There have been several studies about the large operable or locally T3 breast cancer and its survival . However, we have little literature on comparison of survival between NAC and non-NAC groups in T3 patients. In this real world research, we found for clinical T3 patients there were more patients taking surgery as their initial therapy other than neo-adjuvant chemotherapy. The major operation is modified radical mastectomy even if they have had neoadjuvant chemotherapy. The inconsistency rate between imaging examination and histopathologic analysis has affected the following therapies. Moreover, patients with aggressive subtypes (lymph node positive, HER2 positive, HR negative) showed inferior outcome in DFS compared with these mild ones. We can witness the improvements in patients received neoadjuvant chemotherapy as there were more aggressive subtypes in NAC group.
Many researches have tried to explore whether imaging modalities such as magnetic resonance imaging, sonography, and mammography are as accurate at predicting breast tumor size as histopathologic analysis of resected tumors. However, we paid less attention to the impact of medical resources on breast cancer. Although the number of primary health-care professionals is increasing recently in China, the regional distribution of health-care doctors and medical equipment is still uneven . For example, only a small part of patients received all the imaging examinations to evaluate the dimension of tumor lesions. Most of patients would receive biopsy or surgery after a routine ultrasound examination, let alone a simple physical examination. There is no doubt that different imagings have their own characteristics and all these haves been recommended by Chinese guideline . The irrational use of imagings contributed to the high proportion of overestimation and underestimation.
In this study, we found less than 5% of patients choose breast conserving surgery neither received NAC or not, at odds with other literature. For these in non-NAC group, the low proportion of BCS is appropriate as the high burden of tumor lesion. Nevertheless, for these received NAC, it deserves further discussion as the main rationale for NAC is to down-staging the cancer. This down-staging was initially to convert inoperable patients to operable and later to increase rates of breast conservation in patients initially deemed mastectomy only candidates. However, we did not find such changes in this study. In some cases, such proportion may be appropriate, because patients with poor financial status must save precious resources to continue their costly and lasting therapies especially for these T3 breast cancer patients. Although it has been proved that breast conserving surgery plus radiotherapy is as effective as mastectomy, sometimes better, the additional high price of radiotherapy, the old fashioned aesthetic concept and the complex breast conserving technology in China all contributed to the low rate of BCS. Besides, there is no rigorous randomized clinical trials (RCT) to prove the survival benefit of BCS at present.
Although the latest guideline of American society of clinical oncology indicated no SLNB should be performed in large or locally advanced invasive breast cancers, we can also find more than 10% of patients underwent SLN, not to mention some were clinical lymph nodes positive patients. Some trials has explored the feasibility of SLNB after NAC with T0-4, N1-2, M0 patients, and has found an acceptable false negative rate (9.8%) when combined normal axillary ultrasound with more than two SLNs removed or some other methods[12, 13], it is not widely accepted by experts in China. Under such circumstance, radical lymph node dissection is deemed necessary when lymph nodes are clinically positive after NAC. However, when lymph nodes are clinically negative after NAC, although SLNB appears a reasonable compromise between axillary lymph node dissection and no surgery at all, we still encouraged more clinical trials due to the little evidence of survival to SLN alone.
Neoadjuvant chemotherapy, compared to conventional adjuvant therapy, does not seem to improve the overall survival of patients with breast cancer. Indeed, several RCTs have demonstrated similar outcomes, in terms of DFS and overall survival, between NAC and adjuvant chemotherapy in patients with breast cancer. A recent meta-analysis found NAC to be associated with a higher frequency of local recurrence than was the same chemotherapy started after surgery due to the increased BCS rates. Reassuringly, the increase in local recurrence was not associated with any significant increase in distant recurrence or breast cancer mortality, which indirectly supported the low rate of BCS in real world. As the RCTs have indicated the scientific evidence about the safety and efficacy of NAC for T3 breast cancer, we used real world evidence to investigate the survival benefit of NAC to T3 patients. In our study, there were little survival benefit gained from NAC, comparable to those in the pivotal randomized controlled trials. However, patients received NAC were more likely to have lymph node positive with aggressive subtypes (HER2-positive or hormonal receptor negative). These subtypes are the major recurrence risks for patients.
From this prospective, NACT does moderately reduce distant recurrence compared with the same chemotherapy given postoperatively. Although for all T3 breast cancer, there was no difference of EFS in NAC group and surgery group. In this study, we find in T3 breast cancer patient who had lymph node positive, HE R2 positive or HR negative tumors, NAC can also improve the survival. In multivariate analysis, Lymph node metastasis, Her2 status and neoadjuvant chemotherapy were found to be an independent poor prognostic factor of survival in the T3 breast cancer patient. As the pathological and molecular features of the primary tumor are getting more and more importance in the decision-making process, once we find T3 breast cancer patients with these risks, like lymph node positive, HER2 positive or HR negative, we will recommend neoadjuvant chemotherapy rather than surgery first.
There were several limitations in this study. First, we selected these data from 17,000 patient cases in CSCO BC database. However, this database has expanded to more than 34,000 cases now (until Jan 1, 2018). The allure of analyzing existing data may lead to flawed conclusions, and the survival benefit might be improved if data expended. Second, the regimens and courses of neoadjuvant or adjuvant therapy were not taken into consideration, which would be obscure the association between NAC and survival if different regimens were necessary to meaningfully affect long-term outcomes. Third, the incomplete data of pathologic complete remission set measures to our further exploration. The number of patients in this group were too small to draw conclusions.
The importance of NAC should be taken seriously. In next step, we will set a randomized clinical trial to compare NAC with adjuvant chemotherapy. In real world study, we will also explore the survival benefit in different molecular subtypes. Neither RCT nor RWS could be overlooked. We will combine these two methods to explore the optimal scheme to breast cancer patients.