
==== Front
Sci Rep
Sci Rep
Scientific Reports
2045-2322
Nature Publishing Group UK London

39227511
70874
10.1038/s41598-024-70874-w
Article
Optimal management of breast cancer with physical exam negative/radiological abnormal axilla
Bi Zhao 1
Li Lei 2
Chen Peng 1
Li Zhe-Dong 1
Qiu Peng-Fei qiu.pf@outlook.com

1
Wang Yong-Sheng yswang@sdfmu.edu.cn

1
1 grid.410587.f 0000 0004 6479 2668 Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Ji Yan Road 440, Jinan, 250000 Shandong People’s Republic of China
2 https://ror.org/046x15q93 grid.413150.2 0000 0004 0369 0780 The 970th Hospital of the Chinese People’s Liberation Army, Wehai, 264200 Shandong People’s Republic of China
3 9 2024
3 9 2024
2024
14 2050423 5 2024
22 8 2024
© The Author(s) 2024
2024
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For breast cancer patients with physical exam node negative but radiological finding node abnormal (cN0/rNa), the NCCN and ASCO guidelines recommend sentinel lymph node biopsy (SLNB) as the first-line axillary staging. However, patients who undergo surgery firstly may be upstaged to pathological II–III status, and these patients happen to be the adaptive population of neoadjuvant therapy (NAT). There is no consensus on the optimal management of cN0/rNa patients. The aim is to explore the optimal management strategy of these patients. We performed a retrospective real-world study of 1414 cN0/rNa patients from June 2014 to October 2022. There were 1003 patients underwent surgery first and 411 patients underwent surgery after NAT. We analyzed the real-world conditions of these patients, compared axilla tumor burden between these two groups. In addition, we compared benefit ratio of axillary surgery and regional nodal irradiation (RNI) de-escalation under the two strategies. Among 1003 patients underwent surgery first, the positive and negative rates of fine needle aspiration (FNA) were 18.5% and 81.5%, respectively. There were 66.1% had ≤ 2 lymph nodes+. There were 40.8% of FNA+ patients could be exempted from ALND underwent surgery first. In 411 patients underwent surgery after NAT, the FNA positive and negative rates were 60.8% and 49.2%, respectively. There were 54.4% of FNA+ patients achieved axilla pathologic complete response (apCR) and could omit ALND after NAT. The apCR was 67.3% in HER2+/TNBC subtypes. According to the NSABP-B51 trial, there were 0 and 54.4% of FNA+ patients could omit RNI among surgery first and after NAT, respectively. Among 1–2 sentinel lymph node (SLN)-positive patients underwent surgery first, with a median follow-up 49 months, there was no difference of survival benefit between SLNB-only and SLNB-ALND. Compared with 1–2 SLN+ patients without RNI, RNI could bring better invasive disease-free survival (97.38% vs. 89.36%, P = 0.046) and breast cancer special survival (100% vs. 94.68%, P = 0.020). It is safe to perform SLNB omitting ALND when detected 1–2 positive SLNs in cN0/rNa patients. Patients with HER2+/TNBC subtypes underwent surgery after NAT had more chance to benefit from dual de-escalation, including axillary surgery and RNI de-escalation.

Keywords

Breast cancer
Surgery
Neoadjuvant therapy
Sentinel lymph node biopsy
Regional nodal irradiation
Subject terms

Cancer
Cancer
http://dx.doi.org/10.13039/501100002858 China Postdoctoral Science Foundation 2022M721987 issue-copyright-statement© Springer Nature Limited 2024
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pmcIntroduction

The evidence-based medical evidence supported that sentinel lymph node biopsy (SLNB) could replace safely axillary lymph node dissection (ALND) in patients with limited positive sentinel lymph node (SLN). SLNB has become the standard staging technique for patients with clinical nodal negative (cN0) disease. It is worth noting that the definition of cN0 is only focused on physical exam node negative in NSABP-B32, ACOSOG Z0011, and AMAROS trials, while the radiological findings are not required to be negative1–3. Earlier and smaller ALN metastases are detected with the increasing sensitivity of axillary imaging technology. And more patients with physical exam node negative but are found suspicious radiological abnormal nodes (cN0/rNa)4. The axillary treatment strategy of patients with cN0/rNa disease has gradually become a hot topic of controversy among clinicians.

According to the traditional viewpoint, SLNB is the standard treatment for those patients. The American Society of Clinical Oncology (ASCO) guideline recommend that patients who are physical exam node negative but are found to be radiological node abnormal with or without confirmatory biopsy can be offered SLNB as first-line axillary staging5. The National Comprehensive Cancer Network (NCCN) guideline also recommend SLNB for patients with no palpable lymph node at diagnosis or ≤ 2 suspicious lymph nodes on imaging or ≤ 2 positive lymph nodes confirmed by needle biopsy6. However, these patients need to receive regional nodal irradiation (RNI) as the supplement of axillary de-escalation surgery. In Chinese Anti-Cancer Association guideline, most experts believe that for patients who are cN0/rNa with fine needle aspiration (FNA) positive. However, these patients would upstage to pathological II–III status if undergo surgery firstly, and they happen to be the adaptive population of neoadjuvant therapy (NAT)7. Effective chemotherapy regimens, as well as targeted therapies in the neoadjuvant setting, have increased the rate of axillary pathologic complete response (apCR) after NAT. Patients achieved apCR had more chance to avoid RNI and ALND after NAT8. The optimal management of cN0/rNa patients become the focus of current research in clinical practice. However, there is no consensus on the optimal management of cN0/rNa patients. Therefore, the aim of this study is to analyze the real-world conditions of cN0/rNa patients in order to explore the optimal management strategy for these patients.

Methods

Eligibility criteria and study population

We retrospectively surveyed adult patients with newly diagnosed primary breast cancer who were treated from June 2014 to 2022 at Shandong Cancer Hospital. The inclusion criteria including: (1) patients had cN0/rNa disease according to the World Health Organization criteria, (2) had complete clinical, pathology, and follow-up data. Patients were not eligible if they had a medical history of previous malignancy, bilateral breast cancer, had T4 disease for the primary breast cancer, or had received treatment of the axilla by surgery or radiotherapy. The wishes of doctors and patients were decided whether to accept surgery first or after NAT. Finally, the study was divided into two cohorts, of which 1003 patients underwent surgery first and 411 patients underwent NAT before surgery.

The primary end-point is to compare the axilla tumor burden between surgery first and after NAT group. In addition, we compare the de-escalation benefit ratio of axillary surgery and RNI under the two strategies.

Informed consent was not required because this study was a retrospective study, which is a retrospective analysis of clinical data with no relevant to human biological ethic problems. The need of informed consent was waived by the ethical committee of the Shandong Cancer Hospital. The study protocol was approved by the Institutional Review Board of the Shandong Cancer Hospital and the study was performed in accordance with the principles of the Declaration of Helsinki. All methods were performed in accordance with the relevant guidelines and regulations. The work has been reported in line with the STROCSS criteria9.

Pathological evaluation

All patients received core biopsy of breast tumor taken by ultrasound. The pathological evaluation including hematoxylin and eosin and immunohistochemical staining. Positive hormone receptor (HR) status was defined as one percent of tumor cells expressing the receptor. HER-2 status was determined based on the ASCO/College of American Pathologists guidelines. Positive HER-2 was defined as HER-2 over-expression (3 +) detected by immune-histochemical staining or fluorescence in situ hybridization. To accurately evaluate the effect of molecular subtypes, patients were further classified into HR positive/HER-2 negative (HR+/HER2 −), triple negative (TNBC) and HER-2 positive (HER2 +) subtype.

Each SLN was examined at multiple histologic levels. Tumor deposits were categorized as isolated tumor cells (< 0.2 mm), micro-metastases (0.2–2 mm), or macro-metastases (> 2 mm). In this study, we defined macro-metastases and micro-metastases as positive lymph nodes.

The treatment of axillary lymph nodes (ALNs)

Physical exam of axilla region

Two breast experienced surgeons who had 12 and 15 years of experience respectively performed preoperative axillary physical examination. The physical examination result of axilla was regarded as negative when all of those two experienced surgeons did not find enlarged ALNs. To evaluate the intra-observer agreement for axillary physical examination, one surgeon repeated evaluating the same 30 patients at a time interval of 1 week. Inter-observer agreement was tested by two surgeons.

Conventional axillary ultrasound (US) examinations

One of five radiologists who had 10, 6, 3, 2, and 2 years of experience in breast US respectively performed preoperative axillary US with Siemens S2000 ultrasound scanner (Siemens Healthineers, Mountain View, CA, USA) equipped with a 4–9 MHz linear array transducer. After performing whole-breast US, the same radiologists performed axillary US routinely and recorded suspicious US features of ALN10. Suspicious US features of ALN include the ratio of long axis diameter to short axis diameter < 2, diffuse cortical thickening > 3 mm, focal cortical bulge > 3 mm, eccentric cortical thickening > 3 mm, rounded hypoechoic node complete or partial effacement of the fatty hilum, nonhilar cortical blood flow on color Doppler images, complete or partial replacement of the node with an ill-defined or irregular mass and microcalcifications in the node (Fig. 1)10. The result of axillary US evaluated by the experienced radiologist was regarded as abnormal as long as at least one suspicious US finding was found. The result of axillary US was regarded as negative when no suspicious findings of ALN were found. To evaluate the intra-observer agreement for axillary US, one radiologist repeated evaluating the same 30 ALNs at a time interval of 1 week. Inter-observer agreement was tested by two radiologists, evaluating the same ALNs independently in another 30 ALNs.Fig. 1 Suspicious US of axillary lymph nodes.

FNA of suspicious ALNs

If patients had multiple suspicious ALNs on US, the largest ALN was selected for accessing by FNA prior to treatment according to the wishes of doctors and patients. Repeated negative pressure aspiration was performed for the abnormal parts of the ALN guided by ultrasound, and the biopsy specimens were examined by cytology. For patients with FNA positive, metal and radioactive marker clips were placed in positive lymph nodes before NAT.

The surgery of axilla

According to the newest NCCN guideline, the axillary surgery is based on the doctors’ decision and patients’ wishes. The axillary surgery included SLNB and ALND. The sentinel node procedure had to be done with a Technetium-99 m colloid, preferably combined with blue dye. Among lymph nodes including radioactive or blue-stained lymph nodes were excised as SLNs for histopathological evaluation. Each SLN was examined at multiple histologic levels. ALND was defined as a dissection of at least ten nodes from anatomical levels I and II. Local treatment of the breast included breast-conserving surgery (BCS) and mastectomy.

Systemic therapy regimens

The actual chemotherapies, target therapies and endocrine therapies were applied at the discretion of the treating multidisciplinary team. To obtain an objective criterion for the administration of adjuvant therapy, we used the clinicopathologic risk as predicted by Adjuvant! online system and a predefined cut off value of clinical high-and low-risk patients. Surgery was performed within 2 weeks after the end of NAT.

The radiotherapy

The target fields of postoperative radiotherapy were determined by the radiotherapy doctor. In principle, the target field after BCS was the whole breast + tumor bed ± RNI. The target field after mastectomy was chest wall ± RNI11.

Follow-up

We performed follow-up for patients performed surgery first. Patients were followed up via telephone manner. The median follow-up time was 49 months (7–110 months) from the first postoperative day to October 2023. Data with observed end-point events (recurrence or death) during the study period were recorded as complete data, and data that were lost to follow-up or did not meet the study endpoint were recorded as deleted data. The invasive disease-free survival (iDFS) was defined as the time from the first postoperative day to the first occurrence of local recurrence or distant metastasis. The axillary recurrence-free survival (ARFS) was defined as the time from the first postoperative day to axillary recurrence of breast cancer. The breast cancer special survival (BCSS) was defined as the time from the first postoperative day to breast cancer-related death. And overall survival (OS) was defined as the time from the first postoperative day to death.

Data collection

The clinical and histopathologic data were obtained from the medical records. Clinical data included patients’ age, ALN size from US, and tumor location. Histopathologic results of breast cancer included tumor type, ER status, PR status, HER-2, and Ki-67 index. Histopathologic results of SLNB and ALND including the total number of resected lymph nodes and total number of positive nodes were recorded.

Statistical analysis

Pearson chi-square test or Fisher exact test was used to perform univariate analysis on categorical variables. Multivariable logistic regression analysis was conducted by using backward stepwise analysis. The survival analysis was performed by Kaplan–Meier test. Statistical analysis were performed using SPSS Statistics 22.0 software (IBM Corporation, Armonk, NY, USA) and R version 3.3.3 software (The R Foundation for Statistical Computing, Austria, Vienna). A P < 0.05 was considered statistically significant.

Results

The characteristics of enrolled patients

The consort diagram of the study was illustrated in Fig. 2. Based on the database, we identified a total of 5878 clinical node negative breast cancer patients who underwent surgery between June 2014 and 2022. After excluding cases lacking medical examination data, a total of 1414 patients with cN0/rN+ disease was included in the final analysis. The study was divided into two cohorts, of which 1003 patients underwent surgery first and 411 patients underwent NAT before surgery.Fig. 2 The consort diagram of the study.

The demographic and clinical-pathological characteristics were summarized in Table 1. Among 1003 patients underwent surgery first, the median age of these patients was 48 years (range 21–76 years). There were 43.3%, 53.0%, and 3.7% of patients had pT1, pT2, and pT3 tumor. Less than half of patients (33.9%) have more than 2 positive ALNs. Notably, among these population, 601 (59.9%), 291 (29.0%), and 111 (11.1%) patients had HR+/HER2− , HER2+, and TNBC subtypes, respectively. Among 411 patients underwent surgery after NAT, the median age of these patients was 44 years (range 20–68 years). There were 44.3%, 38.0%, 14.8%, and 2.9% of patients had ypT0, ypT1, ypT2, and ypT3 tumor. More than half of patients (63.0%) have negative ALNs. Among these population, 143 (34.8%), 170 (41.4%), and 98 (23.8%) patients had HR+/HER2− , HER2+, and TNBC subtypes, respectively.Table 1 Clinical and pathological characteristics of the enrolled patients.

Characteristics	Surgery first (n = 1003)	NAT followed by surgery (n = 411)	P value	
Age			0.011	
 < 50	476 (47.5%)	223 (54.3%)		
 ≥ 50	527 (52.5%)	188 (45.7%)		
Laterality			0.119	
Right	460 (45.8%)	193 (47.0%)		
Left	543 (54.2%)	218 (53.0%)		
FNA			0.009	
Positive	186 (18.5%)	250 (60.8%)		
Negative	817 (81.5%)	161 (39.2%)		
Histopathologic type			0.828	
Ductal	966 (96.3%)	400 (97.3%)		
Lobular	14 (1.4%)	4 (1.0%)		
Other	23 (2.3%)	7 (1.7%)		
Histologic grade			0.505	
Grade 1	17 (1.7%)	8 (2.1%)		
Grade 2	534 (53.3%)	202 (49.2%)		
Grade 3	379 (37.8)	174 (42.3%)		
Unknow	73 (7.2%)	27 (6.4%)		
Subtypes			0.045	
HR+/HER2− 	601 (59.9%)	143 (34.8%)		
HER2+	291 (29.0%)	170 (41.4%)		
TNBC	111 (11.1%)	98 (23.8%)		
Pathological tumor stage			 < 0.001	
pT0 stage	0 (0)	182 (44.3%)		
pT1 stage	434 (43.3%)	156 (38.0%)		
pT2 stage	536 (53.0%)	61 (14.8%)		
pT3 stage	33 (3.7%)	12 (2.9%)		
No. of positive ALN			 < 0.001	
0	334 (33.3%)	259 (63.0%)		
1–2	329 (32.8%)	75 (18.3%)		
 ≥ 3	340 (33.9%)	77 (18.7%)		
Breast surgery			0.428	
Mastectomy	825 (82.3%)	330 (80.3%)		
BCS	178 (17.7%)	81 (19.7%)		
If omitting ALND				
Yes	663 (66.1%)	259 (63.0%)	0.099	
No	340 (33.9%)	152 (37.0%)		
If omitting RNI			0.004	
Yes	334 (33.3%)	259 (63.0%)		
No	669 (66.7%)	152 (37.0%)		

Analysis of axillary tumor burden in patients with different FNA states

The axillary tumor burden among patients performed surgery firstly

Among 1003 underwent surgery first, the percentages of FNA positive and negative were 18.5% and 81.5%, respectively. The axillary tumor burden between different FNA status was shown in Table 2. There were 66.1% (663/1003) of patients had ≤ 2 positive ALN and could omit ALND. In patients receiving FNA, sensitivity was 61.2% and specificity was 100%.Table 2 Axillary tumor burden in patients performed surgery first.

Items	ALN+	No. (%)	stage	No. (%)	
FNA positive (n = 186)	
 HER2+/TNBC (n = 74)	
	1–2	28 (37.8%)	II	33 (44.2%)	
	 > 2	46 (62.2%)	III	41 (55.8%)	
 HR+/HER2− (n = 112)	
	1–2	49 (43.7%)	II	64 (57.1%)	
	 > 2	63 (56.3%)	III	48 (42.9%)	
FNA negative (n = 817)	
 HER2+/TNBC (n = 328)	
	0	161 (49.1%)	I	57 (17.4%)	
	1–2	95 (29.0%)	II	209 (63.7%)	
	 > 2	72 (21.9%)	III	52 (15.9%)	
 HR+/HER2− (n = 489)	
	0	173 (35.4%)	I	90 (18.4%)	
	1–2	157 (32.1%)	II	260 (53.2%)	
	 > 2	159 (32.5%)	III	139 (28.4%)	

Among the FNA positive patients, 39.8% (74/186) of them had HER2+/TNBC subtypes and 60.2% (112/186) had HR+/HER2− subtypes. The proportion of 1–2 positive ALN was 40.8% (76/186). The proportion of 1–2 ALN+ and > 2 ALN+ was 37.8% and 62.2% in HER2+/TNBC patients, respectively.

Among the FNA negative patients, 40.1% (328/817) had HER2+/TNBC subtypes, of which 81.4% had stage II and above, and these patients were also the preferred population for NAT. There were 59.9% (489/817) of patients had HR+/HER2− subtypes. The incidence of negative ALN and 1–2 positive ALN was 41.1% (336/817) and 27.5% (225/817), respectively. The proportion of ALN-, 1–2 ALN+ and > 2 ALN+ was 49.1%, 29.0% and 21.9% in HER2+/TNBC patients, respectively.

The axillary tumor burden among patients performed surgery after NAT

Among 411 underwent surgery after NAT, the percentages of FNA positive, and negative were 60.8% and 39.2%, respectively. The axillary tumor burden between different FNA status was shown in Table 3. There were 63.0% (259/411) of patients had negative ALN and could omit ALND.Table 3 Axillary tumor burden in patients with NAT followed by surgery.

Items	All subtypes	HR+/HER2− 	HER-2+	TNBC	
FNA positive	
 ALN+	136 (54.4%)	63 (67.0%)	25 (25.5%)	26 (44.8%)	
 ALN-	114 (45.6%)	31 (33.0%)	73 (74.5%)	32 (55.2%)	
FNA negative	
 ALN+	38 (23.6%)	26 (53.1%)	5 (9.3%)	7 (12.1%)	
 ALN-	123 (76.4%)	23 (46.9%)	49 (90.7%)	51 (87.9%)	

In patients with FNA positive disease, 62.4% (156/250) of them had HER2+/TNBC subtypes and 37.6% (94/250) had HR+/HER2− subtypes. The proportion of apCR after surgery was 54.4% (136/250), and it was 67.3% (105/156) and 33.0% (31/94) among HER2+/TNBC and HR+/HER2− subtypes, respectively.

Among the FNA negative patients, 69.6% (112/161) of them had HER2+/TNBC subtypes, 30.4% (49/161) had HR+/HER2− subtypes. The incidence of negative ALN after surgery was 76.4% (123/161), and it was 89.3% (100/112) and 47.0% (23/49) among HER2+/TNBC and HR+/HER2− subtypes, respectively.

The above results showed that there were about 40% of patients with FNA positive can be exempted from ALND if performed surgery firstly. However, more than half of patients with FNA positive can benefit from axillary surgery de-escalation after NAT. And the proportion of apCR after NAT can exceed 60% in HER2+/TNBC patients. According to the results of NSABP-B51 trial12, in the whole population, there were 33.3% and 63.0% of patients could omit RNI among patients performed surgery first and after NAT, respectively. In FNA-positive population, there were 0 and 54.4% of patients could omit RNI among patients performed surgery first and after NAT, respectively. It was suggested that patients underwent surgery after NAT had more chance to benefit from dual de-escalation, including axillary surgery and RNI de-escalation.

The feasibility of SLNB among cN0/rNa patients performed surgery first

The overall data of SLNB

A total of 748 patients received SLNB, and 236 and 512 patients received SLNB only and SLNB-ALND, respectively. The clinical-pathological features of these patients were showed in Table 4. Among 236 patients who only received SLNB, the median SLN was 3 (1–6), and the SLN metastasis rate was 23.7% (56/236) (1 case had micro-metastasis). The proportion of SLN negative, 1–2 SLN positive and ≥ 3 SLN positive were 76.3% (180/236), 22.5% (53/236) and 1.2% (3/236), respectively.Table 4 Clinical and pathological characteristics of the patients received SLNB.

Characteristics	SLNB (n = 236)	SLNB-ALND (n = 512)	P value	
Age			0.011	
 < 50	123 (52.1%)	233 (45.5%)		
 ≥ 50	113 (47.9%)	279 (54.5%)		
Laterality			0.119	
Right	111 (47.0%)	241 (47.1%)		
Left	125 (53.0%)	271 (52.9%)		
FNA			0.739	
Positive	2 (0.9%)	63 (12.3%)		
Negative	234 (99.1%)	449 (87.7%)		
Histopathologic type			0.828	
Ductal	226 (95.8%)	494 (96.5%)		
Lobular	4 (1.7%)	8 (1.8%)		
Other	6 (2.5%)	10 (1.7%)		
Histologic grade			0.505	
Grade 1	5 (2.1%)	9 (1.7%)		
Grade 2	116 (49.2%)	273 (53.3%)		
Grade 3	100 (42.4%)	194 (37.9%)		
Unknow	15 (6.3%)	36 (7.1%)		
Subtypes			0.465	
HR+/HER2− 	143 (60.6%)	307 (59.9%)		
HER2+	54 (22.9%)	161 (31.5%)		
TNBC	39 (16.5%)	44 (8.6%)		
Pathological tumor stage			0.473	
pT1 stage	116 (49.1%)	232 (45.3%)		
pT2 stage	113 (47.9%)	267 (52.2%)		
pT3 stage	7 (3.0%)	13 (2.5%)		
No. of positive SLN			 < 0.001	
0	180 (76.3%)	170 (33.2%)		
1	41 (17.4%)	186 (36.3%)		
2	12 (5.1%)	104 (20.3%)		
 ≥ 3	3 (1.2%)	52 (10.2%)		
Breast surgery			0.028	
Mastectomy	141 (59.7%)	455 (88.8%)		
BCS	95 (40.3%)	57 (11.2%)		
pN(sn)/pN			 < 0.001	
pN0	180 (76.3%)	130 (25.4%)		
pN1	56 (23.7%)	246 (48.0%)		
pN2		87 (15.8%)		
pN3		49 (10.8%)		

In the SLNB-ALND subgroup, the median number of SLN was 2 (1–6), and the SLN metastasis rate was 66.8% (342/512) (2 cases had micro-metastasis). There were 56.6% (290/512) of patients had only 1–2 positive SLNs, and 10.2% (52/512) of patients had more than 3 positive SLNs. Among patients with 1–2 SLN-positive disease, 56.9% (165/290) of them had non-SLN metastases.

The incidence of ALN positive ≤ 2 and > 2 was 63.5% (325/512) and 36.5% (187/512), respectively. In FNA positive group, the proportion of ALN positive ≤ 2 and > 2 was 44.4% (28/63) and 55.6% (35/63), respectively. In FNA positive group, the proportion of ALN positive ≤ 2 and > 2 was 66.1% (297/449) and 33.9% (152/449), respectively.

The survival data of patients with 1–2 SLN positive disease

We made follow-up of 1–2 SLN positive patients, and the rate of lost to follow-up was 6.9%. The clinical-pathological characteristics of 1–2 SLN-positive patients were shown in Table 5. Among 1–2 SLN positive patients, only 1 case of ipsilateral axillary recurrence was observed in the SLNB-only group (n = 53), and no death related events occurred. In the SLNB-ALND group (n = 290), we observed 11 cases of recurrence and metastasis (1 ipsilateral axillary recurrence with distant metastasis, 1 ipsilateral supravicular lymph node metastasis, 9 distant metastasis) and 8 deaths (5 of which were breast cancer-related deaths). There was no statistical difference between SLNB-only group and SLNB-ALND group in IDFS (98.11% vs. 94.48%; HR = 0.58, 95%CI 0.13–2.58), ARFS (98.11% vs. 99.66%; HR = 41.35, 95%CI 0.55–3111), BCSS (100% vs. 98.28%; HR = 0.33, 95%CI 0.02–7.01) and OS (100% vs. 97.24%; HR = 0.33, 95%CI 0.03–3.24) (Fig. 3; all P > 0.05).Table 5 Clinical-pathological data of 1–2 SLN-positive patients in surgery first group.

Characteristics	SLNB (n = 53)	SLNB-ALND (n = 290)	P value	
Age			0.020	
 < 50	32 (74.4%)	125 (43.1%)		
 ≥ 50	21 (25.6%)	165 (56.9%)		
Laterality			0.091	
Right	20 (37.7%)	146 (50.33%)		
Left	33 (62.3%)	144 (49.7%)		
FNA			0.014	
Positive	2 (3.8%)	44 (15.2%)		
Negative	51 (96.2%)	246 (84.8%)		
Histopathologic type			0.015	
Ductal	48 (90.6%)	281 (96.9%)		
Lobular	2 (3.8%)	5 (1.7%)		
Other	3 (5.6%)	4 (1.4%)		
Histologic grade			0.612	
Grade 1	1 (1.9%)	2 (0.7%)		
Grade 2	27 (50.9%)	169 (58.3%)		
Grade 3	18 (33.9%)	101 (34.8%)		
Unknow	7 (13.3%)	18 (6.2%)		
Subtypes			0.272	
HR+/HER2− 	37 (69.8%)	190 (57.9%)		
HER2+	10 (18.8%)	83 (28.6%)		
TNBC	6 (11.4%)	17 (13.5%)		
Pathological tumor stage			0.751	
pT1 stage	25 (47.2%)	140 (48.3%)		
pT2 stage	26 (49.1%)	144 (49.7%)		
pT3 stage	2 (3.7%)	6 (2.0%)		
No. of positive ALN			0.099	
0	0	0		
1–2	53 (100%)	259 (89.3%)		
 ≥ 3	0	31 (10.7%)		
Breast surgery			 < 0.001	
Mastectomy	32 (60.4%)	256 (88.3%)		
BCS	21 (39.6%)	34 (11.7%)		
No. of SLN positive			0.016	
1	43 (81.1%)	186 (64.1%)		
2	10 (18.9%)	104 (35.9%)		

Fig. 3 The survival analysis between SLNB-only and SLNB-ALND group among patients with 1–2 positive SLN.

Among 1–2 SLN-positive patients with ALND, there was no significant difference in OS (98.95% vs. 93.61%, P = 0.10) and ARFS (100% vs.98.93%, P = 0.18) between patients with and without RNI. However, IDFS (97.38% vs. 89.36%, P = 0.046) and BCSS (100% vs. 94.68%, P = 0.02) in the RNI group were superior to those without RNI group (Fig. 4).Fig. 4 The survival analysis between patients with and without RNI among 1–2 SLN-positive patients with ALND.

These results suggested that for cN0/rNa patients with or without positive FNA, it is safe and feasible to perform SLNB omitting ALND when detected 1–2 positive SLNs. However, SLN-positive patients omitting ALND still need RNI as the supplement of axillary de-escalation surgery. For patients with ALN positive, RNI can still provide survival benefits even performed ALND.

Discussion

This study analyzed the real-world conditions of a total of 1414 patients with cN0/iNa disease. In cN0/rNa patients performed surgery first, with a median follow-up time of 49 months, ALND did not affect the IDFS, ARFS, BCSS or OS when detected 1–2 positive SLNs. It suggested that it was safe to perform SLNB omitting ALND when detected 1–2 positive SLNs in patients with cN0/rNa disease. Among patients undergoing surgery first, the proportion of ≤ 2 positive ALNs in FNA positive group was 41.4%, which could benefit from axillary surgery de-escalation. However, these patients still need RNI as the supplement of axillary de-escalation surgery. Among patients underwent surgery after NAT, the proportion of negative ALN was 54.4%. And it was 67.3% in HER2+/TNBC subgroup. These patients achieved apCR not only could benefit from axillary surgery de-escalation, but also had chance to be exempted from postoperative RNI. Therefore, this study indicated that NAT could provide cN0/rNa patients with a better strategy of dual de-escalation management, including the de-escalation of both axillary surgery and RNI.

The benefit of axillary surgery de-escalation

The axillary surgery de-escalation in patients underwent surgery first

The IBCSG 23–01, ACOSOG Z0011 and AMAROS trials provided evidence support for omitting ALND in patients with low SLN tumor burden2,3,13. These studies only focused on physical examination negative, while the imaging tests were not required to be negative. It raised a new scientific question in the current clinical practice: was SLNB recommended for patients with cN0/rNa disease? A meta-analysis comprising 4271 patients assessed the proportion of patients with involved nodes on pre-operative axillary ultrasound, which would fit low axillary burden criteria. The cumulative probabilities revealed that 56.8% of US positive patients have less than two involved nodes14. These patients may be overtreated if they receive ALND. Therefore, the ASCO guideline recommended that patients who were cN0/rNa with or without confirmatory biopsy could be offered SLNB as first-line axillary staging5. At the same time, the NCCN guideline also recommended that SLNB was applicable for patients with cN0/rNa disease if they meet all the ACOSOG Z0011 trial criteria listed as well as low tumor burden (image-detected disease is not apparent on clinical exam and appears to be limited to one or two axillary nodes)6. These patients could omit ALND when detect 1–2 positive SLNs. In our study, the follow-up results also showed that the axillary surgery did not affect the IDFS, ARFS, BCSS and OS when cN0/rNa patients detected 1–2 positive SLNs. The follow-up results support that it is safe to perform SLNB in patients with cN0/rNa disease.

The axillary surgery de-escalation in patients underwent surgery after NAT

NAT is currently administered to patients with locally advanced breast cancers, to breast cancer of poor prognosis (HER2+/TN tumors, or with nodal involvement and/or high proliferation rates), or to early-stage breast cancer having an indication of systemic therapy. The efficacy of NAT should be evaluated periodically15,16. The ASCO guideline recommend that axillary de-escalation surgery can be achieved by placing a biopsy clip into the biopsied positive node and localizing it at surgery along with SLNB or, performing SLNB with dual tracer and excising at least three SLNs17. According to the first result of OPBC05 trial, patients need to receive ALND when they had any residual disease after NAT, including micro-metastasis, and macro-metastasis18.

In our study, there were 63.0% of patients had negative ALN after NAT. The proportions of negative ALN after NAT were 76.5% and 37.8%, among patients with HER2+/TNBC and HR+/HER2− subgroups, respectively. So, more than 60% of patients who underwent surgery after NAT could reach the axillary surgery de-escalation. And HER2+/TNBC patients had more chance to reach the axillary surgery de-escalation after NAT. For FNA-positive patients, the proportion of axillary surgery de-escalation was only 40.8% if surgery first, while the proportion would increase into 54.4% when performed surgery after NAT. And more than 60% of HER2+/TNBC patients could omit ALND. Therefore, NAT can benefit more patients from axillary surgery de-escalation, especially for HER2+/TNBC patients. In addition, in cN0/iNa patients with FNA negative disease, there were 89.3% of HER2+/TNBC patients could achieve apCR. These patients might be safely omitted SLNB after NAT.

The benefit of RNI de-escalation

The Z0011 and AMAROS trials have shown that omission of ALND, followed by RNI, is safe and produces no difference in axillary local recurrence rate (LRR) among patients with limited SLNs involvement2,3. Recent data from the EBCTCG meta-analysis also showed that in women with node positive breast cancer, the addition of RNI could reduce LRR, overall recurrence (any first recurrence, irrespective of whether locoregional or distant) and breast cancer mortality19. In our study, the IDFS and BCSS in the RNI group were superior to those without RNI group, even after ALND. These findings demonstrated to some extent the role of RNI in local regional control in node-positive patients. For patients with cN0/rNa, 63.5% of them could benefit from axillary surgery de-escalation if surgery first, and 33.3% of them with ALN negative could benefit from RNI de-escalation. Therefore, only one-third of patients could benefit from dual de-escalation if surgery first, including axillary surgery and RNI de-escalation. However, there were no patients with FNA-positive could except from RNI if performed surgery first.

In patients with NAT, the indication and target volumes for RNI need to be individualized based on the initial tumor stage and tumors response to treatment5. The NCCN guideline recommend that in patients treated with NAT, adjuvant radiotherapy was based on the maximal disease stage at diagnosis and pathology results after NAT6. The 2023 St.Gallen International Consensus Conference strongly endorsed that the extent of RNI could be individualized by several risk factors: (1) lowest-risk patients (cN0 at baseline with apCR after NAT) not required RNI; (2) intermediate-risk patients (cN1 at baseline with apCR after NAT; or without ALND) receiving exclusive level 1–2 axillary radiotherapy; (3) highest-risk patients (cN2-3 at baseline with apCR after NAT ; or those with residual nodal involvement after NAT) receiving RNI to level 1–3 ALN, and to supraclavicular and internal mammary nodes20. The NSABP B-51 trial evaluated whether RNI significantly improves survival in cN1 patients who are found to be ypN0 after NAT11. The first result of B-51 trial showed that RNI after surgery did not improve the 5-year invasive breast cancer recurrence-free interval, DFS or OS11. These findings suggested that it was feasible to exempt from RNI after NAT for patients with cN0/rN+ and convert ypN0 after NAT. In our study, the proportion of negative ALN after NAT was 63.0%, and it was more than 70% in HER2+/TNBC subgroup. There were 54.4% of FNA-positive patients could except from RNI after NAT. Therefore, compared with surgery first, more patients could benefit from dual de-escalation when performed surgery after NAT.

The optimal management of HR+/HER2− patients with cN0/rN+ disease

Our study showed that the apCR rate after NAT was lower in HR+/HER2− subgroup, and it was only 33.0% for FNA-positive patients. These patients benefited less from chemotherapy. Neoadjuvant endocrine therapy (NET) has gained more and more attention21–23. The 2023 St. Gallen international consensus recommended a short course of NET (2–4 weeks) before surgery can provide valuable information for avoiding chemotherapy20. Patients with cN0/rNa disease always have the low axilla tumor burden, especially in FNA-positive patients, approximately 78.8% of them have 1–3 positive ALNs. Genomic tests, such as 70-gene test (MammaPrint) and 21-gene test (Oncotype DX) could be used to inform decisions on withholding adjuvant chemotherapy in HR+ /HER2− patients with 1–3 positive ALNs24,25. However, genomic tests can only classified patients as high and low risk according to the recurrence score (RS), it could not predict the efficacy of endocrine therapy (ET). According to the genomic tests, they would avoid adjuvant chemotherapy if they had low-RS. However, they would be recurrence in the future if they were resistant to ET. Therefore, NET has a better advantage than genomic tests. It can individually evaluate the efficacy of ET. The 2021 St. Gallen Consensus also supported NET for HR+/HER2− patients in low-genomic risk groups26. Therefore, we recommend to adopt an “adaptive design” for high-risk, early-stage HR+/HER2− patients with cN0/rNa disease. Patients receive NET firstly. Then, those patients could not benefit from NET can be screened out according to the evaluation of Ki-67 index. Finally, those patients with insensitive to NET, would receive neoadjuvant chemotherapy or even combined with immune checkpoint inhibitors to achieve a better therapeutic outcome.

In our study, patients received the same systemic treatment strategy regardless of whether they performed surgery first or after NAT. The cost benefit of systemic therapy had no difference between these two groups. In terms of surgical treatment strategy, because all patients have received SLNB and/or ALND, there is less cost benefit difference of surgery in these two groups. We think the most important is the cost benefit of RNI, because more patients could omit RNI after NAT. Therefore, NAT could bring more cost-effectiveness. For patients with cN0/rNa disease, we make the following recommendation: (1) Patients need to undergo a biopsy guided by US to determine the status of ALN; (2) If the FNA is positive, patients need to receive NAT/NET first. In patients who have a good response after NAT/NET, it is possible to receive axillary surgery and RNI dual de-escalation. (3) If FNA is negative, treatment strategies should be developed based on molecular subtype and tumor staging (Fig. 5).Fig. 5 The recommendation of cN0/rNa patients.

This study had certain limitations. Firstly, this retrospective database-based analysis may increase selection bias in the assignment of treatment strategies. Secondly, the sensitivity of FNA was general, and it was necessary to improve the sensitivity of FNA to further improve patient selection.

In conclusion, it is safe and feasible to perform SLNB omitting ALND when detected 1–2 positive SLNs in cN0/rNa patients with or without FNA. Patients with HER2+/TNBC subtypes underwent surgery after NAT had more chance to benefit from dual de-escalation, including axillary surgery and RNI de-escalation. In clinical practice, we need to make full use of the benefits of systemic therapy and radiotherapy to reasonably reduce the scope of surgery and complications, and expand the “net benefit” of efficacy and quality of life.

Author contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by B.Z., L.L., C.P. and L.Z.D.. The first draft of the manuscript was written by B.Z. and L.L.. Q.P.F. and W.Y.S. revised the manuscript. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. All authors agreed to publish this article. Written informed consent was obtained from the patient for publication and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Funding

This work was supported by grants from Shanghai Anti-cancer and Anti-cancer Development Foundation (CYBER-2022-002), and China Postdoctoral Science Foundation (Grant No. 2022M721987).

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare no competing interests.

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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