Neoadjuvant Chemotherapy in Breast Cancer: A Real-World Practice with Multiple Disciplinary Team in Southern China

Material and Methods: Consecutive patients with locally advanced invasive breast cancers who were advised to receive NACT by MDT between 2014 to 2020 were enrolled in this study. Clinic factors were collected retrospectively, as well as compliance of NACT, reasons of noncompliance and outcomes of treatment. A forest plot was presented to summarize the odds ratios of various factors to predict pathological complete response rate (pCR) by univariate logistic analysis. The EFS was calculated by Kaplan–Meier curve and compared by Log-rank test.


Introduction
Neoadjuvant chemotherapy (NACT) is generally recommended for patients with locally advanced breast cancer which are inoperable, or for operable patients who wish to have breastconserving surgery. Based on the current prospective randomized data of 3,946 patients with operable breast cancer, survival rates and disease progression are equivalent for NACT compared to upfront surgery, regardless of histology type [1]. However, the impacts of these two options are different. Some patients may value NACT due to a higher chance of breast conserving surgery rather than mastectomy [2], or make the inoperable advanced tumor become operable [3]. NACT allows a better understanding of tumor response and biology. It can also provide important prognostic information [1,4] and relieve patients' anxiety associated with their cancer [5,6]. Patients with pathological complete response (pCR) had higher DCR (disease control rate) and OS (overall survival) benefits, especially those with triple negative or Human epidermal growth factor receptor 2 (HER2)-positive breast cancer [7][8][9][10].
One study also found the greater the residual cancer burden, the worse the prognosis [11]. In addition, for those patients who had residual tumor after NACT, it may be helpful to determine whether intensive adjuvant therapy or clinical trials should be performed to improve survivals [12,13]. However, if patients can't accept or complete the recommended chemotherapy which can reduce the risk of recurrence and mortality, they can't get any benefits from above evidence either. As we known, compliance with neoadjuvant chemotherapy was carefully monitored and the compliance was usually high in prospective, randomized clinical trials [14][15][16].
However, there is few study to explore patient's compliance to NACT recommended by physicians in real world practice. The compliance to chemotherapy is suboptimal in real world as one study had showed the acceptance and use of adjuvant chemotherapy was as low as 63% [17]. Although NACT might improve patient's compliance compared with adjuvant chemotherapy [18], there remains lots of work to be done to improve patient's compliance.
It is recommended that NACT should be managed by Multiple Disciplinary Team (MDT). However, this treatment strategy is relatively new in China and level of MDT application and NACT acceptance varies in different hospitals. The current retrospective study aimed to evaluate the compliance and outcomes of NACT in real-world practice with the support of Multidisciplinary Team (MDT) in a hospital of Southern China.

Study Population
Review all 251 chart records of MDT on consecutive patients with breast cancers who were advised to receive NACT between July 2014 to July 2020 in the University of Hong Kong-Shenzhen Hospital. MDT comprises of surgeons, pathologists, radiologists, clinical oncologists and nurses. It is held regularly on Wednesday in this hospital and all patients who plan to receive surgery or have received surgery would be regularly recorded after MDT. Criteria of recommending NACT in the University of Hong Kong-Shenzhen Hospital include: patients with pathology confirmed invasive breast cancer, aged 18-year old and above, tumor size more than 2cm (T2 or above) HER2 positive or triple negative breast cancer, clinical axillary node positive or T3/T4 for all disease subtypes. Recurrent or stage IV breast cancer were excluded in this study. During the period of NACT, physical examination was recommended before each cycle of chemotherapy and radiological assessment were arranged at the beginning and end of chemotherapy according to our MDT guideline.

Data Collection
Following information of patients were retrospectively collected:

Outcome Measures
The primary endpoints were compliance of neoadjuvant chemotherapy and pCR. The secondary endpoints were EFS (Eventfree survival) and ORR (Objective response rate). The definition of pCR was absence of residual invasive cancer in the breast and lymph nodes, irrespective of ductal carcinoma in situ (ypT0/is ypN0). EFS was defined as the interval from the beginning of NACT to disease progression, including local progression before surgery or disease recurrence (local, regional, distant) after surgery, or death from any cause. Patients alive without an event as of the analysis cutoff date were censored at last follow-up date.

Statistical Analysis
The EFS was calculated by Kaplan-Meier curve, and compared by Log-rank test. We presented a forest plot to summarize the odds ratios of patient, tumor and treatment factors in subgroups to predict pCR by univariate logistic analysis. Cox regression models was performed to estimated hazard ratios (HRs) and 95% CIs of EFS from stratified with study as a stratification factor. Statistical analysis was performed using R software (version 3.6.2; https:// www.R-project.org). All P values were two-sided and statistical significance was set at P<0.05. All confidence intervals (CIs) were stated at the 95% confidence level.

Characteristics of patients, tumors and treatments at baseline
A total of 135 patients with local advanced breast cancer were recommended of NACT between July 2014 to July 2020 in the University of Hong Kong-Shenzhen Hospital and 128 patients received NACT ( Figure 1).   ddAC-P: Dose-dense doxorubicin/cyclophosphamide followed by paclitaxel every 2 weeks; ddAC*4-P weekly: Dose-dense doxorubicin/cyclophosphamide*4 cycles followed by weekly paclitaxel *12 cycles; AC-D:   The EFS benefits can also be observed in all subtypes excepted for HR-positive and HER2-positive patients which probably due to small study sample. As Table 2

Discussion
There Although the benefit of compliance with NACT in breast cancer has not been previously reported in large study, 5-year local recurrence rate doubled in patients who didn't accept chemotherapy in a study of rectal cancer compared with those accepted chemotherapy [21].  [14]. Among HER2-positive breast cancer, pCR rate of HR-negative subgroup was the highest, which was consistent with the results of other studies [14,15,[24][25][26].
pCR for triple negative breast cancer was 32.1% in this study while it ranged from 22% to 52.1% in clinic trails [10,27,28]. The rate of pCR in patients with HR-positive/HER2-negative breast cancer was the lowest of all subtypes, which was similar with the result (7.5-16.2%) of a pooled analysis [7]. 3 year EFS in this study trended to be better in patients with pCR than those with non-pCR, which was consistent with results of several studies [7][8][9][10]. Since patients with optimal response to NACT had better compliance and improved survival benefits, NACT is more recommended for patients with triple negative and HER2-positive breast cancer, or those with ki67≥30%, except for the need of BCT or better surgery in some local advanced HR-positive/HER2-negative breast cancer.
The limitation of the study includes the nature of a retrospective study, presence of confounding factors and lower compliance rate than rigorously designed clinical trials. However, the study carries significant findings as it can reflect regional real world practice and every patient was regularly recorded after MDT. Secondly, survival data was not mature in this study with inadequate study population. Further research of larger sample and longer followup is needed to validate our findings, help us better perform neoadjuvant chemotherapy and improve long term survival of breast cancer patients.

Conclusion
There was a high compliance rate of neoadjuvant chemotherapy (NACT) with the support of MDT in Southern China. NACT should be managed by MDT to improve both treatment compliance and quality. NACT is more favorable for patients with triple negative and HER2-positive breast cancer or with higher ki67 since they had higher pathological complete response rates, compared to HRpositive/HER2-negative breast cancer.