicate a prolonged life span. In contrast, however, a decrease in ER (survival time left: 34.40±11.91, P = 0.215, survival time right: 41.33±10.76, P = 0.888), PR (survival time left: 34.75±10.35, P = 0.561, survival time right: 43.71±10.17, P = 0.961), and HER2 (due to the limited number of patients, the conclusions can only be draw for survival time of the right in the SPSS software; survival time of right: 39.50±7.1375, P = 0.518) may indicate a shortened life span (Table 8). It is also reminded that changes in tumor type and molecular subtype might influence survival time. Although the life span differed between groups that showed a decrease or no decrease in all characteristics of tumor in both side breasts, this difference did not reach the traditional statistically significant level.
According to patient response to NAC treatment and RECIST 1.1(response evaluation criteria in solid tumors), we classified PCR, CCR(clinical complete response), and PR(partial response) as the response group, and SD(stable disease) and PD(progressive disease) as the non-response group. The Kaplan-Meier survival estimate showed that the life span of the response group (left and right: life time = 57.27±10.58; 95% CI: 36.54–78.01) was longer than the life span of the non-response group (left and right: life time = 25.50±6.75; 95% CI: 12.27–38.73); however, this difference did not reach the traditional statistically significant level (P = 0.518; Table 9). The factors affecting survival also indicated differences in the cumulative survival time between these two groups (Figure 2).