Neoadjuvant chemotherapy, as one of the commonly used tools in the comprehensive treatment of breast cancer, is increasingly used, especially for patients with locally advanced breast cancer. There is a more consistent view that neoadjuvant chemotherapy leads to lower tumor staging and increases the chance of breast conservation, and although there is no significant difference in disease-free survival and overall survival between neoadjuvant and postoperative adjuvant chemotherapy, patients who achieve pCR in neoadjuvant chemotherapy have significantly longer DFS and OS. Another advantage of neoadjuvant chemotherapy can test the sensitivity of new drugs in vivo and drive the development of new drugs for research and clinical trials. With the development of new clinical trials, some of the problems have been solved, but at the same time, new problems have been introduced, which we will expand one by one in the following. I. Program and course of neoadjuvant chemotherapy The program and the number of courses of neoadjuvant chemotherapy are not strictly defined. Generally, the programs currently used for adjuvant chemotherapy can be given as neoadjuvant chemotherapy programs before surgery, and the number and duration of courses vary with different program choices. The Neo-tAnGo study evaluated the efficacy and safety of adding gemcitabine to paclitaxel, epirubicin, and cyclophosphamide therapy and showed that adding gemcitabine did not increase pCR (pCR rate of 17% in both groups). patients, after 2 courses of neoadjuvant chemotherapy with TAC regimen, with different strategies depending on the efficacy. If patients achieved CR/PR (those who were effective), they were randomized to an additional 4 or 6 courses of TAC regimen. If the efficacy was SD (nullifiers), the patients were randomly grouped to give 4 courses of TAC regimen or 4 courses of NX (vincristine + capecitabine). The results showed no difference in pCR between 6 and 8 courses of the TAC regimen, but there was a trend towards a significant prolongation of DFS in patients on the TAC x 8 regimen (HR=0.76, p=0.061). Similarly, for patients who were ineffective, there was no difference in pCR for either continuing TAC or switching to NX, but there was also a significant prolongation of patient DFS for TACx 2-NX x 4 compared to TACx 6 (HR=0.6, p=0.001), with a non-significant difference in OS. Patients with an efficacy-guided treatment strategy (TACx 8 or TAC x 2-NX x 4) had a longer DFS (HR=0.71, p<0.001) and OS (HR=0.79, p=0.048) compared to patients receiving TACx 6. Thus, the implication of this clinical trial is that adapting the chemotherapy regimen to the response to neoadjuvant chemotherapy can help improve DFS and OS in patients and truly take advantage of the "in vivo drug testing" aspect of neoadjuvant chemotherapy. Similarly, in this study, the efficacy of neoadjuvant chemotherapy was further analyzed according to breast cancer phenotype, and the benefit in DFS was mainly in the LuminalA (p=0.003) and LuminalB (HER2 negative, p=0.006; HER2 positive, p=0.04) subtypes. In contrast, for patients with both HER2-positive p=1.0) and triple-negative (p=0.5) subtypes, no additional benefit in DFS was seen by adjusting the regimen according to efficacy. In contrast, for these two subtypes, as well as for the LuminalB (HER2-negative) type, DFS was prolonged in patients who obtained a pCR. Therefore, it also gives us more food for thought that the significance of PCR may be different in different subtypes in terms of predicting the sensitivity of the regimen and whether it improves survival, and cannot be generalized. II. Triple-negative breast cancer We call patients who are negative for ER, PR and HER2 by immunohistochemistry as triple-negative breast cancer, which has a great overlap with basal cell-like breast cancer. Current clinical data show that triple-negative breast cancer is more aggressive, more common in young patients, with poorer prognosis, and also more frequent mutations in the BRCA1 gene. Currently, chemotherapy and surgery are the main therapeutic tools because of the lack of therapeutic targets. In neoadjuvant chemotherapy, Liedtke et al. found a higher pCR rate in triple-negative patients than in non-triple-negative patients and a significant improvement in overall survival in patients with PCR. Therefore, pCR has become a goal to pursue in neoadjuvant chemotherapy studies for triple-negative breast cancer. Triple-negative breast cancers tend to have more {mutations in the BRCA1 gene and may have defects in DNA repair pathways, and thus may be more {sensitive to drugs that interfere with double-stranded linkage, such as platinum, PRPA inhibitors, etc. In the Silver et al. study of 28 stage II?III TNBCs using four courses of single-agent cisplatin as a neoadjuvant chemotherapy regimen, it was found that more than In a study of 28 patients with stage II?III TNBC using four courses of single-agent cisplatin as neoadjuvant chemotherapy, it was found that more than 20% of patients achieved pCR and 50% had an efficacious response. In addition, the German Breast Study Group recently reported a phase II neoadjuvant study (GeparSxito trial) that showed a significantly higher pCR rate with the addition of carboplatin to neoadjuvant chemotherapy compared with no addition (58.7% versus 37.9%, p<0.05). And in 2013 sabcs two other studies calgb40603 and i-spy trial also both showed that the addition of carboplatin to neoadjuvant chemotherapy regimens improved the pcr of patients. this evidence raises new questions about whether platinum-containing chemotherapy regimens may become the standard of care in the treatment of tnbc patients. < span=""> For targeted anti-angiogenic therapy in advanced breast cancer showing a high remission rate in TNBC, it has been explored accordingly in neoadjuvant trials, with a significant difference in pCR rates from 27.9% to 39.3% in the GeparQuito trial comparing the addition of bevacizumab to chemotherapy in EC-T. Similarly in the CALGC40603 trial, an increase in the pCR rate of breast lesions was observed with the addition of bevacizumab to TNBC. However, it remains to be further verified in adjuvant clinical trials whether the final improvement in PCR translates into improved survival. HER2-positive breast cancer Several randomized trials (phase II and III) have explored the efficacy of adding trastuzumab to neoadjuvant chemotherapy for HER2-positive breast cancer and consistently concluded that the pCR was significantly improved with the addition of trastuzumab to neoadjuvant chemotherapy (26% to 65%) compared to without trastuzumab (19% to 27%). However, despite the improved pCR, a significant proportion of patients did not achieve PCR, and among the pCR patients, there was still a certain risk of recurrence or metastasis. Therefore, trastuzumab resistance is a major problem in HER2 overexpressing breast cancer patients, and dual pathway blockade may be one of the strategies to overcome resistance. Five new randomized clinical trials have compared the combination of anti-HER2 agents, among which in the NeoALLTO trial, the results showed higher pCR rates in the breast and axilla in the combination of paclitaxel and dual-targeted inhibition group (46.8%, trastuzumab, lapatinib) than in the paclitaxel combined with trastuzumab group (27.6%, P=0.0007). Two other studies with smaller samples also reported higher pCR rates with dual-targeted inhibition (trastuzumab combined with lapatinib than trastuzumab alone, 74% vs. 47%). In another study, the NSABPB41 trial, AC-P combined with trastuzumab (pCR of 52.5%) or lapatinib (PCR of 53.2%), and trastuzumab + lapatinib group ((PCR of 62.0%) with a similar trend of improved PCR (p=0.095). A new targeted agent, patuximab, has also been tested in neoadjuvant chemotherapy in a small way. Neosphere (- a randomized phase II clinical trial) compared the efficacy of chemotherapy combined with dual-targeted inhibition (trastuzumab and patuximab) with chemotherapy combined with trastuzumab and showed that chemotherapy The results showed that the pCR rate was significantly improved with chemotherapy combined with dual-targeted inhibition compared to chemotherapy combined with single-targeted trastuzumab (39.3% vs. 21.5%, P=0.0063). The other finding of this trial was that the pCR rate was only 11.2% in patients treated with dual HER2-targeted therapy alone. Based on these clinical trials, the efficacy of chemotherapy in combination with dual-targeted therapy in neoadjuvant studies is realistic and the regimen is feasible. Fourth, whether the pCR improvement can eventually be translated into the improvement of survival In neoadjuvant chemotherapy, we are accustomed to pCR as the goal to pursue, so whether the improvement of PCR can eventually be translated into the improvement of disease survival. A review of these clinical trials reveals that the definition of pCR varies, and Von Minckwitz summarized an analysis of different pCRs and outcomes in 6300 patients treated with neoadjuvant chemotherapy containing anthracyclines and paclitaxel. The results showed that PCR defined as the absence of invasive and intraductal cancer residuals in both breast and axilla is a more appropriate definition and can better differentiate the prognosis. At the same time, this study showed that in luminalA (ER/PR-positive and HER2-negative) was the least reached population, and in this subgroup, PCR did not correlate with prognosis. pCR was not a surrogate indicator of survival in luminalB/HER2-positive and luminalA patients. The results of the ALLTO clinical trial, reported at ASCO 2014, showed that the combination of trastuzumab and lapatinib was not superior to trastuzumab alone in adjuvant therapy (4-year DFS 88% and 86%, respectively, P=0.048), whereas the improved pCR rate we observed in the NeoALLTO trial with the combination was not ultimately shown to be a more This may require further observation at longer follow-up. Similarly, in advanced and neoadjuvant chemotherapy, the addition of bevacizumab improved the efficacy, but did not show a survival benefit in adjuvant therapy. Theoretically, neoadjuvant chemotherapy or late-stage rescue therapy targets macroscopic lesions, whereas adjuvant chemotherapy targets micrometastases, the mechanisms of drug action, microenvironment and immune status of the body may not be identical. Therefore, in the complicated process of tumor treatment, understanding tumor biological behavior may be a more worthy direction for us to explore. The tumor microenvironment and its biological behavior may be different under different treatment modes, at different time periods and even at different sites, which requires further analysis and research to find out the intrinsic rules and different biological markers of susceptibility, and ultimately provide ideas for truly individualized neoadjuvant therapy.