
==== Front
J Breast Cancer
J Breast Cancer
JBC
Journal of Breast Cancer
1738-6756
2092-9900
Korean Breast Cancer Society

39069782
10.4048/jbc.2024.0084
Original Article
Effect of Interval Between Neoadjuvant Chemotherapy and Surgery on Oncological Outcomes in Poor Responders With Locally Advanced Breast Cancer
https://orcid.org/0009-0006-7142-3512
Long Man 1*
https://orcid.org/0000-0003-2323-9471
Li Chunxia 2*
https://orcid.org/0009-0002-7298-5841
Mao Keyu 1*
https://orcid.org/0000-0001-5703-0874
Li Zhenhui 1
https://orcid.org/0000-0001-9395-8004
Li Zhen 3
https://orcid.org/0009-0009-5430-4468
Dong Guili 1
https://orcid.org/0000-0003-3364-8324
Zheng Xia 1
https://orcid.org/0009-0000-1230-1327
Gao Songliang 1
https://orcid.org/0000-0001-8327-5904
Li Zhuolin 1
https://orcid.org/0000-0002-2489-8842
Yang Guangjun 1
https://orcid.org/0009-0005-5027-5816
Xie Yu 1
1 Department of Radiology, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Kunming, China.
2 Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China.
3 Third Department of Breast Surgery, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Kunming, China.
Correspondence to Yu Xie. Department of Radiology, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Kunming No. 519 Kunzhou Road, Xishan District, Kunming 650118, China. xieyu@kmmu.edu.cn
Correspondence to Guangjun Yang. Department of Radiology, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Kunming No. 519 Kunzhou Road, Xishan District, Kunming 650118, China. yangguangjun@kmmu.edu.cn
*These authors contributed equally to this work.

8 2024
22 7 2024
27 4 270280
04 4 2024
27 5 2024
15 7 2024
© 2024 Korean Breast Cancer Society
2024
Korean Breast Cancer Society
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Purpose

The interval between neoadjuvant chemotherapy (NAC) and surgery for locally advanced breast cancer (LABC) remains controversial. At the same time, the prognostic effect of delayed surgery in patients with poor responses is currently unclear.

Methods

Data was collected from patients who had poor responses to NAC and underwent modified radical surgery from January 2013 to December 2018. The interval from completion of NAC to surgery was divided into two groups: a longer (greater than four weeks) or shorter (four weeks or less) interval. The associations of these interval groups with overall survival (OS) and recurrence-free survival (RFS) were evaluated by multivariable Cox models adjusting for the existing prognostic factors. Propensity score matching (PSM) was used to minimize election bias.

Results

A total of 1,229 patients (mean age, 47.2 ± 8.9 years; median follow-up duration, 32.67 [6.57–52.63] months) were included. The 5-year OS rates were 73.2% and 60.8% in the shorter (n = 171) and longer interval group (n = 1,058), respectively, while the 3-year RFS rates were 80.8% and 71.7%, respectively. In multivariate Cox analysis, the longer interval was associated with an increased risk of mortality (hazard ratio [HR], 1.43; 95% confidence interval [CI], 1.01–2.02; p = 0.046) and recurrence (HR, 1.50; 95% CI, 1.12–1.99; p = 0.006). There was an interaction between the molecular subtype and the surgery interval for OS (pinteraction = 0.014) and RFS (pinteraction = 0.027). After PSM, no significant difference in OS (p = 0.180) and RFS (p = 0.069) was observed between the two groups.

Conclusion

Among LABC patients with a poor response, those with a longer interval between NAC and surgery had worse OS and RFS. The results indicate that these patients should receive modified radical surgery timely, which may in turn improve their prognosis.

Breast Neoplasms
Neoadjuvant Therapy
Prognosis
Survival Analysis
Yunnan Fundamental Research Projects 202401AT070006 202401AT070009 Major Science and Technology Projects in Yunnan Province https://doi.org/10.13039/501100018531 202201AY070001-148
==== Body
pmcINTRODUCTION

Neoadjuvant chemotherapy (NAC), radical excision surgery, and adjuvant chemotherapy are the standard care for locally advanced breast cancer (LABC). NAC, compared to postoperative adjuvant chemotherapy, offers advantages such as improved resectability and higher breast conservation rates [12]. Following NAC, breast cancer patients exhibit varying degrees of tumor regression. Previous studies have reported that 12%–28% of patients achieve a pathological complete response (pCR), while a significant proportion does not [3456]. Early response evaluation is critical for NAC patients. According to the National Comprehensive Cancer Network guidelines, patients with poor responses to NAC should receive prompt therapy adjustment or timely surgery [7].

However, the recommended interval between NAC and breast surgery has not yet been clearly defined. The coordination of NAC and surgery is crucial because it is associated with varying patient outcomes. In this respect, major studies addressing this issue have shown contrasting results. One prospective study revealed that a longer interval (≥ 8 weeks) was associated with poor trends in disease-free survival (DFS) and overall survival (OS) [8]. The authors of another study found that patients undergoing surgery more than 21 days after NAC had worse DFS and OS [9]. In a retrospective study of 58 patients, the authors observed that delaying surgery beyond 60 days affected 5-year DFS but showed no differences in terms of OS [10]. According to the guidelines of the German Working Group on Gynecologic Oncology, surgery after NAC should be performed once white blood cell counts have returned to normal, with the operation ideally taking place approximately 2–4 weeks after the completion of NAC. We believe that a longer interval between NAC and surgery has an impact on the survival outcome of patients with progressive disease.

This study aimed to determine the prognostic implications of the surgical interval after NAC in LABC patients who had a poor tumor response based on tumor regression grade.

METHODS

Study population

The medical records of breast cancer patients who underwent NAC and modified radical surgery at Yunnan Cancer Hospital from January 2013 to December 2018 were retrospectively studied. All patients included in this study were diagnosed with breast cancer through pathological examination. They underwent NAC followed by postoperative pathological evaluation. The main NAC regimens for all patients included anthracyclines plus taxanes, anthracyclines plus cyclophosphamide followed by taxanes, anthracyclines plus taxanes followed by platinum, and taxanes plus platinum. Each patient received a total of 4–8 cycles of chemotherapy. The exclusion criteria included patients diagnosed with stage IV breast cancer and patients who achieved complete pathological remission. The interval between these procedures was defined as the waiting time from NAC completion until surgery. The study extracted several characteristics, including age at diagnosis, race, age of menarche, menostasia, history of breast disease, family history of malignancy, body mass index, molecular subtype, pre-NAC clinical T and N stage, American Joint Committee on Cancer 8th ed stage, lymphovascular invasion, yield pathologic (yp) T, and N stage. This study was approved by the ethics committee of Yunnan Cancer Hospital (KYLX2023-163). Written informed consent was obtained from all the participants before the enrollment of this study.

Follow-up

Follow-up procedures included clinical examination, ultrasound, mammography, computed tomography of the chest/abdomen/pelvis, or magnetic resonance imaging. Medical records were reviewed, and telephone follow-ups were conducted to collect survival data. The last follow-up occurred on September 13, 2022. The main outcomes were OS and recurrence-free survival (RFS). OS was defined as the duration from the start of treatment until the last follow-up or death from any cause, while RFS was defined as the period from the surgery date to the occurrence of breast cancer recurrence, including local, regional, distant, or cancer-related mortality.

Statistical analysis

All statistical analyses were conducted using SPSS statistical software (version 25.0; IBM Corp., Armonk, USA). The χ2 test was used to compare categorical variables between the two groups. Survival analysis was undertaken using Kaplan-Meier analysis. Univariate comparisons were performed using the log-rank test. Multivariate Cox regression analysis was performed on variables significant in univariate analysis to identify the independent prognostic factors. A Cox proportional hazards regression model was used to estimate the influence of clinicopathological factors on the prognosis of different surgical interval groups. Additionally, to mitigate bias, we conducted a comparison of OS and RFS between the two groups after 1:7 propensity score matching (PSM) based on the molecular subtype, pre-NAC clinical T and N stage, and ypT and N stage. The p < 0.05 was considered statistically significant.

RESULTS

We conducted a retrospective analysis of 1,517 breast cancer patients. Sixty patients with a stage IV diagnosis and 228 who achieved pCR following NAC were excluded. Ultimately, 1,229 patients with poor tumor responses were included in our analysis. A detailed patient selection is shown in Figure 1. Patients were divided into either a longer (greater than four weeks) and shorter interval group (four weeks or less) based on the wait time from completion of NAC to surgery. There were 1,058 patients (86.1%) in the shorter interval group and 171 patients (13.9%) in the longer interval group, for which the median surgical interval was 2.00 and 4.86 weeks, respectively.

Figure 1 Study flow chart.

pCR = pathological complete response.

The demographic characteristics of the patients are summarized in Table 1. There were no statistically significant differences observed between the two groups in terms of all characteristics, indicating that the baseline data of the two groups were comparable.

Table 1 Patient and tumor characteristics by surgical intervals

Variables	Interval ≤ 4 wk (n = 1,058)	Interval > 4 wk (n = 171)	Total (n = 1,229)	p-value	
Baseline					
	Age (yr)	47.1 ± 8.9	48.2 ± 9	47.2 ± 8.9	0.124	
	Race				0.060	
		Ethnic Han	898 (84.9)	155 (90.6)	1,053 (85.7)	
		Ethnic minorities	160 (15.1)	16 (9.4)	176 (14.3)	
	Age of menarche (yr)	14.1 ± 1.6	14 ± 1.6	14.1 ± 1.6	0.360	
	Menostasia	355 (33.6)	67 (39.2)	422 (34.3)	0.289	
	History of breast disease	26 (2.5)	5 (2.9)	31 (2.5)	0.922	
	Family history of malignancy	110 (10.4)	16 (9.4)	126 (10.3)	0.779	
	BMI (kg/m2)	24.1 ± 3.5	23.8 ± 3.7	24.1 ± 3.5	0.230	
	Molecular subtype				0.333	
		Luminal A	159 (15.0)	18 (10.5)	177 (14.4)	
		Luminal B	559 (52.8)	92 (53.8)	651 (53.0)	
		HER2+	98 (9.3)	16 (9.4)	114 (9.3)	
		TN	88 (8.3)	12 (7.0)	100 (8.1)	
		Unknown	154 (14.6)	33 (19.3)	187 (15.2)	
	Pre-NAC T stage				0.085	
		T1	54 (5.1)	9 (5.3)	63 (5.1)	
		T2	695 (65.7)	100 (58.5)	795 (64.7)	
		T3	212 (20.0)	36 (21.1)	248 (20.2)	
		T4	97 (9.2)	26 (15.2)	123 (10.0)	
	Pre-NAC N stage				0.493	
		N0	265 (25.0)	39 (22.8)	304 (24.7)	
		N1	636 (60.1)	99 (57.9)	735 (59.8)	
		N2	127 (12.0)	26 (15.2)	153 (12.4)	
		N3	30 (2.8)	7 (4.1)	37 (3.0)	
	AJCC 8th ed stage				0.077	
		I	19 (1.8)	3 (1.8)	22 (1.8)	
		II	693 (65.5)	97 (56.7)	790 (64.3)	
		III	346 (32.7)	71 (41.5)	417 (33.9)	
	Lymphovascular invasion	19 (1.8)	2 (1.2)	21 (1.7)	0.394	
	ypT stage				0.155	
		T0	81 (7.7)	7 (4.1)	88 (7.2)	
		T1	349 (33.0)	60 (35.1)	409 (33.3)	
		T2	550 (52.0)	86 (50.3)	636 (51.7)	
		T3	55 (5.2)	10 (5.8)	65 (5.3)	
		T4	23 (2.2)	8 (4.7)	31 (2.5)	
	ypN stage				0.013	
		N0	452 (42.7)	67 (39.2)	519 (42.2)	
		N1	330 (31.2)	46 (26.9)	376 (30.6)	
		N2	211 (19.9)	36 (21.1)	247 (20.1)	
		N2	211 (19.9)	36 (21.1)	247 (20.1)	
		N3	65 (6.1)	22 (12.9)	87 (7.1)	
Outcome					
	5-yr OS rate (%)	73.2 (69.2–77.4)	60.8 (51.2–72.2)		
	3-yr RFS rate (%)	80.8 (77.8–83.8)	71.7 (64.0–80.4)		
Data are mean ± standard deviation or median (quartile) for continuous variables and number (%) for categorical variables.

BMI = body mass index; HER2+ = human epidermal growth factor receptor 2-positive; TN= triple negative; NAC = neoadjuvant chemotherapy; AJCC = American Joint Committee on Cancer; yp = yield pathologic; OS = overall survival; RFS = recurrence-free survival.

The median follow-up time was 32.67 months (interquartile range, 6.57–52.63). During the follow-up, 209 patients (17%) died and 316 patients (25.7%) experienced disease recurrence. Patients in the longer interval group had significantly worse OS (log-rank test, p = 0.02) and RFS (log-rank test, p = 0.01) than those in the shorter interval group (Figure 2). The 5-year OS rates were 73.2% and 60.8% in the shorter and the longer interval group, respectively, while the 3-year RFS rates were 80.8% and 71.7%, respectively.

Figure 2 Survival curve of the indicated patients. Kaplan-Meier analysis of (A) overall survival and (B) recurrence-free survival in patients stratified for different surgical intervals (≤ 4 weeks vs. > 4 weeks).

Univariate analysis found that the surgery interval, molecular subtype, pre-NAC clinical N stage, ypT, and N stage were statistically significant factors affecting OS (Table 2). However, the surgery interval, age of menarche, molecular subtype, pre-NAC T and N stage, and ypT and N stage were identified as statistically significant factors affecting RFS (Table 3). Age, race, menostasia, family history of malignancy, and lymphovascular invasion did not show any significant effect on neither OS nor RFS.

Table 2 Univariate and multivariate analyses of the factors for overall survival

Variables	Univariate analysis	Multivariate analysis	
HR (95% CI)	p-value	HR (95% CI)	p-value	
Interval					
	≤ 4 wk	Reference		Reference		
	> 4 wk	1.50 (1.06–2.12)	0.021	1.43 (1.01–2.02)	0.046	
Age	1.00 (0.99–1.02)	0.661			
Race					
	Ethnic Han	Reference			
	Ethnic minorities	1.33 (0.93–1.90)	0.125		
Age of menarche	1.07 (0.99–1.15)	0.106			
Menostasia					
	No	Reference			
	Yes	1.12 (0.85–1.49)	0.413		
History of breast disease					
	No	Reference			
	Yes	0.68 (0.28–1.66)	0.402		
Molecular subtype					
	Luminal A	Reference		Reference		
	Luminal B	1.87 (1.11–3.16)	0.019	1.79 (1.05–3.02)	0.031	
	HER2+	1.97 (1.02–3.79)	0.044	1.58 (0.81–3.07)	0.182	
	TN	3.32 (1.75–6.30)	< 0.001	2.91 (1.52–5.58)	0.001	
	Unknown	2.44 (1.35–4.42)	0.003	2.39 (1.32–4.34)	0.004	
Pre-NAC T stage					
	T1	Reference		Reference		
	T2	1.12 (0.55–2.29)	0.760	1.34 (0.65–2.77)	0.434	
	T3	1.98 (0.94–4.16)	0.072	2.25 (1.06–4.77)	0.035	
	T4	2.36 (1.10–5.09)	0.028	2.43 (1.12–5.30)	0.025	
Pre-NAC N stage					
	N0	Reference		Reference		
	N1	1.46 (1.01–2.11)	0.043	1.34 (0.92–1.95)	0.125	
	N2	1.76 (1.08–2.85)	0.022	1.38 (0.84–2.28)	0.203	
	N3	2.83 (1.55–5.15)	0.001	2.38 (1.26–4.47)	0.007	
Lymphovascular invasion					
	No	Reference			
	Yes	1.44 (0.24–8.68)	0.689		
	Unknown	1.17 (0.29–4.75)	0.821		
ypT stage					
	T0	Reference				
	T1	0.60 (0.33–1.10)	0.097	Reference		
	T2	1.00 (0.57–1.75)	0.996	0.83 (0.45–1.53)	0.543	
	T3	2.08 (1.06–4.07)	0.034	1.21 (0.68–2.15)	0.521	
	T4	2.54 (1.19–5.40)	0.016	1.86 (0.90–3.84)	0.095	
ypN stage					
	N0	Reference		Reference		
	N1	2.04 (1.42–2.93)	< 0.001	1.72 (1.18–2.52)	0.005	
	N2	2.15 (1.46–3.17)	< 0.001	1.79 (1.19–2.69)	0.005	
	N3	3.94 (2.58–6.02)	< 0.001	2.94 (1.86–4.64)	< 0.001	
Data are median (quartile) for continuous variables and number (%) for categorical variables.

HR = hazard ratio; CI = confidence interval; HER2+ = human epidermal growth factor receptor 2-positive; TN = triple negative; NAC = neoadjuvant chemotherapy; yp = yield pathologic.

Table 3 Univariate and multivariate analyses of the factors for recurrence-free survival

Variables	Univariate analysis	Multivariate analysis	
HR (95% CI)	p-value	HR (95% CI)	p-value	
Interval					
	≤ 4 wk	Reference		Reference		
	> 4 wk	1.58 (1.19–2.08)	0.001	1.50 (1.12–1.99)	0.006	
Age	1.00 (0.99–1.01)	0.719			
Race					
	Ethnic Han	Reference			
	Ethnic minorities	1.20 (0.89–1.63)	0.235		
Age of menarche	1.08 (1.02–1.15)	0.015	1.08 (1.01–1.14)	0.023	
Menostasia					
	No	Reference			
	Yes	1.22 (0.97–1.53)	0.089		
Family history of malignancy					
	No	Reference			
	Yes	0.84 (0.42–1.70)	0.626		
Molecular subtype					
	Luminal A	Reference		Reference		
	Luminal B	1.67 (1.12–2.49)	0.012	1.57 (1.05–2.35)	0.028	
	HER2+	1.64 (0.98–2.76)	0.062	1.27 (0.74–2.16)	0.386	
	TN	2.96 (1.79–4.88)	< 0.001	2.62 (1.57–4.37)	< 0.001	
	Unknown	2.21 (1.40–3.50)	0.001	2.02 (1.27–3.21)	0.003	
Pre-NAC clinical T stage					
	T1	Reference		Reference		
	T2	1.33 (0.72–2.45)	0.358	1.43 (0.77–2.64)	0.254	
	T3	2.06 (1.09–3.88)	0.025	2.18 (1.15–4.12)	0.017	
	T4	2.81 (1.47–5.39)	0.002	2.50 (1.30–4.83)	0.006	
Pre-NAC clinical N stage					
	N0	Reference		Reference		
	N1	1.49 (1.11–2.00)	0.008	1.38 (1.02–1.86)	0.034	
	N2	1.90 (1.29–2.80)	0.001	1.55 (1.04–2.31)	0.030	
	N3	2.74 (1.63–4.61)	< 0.001	2.05 (1.19–3.55)	0.010	
Lymphovascular invasion					
	No	Reference			
	Yes	1.53 (0.38–6.11)	0.551		
	Unknown	1.11 (0.35–3.45)	0.863		
ypT stage					
	T0	Reference		Reference		
	T1	0.66 (0.41–1.05)	0.080	0.95 (0.58–1.55)	0.831	
	T2	1.01 (0.65–1.58)	0.961	1.26 (0.79–2.01)	0.342	
	T3	2.24 (1.29–3.90)	0.004	2.23 (1.21–4.08)	0.010	
	T4	3.11 (1.70–5.70)	< 0.001	2.24 (1.11–4.51)	0.024	
ypN stage					
	N0	Reference		Reference		
	N1	2.09 (1.55–2.80)	< 0.001	1.87 (1.38–2.54)	< 0.001	
	N2	2.25 (1.65–3.08)	< 0.001	1.89 (1.36–2.64)	< 0.001	
	N3	4.98 (3.52–7.03)	< 0.001	3.86 (2.66–5.62)	< 0.001	
Data are median (quartile) for continuous variables and number (%) for categorical variables.

HR = hazard ratio; CI = confidence interval; HER2+ = human epidermal growth factor receptor 2-positive; TN = triple negative; NAC = neoadjuvant chemotherapy; yp = yield pathologic.

Multivariate Cox analysis revealed that the longer interval was associated with an increased risk of mortality (hazard ratio [HR], 1.43; 95% confidence interval [CI], 1.01–2.02; p = 0.046) and recurrence (HR, 1.50; 95% CI, 1.12–1.99; p = 0.006). Furthermore, it was discovered that the molecular subtype, pre-NAC clinical N stage, and ypN stage were also independently linked to both OS and RFS in individuals with inadequate responses.

The forest plot in Figures 3 and 4 demonstrates the significant interaction between the molecular subtypes and the surgical interval for both OS (p interaction = 0.014) and RFS (p interaction = 0.027), respectively. This suggests that the effect of surgical interval time on OS and RFS may vary depending on the molecular subtype of LABC patients. After PSM, no significant difference was observed in the 5-year OS (p = 0.180) and 3-year RFS (p = 0.069) between the two groups (Supplementary Figure 1).

Figure 3 Forest plot for performance on overall survival of different surgical interval groups stratified by clinicopathological features based on the Cox models. The p-values for interaction were calculated using the Cox regression model; HR and 95% CIs were given and visually represented by the squares and error bars.

HR = hazard ratio; 95% CI = 95% confidence interval; HER2+ = human epidermal growth factor receptor 2-positive; TN = triple negative.

Figure 4 Forest plot for performance on recurrence-free survival of different surgical interval groups stratified by clinicopathological features based on the Cox models. The p-values for interaction were calculated using the Cox regression model; HR and 95% CIs were given and visually represented by the squares and error bars.

HR = hazard ratio; 95% CI = 95% confidence interval; HER2+ = human epidermal growth factor receptor 2-positive; TN = triple negative.

DISCUSSION

This retrospective comparative study aimed to investigate the effect of the interval between surgery after NAC on survival in LABC patients with a poor tumor response. The results indicated that patients in the shorter interval group had better OS and RFS compared with those in the longer interval group. In addition, according to the multivariate Cox regression analysis, the interval between molecular typing and surgery interacted with OS and RFS, respectively.

The decision to schedule surgery for patients after NAC is determined by various factors, mainly including chemotherapy toxicity, patient anxiety, and hospital operating room availability [111213]. However, there is no clear evidence in previous literature regarding the optimal timing of surgery after NAC.

Previous studies have categorized patients into different surgical interval groups to examine the impact on patient survival. Al-Masri et al. [14] found no significant difference in OS, local RFS, or RFS among patients divided into pCR and non-pCR groups within different surgical intervals (0–4 weeks, 4–6 weeks, and > 6 weeks). However, the observed discrepancy could potentially be attributed to the limited number of non-pCR patients included in this study and the differences in the study population compared to ours. Our research primarily focused on patients with non-pCR, whereas the study in question performed subgroup analyses based on the entire study population. Yoo et al. [15] suggested that due to the lower pCR rate in the longer interval group (> 6 weeks) and the potential survival benefit for individual patients, there may be a significant reluctance to postpone surgery beyond six weeks. A retrospective study conducted multivariate analysis and revealed that patients without pCR had better survival outcomes when the surgical interval was shorter (< 4 weeks) (HR, 1.12; 95% CI, 0.99–1.26; p = 0.08) [16]. The research findings align with the conclusions of our study, suggesting a potential association between a shorter surgical interval (< 4 weeks) and improved survival outcomes in non-pCR patients. However, it is worth noting that our study yielded statistically significant results. Variations in study design, patient characteristics, and methodology may have contributed to this disparity.

To the best of our knowledge, this study represents the first attempt to investigate the impact of the surgical interval after NAC on LABC patients with a poor tumor response. Our objective was to determine whether this subgroup of patients with poor tumor responses is more likely to experience poorer survival outcomes with longer intervals between surgeries.

However, it is important to acknowledge the limitations of this study. Firstly, this study may be subject to selection bias and confounding as a single-center retrospective study with a > 4-week interval set for a small sample size. As such, caution should be exercised in generalizing the result. Further validation through larger multi-center studies will be needed to provide more conclusive evidence to guide clinical decision-making. Secondly, this study focused on patients who did not respond well to NAC, and a detailed stratified analysis of patients according to residual cancer burden categories would be essential in future. Finally, because this cohort was a retrospective analysis, we found that most of the data were unavailable, and not all patients could be grouped according to the Response Evaluation Criteria in Solid Tumors criteria for analysis, which is unfortunate for this study. However, we hope that this work will be improved through further research in order to make this possible.

In summary, among LABC patients with poor responses, patients with a longer time interval between NAC and surgery had worse OS and RFS. For these patients, we suggest that modified radical surgery should be performed in time, which may improve their prognosis.

ACKNOWLEDGMENTS

This study is a joint effort of many investigators and staff members, and their contribution is gratefully acknowledged. We especially thank all the patients who participated in this study.

SUPPLEMENTARY MATERIAL

Supplementary Figure 1

Propensity-score matching adjusted for molecular subtype, pre-neoadjuvant chemotherapy clinical T and N stages, and yield pathologic triple negative stage to estimate overall survival (A) and recurrence-free survival (B).

Funding: This research was funded by Yunnan Fundamental Research Projects (202401AT070006), Major Science and Technology Projects in Yunnan Province (202201AY070001-148), and Yunnan Fundamental Research Projects (202401AT070009).

Conflict of Interest: The authors declare that they have no competing interests.

Data Availability: All original data are available upon reasonable request to the corresponding authors.

Author Contributions: Formal analysis: Long M, Li C.

Funding acquisition: Xie Y.

Investigation: Long M, Li C.

Methodology: Long M, Li C, Mao K.

Resources: Dong G, Zheng X, Gao S.

Supervision: Li Z1, Li Z2, Yang G.

Writing - original draft: Long M, Li C, Mao K.

Writing - review & editing: Li Z3, Xie Y.

Li Z1, Zhenhui Li; Li Z2, Zhen Li; Li Z3, Zhuolin Li.
==== Refs
1 Murchison S Truong P Locoregional therapy in breast cancer patients treated with neoadjuvant chemotherapy Expert Rev Anticancer Ther 2021 21 865 875 33719866
2 Yao L Jia G Lu L Ma W Breast cancer patients: who would benefit from neoadjuvant chemotherapies? Curr Oncol 2022 29 4902 4913 35877249
3 Wang-Lopez Q Chalabi N Abrial C Radosevic-Robin N Durando X Mouret-Reynier MA Can pathologic complete response (pCR) be used as a surrogate marker of survival after neoadjuvant therapy for breast cancer? Crit Rev Oncol Hematol 2015 95 88 104 25900915
4 Fayanju OM Ren Y Thomas SM Greenup RA Plichta JK Rosenberger LH The clinical significance of breast-only and node-only pathologic complete response (pCR) after neoadjuvant chemotherapy (NACT): a review of 20,000 breast cancer patients in the National Cancer Data Base (NCDB) Ann Surg 2018 268 591 601 30048319
5 Haque W Verma V Hatch S Suzanne Klimberg V Brian Butler E Teh BS Response rates and pathologic complete response by breast cancer molecular subtype following neoadjuvant chemotherapy Breast Cancer Res Treat 2018 170 559 567 29693228
6 Matthews CM Nymberg K Berger M Vargo CA Dempsey J Li J Pathological complete response rates with pertuzumab-based neoadjuvant chemotherapy in breast cancer: a single-center experience J Oncol Pharm Pract 2020 26 572 579 31256745
7 Gradishar WJ Moran MS Abraham J Aft R Agnese D Allison KH Breast cancer, version 3.2022, NCCN clinical practice guidelines in oncology J Natl Compr Canc Netw 2022 20 691 722 35714673
8 Suleman K Almalik O Haque E Mushtaq A Badran A Alsayed A Does the timing of surgery after neoadjuvant therapy in breast cancer patients affect the outcome? Oncology 2020 98 168 173 31918425
9 Omarini C Guaitoli G Noventa S Andreotti A Gambini A Palma E Impact of time to surgery after neoadjuvant chemotherapy in operable breast cancer patients Eur J Surg Oncol 2017 43 613 618 27793416
10 Lin J Anna L Clinical impact of delaying surgery in patients undergoing neoadjuvant chemotherapy on breast cancer recurrence and survival J Glob Oncol 2018 4 70s
11 Mauri D Pavlidis N Ioannidis JPA Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis J Natl Cancer Inst 2005 97 188 194 15687361
12 Drageset S Lindstrøm TC Giske T Underlid K Being in suspense: women’s experiences awaiting breast cancer surgery J Adv Nurs 2011 67 1941 1951 21466581
13 Tokunaga S Takashima T Kashiwagi S Noda S Kawajiri H Tokumoto M Neoadjuvant chemotherapy with nab-paclitaxel plus trastuzumab followed by 5-fluorouracil/epirubicin/cyclophosphamide for HER2-positive operable breast cancer: a multicenter phase II trial Anticancer Res 2019 39 2053 2059 30952749
14 Al-Masri M Aljalabneh B Al-Najjar H Al-Shamaileh T Effect of time to breast cancer surgery after neoadjuvant chemotherapy on survival outcomes Breast Cancer Res Treat 2021 186 7 13 33475879
15 Yoo TK Moon HG Han W Noh DY Time interval of neoadjuvant chemotherapy to surgery in breast cancer: how long is acceptable? Gland Surg 2017 6 1 3 28210546
16 Loibl S Werutsky G Nekljudova V Seiler S Blohmer JU Denkert C Impact in delay of start of chemotherapy and surgery on pCR and survival in breast cancer: a pooled analysis of individual patient data from six prospectively randomized neoadjuvant trials J Clin Oncol 2017 35 571 27870569
