Breast-Conserving Surgery in Triple-Negative Breast Cancer: A Retrospective Cohort Study

Objectives The aim of the study is to evaluate the efficacy and prognosis of neoadjuvant chemotherapy (NAC) combined with breast-conserving surgery (BCS) in treating triple-negative breast cancer (TNBC) and analyze the influencing factors and predictors of the efficiency and prognosis of NAC. Methods A retrospective cohort study was conducted by dividing patients into two groups according to two different therapy methods. With BCS as the exposure factor, 46 cases were assigned to the exposed group and 80 cases to the nonexposed group. We compare the difference in operation-related indicators, postoperative complications, local recurrence rate, distant metastasis rate, and overall survival (OS) rate between the two groups. The factors affecting the efficiency and prognosis of NAC were analyzed by binary logistic regression, and the optimal cutoff value was determined by the area under the ROC curve (AUC). The survival curve was plotted, and the univariate log-rank test was performed to analyze the difference in OS between the two groups. The influencing factors of OS were analyzed by the Cox risk regression model. Results NAC + BCS resulted in significantly less intraoperative blood loss, lower incidence of postoperative complications, and shorter operative time and length of hospital stay than that in NAC (P < 0.05). There was no significant difference in local recurrence, distant metastasis, or OS between the two groups (P > 0.05). Multivariate analysis showed that the clinical stage I and Ki-67 high expression were independent protective factors of the efficacy of NAC. The high expression of Ki-67 and nondecline expression of Ki-67 were independent risk factors of prognosis. Ki-67 high expression was an independent risk factor of OS (P < 0.05). The ROC curve showed that the AUC of Ki-67 for NAC efficacy, prognosis, and OS were 0.706, 0.820, and 0.687, respectively, with optimal cutoff values of 25.5%, 29.0%, and 32.5%, respectively. Survival analysis showed that the OS of patients with NAC + BCS was 73.9% and NAC + MRM was 70.0% (P > 0.05). In the low expression subgroup of Ki-67, the OS of the two groups were 100.0% and 77.8%, respectively (P=0.060). In the high expression subgroup of Ki-67, the OS of the two groups were 53.8% and 63.6%, respectively (P=0.419). Conclusions NAC + BCS is a good method for treating TNBC, which has an obvious short-term effect and a good long-term prognosis. Clinical stage I and the high expression of Ki-67 are independent protective factors for the efficacy of NAC. The high expression of Ki-67 and nondecline expression of Ki-67 are independent risk factors of prognosis. Ki-67 is a potential predictor for the efficacy, prognosis, and OS of NAC in TNBC patients. The high expression of Ki-67 indicates better NAC efficacy, a poorer prognosis, and a lower OS.


Introduction
Breast cancer is a high-incidence tumor that seriously threatens the health of women [1][2][3]. Breast cancer patients with negative results in the tests of ER, PR, and HER-2 are diagnosed with triple-negative breast cancer (TNBC), which has a poor prognosis [4][5][6]. Although TNBC has no response to conventional treatment, it is sensitive to neoadjuvant chemotherapy (NAC) and signifcantly improves the clinical beneft rate [7,8]. At present, modifed radical mastectomy (MRM) is the routine operation for operable breast cancer, but research has suggested that breast-conserving surgery (BCS) is considered the preferred strategy for early breast cancer [9]. At the present stage, the treatment of TNBC has aroused great clinical attention, and the emphasis lies on the efective improvement of treatment efciency. Evidence has revealed signifcant benefts in short-term efcacy and longterm prognosis for TNBC patients treated with NAC + BCS [10]. To this end, the present study was performed to analyze the efcacy and prognosis of NAC + BCS in treating TNBC and explore the infuencing factors and prediction indicators about the efciency and prognosis of NAC.

Research Objective.
A retrospective cohort analysis method was used to collect general clinical data of TNBC patients treated with NAC + MRM or BCS in Cangzhou Central Hospital from January, 2016, to December, 2018. All patients received biopsy to obtain the pathological tissue before treatment, and their immunohistochemical results met the diagnostic criteria for TNBC. A total of 126 patients were collected and assigned to receive either NAC + BCS (exposure group, n = 46) or NAC + MRM (nonexposure group, n = 80) by using a retrospective cohort study method with BCS as the exposure factor. Te patient characteristics between the two groups were comparable (P > 0.05) ( Table 1).
Te inclusion criteria were as follows: (1) aged 26-72; (2) patients without receiving other treatments; (3) the patient was pathologically diagnosed with breast cancer; (4) clinical stage I or II breast cancer; and (5) the diameter of single breast tumor less than 4 cm. According to the inclusion criteria, 140 cases met the inclusion criteria.
Te exclusion criteria were as follows: (1) patients with poor compliance; (2) patients who were in pregnancy or lactation; (3) patients who did not meet the diagnostic criteria of TNBC; (4) patients with poor heart, liver, and kidney function who cannot tolerate chemotherapy; (5) patients who had serious adverse reactions and change chemotherapy plan or refuse chemotherapy; (6) patients who found distant metastases before treatment; and (7) patients who had other malignant tumors. Finally, 126 patients were included.

Treatment Methods.
In this study, patients were divided into the exposed group and the nonexposed group. Patients in the exposed group received NAC + BCS, and patients in the nonexposed group received NAC + MRM. Neoadjuvant therapy: On day 1, all patients received 30 mg/m 2 of doxorubicin liposomal (A) and 80 mg/m 2 of docetaxel (T), referred to as the AT method, 21 days is one cycle, and there are 6 cycles in total. Te efect of NAC was evaluated every 2 cycles. Routine symptomatic treatment was performed during NAC. Te original chemotherapy was carried out for 4 cycles after the operation.

Immunohistochemistry.
Before and after treatment, the expression of Ki-67 was determined by immunohistochemistry (IHC), and the staining ratio of cancer cells (positive cells) was calculated. A proportion of positive cells ≥30% indicated Ki-67 had high expression and <30% indicated Ki-67 had low expression. After NAC, the Ki-67 was divided into a nondecline group (no change and increase) and decline group according to the Ki-67 expression levels.

Observation
Indicator. Te related indicators between the two groups were compared: (1) surgery-related indicators (intraoperative blood loss, operation time, and length of hospital stay); (2) postoperative complications (tissue edema, skin infection, and postoperative bleeding); and (3) local recurrence rate, distant metastasis rate, and overall survival rate (OS).

Efcacy Criteria and Evaluation.
According to the Response Evaluation Criteria for Solid Tumors Version 1.1 [11], complete response (CR): all target lesions disappeared and the diameter of lymph nodes was less than 10 mm; partial response (PR): reduction ratio of the sum of target lesions' diameters exceeds 30%; disease progression (PD): at least 20% increase or the appearance of one or more new lesions; stable disease (SD): the proportion of target lesion reduction or increase did not meet the requirements of PR and PD.
Overall survival rate (OS) was the clinical endpoint, and recurrence and metastasis were the secondary endpoints. Te curative efect was divided into the efective group (CR + PR) and the inefective group (SD + PD). Te prognosis was assessed by local recurrence and distant metastasis, and the patients were divided into a good prognosis group and a poor prognosis group.
2.6. Follow-Up. Postoperative follow-up was performed by outpatient clinics and telephone calls and terminated in December, 2021. Te follow-up was carried out once every 3 months in the frst year and once every six months after one year. Overall survival was measured from the day of cancer diagnosis to death or the cutof date. Te overall survival rate referred to the proportion of the total number of survivors by the cutof date.

Statistical
Methods. Data were statistically processed by using SPSS 25.0. Te measurement data were expressed as mean ± standard deviation and analyzed using the independent samples t-test. Te count data were expressed as rate and analyzed using the chi-square test and continuity correction method. A binary logistic regression analysis was used to analyze the independent infuencing factors about the efcacy, prognosis, and OS of NAC. Te area under the ROC curve (AUC) was used to evaluate the predictive value of Ki-67 for the efcacy, prognosis, and OS of NAC and to determine the optimal cut-of value. Te survival curve was plotted, and the diference in OS between groups was analyzed by a univariate log-rank test. Te Cox risk regression model was used to analyze the infuencing factors of OS. P < 0.05 indicated that the diference was statistically signifcant.

General Clinicopathological Features.
Te patients were aged 26-72 years, with 41 cases in <36 years, 57 cases in 36-60 years, and 28 cases >60 years. Tere were 38 cases in clinical stage I and 88 cases in stage II. Tere were 34 cases in histological grade I, 68 cases in grade II, and 24 cases in grade III. 55 cases had a tumor diameter that was less than or equal to 2 cm and 71 cases had a tumor diameter that was more than 2 cm. Ki-67 showed low expression in 56 cases and high expression in 70 cases.

Surgery-Related Indicators in the Two Groups.
NAC + BCS resulted in signifcantly less intraoperative blood loss, a lower incidence of postoperative complications, and shorter operative time and length of hospital stay without BCS, and the diference was signifcant (P < 0.05) ( Table 2).

Postoperative Complications in the Two Groups.
Te comparison of postoperative complications in the two groups and the diference was signifcant (P < 0.05) ( Table 3).

Long-Term Prognosis of the Two Groups.
Tere was no statistically signifcant diference between the two groups in local recurrence rate, distant metastasis rate, and overall survival rate (P > 0.05) ( Table 4).

Analysis of Infuencing Factors of NAC Efcacy.
Univariate analysis showed that the clinical stage and Ki-67 were both infuencing factors of NAC efcacy (P < 0.05). Multivariate analysis showed that clinical stage I and high expression of Ki-67 were independent protective factors of NAC efcacy, and the diference was signifcant (P < 0.05) ( Tables 5 and 6).

Analysis of Infuencing Factors of Prognosis and Overall
Survival Rate. Univariate analysis showed that clinical stage, tumor size, Ki-67, and Ki-67 alterations were infuencing factors of prognosis, and tumor size, Ki-67, and Ki-67 changes were infuencing factors of OS (P < 0.05). Multivariate analysis showed that the high expression of Ki-67 and nondecline expression of Ki-67 were independent risk factors of prognosis. Te Cox risk regression model showed that only high expression of Ki-67 was an independent risk factor for OS, and the diference was signifcant (P < 0.05) (Tables 7-9). Te ROC curve showed that the AUC of Ki-67 for evaluating the efcacy of NAC was 0.706 (95% CI: 0.612-0.801), the optimal cutof value was 25.5%, the sensitivity was 76.5%, and the specifcity was 62.2% ( Figure 1).

Survival
Analysis. Survival analysis showed that as of December, 2021, the median follow-up time was 49 months; there were 23 cases of local recurrence, 27 cases of distant metastasis, and 36 cases of death. Te overall survival time was 27-72 months, and the overall survival rate was 71.4%. Te OS of the two groups was 73.9% and 70.0%, respectively (χ 2 � 0.369, P > 0.05). As Ki-67 was an independent infuencing factor of OS, a single-factor hierarchical analysis was performed. In the low expression subgroup of Ki-67, the OS of the two groups were 100.0% and 77.8% (χ 2 � 3.529, P � 0.060). In the high expression subgroup of Ki-67, the OS of the two groups were 53.8% and 63.6% (χ 2 � 0.653, P � 0.419). (Figures 4-6).

Discussion
TNBC, which accounts for 10%-20% of breast cancer, is insensitive to conventional local treatment and has a poor prognosis [12]. Research has shown that NAC based on anthracyclines combined with taxanes has a favorable overall response and demonstrates good potential as an efective treatment strategy for breast cancer [13]. NAC can efectively improve the therapeutic efect of TNBC [7,8]. Breastconserving surgery is the preferred scheme for early breast cancer [9]. Te author will discuss the following 5 aspects and summarize the full text.

Analysis of Short-Term Efcacy and Long-Term Prognosis
in the Two Groups. Our study found that the exposed Evidence-Based Complementary and Alternative Medicine group was superior to the nonexposed group in terms of surgical indicators and postoperative complications, indicating that NAC can provide a good material basis for surgery, reduce the risk of postoperative complications, and improve the efcacy of BCS. Our study found that the long-term prognosis of the exposed group was slightly better than that of the exposed group (P > 0.05), but TNBC patients who had received the BCS regimen achieved a higher clinical beneft rate. For operable patients, NAC + BCS is safe and feasible [14]. Terefore, NAC + BCS can efectively improve the clinical beneft rate of TNBC patients.      [15][16][17], which is consistent with the results of our study. Our study found that the high expression of Ki-67 and nondecline expression of Ki-67 were both independent risk factors for the prognosis of TNBC. Studies have revealed that high expression of Ki67 in residual lesions of locally advanced breast cancer after surgery was associated with poor recurrence-free survival (P � 0.004) and decreased Ki67 expression (the degree of reduction is greater than 12.5%) after NAC was associated with longer recurrence-free survival (P � 0.007) [18]. Our study also identifed high expression of Ki-67 as an independent risk factor for OS. It has been reported that high expression of Ki-67 in TNBC patients is associated with low OS [19]. Tus, our study concluded that Ki-67 expression was related to the efcacy, prognosis, and OS of NAC, and TNBC patients with high expression of Ki-67 were predisposed to good NAC efcacy but poor long-term prognosis.

Te Predictive Value of Ki-67 for NAC Efcacy, Prognosis, and OS.
Our study found that Ki-67 had a certain predictive potential for the efcacy, prognosis, and OS of NAC, and the high expression of Ki-67 might suggest better efcacy, a worse prognosis, and a lower OS of NAC.   It has been shown that the high expression of Ki-67 could predict a poor long-term prognosis [19] and better efcacy of NAC [20], which is consistent with the results of our study. Terefore, we believe that Ki-67 may act as a predictor of efcacy and long-term prognosis of NAC in TNBC patients.

Survival Analysis of Ki-67 Expression Subgroup.
Our study found that the diference in OS between the two groups was not statistically signifcant, but Ki-67 was an independent infuencing factor of OS. Univariate stratifed analysis found that in the low expression subgroup of Ki-67, the OS of the two groups were 100.0% and 77.8%, respectively, and in the high expression subgroup of Ki-67, the OS of the two groups were 53.8% and 63.6%, respectively. Terefore, our study considers that TNBC patients with a low expression subgroup of Ki-67 have a higher OS and may beneft from breast-conserving surgery; however, TNBC patients with a high expression subgroup of Ki-67 have a lower OS, and they are not suitable for breastconserving surgery.

Limitation.
Compared with prospective cohort studies, the limitations of the current study include the small sample size, short follow-up, and data bias. Terefore, more rigorous prospective studies will be carried out to further verify the results of our study.

Group
Exposure group Non-exposed group Exposure group -after culling Non-exposed group -after culling

Conclusions
NAC combined with BCS is a promising regimen for the treatment of TNBC, providing favorable short-term therapeutic benefts, an enhanced prognosis, and an improved OS. Clinical stage I and the high expression of Ki-67 are independent protective factors for the efcacy of NAC. Te high expression of Ki-67 and nondecline expression of Ki-67 are independent risk factors of prognosis. Ki-67 is a potential predictor of NAC efcacy, prognosis, and OS in TNBC patients. Te high expression of Ki-67 indicates better NAC efcacy, a poorer prognosis, and a lower OS.

Consent
All patients signed an informed consent.

Data Availability
Te datasets of this study are available from the frst author upon reasonable request.

Ethical Approval
Tis study complies with the Declaration of Helsinki, which was approved by the Ethics Committee of Cangzhou Central Hospital.

Conflicts of Interest
Te authors declare that they have no conficts of interest.

Authors' Contributions
Conceptualization, data collection and analysis, and interpretation of results were done by Hengle Zhang; he also wrote, reviewed and edited the article. Data collection, result analysis-review, and editing was carried out by Zunyi Wang. Wei Liu carried out the analysis and interpretation of results-review and editing. Peng Wang conducted the analysis and interpretation of results-review and editing. Xiaoyu Zhang carried out the analysis and interpretation of results, supervision, and project management-review and editing. All authors reviewed the results and approved the fnal version of the manuscript.

Group
Exposure group Non-exposed group Exposure group -after culling Non-exposed group -after culling   Exposure group Non-exposed group Exposure group -after culling Non-exposed group -after culling Evidence-Based Complementary and Alternative Medicine 7