TNBC is an aggressive form of breast cancer which is highly invasive and prone to recurrence and metastasis. Therefore, using NACT as early as possible to suppress tumor development and eliminate micrometastasis may have better survival benefits than ACT. We analyzed 36480 patients in 9 studies and concluded that for TNBC patients, the OS of ACT was higher than that of NACT and there was no significant difference in DFS between them.Compared with ACT,patients with RD following NACT had worse OS and DFS,while those who achieved pCR had a better OS and DFS.
The NSABP B-18, EORTC 10902, and IBBGS, three large randomized trials estimating NACT and ACT revealed that there was no significant difference in survival between NACT and ACT[22–24]. However, It did not differentiate breast cancer molecular subtypes and it represent a heterogenous group of patients with multiple tumor subtypes. The results of the our study is unique to the TNBC subtype.In our analysis, Compared with NACT, ACT shows the advantage of survival.This may be related to the fact that patients having severe disease were more likely to receive NACT. Our studies have shown that patients undergoing NACT have increased tumor size, nodal positivity, and advanced clinical stage compared to patients receiving ACT[13, 14, 16]. The worse outcome may partly caused by the biology of disease in patients undergoing NACT. Although in the multivariate model, they try to control these factors that may affect the survival results, but we do not exclude some factors that are not included in the model but can still interfere with the choice of NACT or ACT, so it is still noteworthy. Another reason for lower OS for patients with TNBC undergoing NACT can be explained by a ‘‘delay effect’’[14]. TNBCs demonstrates a higher metastatic potential with an increased risk of bone metastasis and central nervous system metastases compared with non-TNBCs[25–27]. NACT does not remove tumors for the first time as surgery does. Leaving the possibility of primary tumors and / or axillary metastases. May cause systemic metastasis of the tumor. Therefore, the observed survival benefit of ACT in our study may be as a result of earlier tumor debulking, decreased opportunity for systemic tumor seeding and systemic micro-metastases.
Same as our study,most studies have confirmed that patients with TNBC have a better prognosis after achieving pCR in NACT[7, 28].Although patients who received NACT may have more serious diseases, we still found that NACT with pCR significantly improved survival. This suggest that in our study, compared with all patients receiving NACT, the survival advantage of ACT is determined by the part of patients with residual disease after NACT. In our meta-analysis, the pCR rate is 35% (95% CI = 0.23–0.48; P < 0.01) (Fig. 2). In these studies, patients with early stage, small tumor and negative lymph node are more likely to obtain pCR. Only the study by Clifton showed a pCR rate of 54% with all the rest of the studies having pCR rate below 50%. Therefore, the high rate of RD is associated with a poor survival rate of NACT.
In our study, there is no statistically significant difference in the DFS between the ACT and ACT arms. It’s different to other study. A study involving 4,756 breast cancer patients showed that women who received NACT had higher local recurrence rates within 15 years (21.4% vs 15.9%) than women who received ACT, and the risks were significantly different ( RR 1.37; 95% CI = 1.17–1.61;P = 0.0001)[29]. Among them, the risk increased significantly after 0–4 years (RR 1.35; 95% CI = 1.11–1.64) and 5–9 years (RR = 1.53; 95% CI = 1.08–2.17). Women who received NACT in their study were more likely to take breast-conserving treatments than women who received ACT (65% vs 49%) .The higher rate of breast-conserving surgery after NACT may lead to a significantly higher risk of local recurrence. Mauri validated this by conducted a meta-analysis of 9 randomized trials involving 3,946 patients, the results show that the local recurrence risk of the NACT group is significantly higher than that of ACT group due to the higher breast-conserving surgery rate in NACT(RR = 1. 22; 95% CI = 1. 04 − 1. 43; P = 0. 018)[30]. This may be related to the disunity of tumor regression model after NACT, the difficulty of tumor localization, and the increased difficulty of breast-conserving surgery [31, 32].But in our study, there was no significant difference between NACT and ACT in breast conserving surgery rate (RR = 0.84; 95% CI = 0.57–1.23; P = 0.37)(Fig. 3).This can be used to explain why our study has different results from other studies.
This meta-analysis has some limitations. One of the limitations is that 8 of the 9 studies we included analyzed the overall survival benefits of TNM stage I-III patients without distinguishing the early and late stages of the disease, so our analysis could not compare the survival benefits according to different stages of the disease.As proved in this study, TNBC with negative lymph node, small tumor and early stage is more likely to get pCR in NACT. The poor survival benefit of NACT compared with ACT is determined by patients with RD. If all patients were restricted to the early stage of disease, we speculated that it might be possible to obtain a higher pCR rate and a better survival benefit for NACT compared to ACT. Despite this limitation, our study also concluded that NACT with pCR can significantly improved survival in TNBC. It gives us some hints and thoughts, such as how to screen out the patients with TNBC who may achieve pCR with NACT to improve survival. In addition, The HR and 95% CI extracted from the survival curves may be less reliable than those directly obtained from the articles.