Baseline characteristics of qualified researches
In the systematic literature retrieval, we found 617 researches. By reviewing the title and abstract, 74 possible related researches were identified. In the remaining 74 studies, 41 of these studies were later excluded because they did not meet the selection standards. Eventually, we determined that 33 researches met the inclusion standards.[4, 5, 11–41] Fig. 1, summarized the search and screening process. The 33 researches comprised 18170 qualified patients with breast cancer (sample capacity, median: 331 [50–3771], mean: 550). These studies were published between 2010 and 2020 from the Europe, America, Australia and Asia (Spain, France, Italy, United Kingdom, Belgium, Finnish, Germany, Ireland, USA, Canada, Australia, Japan, Korea, China ). Eligible researches evaluated TILs by hematoxylin and eosin stained sections. Twelve studies provided OR on pCR to complete the meta-analysis[13, 23, 25, 26, 28, 31, 33–35, 37, 38, 41]. Fifteen of these researches provided HRs data of DFS or OS and we performed the pooled analysis. Twelve researches furnished HRs data of DFS [5, 13, 15–17, 24, 26, 29–31, 37, 40], and ten researches furnished HRs data of OS [5, 13, 15, 17, 18, 20, 21, 24, 26, 29]. Table 1, summarized the main baseline characteristics. We estimated the quality of selected researches based on the NOS and As shown in Table 2.
Relationship of the lymphocyte-predominant breast cancer (LPBC) with clinicopathological parameters
T stage
The incidence of LPBC in the T3,T4 group was lower than T1,T2 group, the difference achieve statistical significance [ OR = 0.646, 95%CI(0.542, 0.771), I²= 0.0%, z = 4.85, p < 0.001]. After that, subgroup analysis were conducted on different ethnicity [Europe: OR = 0.661, 95%CI(0.546, 0.800), I²=0.0%, z = 4.25, p < 0.001; Asia: OR = 0.516, 95% CI(0.297, 0.898), I²=0.0%, z = 2.34, p = 0.019; America: OR = 0.695, 95% CI (0.294, 1.643), z = 0.83, p = 0.407] and different study design [RCT: OR = 0.663, 95% CI (0.550, 0.798), I²= 0.0%, z = 4.33, p < 0.001; retrospective: OR = 0.516, 95% CI (0.297, 0.898), I²=0.0%, z = 2.34, p = 0.019]. In the Asian group and the European group, the difference were statistically significant.
Lymph node status
The pooled analysis indicated that the incidence of the lymphocyte-predominant breast cancer (LPBC) detection between the lymph node metastasis group and the non lymph node metastasis group has no significant difference (overall: OR = 0.941, 95% CI 0.681, 1.298], I²= 76.4%, z = 0.37, p = 0.709). After that, subgroup analysis were carried out on different ethnicity [Europe: OR = 0.991, 95% CI (0.633, 1.551), I²= 80.8%, z = 0.04, p = 0.968; Asia: OR = 1.013, 95% CI (0.595, 1.726), I²=60.8%, z = 0.05, p = 0.962; America: OR = 0.549, 95% CI (0.322, 0.936), z = 2.20, p = 0.028]. The difference was statistically significant in the America group.
Histological type
The incidence of the lymphocyte-predominant breast cancer (LPBC) was significantly different between the invasive ductal carcinoma and invasive lobular carcinoma groups (overall: OR = 2.654, 95% CI [1.132, 6.223], I²= 68.0%, z = 2.24, p = 0.025). Then subgroup analysis were performed on different study design (RCT: OR = 4.735, 95% CI [2.850, 7.867], I²= 0.0%, z = 6.00, p < 0.001; retrospective: OR = 1.101, 95% CI [0.622, 1.951], I²=0.0%, z = 0.33, p = 0.740). The difference was statistically significant in the RCT group.
Histological grade
The detection of the lymphocyte-predominant breast cancer (LPBC) in pathological specimen can show histological grading [III versus Ⅱ and I, overall: OR = 2.889, 95%CI (2.218, 3.762), I²=49.5%, z = 7.87, p < 0.001]. After that, subgroup analysis were conducted on different ethnicity [Europe: OR = 2.871, 95% CI (2.290, 3.600), I²= 25.5%, z = 9.14, p < 0.001; Asia: OR = 5.636, 95% CI (3.050, 10.415), I²=0.0%, z = 5.52, p < 0.001; America: OR = 1.659, 95% CI (0.982, 2.804), z = 1.89, p = 0.059] and different study design [RCT: OR = 2.763, 95% CI (2.188, 3.489), I²= 39.7%, z = 8.53, p < 0.001; retrospective: OR = 3.284, 95% CI (1.359, 7.934), I²= 64.0%, z = 2.64, p = 0.008]. In the Asian group and the European group, the difference were statistically significant.
Gene expression of ER, PR and HER2
The lymphocyte-predominant breast cancer (LPBC) incidence rate in the ER་group was significantly lower than that in the ER- group [total: OR = 0.291, 95%CI (0.185, 0.458), I²= 70.0%, z = 5.35, p < 0.001];After that, subgroup analysis were conducted on different ethnicity [Europe: OR = 0.348, 95%CI (0.197, 0.614), I²= 61.1%, z = 3.65, p < 0.001; Asia: OR = 0.154, 95%CI (0.090, 0.264), z = 6.80, p < 0.001; America: OR = 0.342, 95%CI (0.216, 0.540), z = 4.60, p < 0.001]and different study design [RCT: OR = 0.360, 95%CI (0.230, 0.563), I²= 60.1%, z = 4.49, p < 0.001; retrospective: OR = 0.191, 95%CI (0.105, 0.346), I²= 30.4%, z = 5.44, p < 0.001]. In addition, PR་and PR། groups [total:OR = 0.396, 95%CI (0.173, 0.906), I²=0.0%, z = 2.19, p = 0.028]. Furthermore, the detection rate of lymphocyte predominant breast cancer (LPBC) between HER2་group and HER2། group has not significant difference. [total: OR = 1.359, 95%CI (0.646, 2.858), z = 0.81, p = 0.419]. different ethnicity [Europe: OR = 1.443, 95% CI (0.529, 3.933), I²= 92.0%, z = 0.72, p = 0.474; Asia: OR = 1.097, 95% CI (0.539, 2.230), z = 0.25, p = 0.799].
Ki-67 status
The incidence of the lymphocyte-predominant breast cancer (LPBC) was significantly different between the high Ki-67 groups and the low Ki-67 groups (overall: OR = 6.378, 95% CI [3.674, 11.073], I²= 30.1%, z = 6.58, p < 0.001).
Menopausal status
The lymphocyte-predominant breast cancer (LPBC) detection rate between the premenopausal group and the postmenopausal group has not significant difference [total: OR = 0.963, 95%CI (0.716, 1.296), I²=0.0%, z = 0.25, p = 0.804]. After that, subgroup analysis were conducted on different ethnicity [Asia: OR = 1.036, 95%CI (0.629, 1.708), I²= 29.3%, z = 0.14, p = 0.888; America: OR = 0.874, 95% CI (0.571, 1.339), z = 0.62, p = 0.537].
TNM stage
The lymphocyte-predominant breast cancer (LPBC) detection rate between the III, Ⅳ group and I, II group has not significant difference [total: OR = 0.825, 95%CI (0.220, 3.095), I²= 81.4%, z = 0.29, p = 0.775]. After that, subgroup analysis were conducted on ethnicity [Europe: OR = 0.431, 95% CI (0.211, 0.881), I²=0.0%, z = 2.31, p = 0.021; Asia: OR = 1.268, 95% CI (0.684, 4.050), I²=0.0%, z = 1.12, p = 0.261]. The difference was statistically significant in the Europe group. The results of pooled analysis were summarized in Table 3.
Impact of TILs on pathological complete response (pCR)
In order to further assess the predictive effect of TILs detection in breast cancer patients with different molecular subtypes, the OR value of PCR was analyzed by meta-analysis. In this meta-analysis, we chose those studies that focused on TILs as a continuous parameter (per 10% increments). OR value of pCR were available in three studies including luminal molecular subtype breast cancer. There was no significant increase of PCR in high TILs group [OR = 1.154, 95%CI (0.789–1.690), p = 0.460]. OR value of pCR were available in seven studies including HER2 enriched molecular subtype breast cancer. The assessed pooled OR value confirmed that high TILs was correlated with a significantly increased pCR [OR = 1.137, 95%CI (1.061–1.218), p < 0.001]. OR value of pCR were available in seven studies including TNBC molecular subtype breast cancer. The estimated pooled OR value showed that high TILs was related to significantly increased pCR [OR = 1.120, 95%CI (1.061–1.182), p < 0.001]. OR value of pCR were available in nine studies including all breast cancer patients. The assessed pooled OR value confirmed that high TILs was related to significantly increased pCR [OR = 1.214, 95% CI (1.108–1.329), p < 0.001]. High quality researches (NOS score > 6) were used to perform the sensitivity analysis and the results were consistent (HER2 enriched molecular subtype breast cancer: OR = 1.133, 95%CI 1.057–1.215, P < 0.001; TNBC molecular subtype breast cancer: OR = 1.237, 95%CI 1.094–1.399, P = 0.001). But in breast cancer patients with luminal molecular subtype, estimated pooled OR value showed that high TILs was correlated with significantly increased pCR [OR = 1.298, 95% CI (1.157–1.456), p < 0.001]. Figure 2 summarized the results of the PCR assessment. The publication bias was detected by Begg’s test (Fig. 3).
Effect of TILs on prognosis (OS and DFS)
In order to further estimate the survival impact of TILs detection in breast cancer patients with different molecular subtypes, the HR value of DFS or OS was analyzed by meta-analysis. In this meta-analysis, we chose those studies that focused on TILs as a continuous parameter (per 10% increments). Four studies about luminal molecular subtype breast cancer provide HRs values of DFS. There was no significant improvement of DFS in high TILs group [HR = 0.998, 95%CI (0.977–1.019), p = 0.840]. Four studies about HER2 enriched molecular subtype breast cancer provide HRs values of DFS. The assessed pooled HRs value confirmed that high TILs was correlated with a significantly increased DFS [HR = 0.940, 95%CI (0.903–0.979), p = 0.003]. Six studies about TNBC molecular subtype breast cancer provide HRs values of DFS. The estimated pooled HRs value showed that high TILs was related to significantly increased DFS [HR = 0.907, 95%CI (0.862–0.954), p < 0.001]. Four studies about all breast cancer patients provide HRs values of DFS. The assessed pooled HRs value confirmed that high TILs was correlated with significantly increased DFS [HR = 0.988, 95%CI (0.979–0.997), p = 0.012]. High quality researches (NOS score > 6) were used to carry out the sensitivity analysis and the results were consistent (breast cancer with HER2 enriched molecular subtype: HR = 0.946, 95% CI 0.913 ~ 0.980, P = 0.002; breast cancer with TNBC molecular subtype: HR = 0.893, 95% CI 0.867 ~ 0.921, P < 0.001; breast cancer with luminal molecular subtype: HR = 0.998, 95% CI 0.977 ~ 1.019, P = 0.840). Figure 4 summarized the results of the DFS assessment. The publication bias was detected by Begg’s test. No significant publication bias was found (Fig. 5).
In addition, the HRs values of OS were obtained in four researches. The pooled analysis confirmed that the high TILs group of luminal molecular subtype breast cancer was significantly correlated with unfavorable OS [HR = 1.077, 95%CI (1.016 ~ 1.141), p = 0.012]. By contrary, the HRs values of OS were obtained in three researches about HER2 enriched molecular subtype patients. The assessed pooled HRs value showed that high TILs was related to significantly favourable OS [HR = 0.910, 95%CI (0.866–0.957), p < 0.001]. The HRs values of OS were obtained in eight researches about breast cancer with TNBC molecular subtype. The evaluated pooled HRs value indicated that high TILs was correlated with significantly favourable OS [HR = 0.869, 95%CI (0.836 ~ 0.904), p < 0.001]. The HRs values of OS were obtained in four researches about all breast cancer patients. The estimated pooled HRs value confirmed that high TILs was correlated with significantly favourable OS [HR = 1.017, 95%CI (0.983–1.052), p = 0.324]. High quality researches (NOS score > 6) were applied to conduct the sensitivity analysis and the results were consistent. Figure 6 summarized the results of the OS assessment. The publication bias was tested by Begg’s test. No significant publication bias was found (Fig. 7).