In total, 232 patients (22.2%) achieved pCR. Multivariate analysis indicated that clinical T stage, clinical N stage, and molecular subtype were independent predictors to pCR. A total of 90 patients (8.6%) developed LRR of which 9 were in the pCR group and 81 were in the non-pCR group. Our study confirmed that pCR after NAC provided better local control in all subtypes of breast cancer. The result was in line with the findings of our previous report published in 2018, in which no LRR occurred in the pCR group and 31 patients (13.2%) in the non-pCR group with significant difference in total 263 patients all receiving neoadjuvant weekly epirubicin and docetaxel regimens. One of the aims of this study was to enroll patients with all different subtypes of the same indication to avoid patient bias. Trastuzumab was included as a neoadjuvant treatment in 2010 in our institution. Our study revealed that 232 patients (22.2%) achieved pCR among the 1047 patients underwent while the BCS rate is 41% and the rest of patients received mastectomy (59%). Overall, 240 patients experienced tumor recurrence (22.9%).
Although CTNeoBC pooled analysis did not validate pCR as a surrogate endpoint for an improved event-free survival or overall survival in all breast cancer subtypes, pCR was a suitable surrogate endpoint for selected patients in aggressive subtypes. A recent comprehensive meta-analysis concluded that pCR followed by NAC was associated with significantly better event-free survival (EFS) and overall survival (OS), especially for patients with triple-negative and HER2 + breast cancer. The tumor response effect observed in the pCR group was similar in adjuvant chemotherapy and NAC patients. Moreover, data from the combined analysis of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 and B-27 showed that the residual tumor status was an independent predictor of LRR in all patients at the 10 year follow-up, regardless of surgery type. Another large analysis of the European Organisation for Research and Treatment of Cancer (EORTC) 10994/BIG 1 − 00 study of patients with locally advanced breast cancer receiving NAC showed that pCR was a favorable factor with regards to the prediction of LRR after NAC. Several retrospective series also demonstrated that achieving pCR after NAC can result in better local control following surgery[1–2, 17–18]. Therefore, achieving pCR was an important factor not only for distant disease control but also for local control.
The results from the EORTC 10994/BIG 1 − 00 study of patients with locally advanced breast cancer receiving NAC showed that breast cancer subtypes, including HER2 + with or without trastuzumab and triple-negative, are predictive factors for high LRR after NAC. Yang et al. reported that 233 patients with stage II–III disease who were treated with NAC, mastectomy, and post-mastectomy radiotherapy had an 8% LRR rate over 5 years with a median follow-up of 62 months. The authors concluded that patients with triple-negative breast cancer had the highest LRR rate and those with HR + and HER2 + breast cancer had favorable LRR rates, regardless of NAC response. In other several retrospective studies, molecular subtypes including HER2 + and triple-negative also showed poor LRR in BCS patients[1, 2]. In our study, HR-/HER2 + and HR-/HER2- subtypes were found independent significant factors for the prediction of LRR, regardless of treatment response.
The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) recently reported that NAC was associated with more frequent local recurrence than that of adjuvant chemotherapy. The 15-year local recurrence rate was reported to be 21.4% for NACT compared with 15.9% for adjuvant chemotherapy from a meta-analysis of individual patient data from 10 randomized trials with average 9 years of follow-up. The study group also found that patients who underwent NAC had an increased frequency of breast-conserving therapy (65%) versus those treated with adjuvant chemotherapy (49%). The largest difference of LRR appeared in planned mastectomy patients and surgery less commonly used patients. The authors concluded tumors downsized by NAC might have higher local recurrence after BCS than tumors of the same dimensions in women who did not undergo NAC. Furthermore, the majority of patients only received anthracycline-based chemotherapy and final enrollment of patients occurred in 2002. Previous reports from the NSABP B27 trial showed that anthracycline-based regimens with the addition of taxane were associated with increased pCR rates and better local control. Moreover, neoadjuvant chemotherapy plus trastuzumab was shown to be a predictor factor for favorable long-term survival but trastuzumab cannot be used before 2002. In our studies, the majority of patients received anthracycline-based regimens combined with taxane-based chemotherapy and every patient underwent appropriate surgery. The results from the combined analysis of NSABP B-18 and B-27 showed that the 10-year cumulative incidence of LRR was 12.3% for mastectomy patients and 10.3% for lumpectomy plus breast radiotherapy patients, indicating no difference between the mastectomy and BCS groups after NAC. There was no significant difference in LRR between the BCS and mastectomy groups in the I-SPY trial, despite the fact that the BCS group on average had lower clinical staging. Importantly, a higher rate of breast conservation would not increase the incidence of LRR, which was also confirmed by the NSABP B-18 and the EORTC studies[22–23]. In another pooled analysis of 5500 women, the mastectomy rate was found to be lower in the NAC group than in the adjuvant chemotherapy group, without hampering local control. In our report, 615 (58.7%) patients chose mastectomy, while 432 (41.3%) received BCS. However, the choice of surgery types did not affect the LRR rate—8.9% in mastectomy patients and 8.1% in BCS patients in the total population.
Subgroup analysis revealed 35 cases of LRR (14.3%) following BCS, in which 4.3% achieved pCR group. Further investigation according to the molecular subtype showed that in the BCS group, HR-/HER2 + non-pCR patients had significantly increased LRR than HR-/HER2 + pCR patients and that HR-/HER2-non-pCR patients had a significantly increased LRR than HR-/HER2-pCR patients. In the mastectomy group, an increasing trend with regards to the risk of LRR in the non-pCR group was observed, but this was not significant. Caudle et al. reported that 595 patients with HR-/HER2 + and HR-/HER2- subtypes with a poor response to NAC had worse LRR-free survival after BCS. Furthermore, the authors noted that patients with HR+/HER2- and HR+/HER2 + subtypes had excellent LRR-free survival, regardless of tumor response to neoadjuvant chemotherapy. Another study group from Korea revealed HR-/HER2- subtypes and HER2 + without trastuzumab subtypes predicted higher rates of LRR after NAC and BCT, while A pCR was predictive of improved LRR in HR-/HER2- subtype. Moreover, the I-SPY 1 Trial reported that the 5-year local recurrence risk was 0% for mastectomy and 9% for breast conservation in patients with an excellent response to NAC while the local recurrence rate was 12% for mastectomy and 7% for breast conservation in significant residual disease . Another critical point was the resection area of operation after NAC. In patients who undergo NAC in order to achieve breast-tumor downstaging to enable BCS, the tumor site should be marked with a clip before initiating NAC, and resection of the entire volume of breast tissue originally occupied by tumor is not necessary. However, the difference of resection area influencing local recurrence was still unknown in neoadjuvant setting. Local control appeared to be worse in HR-subtype non-pCR BCS patients after NAC in our study, but the effect on overall survival remains unknown. Further investigation is needed to determine survival outcomes.