Sage Journals: Discover world-class research

Abstract

Background:

There is an interest in performing de-escalating axillary surgery after neoadjuvant chemotherapy (NAC). However, the significance of residual axillary node disease after NAC has not been well studied.

Objectives:

To investigate the pathological residual axillary lymph node tumor burden (ypN) of patients with initial clinical nodal stage cN0-1 breast cancer after NAC and determine its prognostic value.

Design:

Initial cN0-1 breast cancer patients who received NAC followed by axillary surgery at the First Hospital of Jilin University and the First Affiliated Hospital of Xi’an Jiaotong University between January 2011 and December 2019 were included.

Methods:

Survival outcomes were compared according to different clinical and pathological stage and nodal response to NAC. The main outcomes were disease-free survival (DFS) and overall survival (OS). Factors associated with survival were defined by Cox regression analysis.

Results:

A total of 911 patients were included, among whom 260 had cN0 and 651 had cN1 tumors. After NAC, 410 patients were ypN0, and another 501 were ypN+. The median follow-up time was 63 months. There was no significant difference in DFS or OS between the cN0 and cN1 groups in hormone receptor positive (HR+)/human epidermal growth factor receptor 2 positive (HER2+) and HR−/HER2− subtypes; instead, ypN status was significantly related to DFS and OS. In HR+/HER2− subtype, both cN and ypN stages did not show significant survival differences, but the ypN number and the nodal response to NAC showed significant prognostic value (p < 0.05). Among HR−/HER2+ patients, all cN status, ypN status, ypN number, and nodal response were significantly associated with survival (p < 0.05). Furthermore, tumor biology, axillary surgery, ypN status, pathological tumor size, and radiotherapy were independent prognostic factors for DFS and OS.

Conclusion:

The ypN status after NAC provide more prognostic information than the initial cN stage in cN0-1 patients, and the surgical axillary staging after NAC may have high clinical value.

Keywords

axillary lymph nodes breast cancer neoadjuvant chemotherapy pathological response

Introduction

Neoadjuvant chemotherapy (NAC) used to be a treatment option for patients with locally advanced breast cancer, mostly those with clinical lymph node metastasis (cN+).¹ With the continuous optimization of chemotherapy regimens and the combined use of targeted drugs, NAC increases the rate of tumor downstaging and permits less extensive breast and axillary surgery.² NAC also allows treatment response to be clinically assessed and provides strong evidence for postoperative adjuvant therapy.³ Based on these advantages and the recognition of that breast tumor biology rather than anatomic tumor staging is the driver of NAC decisions, NAC is increasingly being used in early-stage patients, even those with cN0 disease.⁴

Traditionally, axillary lymph node dissection (ALND) performed in patients who underwent NAC both as staging and therapeutic procedure, but it comes with many postoperative complications, such as lymphedema, range-of-motion restriction, arm paresthesia, and pain.⁵ There have been increasing efforts to investigate the feasibility of less morbid sentinel lymph node biopsy (SLNB) before or after NAC. When a positive lymph node was found by SLNB, a supplemental ALND used to be performed.

Since the advent of the ACOSOG Z0011 trial,⁶ in which a 10-year follow-up showed that ALND was not needed in women with early breast cancer with only one or two sentinel node metastases who underwent breast-conserving surgery before adjuvant systematic therapy, the question of whether it is necessary to perform surgical staging of axillary lymph nodes has emerged.⁷ Recently, the results of the SOUND trial, in which patients who did not receive NAC were also enrolled, demonstrated that the omission of axillary surgery was not inferior to SLNB in 5 years disease-free survival (DFS) and overall survival (OS) in patients with small tumor and cN0.⁸ For patients receiving NAC before surgery, new prospective trials are ongoing to determine whether axillary surgery can be abandoned in selected patients [the EUBREAST1-trial (NCT04101851) and the ASICS trial (NCT04225858)].^9,10 At the same time, there are some voices saying that pathological nodal status after NAC offers significant prognostic value; thus, surgical axillary staging is essential after NAC.^11,12 However, there are not enough data about the final residual axillary lymph node tumor burden of patients with initial stage cN0-1 disease, those who are most likely be candidates for axillary surgery omission after NAC. Although multiple studies have reported a correlation between breast or axillary pathological complete response (pCR) and survival,^13,14 the prognostic value of upstaging or downstaging of lymph nodes has not been well studied. Therefore, we retrospectively investigated the residual axillary tumor burden of stage cN0-1 patients and then performed a survival analysis to evaluate the association between residual nodal disease and long-term outcomes.

Materials and methods

Patients

A total of 1208 female patients underwent NAC followed by axillary surgery at the Department of Breast Surgery at the First Hospital of Jilin University and the First Affiliated Hospital of Xi’an Jiaotong University between January 2011 and December 2019. Patients with distant metastasis during the NAC period, cN2-3, unknown cN, or missing follow-up data were excluded (Figure 1). A total of 911 eligible patients were included for further analysis. The Ethics Committees of Xi’an Jiaotong University (No. XJTU1AF2023LSK-301) and the Ethical Review Committee of the First Hospital of Jilin University (No. 2023-510) approved the study protocol. Informed consent was waived due to the retrospective study design.

Figure 1.

Flow diagram of the study.

Variables

Clinicopathological data, which included age at diagnosis, clinical tumor size, tumor histology, estrogen receptor (ER) status, progesterone receptor (PR) status, human epidermal growth factor receptor 2 (HER2) status, Ki-67 status, surgery type, pathologic tumor and nodal status after surgery, number of positive lymph nodes, and survival data (month), were obtained. Clinical and pathological stage classifications were determined according to the 8th edition of the American Joint Cancer Commission.¹⁵ cN0 was defined as no suspicious lymph nodes on axillary ultrasound, computed tomography, magnetic resonance imaging, or suspicious lymph nodes on imaging but negative on either fine needle aspiration cytology or core needle biopsy prior to NAC. Immunohistochemistry (IHC) was used to the detect ER, PR, HER2, and Ki-67. ER and PR were defined as positive if ⩾1% of cells were positive. HR was defined as positive if ER and/or PR were positive. HER2 expression was defined as positive if 3+ by IHC or 2+ by IHC and positive by in situ hybridization. Tumor subtypes were categorized using the St Gallen criteria¹⁶: HR+/HER2−, HR+/HER2+, HR−/HER2+, and HR−/HER2− (TNBC). The breast pathological complete response (bpCR) was defined as the absence of residual invasive carcinoma or carcinoma in situ of the breast. ypN0 was defined as the absence of any tumor metastasis in the lymph node.

Treatment

Standardized treatment plans including NAC for patients were developed in accordance with the Chinese Society of Clinical Oncology Breast Cancer guidelines. All patients underwent surgery involving breast conserving, mastectomy, breast prosthesis implantation, or other methods. All patients underwent axillary surgery involving SLNB, ALND, or SLNB + ALND.

Follow-up

Follow-up continued until February 2023. Telephone follow-up was performed every 3 months. DFS was defined as the period from the date of diagnosis until the date of diagnosis of locoregional or distant metastasis. OS was defined as the period from the date of diagnosis until the date of death from any cause.

Statistical analysis

Pearson χ² tests were applied to compare clinicopathologic factors. The Kaplan–Meier method was used to generate survival plots. The log-rank test was used to verify the statistical significance of differences in survival among groups. Univariable and multivariable Cox regression analyses were used to analyze the prognostic significance of variables for DFS and OS. A two-sided p value < 0.05 was considered to indicate statistical significance. All the statistical analyses were performed with SPSS version 25.0 (IBM SPSS Statistics, Chicago, IL, USA) and R 4.2.2 (R Project for Statistical Computing) (http://www.r-project.org) software. The reporting of this study conforms to Strengthening the Reporting of Observational Studies in Epidemiology (Supplemental Table 1).¹⁷

Results

Clinicopathological factors

A total of 911 patients with cT1-4cN0-1 disease were enrolled (Figure 1). The patients’ baseline clinicopathological factors are described in Table 1. Mastectomy was performed in most patients (86.5%, 788/911), while 11.5% (105/911) of patients accepted breast conservation therapy. SLNB alone was performed in 107 patients, and 801 patients underwent direct ALND or SLNB + ALND. A total of 18.8% (171/911) of patients achieved bpCR. Among 610 patients who HR positive, 570 patients received adjuvant endocrinotherapy while 14 patients did not, and 26 patients unknown.

Table 1.

Baseline characteristics of patients and ypN status.

Characteristic	Total (n = 911)	ypN0 (n = 410)	ypN+ (n = 501)
Age
⩽35	96	22	19
35–50	394	211	238
⩾51	421	177	244
cT
T1	172	83	89
T2	624	274	350
T3	85	38	47
T4	21	9	12
Unknown	9	6	3
cN
N0	260	199	61
N1	651	211	440
Histology
Ductal	734	307	427
Lobular	114	60	54
Others	45	29	16
Unknown	18	14	4
ER
Negative	319	193	126
Positive	590	215	375
Unknown	2	2	0
PR
Negative	423	235	188
Positive	486	173	313
Unknown	2	2	0
HR
Negative	299	182	117
Positive	610	226	384
Unknown	2	2	0
HER2
Negative	585	243	342
Positive without targeted	135	59	76
Positive with single targeted	146	80	66
Positive with double targeted	16	14	2
Unknown	29	18	11
Ki67
⩽20	206	62	144
>20	695	341	354
Unknown	10	7	3
Subtype
HR+/HER2+	162	76	86
HR+/HER2−	425	140	285
HR−/HER2+	135	77	58
HR−/HER2−	160	103	57
Unknown	29	18	11
NAC regimen
Anthracyclines + Taxanes	756	318	438
Taxanes + Platinums	104	64	40
Others	51	32	19
Breast surgery
BCS	105	71	34
Mastectomy	788	333	455
Others	18	5	9
Unknown	4	1	3
Axillary surgery
SLNB alone	107	104	3
ALND	801	304	497
Unknown	3	2	1
ypT
T0	171	140	31
T1	473	197	276
T2	226	61	165
T3	33	10	23
T4	8	2	6
bpCR
Yes	171	140	31
No	740	270	470
Radiotherapy
Yes	704	285	419
No	188	114	74
Unknown	19	11	8
Endocrinotherapy
Yes	570	181	103
No	284	204	366
Unknown	57	25	32

ALND, axillary lymph node dissection; BCS, breast conservation therapy; bpCR, breast pathological complete response; cN, clinical nodal stage prior to NAC; cT, clinical tumor stage prior to NAC; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; NAC, neoadjuvant chemotherapy; PR, progesterone receptor; SLNB, sentinel lymph node biopsy; ypN, pathological nodal stage after NAC; ypT, pathological breast tumor size after NAC.

Conversion of axillary staging after neoadjuvant therapy

After NAC, 199 of 260 patients (76.5%) with cN0 disease remained negative (cN0-ypN0), and another 61 patients (23.5%) were upstaged (cN0-ypN+); 215 of 651 patients (33.0%) with cN1 disease were downstaged (cN1-ypN0), while another 436 patients (67.0%) still had positive lymph nodes (cN1-ypN+) (Figure 1). Patients who achieved bpCR were more likely to achieve ypN0 not only in the cN1 subgroup but also in cN0 subgroup. In total, 127 cN1 patients achieved bpCR, among whom 97 patients (76.4%) achieved lymph node downstage (cN1-ypN0), and 30 patients (23.6%) did not achieve downstaging (cN1-ypN+); 44 cN0 patients achieved bpCR, among whom 43 remained node negative (cN0-ypN0), and only 1 patient experienced lymph node upstage (cN0-ypN+). Conversely, in non-bpCR group, (cN1-ypN+) and (cN0-ypN+) patients accounted for a greater proportion of the population [Figure 2(a)]. Among the different subtypes, the HR−/HER2+ subtype most easily achieved downstaging and the HR+/HER2− subtype had the highest risk of upstaging [Figure 2(b)].

Figure 2.

Association of nodal stage conversion after NAC with the bpCR and biological subtype. (a) Distribution of bpCRs and non-bpCRs in different conversion groups according to nodal stage after neoadjuvant chemotherapy. (b) Distribution of nodal response to NAC according to different surrogate molecular tumor subtypes.

Survival outcomes

The median follow-up time from the day of breast cancer diagnosis was 63 (range 7–144) months. The 5-year DFS rate was 82.3% and the OS rate was 85.7%. During the follow-up period, 158 (17.3%) patients died from any cause, and 145 (15.9%) died from breast cancer. A total of 187 (20.5%) patients experienced recurrence, among which the first events were local in 6 (3.2%), regional in 12 (6.4%), and distant in 166 (88.8%) patients. In HR+/HER2+ patients, ypN stage was more strongly associated with survival than cN stage [DFS (p = 0.02) and OS (p = 0.072) versus DFS (p = 0.56) and OS (p = 0.64)] (Figure 3). Positive ypN number after NAC and nodal stage response to NAC were not significantly associated with survival in this subtype (Supplemental Figure 1). In the HR+/HER2− group, both cN and ypN stage did not show statistical survival differences (Supplemental Figure 2), but positive ypN number after NAC and nodal stage response to NAC did (p ⩽ 0.05), especially for DFS (p ⩽ 0.01) (Figure 4). Among HR−/HER2+ patients, all cN status, ypN status, positive ypN number after NAC, and nodal response to NAC were significantly associated with DFS and OS (p < 0.05) (Figure 5 and Supplemental Figure 3). For the HR−/HER2− subtype, similar to HR+/HER2+, ypN status was significantly associated with DFS (p < 0.05) and OS (p < 0.01); however, cN status was not significantly associated with survival (Figure 6). In this subtype, the number of positive ypNs did not show relationship with survival, while, nodal response to NAC show association with survival (p < 0.05) (Supplemental Figure 4).

Figure 3.

Kaplan–Meier survival curves of HR+/HER2+ patients for disease-free survival and overall survival according to cN status (a, b), ypN status (c, d).

Figure 4.

Kaplan–Meier survival curves of HR+/HER2− patients for disease-free survival and overall survival according to pathological positive nodal number after NAC (a, b), and nodal response to NAC (c, d).

Figure 5.

Kaplan–Meier survival curves of HR−/HER2+ patients for disease-free survival and overall survival according to cN status (a, b), ypN status (c, d).

Figure 6.

Kaplan–Meier survival curves of HR−/HER2− patients for disease-free survival and overall survival according to cN status (a, b), ypN status (c, d).

Multivariable modeling

Multivariate Cox regression analysis revealed that biological subtype, axillary surgery, ypN status, pathological breast tumor size after NAC (ypT), and radiotherapy were associated with DFS and OS (Tables 2 and 3).

Table 2.

Univariable and multivariable Cox regression analyses for disease-free survival.

Variables	Univariate analysis			Multivariate analysis
Variables	Hazard ratio	95% CI	p Value	Hazard ratio	95% CI	p Value
cT			0.282			0.523
T1	1			1
T2	1.52	0.98–2.34	0.060	1.45	0.94–2.25	0.094
T3	1.84	1.02–3.30	0.042	1.55	0.86–2.80	0.149
T4	1.83	0.70–4.79	0.220	1.56	0.59–4.11	0.371
Biologic subtype			0.137			0.164
HR+/HER2+	1			1
HR+/HER2−	1.74	1.04–2.92	0.036	1.70	1.01–2.85	0.046
HR−/HER2+	1.82	0.98–3.39	0.059	1.98	1.06–3.69	0.032
HR−/HER2−	1.34	0.72–2.50	0.354	1.58	0.85–2.97	0.152
Breast surgery			0.089			0.149
BCS	1			1
Mastectomy	2.07	1.06–4.06	0.034	1.91	0.97–3.76	0.062
Others	1.31	0.28–6.08	0.728	1.23	0.26–5.70	0.794
Axillary surgery			0.004			0.015
ALND	1			1
SLNB alone	0.188	0.07–0.51	0.001	0.23	0.08–0.62	0.004
ypT			0.202			0.152
T0	1			1
T1	1.284	0.80–2.06	0.298	1.326	0.80–2.20	0.276
T2	1.325	0.78–2.24	0.294	1.303	0.73–2.32	0.370
T3–4	2.420	1.08–5.44	0.032	2.691	1.15–2.27	0.022
bpCR
No	1			1
Yes	0.68	0.42–1.10	0.114	0.734	0.45–1.21	0.222
ypN0
No	1			1
Yes	0.61	0.44–0.86	0.004	0.672	0.46–0.97	0.035
Radiotherapy
No	1			1
Yes	1.86	1.15–3.01	0.011	1.68	1.03–2.72	0.037

ALND, axillary lymph node dissection; BCS, breast conservation therapy; bpCR, breast pathological complete response; CI, confidence interval; cT, clinical tumor stage prior to NAC; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; NAC, neoadjuvant chemotherapy; PR, progesterone receptor; SLNB, sentinel lymph node biopsy; ypN, pathological nodal stage after neoadjuvant chemotherapy; ypT, pathological breast tumor size after NAC.

Table 3.

Univariable and multivariable Cox regression analyses for overall survival.

Variables	Univariate analysis			Multivariate analysis
Variables	Hazard ratio	95% CI	p Value	Hazard ratio	95% CI	p Value
cT			0.143			0.261
T1	1			1
T2	1.76	1.07–2.89	0.026	1.697	1.03–2.79	0.068
T3	2.24	1.18–4.27	0.014	1.951	1.02–3.75	0.054
T4	1.93	0.65–5.70	0.235	1.694	0.57–5.03	0.342
Biologic subtype			0.103			0.166
HR+/HER2+	1			1
HR+/HER2−	2.01	1.12–3.61	0.019	1.94	1.08–3.48	0.027
HR−/HER2+	1.80	0.89–3.65	0.102	1.93	0.95–3.91	0.070
HR−/HER2−	1.50	0.75–3.00	0.250	1.69	0.84–3.40	0.142
Axillary surgery			0.006			0.012
ALND	1			1
SLNB alone	0.22	0.08–0.60	0.003	0.25	0.09–0.68	0.007
ypT			0.113			0.091
T0	1			1
T1	1.337	0.81–2.21	0.259	1.370	0.79–2.35	0.254
T2	1.440	0.82–2.51	0.201	1.396	0.75–2.58	0.287
T3–4	2.773	1.21–6.33	0.016	3.062	1.29–7.27	0.011
bpCR
No	1			1
Yes	0.77	0.50–1.18	0.231	0.701	0.43–1.19	0.189
ypN0
No	1			1
Yes	0.65	0.45–0.92	0.015	0.662	0.46–0.96	0.027
Radiotherapy
No	1			1
Yes	2.40	1.35–4.25	0.003	2.14	1.21–3.80	0.009

ALND, axillary lymph node dissection; bpCR, breast pathological complete response; CI, confidence interval; cT, clinical tumor stage prior to NAC; ER, estrogen receptor; HR, hormone receptor; HER2, human epidermal growth factor receptor 2; NAC, neoadjuvant chemotherapy; PR, progesterone receptor; SLNB: sentinel lymph node biopsy; ypN, pathological nodal stage after neoadjuvant chemotherapy; ypT, pathological breast tumor size after NAC.

Discussion

The use of de-escalation strategies for lymph node surgery after NAC in early-stage breast cancer patients has recently been under debate.^18,19 After Tadros et al.²⁰ reported in a single-institution study that breast pCR is highly correlated with nodal status after NAC, Barron et al.²¹ analyzed 30,821 patients with cT1-2 cN0-1 breast cancer treated with NAC followed by surgery from the National Cancer Database and found that in patients with cN0 HER2+ or TNBC disease who achieved bpCR, the ypN0 rate was less than 2%, which supports the omission of any axilla surgery, including SLNB, in this subset of patients. Since then, a number of clinical studies have advocated the omission of axillary surgery in patients with a low lymph node tumor burden.^9,10,22–25 However, the negative effects of omitting axillary surgery on patient outcomes must be avoided. There are few data regarding the pathological nodal burden after NAC in breast cancer patients with initial cN0-1 and its prognostic value for long-term survival outcomes.

To our knowledge, this is the first real-world study in which the pathological nodal burden of initially cN0-1 patients after NAC was analyzed separately and how the differences in nodal stage affect patient survival was investigated. In this study, after NAC, 76.5% of patients with cN0 disease remained negative (cN0-ypN0), and another 23.5% were upstaged (cN0-ypN+); 33.0% of patients with cN1 disease achieved ypN0 (cN1-ypN0), while another 67.0% of patients still had positive lymph nodes (cN1-ypN+). Consistent with the findings of previous studies we mentioned above, we also found that ypN was associated with breast pCR as well as breast cancer subtype. Among the cN1 patients who achieved bpCR, 76.4% achieved lymph node downstage (cN1-ypN0), and 23.6% did not (cN1-ypN+); among the cN0 patients who achieved bpCR, 97.7% were still node negative after NAC (cN0-ypN0), and only 2.3% experienced lymph node upstage (cN0-ypN+). Conversely, in the non-bpCR group, (cN0-ypN+) and (cN1-ypN+) patients take more proportion than (cN0-ypN0) and (cN1-ypN0) patients (55.2% and 21.2% versus 15.5% and 7.9%, respectively). Among the different subtypes, HR−/HER2+ patients comprised a greater proportion of cN1-ypN0 patients, and HR−/HER2− patients comprised a greater proportion of cN0-ypN0 patients. However, the HR+/HER2− subgroup had the highest risk of developing cN0-ypN+ and cN1-ypN+ (Figure 2). In a study conducted by Ryu et al.²⁶ using the Korean Breast Cancer Society Registry database, all patients with cT1-3N0 disease were found to have a breast pCR rate of 19.7% and a ypN+ rate of 16.7% regardless of the biological subtype. Murphy et al.²⁷ from the Mayo Clinic reported a ypN+ rate of 22% in cT1-4N0 patients without biological classification. In our study, we included cT4 patients, so the ypN+ rate was 23.5% which was higher than that reported by Ryu et al. Furthermore, among the cT1-4N0 patients in our study, 16.9% achieved breast pCR, which also consistent with the Korean study.

In the present study, we found that the residual nodal disease burden after NAC was a better predictor of prognosis than the initial cN stage. In the HR+/HER2+ subgroup, ypN stage was more strongly associated with survival than were cN stage [DFS (p = 0.02) and OS (p = 0.072) versus DFS (p = 0.56) and OS (p = 0.64)] (Figure 3). No significant difference in DFS/OS between patients with pCR/non-pCR in the luminal-A subgroup has been reported in pooled or meta-analyses.²⁸ In the present study, although we did not categorize patients by luminal type, we found that in the HR+/HER2− subtype which include luminal-A and HER2-negative luminal-B patients, both cN and ypN stage did not show statistical significant survival differences, which is consistent with the findings above. However, the number of pathologically positive nodes after NAC and the nodal stage response to NAC showed great prognostic value (p ⩽ 0.05), especially for DFS (p ⩽ 0.01) in this subtype (Figure 4). In the HR−/HER2+ subgroup, all cN status, ypN status, ypN positivity number after NAC, and nodal response to NAC were significantly associated with DFS and OS (p < 0.05) (Figure 5). This may be because of the widespread use of targeted drugs. Similarly to HR+/HER2+ group, ypN status was significantly associated with DFS (p < 0.05) and OS (p < 0.01) in the HR−/HER2− subtype; however, cN status was not (Figure 6). Instead of the number of positive ypNs, the nodal response to NAC was associated with survival (p < 0.05) in this subgroup (Supplemental Figure 4). Apart from the HR+/HER2− subtype, patients with ypN0 had significantly better DFS and OS than patients with ypN+. It can suggest that ypN+ patients do need intensive postoperative systematic therapy to improve their prognosis. Patients in the cN1-ypN0 group had comparable DFS and OS trends to those in the cN0-ypN0 group; however, patients that in the cN0-ypN+ group had a worse prognosis than did those in the cN1-ypN+ group. This suggests that lymph node upstaging represents strong tumor heterogeneity. Among patients with ypN+, an increased number of positive lymph nodes were associated with worse survival.

There was a follow-up analysis from a Swedish prospective multicenter trial in which all patients with initial cN0 disease underwent SLNB before NAC and cytologically confirmed cN+ patients underwent SLNB after NAC; however, all patients underwent completion ALND after NAC because of the original experimental design. The 5-year DFS and OS results showed a lack of association between nodal status before NAC and survival outcomes but pathological nodal stage after NAC predicted survival; thus, they claimed that the axillary status after NAC has important prognostic value and supported the practice of surgical axillary staging after NAC in all patients.¹¹ In our study, for patients with cN1 or cN0 disease, achieving ypN0 can significantly improve the prognosis compared with not achieving ypN0. In addition, we performed a logistic regression analysis to determine which characteristics were associated with survival in this study cohort. In addition to ypN status, biological subtype, axillary surgery subtype, ypT, and radiotherapy were significantly related to OS and DFS, which agrees with previous reports. It was previously commonly reported that achievement of breast pCR is correlated with improved survival outcomes.^29,30 Actually, in the present study cohort, we find that bpCR did not significantly related to DFS or OS (Tables 2 and 3), while the pT stage was an independent influencing factor of DFS or OS. The ypT stage 3 or 4 patients had poorer outcomes than ypT0 (bpCR); however, ypT stage 1 or 2 patients did not have significantly better survival than ypT0 (bpCR). There were also studies in which results were consistent with our findings. A meta-analysis of the 14,640 patients from 29 heterogeneous neoadjuvant trials concluded that the bpCR cannot be a surrogate endpoint for DFS and OS, because the regression of either the log(HR) for DFS or the log(HR) for OS on the log(OR) for bpCR demonstrated only weak associations [R(2) = 0.08; 95% confidence interval (CI), 0–0.47; and R(2) = 0.09; 95% CI, 0.01–0.41, respectively].³¹ Some other researchers believe that the bpCR is a prognostic indicator of the DFS and OS in HER2 positive patients and TNBC patients.³² On this subject, scholars argue that patients who achieve bpCR do not necessarily benefit from survival, but patients who do not achieve pCR provide in vivo information to facilitate more individualized adjuvant treatment.³³

Nevertheless, this study has several limitations. First, clinical nodal stage information after NAC was not collected in the first step; thus, we cannot clearly state how many patients who were in the initial cN0 group remained in the cN0 group and how many patients converted to the cN+ after NAC; how many initial cN1 patients remained in the cN1 group; and how many converted to the cN0 or more than cN1 after NAC. This plays a role in surgical decision making if one needs de-escalation. However, the main purpose of the present study was to determine what the final pathological profile of patients with initial stage cN0-1 disease and the prognostic value of the initial and pathological status for survival. Second, molecular targeted therapy was not used in all patients with HER2-positive disease because targeted drugs were not covered by medical insurance in the early years.

Conclusion

The ypN status after NAC provides more prognostic information than initial cN stage in cN0-1 patients, and the surgical axillary staging after NAC may have high clinical value.

Supplemental Material

sj-docx-5-tam-10.1177_17588359241248318 – Supplemental material for Prognostic value of pathological nodal burden after neoadjuvant chemotherapy in initially cN0-1 breast cancer patients: a dual-center, 10-year survival analysis

Supplemental material, sj-docx-5-tam-10.1177_17588359241248318 for Prognostic value of pathological nodal burden after neoadjuvant chemotherapy in initially cN0-1 breast cancer patients: a dual-center, 10-year survival analysis by Amina Maimaitiaili, Zhimin Fan, Jingyi Zhang, Yidi Wang, Bohui Shi, Jie Zheng, Gefei Li, Yuting Zhao, Shengyu Pu, Jianjun He, Fengjiang Qu and Huimin Zhang in Therapeutic Advances in Medical Oncology

Supplemental Material

sj-jpg-1-tam-10.1177_17588359241248318 – Supplemental material for Prognostic value of pathological nodal burden after neoadjuvant chemotherapy in initially cN0-1 breast cancer patients: a dual-center, 10-year survival analysis

Supplemental material, sj-jpg-1-tam-10.1177_17588359241248318 for Prognostic value of pathological nodal burden after neoadjuvant chemotherapy in initially cN0-1 breast cancer patients: a dual-center, 10-year survival analysis by Amina Maimaitiaili, Zhimin Fan, Jingyi Zhang, Yidi Wang, Bohui Shi, Jie Zheng, Gefei Li, Yuting Zhao, Shengyu Pu, Jianjun He, Fengjiang Qu and Huimin Zhang in Therapeutic Advances in Medical Oncology

Supplemental Material

sj-jpg-2-tam-10.1177_17588359241248318 – Supplemental material for Prognostic value of pathological nodal burden after neoadjuvant chemotherapy in initially cN0-1 breast cancer patients: a dual-center, 10-year survival analysis

Supplemental material, sj-jpg-2-tam-10.1177_17588359241248318 for Prognostic value of pathological nodal burden after neoadjuvant chemotherapy in initially cN0-1 breast cancer patients: a dual-center, 10-year survival analysis by Amina Maimaitiaili, Zhimin Fan, Jingyi Zhang, Yidi Wang, Bohui Shi, Jie Zheng, Gefei Li, Yuting Zhao, Shengyu Pu, Jianjun He, Fengjiang Qu and Huimin Zhang in Therapeutic Advances in Medical Oncology

Supplemental Material

sj-jpg-3-tam-10.1177_17588359241248318 – Supplemental material for Prognostic value of pathological nodal burden after neoadjuvant chemotherapy in initially cN0-1 breast cancer patients: a dual-center, 10-year survival analysis

Supplemental material, sj-jpg-3-tam-10.1177_17588359241248318 for Prognostic value of pathological nodal burden after neoadjuvant chemotherapy in initially cN0-1 breast cancer patients: a dual-center, 10-year survival analysis by Amina Maimaitiaili, Zhimin Fan, Jingyi Zhang, Yidi Wang, Bohui Shi, Jie Zheng, Gefei Li, Yuting Zhao, Shengyu Pu, Jianjun He, Fengjiang Qu and Huimin Zhang in Therapeutic Advances in Medical Oncology

Supplemental Material

sj-jpg-4-tam-10.1177_17588359241248318 – Supplemental material for Prognostic value of pathological nodal burden after neoadjuvant chemotherapy in initially cN0-1 breast cancer patients: a dual-center, 10-year survival analysis

Supplemental material, sj-jpg-4-tam-10.1177_17588359241248318 for Prognostic value of pathological nodal burden after neoadjuvant chemotherapy in initially cN0-1 breast cancer patients: a dual-center, 10-year survival analysis by Amina Maimaitiaili, Zhimin Fan, Jingyi Zhang, Yidi Wang, Bohui Shi, Jie Zheng, Gefei Li, Yuting Zhao, Shengyu Pu, Jianjun He, Fengjiang Qu and Huimin Zhang in Therapeutic Advances in Medical Oncology

Footnotes

Acknowledgements

None.

Declarations

ORCID iD

Amina Maimaitiaili

Supplemental material

Supplemental material for this article is available online.

References

Asaoka

Gandhi

Ishikawa

, et al. Neoadjuvant chemotherapy for breast cancer: past, present, and future. Breast Cancer (Auckl) 2020; 14: 1178223420980377.

Mauri

Pavlidis

Ioannidis

JP.

Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis. J Natl Cancer Inst 2005; 97: 188–194.

Rastogi

Tang

Hassan

, et al. Long-term outcomes of dual vs single HER2-directed neoadjuvant therapy in NSABP B-41. Breast Cancer Res Treat 2023; 199: 243–252.

Montemurro

Nuzzolese

Ponzone

Neoadjuvant or adjuvant chemotherapy in early breast cancer?

Expert Opin Pharmacother 2020; 21: 1071–1082.

Bromham

Schmidt-Hansen

Astin

, et al. Axillary treatment for operable primary breast cancer. Cochrane Database Syst Rev 2017; 1: Cd004561.

Giuliano

Ballman

McCall

, et al. Effect of axillary dissection vs no axillary dissection on 10-year overall survival among women with invasive breast cancer and sentinel node metastasis: the ACOSOG Z0011 (alliance) randomized clinical trial. JAMA 2017; 318: 918–926.

Gao

Zeng

, et al. Axilla lymph node dissection can be safely omitted in patients with 1–2 positive sentinel nodes receiving mastectomy: a large multi-institutional study and a systemic meta-analysis. Breast Cancer Res Treat 2022; 196: 129–141.

Gentilini

Botteri

Sangalli

, et al. Sentinel lymph node biopsy vs no axillary surgery in patients with small breast cancer and negative results on ultrasonography of axillary lymph nodes: the SOUND randomized clinical trial. JAMA Oncol 2023; 9: 1557–1564.

Reimer

Glass

Botteri

, et al. Avoiding axillary sentinel lymph node biopsy after neoadjuvant systemic therapy in breast cancer: rationale for the prospective, multicentric EUBREAST-01 trial. Cancers (Basel) 2020; 12: 3698.

10.

Reimer

Omission of axillary sentinel lymph node biopsy in early invasive breast cancer. Breast 2023; 67: 124–128.

11.

Zetterlund

Celebioglu

Hatschek

, et al. Long-term prognosis in breast cancer is associated with residual disease after neoadjuvant systemic therapy but not with initial nodal status. Br J Surg 2021; 108: 583–589.

12.

Gerber

Schneeweiss

Möbus

, et al. Pathological response in the breast and axillary lymph nodes after neoadjuvant systemic treatment in patients with initially node-positive breast cancer correlates with disease free survival: an exploratory analysis of the GeparOcto trial. Cancers (Basel) 2022; 14: 521.

13.

Werutsky

Untch

Hanusch

, et al. Locoregional recurrence risk after neoadjuvant chemotherapy: a pooled analysis of nine prospective neoadjuvant breast cancer trials. Eur J Cancer 2020; 130: 92–101.

14.

Cirier

Body

Jourdan

M-L

, et al. [Impact of pathological complete response to neoadjuvant chemotherapy in invasive breast cancer according to molecular subtype]. Gynecol Obstet Fertil Senol 2017; 45: 535–544.

15.

Edge

Compton

CC.

The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol 2010; 17: 1471–1474.

16.

Goldhirsch

Winer

Coates

, et al. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol 2013; 24: 2206–2223.

17.

von Elm

Altman

Egger

, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol 2008; 61: 344–349.

18.

de Wild

Simons

Vrancken Peeters

M-JTFD

, et al. De-escalating axillary surgery in node-positive breast cancer treated with neoadjuvant systemic therapy. Breast Care (Basel) 2021; 16: 584–589.

19.

Beck

Morrow

Axillary lymph node dissection: dead or still alive?

Breast 2023; 69: 469–475.

20.

Tadros

Yang

Krishnamurthy

, et al. Identification of patients with documented pathologic complete response in the breast after neoadjuvant chemotherapy for omission of axillary surgery. JAMA Surg 2017; 152: 665–670.

21.

Barron

Hoskin

Day

, et al. Association of low nodal positivity rate among patients with ERBB2-positive or triple-negative breast cancer and breast pathologic complete response to neoadjuvant chemotherapy. JAMA Surg 2018; 153: 1120–1126.

22.

Jatoi

Kunkler

IH.

Omission of sentinel node biopsy for breast cancer: historical context and future perspectives on a modern controversy. Cancer 2021; 127: 4376–4383.

23.

Carleton

Oesterreich

Marroquin

, et al. Is the choosing wisely recommendation for omission of sentinel lymph node biopsy applicable for invasive lobular carcinoma? Ann Surg Oncol 2022; 29: 5379–5382.

24.

Tran

Pack

Mylander

, et al. Ultrasound-based nomogram identifies breast cancer patients unlikely to harbor axillary metastasis: towards selective omission of sentinel lymph node biopsy. Ann Surg Oncol 2020; 27: 2679–2686.

25.

Hersh

King

TA.

De-escalating axillary surgery in early-stage breast cancer. Breast 2022; 62(Suppl. 1): S43–S49.

26.

Ryu

Choi

Park

, et al. Relationship between breast and axillary pathologic complete response according to clinical nodal stage: a Nationwide Study from Korean Breast Cancer Society. J Breast Cancer 2022; 25: 94–105.

27.

Murphy

Hoskin

Heins

CDN

, et al. Preoperative prediction of node-negative disease after neoadjuvant chemotherapy in patients presenting with node-negative or node-positive breast cancer. Ann Surg Oncol 2017; 24: 2518–2525.

28.

von Minckwitz

Untch

Blohmer

J-U

, et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol 2012; 30: 1796–1804.

29.

Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis of individual patient data from ten randomised trials. Lancet Oncol 2018; 19: 27–39.

30.

LeVasseur

Sun

Gondara

, et al. Impact of pathologic complete response on survival after neoadjuvant chemotherapy in early-stage breast cancer: a population-based analysis. J Cancer Res Clin Oncol 2020; 146: 529–536.

31.

Berruti

Amoroso

Gallo

, et al. Pathologic complete response as a potential surrogate for the clinical outcome in patients with breast cancer after neoadjuvant therapy: a meta-regression of 29 randomized prospective studies. J Clin Oncol 2014; 32: 3883–3891.

32.

Saltalamacchia

Bernardo

Quaquarini

Prognostic role of pathological complete response in early stage epithelial solid tumors. Cancer Control 2023; 30: 10732748231161466.

33.

Mougalian

Hernandez

Lei

, et al. Ten-year outcomes of patients with breast cancer with cytologically confirmed axillary lymph node metastases and pathologic complete response after primary systemic chemotherapy. JAMA Oncol 2016; 2: 508–516.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.03 MB

0.47 MB

0.48 MB

0.47 MB

Prognostic value of pathological nodal burden after neoadjuvant chemotherapy in initially cN0-1 breast cancer patients: a dual-center,10-year survival analysis

Abstract

Background:

Objectives:

Design:

Methods:

Results:

Conclusion:

Keywords

Introduction

Materials and methods

Patients

Variables

Treatment

Follow-up

Statistical analysis

Results

Clinicopathological factors

Conversion of axillary staging after neoadjuvant therapy

Survival outcomes

Multivariable modeling

Discussion

Conclusion

Supplemental Material

sj-docx-5-tam-10.1177_17588359241248318 – Supplemental material for Prognostic value of pathological nodal burden after neoadjuvant chemotherapy in initially cN0-1 breast cancer patients: a dual-center, 10-year survival analysis

Supplemental Material

sj-jpg-1-tam-10.1177_17588359241248318 – Supplemental material for Prognostic value of pathological nodal burden after neoadjuvant chemotherapy in initially cN0-1 breast cancer patients: a dual-center, 10-year survival analysis

Supplemental Material

sj-jpg-2-tam-10.1177_17588359241248318 – Supplemental material for Prognostic value of pathological nodal burden after neoadjuvant chemotherapy in initially cN0-1 breast cancer patients: a dual-center, 10-year survival analysis

Supplemental Material

sj-jpg-3-tam-10.1177_17588359241248318 – Supplemental material for Prognostic value of pathological nodal burden after neoadjuvant chemotherapy in initially cN0-1 breast cancer patients: a dual-center, 10-year survival analysis

Supplemental Material

sj-jpg-4-tam-10.1177_17588359241248318 – Supplemental material for Prognostic value of pathological nodal burden after neoadjuvant chemotherapy in initially cN0-1 breast cancer patients: a dual-center, 10-year survival analysis

Footnotes

Acknowledgements

Declarations

ORCID iD

Supplemental material

References

Supplementary Material