Axillary de-escalation after neoadjuvant systemic therapy in cN0-1 breast cancer patients

Axillary de-escalation after neoadjuvant systemic therapy in cN0-1 breast cancer patients | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Axillary de-escalation after neoadjuvant systemic therapy in cN0-1 breast cancer patients Yuhan Zhang, Xiaoya Chen, Yi Pan, Zhihao Liu, Chenrong Zhang, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8154244/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Recent advancements in breast cancer management have focused on de-escalating axillary surgery to minimize morbidity and improve quality of life, without compromising survival outcomes. Prior clinical trials have provided evidence supporting the use of less extensive axillary procedures in patients with favorable characteristics. However, research and evidence regarding optimal axillary lymph node surgical decisions after neoadjuvant systemic therapy (NAS) remain limited. Our study aimed to identify key factors in a real-world setting that predict the feasibility of omitting axillary surgery following NAS in clinically node negative (cN0) and clinically staged N1 (cN1) breast cancer. Methods We retrospectively analyzed 1068 clinical N0-1 breast cancer patients who received NAS followed by surgery. Univariable and multivariable logistic regression analyses were used to identify clinicopathological predictors for: (1) ypN0 after NAS in newly diagnosed cN0 patients, which could guide sentinel lymph node biopsy (SLNB) omission; and (2) ypN0 after NAS in newly diagnosed cN1 patients, which could guide axillary lymph node dissection (ALND) omission. Results In newly diagnosed cN0 patients (n = 302), 274 (90.7%) achieved ypN0. Achieving radiological partial response (rPR) after NAS (odds ratio (OR), 0.27; 95% CI, 0.11–0.65; P = 0.003) was associated with a higher ypN0 rate, suggesting potential for SLNB omission. Conversely, higher clinical T stage (cT3-4) (OR, 3.06; 95% CI, 1.11–8.39; P = 0.030) and estrogen receptor (ER) positivity (OR, 3.94; 95% CI, 1.24–12.54; P = 0.020) were associated with a lower ypN0 rate, indicating a tendency towards retaining SLNB. In newly diagnosed cN1 patients (n = 766), the ypN0 rate was 50.3% (385/766). Human epidermal growth factor receptor 2 (HER2) positivity (OR, 0.34; 95% CI, 0.25–0.48; P < 0.001), achieving rPR (OR, 0.38; 95% CI, 0.24–0.59; P < 0.001), and achieving radiological complete response (rCR) (OR, 0.06; 95% CI, 0.02–0.14; P < 0.001) were associated with a higher ypN0 rate, potentially allowing for selective ALND omission. However, tumors located in the central quadrant (OR, 2.99; 95% CI, 1.05–8.50; P = 0.040), along with ER positivity (OR, 1.82; 95% CI, 1.16–2.84; P = 0.009), progesterone receptor (PR) positivity (OR, 1.67; 95% CI, 1.08–2.56; P = 0.020) and invasive breast carcinoma of special type (IBC-ST) (OR, 2.76; 95% CI, 1.05–7.22; P = 0.039) were associated with a lower ypN0 rate, suggesting caution in omitting ALND. Conclusion For newly diagnosed cN0-1 breast cancer patients undergoing NAS, the post-NAS radiological assessment was a critical factor in guiding axillary surgical management decisions. Furthermore, in newly diagnosed cN1 patients, HER2 positivity was also associated with a higher ypN0 rate, which may inform the omission of ALND. breast cancer neoadjuvant systemic therapy de-escalation axillary treatment cN0 and cN1 disease retrospective study Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Recent years have witnessed a profound shift in breast cancer management, attributable to both advancements in early diagnosis of tumors and significant progress in therapeutic modalities. The treatment paradigm has evolved beyond solely focusing on tumor eradication to prioritizing the minimization of treatment-related complications while ensuring optimal oncologic efficacy. Axillary surgery, a crucial component of breast cancer treatment, is essential for prognostication and guiding subsequent adjuvant therapy. However, both axillary lymph node dissection (ALND) and sentinel lymph node biopsy (SLNB), being invasive procedures, can lead to a range of complications. Beyond common issues like pain, seroma formation, and wound infection associated with any surgical intervention, axillary surgery specifically carries risks of restricted shoulder mobility and nerve sensory abnormalities. Furthermore, due to the disruption of normal lymphatic circulation following lymph node removal, lymphedema represents a significant long-term risk for breast cancer survivors, often becoming a lifelong burden once it occurs. While SLNB removes fewer lymph nodes compared to ALND and is associated with a relatively lower incidence of complications, it remains an invasive procedure with inherent risks. More importantly, not all patients underwent SLNB or ALND can benefit from it. Therefore, developing and implementing strategies for axillary surgical de-escalation, without compromising survival, is crucial for alleviating the burden of complications and enhancing patients' quality of life. Evidence from numerous prior clinical trials supported the reduction of axillary nodal intervention in carefully selected patient populations with favorable prognoses. For instance, prospective, randomized trials such as SOUND, INSEMA, SOAPET, BOOG 2013-08, and NAUTILUS were actively evaluating the feasibility of omitting SLNB in breast cancer patients with smaller tumors (less than 2 cm or 5 cm), clinically negative axillary lymph nodes, who were undergoing breast-conserving surgery and whole breast radiation therapy [ 1 – 5 ] . The primary results of the SOUND and INSEMA trials have been reported, demonstrating the non-inferiority of outcomes in the axillary surgery omission group compared to the SLNB group in eligible patients. Additionally, 10-year follow-up data from trials like ACOSOG Z0011, SINODAR-ONE, and IBCSG 23 − 01 have indicated that ALND can be safely omitted for early breast cancer patients with low-burden axillary metastasis who undergo breast-conserving treatment [ 6 – 8 ] . The 10-year follow-up results from the EORTC 10981–22023 AMAROS study further confirmed that axillary radiation therapy can be considered as an alternative to ALND for early breast cancer patients with positive SLNB. Collectively, the evidence from these studies suggests that reducing or omitting axillary surgery is a safe and feasible treatment option in appropriately selected breast cancer patients. In recent years, owing to the rapidly developed multidiscipline treatment, the pathologic complete response (pCR) and ypN0 rate following neoadjuvant systemic therapy (NAS) has been improved. In clinically node negative (cN0) patients, the pCR rate was 34%-38.9% and the ypN0 rate was 85.5%-91.1% [ 9 – 11 ] . In clinically staged N1 (cN1) patients, pCR rates ranged from 21% to 37%, and ypN0 rates ranged from 38% to 63% [ 11 – 13 ] . These rates were often even higher in human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancer (TNBC) subtypes [ 10 , 11 , 13 – 15 ] . These trends highlight the need to evaluate the effectiveness of neoadjuvant systemic therapy (NAS) and consider de-escalation of axillary treatment. Patients with cN0 disease who achieve ypN0 may not require further axillary surgery, and patients with pre-NAS node-positive disease may safely avoid ALND if they exhibit a complete response of axillary metastases after NAS, resulting in complete eradication of axillary tumor burden. Taking together, accurate prediction of ypN0 is crucial for guiding individualized surgical management. However, the specific predictors of ypN0 following NAS, and the evidence guiding axillary lymph node surgical decisions based on these predictors, remain insufficiently defined. Addressing this clinical need, our study conducted a real-world big data retrospective analysis to identify and evaluate the key factors in patients with cN0 and cN1 breast cancer who received NAS that can effectively predict ypN0, thereby facilitating axillary surgical de-escalation and providing more precise decision support for clinical practice. Patients and methods Study population This retrospective study included female patients with clinical stage T1-4N0-1M0 invasive breast cancer, confirmed by preoperative biopsy, diagnosed at the First Affiliated Hospital of Xi’an Jiaotong University (Xi’an, China) between January 2015 and December 2023. A total of 1162 patients were initially identified and ninety-four patients were excluded based on the criteria presented in Fig. 1 . Consequently, 1068 patients were eligible for analysis. The final cohort consisted of 302 patients with cN0 disease and 766 patients with cN1 disease. All included patients received standard NAS protocols including chemotherapy or anti-HER2 targeted therapy, with treatment response assessed periodically using routine ultrasound and/or magnetic resonance imaging (MRI). The majority of patients (186/302 in the cN0 group; 522/766 in the cN1 group) underwent at least two MRI evaluations during neoadjuvant therapy, including one pre-operative assessment, to evaluate its overall efficacy. For the remaining patients with missing MRI data or those who received only one MRI scan, the efficacy of neoadjuvant therapy was assessed using pre- and post-neoadjuvant ultrasound results. Following completion of NAS, all patients underwent definitive breast surgery (breast-conserving surgery, mastectomy or breast reconstruction surgery) and planned axillary management (SLNB or ALND). Clinicopathologic data Clinicopathologic data were retrospectively collected from the patient database of the First Affiliated Hospital of Xi’an Jiaotong University. Accessible clinical variables were collected. BMI (kg/m 2 ) was classified in line with the National Health Commission of the People’s Republic of China. Occupations were classified as mental workerS, manual workers and others. Mental workers included merchants, teachers, civil servants, technicians and clerks. Manual workers or others included farmers, workers, unemployed and retirees. Higher education was defined as holding a bachelor's degree or above. The determination of menopausal status was based on the International Menopause Society (IMS) 2016 guidelines [ 16 ] . Family history of cancer would be considered positive if breast, prostate, ovarian, or pancreatic cancer was reported among relatives. Clinical Tumor-Node-Metastasis (TNM) staging adhered to the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, 8th Edition (2017) [ 17 ] . In this study, cN0 was defined as follows: at initial evaluation, no suspicious lymph nodes were detected by physical examination and imaging (axillary ultrasound was mandatory, and an additional 235 patients underwent MRI for initial axillary staging); OR, for any suspicious axillary lymph nodes identified by imaging, biopsy confirmed the absence of cancer metastasis. Histological grade was determined using the Nottingham grading system. Pathological classification was performed according to the World Health Organization (WHO) Classification of Tumors criteria for breast tumors [ 18 ] . Preoperative biopsy specimens were analyzed by the hospital's pathology department via immunohistochemistry (IHC) to determine the status of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and the proliferation marker Ki-67, following the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Breast Cancer (Version 4.2023) [ 19 ] , with the institutional cutoff for Ki-67 set at 30. Hormone receptor (HR) positivity was defined as ≥ 1% nuclear staining for either ER or PR. Given the limited number of Luminal A patients in our cohort, and for the convenience of subsequent statistical analysis, molecular subtypes were classified into three categories: HER2-positive (HR-negative), HER2-positive and triple-negative. Postoperative data collected from the surgical pathology reports included breast and axillary pathological results, the total number of axillary lymph nodes removed and the number positive for metastasis. Pathologic complete response in the breast (breast pCR) was defined as the absence of residual invasive carcinoma in the breast specimen (ypT0/is). ypN0 was defined as the absence of any metastasis in the axillary lymph nodes. Cases with only isolated tumor cells (ITCs) in lymph nodes (ypN0(i+)) were classified as not achieving ypN0. Statistical analysis Statistical analyses were performed using SPSS version 18.0 software, GraphPad Prism 10, and MSTATA ( https://www.mstata.com/ ). Categorical variables are presented as frequencies and percentages (n, %). For continuous variables, normality was assessed. Non-normally distributed continuous variables are presented as median and interquartile range (IQR) in baseline comparison tables, while mean (standard deviation, SD) and range are also used for general description. Differences between the ypN0 and non-ypN0 groups were assessed as follows: For categorical variables, Pearson's Chi-squared test or Fisher's exact test was used, as appropriate based on expected cell counts. For continuous variables, the Wilcoxon rank sum test (Mann-Whitney U test) was employed due to the non-normal distribution observed. To identify factors associated with achieving ypN0, univariate and multivariate logistic regression analyses were conducted, with non-ypN0 specified as the outcome event. Odds ratios (OR) and their corresponding 95% confidence intervals (CI) were calculated. Variables demonstrating statistical significance ( P < 0.05) in the univariate analysis, along with any variables considered clinically relevant regardless of statistical significance, were included in the multivariate logistic regression model. In the final multivariate model, variables with a two-sided P -value less than 0.05 were considered independent predictors of achieving ypN0. Results Baseline characteristics Detailed clinicopathological characteristics and the number of ypN0 cases for the overall cohort, cN0, and cN1 groups are presented in Table 1. After NAS, the ypN0 rate was 61.7% (659/1068) overall, with 90.7% (274/302) in cN0 patients and 50.3% (385/766) in cN1 patients. For some variables, the number of cases and events in certain subgroups were limited, and these will be combined for subsequent analyses. Decision-making for selective SLNB omission in cN0 breast cancer Analysis was further focused on 302 patients presenting with cN0 disease prior to NAS. Within this cN0 cohort, 274 patients (90.7%) achieved ypN0 after NAS, while 28 (9.3%) had residual axillary metastasis (non-ypN0). Baseline characteristics comparing the ypN0 and non-ypN0 groups within this cN0 cohort are presented in Supplementary Table 1. Univariate logistic regression analysis was performed to identify factors associated with ypN0 and non-ypN0 in patients with cN0 disease (Table 2). Due to the relatively small sample size of the cN0 cohort and the limited number of outcome events (non-ypN0), several subgroups within certain variables (e.g., age ≥65 years, family history, tumor located in the central quadrant, special type of invasive carcinoma (IBC-ST), radiological complete response (rCR)) exhibited extreme scarcity of outcome events. Consequently, these were not presented in the univariate analysis table and the forest plot. Nevertheless, it is noteworthy that all cN0 patients who achieved a rCR on imaging achieved ypN0, suggesting that for patients with a good response to neoadjuvant therapy as assessed by imaging, omitting SLNB might be a viable consideration. In the multivariate logistic regression analysis, adjusting for potential confounders, the following factors remained independent predictors associated with non-ypN0 (Figure 2): Higher clinical T stage (T3-4 vs T1-2) and ER positivity. Conversely, achieving rPR on post-NAS radiological assessment (compared to radiological progressive disease (rPD) or radiological stable disease (rSD)) remained independently associated with a higher ypN0 rate. Therefore, for newly diagnosed cN0 patients, post-NAS radiological assessment was a predictor of ypN0. This finding suggested that omission of SLNB might be supported. Conversely, a higher clinical T stage and ER positivity were associated with a lower ypN0 rate, suggesting that SLNB should be considered. Decision-making for selective ALND omission in cN1 breast cancer Analysis was then conducted on the 766 patients presenting with cN1 disease prior to NAS. Post-NAS assessment of the cN1 cohort showed an ypN0 rate of 50.3% (385 patients), with the remaining 49.7% (381 patients) having persistent axillary disease (non-ypN0). A comparison of baseline characteristics between the ypN0 and non-ypN0 groups within the cN1 cohort is presented in Supplementary Table 2. To identify factors influencing axillary response in the cN1 subgroup, univariate logistic regression analysis was performed with non-ypN0 as the outcome (Table 3). Following multivariate adjustment (Figure 3), tumors located in the central quadrant, ER positivity, PR positivity and IBC-ST remained independent predictors of non-ypN0. Independently predicting achievement of ypN0 were HER2 positivity and post-NAS rPR and rCR. Therefore, in newly diagnosed cN1 patients, HER2 positivity, rPR and rCR were identified as predictors of a higher rate of ypN0, indicating that omission of ALND might be supported. Conversely, tumors located in the central quadrant, ER positivity, PR positivity and IBC-ST were associated with a lower rate of ypN0, which highlighted the importance of considering ALND. Impact of NAS regimen choice on ypN0 rates in different molecular subtypes The distribution of ypN0 rates across NAS regimens, stratified by clinical nodal status and tumor subtype, is shown in Figure 4. Among patients with cN0, HR-positive breast cancer, significant differences ( P < 0.05) in ypN0 rates were observed among those receiving docetaxel + epirubicin + cyclophosphamide (TEC), epirubicin + cyclophosphamide-docetaxel (EC-T), and other regimens. Furthermore, in cN1, HER2-positive patients, those treated with dual-target anti-HER2 therapy (Herceptin + Pertuzumab) achieved a significantly higher rate of ypN0 compared to those treated with single-target therapy (Herceptin) ( P < 0.01). Among patients with other clinical nodal status and tumor subtype, there was no statistically significant difference in the rates of ypN0 between those receiving different neoadjuvant regimens. In summary, our study found that among cN0, HR-positive patients, the TEC regimen was associated with a higher rate of ypN0 compared to the EC-T regimen, suggesting that SLNB omission might be more strongly recommended for patients treated with TEC. Furthermore, in cN1, HER2-positive patients, Herceptin + Pertuzumab therapy resulted in a higher rate of ypN0, indicating that ALND omission was more likely feasible in this group. Discussion Overall, the cohort of newly diagnosed cN0-1 patients in this study underwent axillary surgery (including SLNB and/or ALND). Among these patients, 61.7% (659/1068) achieved ypN0 after NAS, suggesting that a proportion of patients did not benefit from axillary surgery and experienced reduced quality of life due to its side effects, thus potentially being candidates for de-escalated axillary surgery. Given the differences in initial axillary tumor burden and surgical approaches for newly diagnosed cN0 and cN1 patients, we conducted separate predictive analyses for these two groups. Patients were categorized into ypN0 and non-ypN0 groups to analyze the relationship between pre-surgical clinicopathological characteristics and ypN0 status, aiming to identify key factors guiding decisions regarding axillary surgery de-escalation and provide evidence to support clinical practice. In our study, the ypN0 rate was high in the newly diagnosed cN0 group (n = 302) at 90.7% (274/302). Multivariate analysis revealed that rPR was a predictor of ypN0. Notably, all cN0 patients who achieved a rCR also achieved ypN0. This suggests that assessed by MRI or ultrasound, omission of SLNB can be considered in cN0 patients with a good response to NAS (rPR or rCR), which is consistent with the findings of van der Noordaa et al. [ 10 ] and Zhiqiang Shi et al [ 20 ] . Furthermore, this study found that all patients with breast pCR in the newly diagnosed cN0 group achieved ypN0, aligning with previous reports [ 10 , 11 , 21 – 23 ] . This indicated that breast pCR is a strong predictor of ypN0. However, since breast pCR can typically only be confirmed post-surgically, radiological assessment of NAS efficacy is a more practical predictor for guiding axillary surgery decisions in clinical practice. Conversely, in multivariate analysis, higher clinical T stage (cT3-4) and ER positivity were associated with a lower ypN0 rate, suggesting that patients with these initial tumor biological characteristics may not be suitable candidates for SLNB omission. Numerous prior studies have reported that HER2-positive and TNBC subtypes are associated with higher ypN0 rates compared to HR-positive subtypes [ 10 , 20 , 24 ] , which may be related to the relatively lower sensitivity of ER-positive breast cancer patients to NAS. Additionally, the study by Zhiqiang Shi et al [ 20 ] also confirmed that higher T stage is associated with a lower ypN0 rate. Our study identified key independent predictive factors, indicating that omitting SLNB may be a reasonable option for patients with specific initial tumor biological characteristics and a good response to NAS treatment. Ongoing prospective clinical trials, EUBREAST-01 [ 25 ] and ASICS [ 26 ] , are evaluating the safety of omitting SLNB in selected cN0 patients (T1-3, HER2-positive/TNBC with rCR on radiological assessment) after NAS, and their results will provide higher-level evidence regarding the feasibility of axillary surgery de-escalation in newly diagnosed cN0 patients. In newly diagnosed cN1 patients (n = 766), a substantial proportion (50.3%, 385/766) achieved ypN0. Research by Giacomo Montagna, Andrea V. Barrio, and colleagues has demonstrated that axillary recurrence is a rare event when ALND is omitted in initially node-positive breast cancer patients [ 27 , 28 ] . Although the accuracy of SLNB after NAS in initially node-positive disease has been debated (with reported identification rates (IR) of 87.6–93.8% and false-negative rates (FNR) of 8.4–14% [ 12 , 29 – 32 ] ), techniques such as dual tracer mapping, targeted axillary dissection (TAD), removal of ≥ 3 nodes, and pathological evaluation with IHC have been shown to significantly improve accuracy [ 27 , 33 – 35 ] . Our results, identifying predictors of ypN0, contribute to the refinement of patient selection for SLNB post-NAS in the cN1 setting. Accurate identification of ypN0 predictors helps to further refine patient selection for SLNB. Based on this, multivariate analysis in this study found that in newly diagnosed cN1 patients, HER2 positivity, and achieving rPR or rCR were independent predictors of ypN0, and thus key predictive factors for guiding the omission of ALND. Regarding this finding, the higher ypN0 rate in HER2-positive patients may be attributed to the favorable effects of targeted therapy. Similar to the cN0 population, a good response to NAS assessed by MRI or ultrasound is also a key predictor for axillary de-escalation in cN1 patients. 83.2% of cN1 patients who achieved breast pCR also achieved ypN0, a proportion consistent with previous studies [ 11 , 23 ] . However, the inability to confirm breast pCR pre-surgically limits its practicality in axillary de-escalation decisions. Conversely, tumors located in the central quadrant, ER positivity, PR positivity and IBC-ST were associated with a lower ypN0 rate, suggesting caution when considering ALND omission in the presence of these features. In cN1 patients, many previous studies have also shown that HR-positive is associated with lower ypN0 rates, while HER2-positive and TNBC subtypes are associated with higher ypN0 rates [ 13 , 14 , 24 , 36 ] . Furthermore, there was a trend for lower ypN0 rates in unmarried or other marital status groups compared to married patients ( P = 0.084). In contrast, patients with Ki-67 ≥ 30% exhibited a trend towards a higher ypN0 probability than those with Ki-67 < 30% ( P = 0.094), which might be due to elevated Ki-67 values indicating vigorous cellular proliferation and thus potentially increased responsiveness to NAS. Regarding the impact of omitting ALND on prognosis, Sabrina Kahler-Ribeiro-Fontana et al. followed the oncological outcomes of initially node-positive patients who converted to clinical node-negative (ycN0) after NAS and underwent only SLNB, finding an axillary failure rate of only 1.8% with SLNB alone [ 37 ] . Corrado Tinterri and colleagues categorized initially node-positive patients who converted to ycN0 after NAS based on the final axillary surgery performed (SLNB or ALND) and conducted long-term oncological outcome follow-up, finding that the SLNB group had better prognosis than the ALND group [ 38 ] . However, patients who underwent SLNB in this retrospective study were selected and had relatively less severe disease, so this conclusion requires further validation through more prospective randomized trials. In summary, while our study does not provide direct evidence on the long-term prognostic impact of axillary de-escalation treatment, it identified key independent predictors of achieving ypN0 in initially diagnosed cN1 patients with a good response to NAS, suggesting that substituting ALND with SLNB may be a reasonable option for carefully selected patients, providing evidence for future clinical trials. Furthermore, we subsequently investigated whether the choice of specific NAS regimen further modulates ypN0 rates within key molecular-defined subgroups (TNBC, HER2-positive, and HR-positive subgroups). Our findings highlight potential subtype-specific optimal neoadjuvant regimens for achieving ypN0 and enabling surgical de-escalation. Specifically, in cN0, HR-positive patients, the TEC regimen was associated with a significantly higher ypN0 rate than the EC-T regimen, supporting the potential for SLNB omission with TEC. Furthermore, among cN1, HER2-positive patients, dual-target anti-HER2 therapy (Herceptin + Pertuzumab) resulted in a higher rate of ypN0, which suggests increased opportunity for ALND omission in this group. This finding strongly supports the superior efficacy of dual HER2 blockade not only for the primary tumor but also specifically for achieving axillary nodal clearance. Interestingly, our study did not detect statistically significant differences in ypN0 associated with different NAS regimens when examining combinations of other molecular subtypes and lymph node status. This lack of observed effect should be interpreted cautiously; the relatively recent widespread clinical adoption of platinum-based agents and the continuous emergence of novel drugs and potentially more potent neoadjuvant strategies necessitate ongoing, detailed, and systematic investigation into how specific regimen choices influence ypN0 rates across the full spectrum of breast cancer subtypes. However, this study is subject to the limitations inherent in its retrospective, single-center design, including potential selection and information bias. Therefore, the proposed predictive schemes require validation in prospective, multi-center studies with long-term follow-up to confirm their oncologic safety and applicability to broader populations. Future research incorporating advancements in imaging, genomics, and systemic therapies may further refine patient selection, also allow selected patients with cN1 disease to omit SLNB, and potentially extend axillary de-escalation strategies to patients with higher baseline nodal burdens (cN2-3) [ 39 ] . In this study, a small number of patients did not undergo MRI examinations or completed only one MRI scan, and for these cases, the efficacy of neoadjuvant therapy was solely assessed using pre- and post-neoadjuvant ultrasound results. This was primarily attributed to objective factors such as the high cost of MRI examinations and data incompleteness stemming from the broad span of the study period. Although the sensitivity of axillary ultrasound after neoadjuvant chemotherapy (NAC) may be lower than that of MRI, potentially introducing an assessment bias, this represents an unavoidable limitation in real-world studies. Furthermore, as patients in our study did not undergo targeted axillary dissection (TAD), the impact on the cN1 group remains uncertain, whereas the results for the cN0 group were unaffected. This study, based on detailed real-world big data, identified predictors of ypN0 after neoadjuvant systemic therapy in newly diagnosed cN0 and cN1 patients. These factors can support clinical decisions regarding: (1) whether omission of SLNB can be considered in newly diagnosed cN0 patients after NAS; and (2) whether omission of ALND (performing only SLNB) can be considered in newly diagnosed cN1 patients after NAS. For newly diagnosed cN0-1 breast cancer patients undergoing NAS, the post-NAS radiological assessment is a critical factor in guiding axillary surgery decisions. Additionally, in newly diagnosed cN1 patients, HER2 positivity and higher Ki-67 expression were associated with a higher ypN0 rate, which may provide a basis for omitting ALND. Furthermore, we preliminarily explored the impact of specific neoadjuvant regimens on the ypN0 rate and the potential for axillary surgery omission, providing new insights and directions for selecting suitable candidates for axillary de-escalation therapy. In conclusion, this study highlights the importance of patient selection and evaluation in axillary de-escalation treatment, provides a framework for individualized axillary treatment strategies, and contributes to a deeper understanding of tumor biological characteristics, thereby allowing carefully selected patients with a good response to NAS who remain or convert to ycN0 status to avoid unnecessary axillary lymph node surgery, while ensuring adequate treatment for patients at higher risk of residual disease who would benefit from axillary surgery. Declarations Ethics approval This work was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethics Committee of the First Affiliated Hospital of Xi’an Jiaotong University (Xi’an, China). As a retrospective study, informed consent of patients is not required. The research and data analyses comply with the current laws of the People’s Republic of China. Consent for publication All authors have read and agreed with the content of the manuscript as well as its submission. Competing interests The authors declare no conflict of interest. Acknowledgements We acknowledge MSTATA software (https://www.mstata.com/) for its invaluable data analysis services, which facilitated the completion of Tables 2 and 3. Author contributions Conceptualization, Yuhan Zhang, Guanqun Ge and Yu Ren; Data curation, Xiaoya Chen, Yi Pan and Zhihao Liu; Formal analysis, Yuhan Zhang and Xiaoya Chen; Funding acquisition, Bin Wang; Investigation, Yuhan Zhang, Lizhe Zhu and Xiaoya Chen; Methodology, Guanqun Ge and Bin Wang; Resources, Bin Wang; Software, Chenrong Zhang, Keyuan Du; Supervision, Bin Wang, Guanqun Ge and Yu Ren; Validation, Lizhe Zhu and Yuhan Zhang; Visualization, Yuhan Zhang, Xiaoya Chen and Yi Pan; Writing-original draft, Yuhan Zhang; Writing-review & editing, Yuhan Zhang. Funding This study was funded by National Natural Science Foundation of China (Grant No. 82172798 and 82472749) and Shaanxi Provincial Innovation Support Program (Grant No. 2022PT-24). Availability of data and material The data used or analyzed during the current study are available from the corresponding author on reasonable request. References GENTILINI O D, BOTTERI E, SANGALLI C, et al. 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An ultrasound-based nomogram for predicting axillary node pathologic complete response after neoadjuvant chemotherapy in breast cancer: Modeling and external validation s. Cancer, 2024, 130(S8) : 1513–23. KAHLER-RIBEIRO-FONTANA S, PAGAN E, MAGNONI F, et al. Long-term standard sentinel node biopsy after neoadjuvant treatment in breast cancer: a single institution ten-year follow-up s. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology, 2021, 47(4) : 804–12. TINTERRI C, BARBIERI E, SAGONA A, et al. De-Escalation of Axillary Surgery in Clinically Node-Positive Breast Cancer Patients Treated with Neoadjuvant Therapy: Comparative Long-Term Outcomes of Sentinel Lymph Node Biopsy versus Axillary Lymph Node Dissection s. Cancers (Basel), 2024, 16(18). CAPASSO K, MITRI S, ROLDAN-VASQUEZ E, et al. Axillary de-escalation after neoadjuvant chemotherapy for advanced lymph node involvement in breast cancer s. American journal of surgery, 2024, 236: 115893. Supplementary Files Supplementarymaterials.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8154244","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":556345868,"identity":"afa9a007-b0a0-4762-b53d-7e8e57139dab","order_by":0,"name":"Yuhan 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13:21:01","extension":"html","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":288217,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8154244/v1/1116c23fd9620a013a62b4db.html"},{"id":98072982,"identity":"9d6ee598-c769-4b49-8546-5f7fde4f9fd9","added_by":"auto","created_at":"2025-12-12 13:21:01","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":120108,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram of the study population. NAS, neoadjuvant systemic therapy; cN0, clinically node negative; HER2, human epidermal growth factor receptor 2; cN1, clinically staged N1; SLNB, sentinel lymph node biopsy; ALND, axillary lymph node dissection.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8154244/v1/7038e25f913223a51dabb0f6.png"},{"id":98429783,"identity":"e6f8c949-6767-453e-b30f-7bb671285917","added_by":"auto","created_at":"2025-12-17 16:44:09","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":72085,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of multivariable logistic regression analysis for ypN0 prediction after NAS in patients with cN0 disease. Each point estimate (square) represents the adjusted odds ratio (OR) for the corresponding predictor variable, with horizontal lines indicating the 95% confidence intervals (CIs). The vertical reference line is set at an OR of 1 (indicating no association); factors with point estimates and CIs extending to the right of this line suggest increased odds of ypN0, while those to the left suggest decreased odds of ypN0. CIs crossing the line of no effect indicates a lack of statistical significance (\u003cem\u003eP\u003c/em\u003e \u0026gt; 0.05). Results highlighted in red font are statistically significant (\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05) as determined by binary logistic regression analysis. cN0, clinically node negative; OR, odds ratio; CI, confidence interval; Ref, reference; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2; rPD, radiological progressed disease; rSD, radiological stable disease; rPR, radiological partial response. \u003csup\u003e#\u003c/sup\u003e, given that all patients who demonstrated rCR consistently achieved ypN0, rCR was consequently omitted from the forest plot presentation. *, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.05; **, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.01; ***, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8154244/v1/930d116a9a8d82a81fb60606.png"},{"id":98072988,"identity":"ecc1cbb0-fab7-4496-b0ce-6c8df5d761cc","added_by":"auto","created_at":"2025-12-12 13:21:01","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":99414,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of multivariable logistic regression analysis for ypN0 prediction after NAS in patients with cN1 disease. Each point estimate (square) represents the adjusted odds ratio (OR) for the corresponding predictor variable, with horizontal lines indicating the 95% confidence intervals (CIs). The vertical reference line is set at an OR of 1 (indicating no association); factors with point estimates and CIs extending to the right of this line suggest increased odds of ypN0, while those to the left suggest decreased odds of ypN0. CIs crossing the line of no effect indicates a lack of statistical significance (\u003cem\u003eP\u003c/em\u003e\u0026gt; 0.05). Results highlighted in red font are statistically significant (\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05) as determined by binary logistic regression analysis. cN1, clinically staged N1; OR, odds ratio; CI, confidence interval; Ref, reference; UIQ, upper inner quadrant; UOQ, upper outer quadrant; LIQ, lower inner quadrant; LOQ, lower outer quadrant; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2; IBC-NST, invasive breast carcinoma of no special type; IBC-ST, invasive breast carcinoma of special type; rPD, radiological progressed disease; rSD, radiological stable disease; rPR, radiological partial response; rCR, radiological complete response. *, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.05; **, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.01; ***, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8154244/v1/5f0f3454f8d79ce79ba43deb.png"},{"id":98429165,"identity":"b82f2257-6be0-4689-9ee9-36e8eb893463","added_by":"auto","created_at":"2025-12-17 16:42:54","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":88432,"visible":true,"origin":"","legend":"\u003cp\u003eDistribution of ypN0 rates across neoadjuvant systemic therapy regimens, stratified by clinical nodal status and tumor subtype. Stacked bars show the percentage of patients achieving ypN0 versus non-ypN0 for each NAS regimen (total = 100%). (a-c) Results for clinically node-negative (cN0) patients: (a) TNBC, (b) HER2 positive, (c) HR positive. (d-f) Results for clinically staged N1 (cN1) patients: (d) TNBC, (e) HER2 positive, (f) HR positive. Statistical comparisons of pCR distribution across regimens within each panel were performed using Pearson's Chi-squared test (a, c, d, f) or Fisher's exact test (b, e). TNBC, triple negative breast cancer; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; TEC, docetaxel + epirubicin + cyclophosphamide; EC-T, epirubicin + cyclophosphamide-docetaxel; H, Herceptin; HP, Herceptin + Pertuzumab. *, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.05; **, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.01; ***, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001; ns, no significance.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-8154244/v1/8fc762500f9bb1f0d3c75de0.png"},{"id":99788391,"identity":"d9a6a826-6839-484a-be04-257388c569be","added_by":"auto","created_at":"2026-01-08 12:46:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":902602,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8154244/v1/3b651e02-a8e7-4a56-aa06-3205c679fb88.pdf"},{"id":98428800,"identity":"eeab1f6c-6c04-4b8c-bd3b-7d91a104eeb0","added_by":"auto","created_at":"2025-12-17 16:42:24","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":29063,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarymaterials.docx","url":"https://assets-eu.researchsquare.com/files/rs-8154244/v1/ca6268f9db898a44e9b6fa87.docx"}],"financialInterests":"","formattedTitle":"Axillary de-escalation after neoadjuvant systemic therapy in cN0-1 breast cancer patients","fulltext":[{"header":"Introduction","content":"\u003cp\u003eRecent years have witnessed a profound shift in breast cancer management, attributable to both advancements in early diagnosis of tumors and significant progress in therapeutic modalities. The treatment paradigm has evolved beyond solely focusing on tumor eradication to prioritizing the minimization of treatment-related complications while ensuring optimal oncologic efficacy.\u003c/p\u003e\u003cp\u003eAxillary surgery, a crucial component of breast cancer treatment, is essential for prognostication and guiding subsequent adjuvant therapy. However, both axillary lymph node dissection (ALND) and sentinel lymph node biopsy (SLNB), being invasive procedures, can lead to a range of complications. Beyond common issues like pain, seroma formation, and wound infection associated with any surgical intervention, axillary surgery specifically carries risks of restricted shoulder mobility and nerve sensory abnormalities. Furthermore, due to the disruption of normal lymphatic circulation following lymph node removal, lymphedema represents a significant long-term risk for breast cancer survivors, often becoming a lifelong burden once it occurs. While SLNB removes fewer lymph nodes compared to ALND and is associated with a relatively lower incidence of complications, it remains an invasive procedure with inherent risks. More importantly, not all patients underwent SLNB or ALND can benefit from it. Therefore, developing and implementing strategies for axillary surgical de-escalation, without compromising survival, is crucial for alleviating the burden of complications and enhancing patients' quality of life.\u003c/p\u003e\u003cp\u003eEvidence from numerous prior clinical trials supported the reduction of axillary nodal intervention in carefully selected patient populations with favorable prognoses. For instance, prospective, randomized trials such as SOUND, INSEMA, SOAPET, BOOG 2013-08, and NAUTILUS were actively evaluating the feasibility of omitting SLNB in breast cancer patients with smaller tumors (less than 2 cm or 5 cm), clinically negative axillary lymph nodes, who were undergoing breast-conserving surgery and whole breast radiation therapy\u003csup\u003e[\u003cspan additionalcitationids=\"CR2 CR3 CR4\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. The primary results of the SOUND and INSEMA trials have been reported, demonstrating the non-inferiority of outcomes in the axillary surgery omission group compared to the SLNB group in eligible patients. Additionally, 10-year follow-up data from trials like ACOSOG Z0011, SINODAR-ONE, and IBCSG 23\u0026thinsp;\u0026minus;\u0026thinsp;01 have indicated that ALND can be safely omitted for early breast cancer patients with low-burden axillary metastasis who undergo breast-conserving treatment\u003csup\u003e[\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. The 10-year follow-up results from the EORTC 10981\u0026ndash;22023 AMAROS study further confirmed that axillary radiation therapy can be considered as an alternative to ALND for early breast cancer patients with positive SLNB. Collectively, the evidence from these studies suggests that reducing or omitting axillary surgery is a safe and feasible treatment option in appropriately selected breast cancer patients.\u003c/p\u003e\u003cp\u003eIn recent years, owing to the rapidly developed multidiscipline treatment, the pathologic complete response (pCR) and ypN0 rate following neoadjuvant systemic therapy (NAS) has been improved. In clinically node negative (cN0) patients, the pCR rate was 34%-38.9% and the ypN0 rate was 85.5%-91.1%\u003csup\u003e[\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. In clinically staged N1 (cN1) patients, pCR rates ranged from 21% to 37%, and ypN0 rates ranged from 38% to 63%\u003csup\u003e[\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. These rates were often even higher in human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancer (TNBC) subtypes\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. These trends highlight the need to evaluate the effectiveness of neoadjuvant systemic therapy (NAS) and consider de-escalation of axillary treatment. Patients with cN0 disease who achieve ypN0 may not require further axillary surgery, and patients with pre-NAS node-positive disease may safely avoid ALND if they exhibit a complete response of axillary metastases after NAS, resulting in complete eradication of axillary tumor burden. Taking together, accurate prediction of ypN0 is crucial for guiding individualized surgical management. However, the specific predictors of ypN0 following NAS, and the evidence guiding axillary lymph node surgical decisions based on these predictors, remain insufficiently defined.\u003c/p\u003e\u003cp\u003eAddressing this clinical need, our study conducted a real-world big data retrospective analysis to identify and evaluate the key factors in patients with cN0 and cN1 breast cancer who received NAS that can effectively predict ypN0, thereby facilitating axillary surgical de-escalation and providing more precise decision support for clinical practice.\u003c/p\u003e"},{"header":"Patients and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy population\u003c/h2\u003e\u003cp\u003eThis retrospective study included female patients with clinical stage T1-4N0-1M0 invasive breast cancer, confirmed by preoperative biopsy, diagnosed at the First Affiliated Hospital of Xi\u0026rsquo;an Jiaotong University (Xi\u0026rsquo;an, China) between January 2015 and December 2023. A total of 1162 patients were initially identified and ninety-four patients were excluded based on the criteria presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Consequently, 1068 patients were eligible for analysis. The final cohort consisted of 302 patients with cN0 disease and 766 patients with cN1 disease. All included patients received standard NAS protocols including chemotherapy or anti-HER2 targeted therapy, with treatment response assessed periodically using routine ultrasound and/or magnetic resonance imaging (MRI). The majority of patients (186/302 in the cN0 group; 522/766 in the cN1 group) underwent at least two MRI evaluations during neoadjuvant therapy, including one pre-operative assessment, to evaluate its overall efficacy. For the remaining patients with missing MRI data or those who received only one MRI scan, the efficacy of neoadjuvant therapy was assessed using pre- and post-neoadjuvant ultrasound results. Following completion of NAS, all patients underwent definitive breast surgery (breast-conserving surgery, mastectomy or breast reconstruction surgery) and planned axillary management (SLNB or ALND).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eClinicopathologic data\u003c/h3\u003e\n\u003cp\u003eClinicopathologic data were retrospectively collected from the patient database of the First Affiliated Hospital of Xi\u0026rsquo;an Jiaotong University. Accessible clinical variables were collected. BMI (kg/m\u003csup\u003e2\u003c/sup\u003e) was classified in line with the National Health Commission of the People\u0026rsquo;s Republic of China. Occupations were classified as mental workerS, manual workers and others. Mental workers included merchants, teachers, civil servants, technicians and clerks. Manual workers or others included farmers, workers, unemployed and retirees. Higher education was defined as holding a bachelor's degree or above. The determination of menopausal status was based on the International Menopause Society (IMS) 2016 guidelines\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. Family history of cancer would be considered positive if breast, prostate, ovarian, or pancreatic cancer was reported among relatives. Clinical Tumor-Node-Metastasis (TNM) staging adhered to the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, 8th Edition (2017)\u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. In this study, cN0 was defined as follows: at initial evaluation, no suspicious lymph nodes were detected by physical examination and imaging (axillary ultrasound was mandatory, and an additional 235 patients underwent MRI for initial axillary staging); OR, for any suspicious axillary lymph nodes identified by imaging, biopsy confirmed the absence of cancer metastasis. Histological grade was determined using the Nottingham grading system. Pathological classification was performed according to the World Health Organization (WHO) Classification of Tumors criteria for breast tumors\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003ePreoperative biopsy specimens were analyzed by the hospital's pathology department via immunohistochemistry (IHC) to determine the status of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and the proliferation marker Ki-67, following the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Breast Cancer (Version 4.2023)\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e, with the institutional cutoff for Ki-67 set at 30. Hormone receptor (HR) positivity was defined as \u0026ge;\u0026thinsp;1% nuclear staining for either ER or PR. Given the limited number of Luminal A patients in our cohort, and for the convenience of subsequent statistical analysis, molecular subtypes were classified into three categories: HER2-positive (HR-negative), HER2-positive and triple-negative. Postoperative data collected from the surgical pathology reports included breast and axillary pathological results, the total number of axillary lymph nodes removed and the number positive for metastasis. Pathologic complete response in the breast (breast pCR) was defined as the absence of residual invasive carcinoma in the breast specimen (ypT0/is). ypN0 was defined as the absence of any metastasis in the axillary lymph nodes. Cases with only isolated tumor cells (ITCs) in lymph nodes (ypN0(i+)) were classified as not achieving ypN0.\u003c/p\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eStatistical analyses were performed using SPSS version 18.0 software, GraphPad Prism 10, and MSTATA (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.mstata.com/\u003c/span\u003e\u003cspan address=\"https://www.mstata.com/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). Categorical variables are presented as frequencies and percentages (n, %). For continuous variables, normality was assessed. Non-normally distributed continuous variables are presented as median and interquartile range (IQR) in baseline comparison tables, while mean (standard deviation, SD) and range are also used for general description. Differences between the ypN0 and non-ypN0 groups were assessed as follows: For categorical variables, Pearson's Chi-squared test or Fisher's exact test was used, as appropriate based on expected cell counts. For continuous variables, the Wilcoxon rank sum test (Mann-Whitney U test) was employed due to the non-normal distribution observed. To identify factors associated with achieving ypN0, univariate and multivariate logistic regression analyses were conducted, with non-ypN0 specified as the outcome event. Odds ratios (OR) and their corresponding 95% confidence intervals (CI) were calculated. Variables demonstrating statistical significance (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05) in the univariate analysis, along with any variables considered clinically relevant regardless of statistical significance, were included in the multivariate logistic regression model. In the final multivariate model, variables with a two-sided \u003cem\u003eP\u003c/em\u003e-value less than 0.05 were considered independent predictors of achieving ypN0.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eBaseline characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDetailed clinicopathological characteristics and the number of ypN0 cases for the overall cohort, cN0, and cN1 groups are presented in Table 1. After NAS, the ypN0 rate was 61.7% (659/1068) overall, with 90.7% (274/302) in cN0 patients and 50.3% (385/766) in cN1 patients. For some variables, the number of cases and events in certain subgroups were limited, and these will be combined for subsequent analyses.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDecision-making for selective SLNB omission in cN0 breast cancer\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAnalysis was further focused on 302 patients presenting with cN0 disease prior to NAS. Within this cN0 cohort, 274 patients (90.7%) achieved ypN0 after NAS, while 28 (9.3%) had residual axillary metastasis (non-ypN0).\u003c/p\u003e\n\u003cp\u003eBaseline characteristics comparing the ypN0 and non-ypN0 groups within this cN0 cohort are presented in Supplementary Table 1. Univariate logistic regression analysis was performed to identify factors associated with ypN0 and non-ypN0 in patients with cN0 disease (Table 2). Due to the relatively small sample size of the cN0 cohort and the limited number of outcome events (non-ypN0), several subgroups within certain variables (e.g., age \u0026ge;65 years, family history, tumor located in the central quadrant, special type of invasive carcinoma (IBC-ST), radiological complete response (rCR)) exhibited extreme scarcity of outcome events. Consequently, these were not presented in the univariate analysis table and the forest plot. Nevertheless, it is noteworthy that all cN0 patients who achieved a rCR on imaging achieved ypN0, suggesting that for patients with a good response to neoadjuvant therapy as assessed by imaging, omitting SLNB might be a viable consideration.\u003c/p\u003e\n\u003cp\u003eIn the multivariate logistic regression analysis, adjusting for potential confounders, the following factors remained independent predictors associated with non-ypN0 (Figure 2): Higher clinical T stage (T3-4 vs T1-2) and ER positivity. Conversely, achieving rPR on post-NAS radiological assessment (compared to radiological progressive disease (rPD) or radiological stable disease (rSD)) remained independently associated with a higher ypN0 rate.\u003c/p\u003e\n\u003cp\u003eTherefore, for newly diagnosed cN0 patients, post-NAS radiological assessment was a predictor of ypN0. This finding suggested that omission of SLNB might be supported. Conversely, a higher clinical T stage and ER positivity were associated with a lower ypN0 rate, suggesting that SLNB should be considered.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDecision-making for selective ALND omission in cN1 breast cancer\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAnalysis was then conducted on the 766 patients presenting with cN1 disease prior to NAS. Post-NAS assessment of the cN1 cohort showed an ypN0 rate of 50.3% (385 patients), with the remaining 49.7% (381 patients) having persistent axillary disease (non-ypN0).\u003c/p\u003e\n\u003cp\u003eA comparison of baseline characteristics between the ypN0 and non-ypN0 groups within the cN1 cohort is presented in Supplementary Table 2. To identify factors influencing axillary response in the cN1 subgroup, univariate logistic regression analysis was performed with non-ypN0 as the outcome (Table 3). Following multivariate adjustment (Figure 3), tumors located in the central quadrant, ER positivity, PR positivity and IBC-ST remained independent predictors of non-ypN0. Independently predicting achievement of ypN0 were HER2 positivity and post-NAS rPR and rCR.\u003c/p\u003e\n\u003cp\u003eTherefore, in newly diagnosed cN1 patients, HER2 positivity, rPR and rCR were identified as predictors of a higher rate of ypN0, indicating that omission of ALND might be supported. Conversely, tumors located in the central quadrant, ER positivity, PR positivity and IBC-ST were associated with a lower rate of ypN0, which highlighted the importance of considering ALND.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImpact of NAS regimen choice on ypN0 rates in different molecular subtypes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe distribution of ypN0 rates across NAS regimens, stratified by clinical nodal status and tumor subtype, is shown in Figure 4. Among patients with cN0, HR-positive breast cancer, significant differences (\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05) in ypN0 rates were observed among those receiving docetaxel + epirubicin + cyclophosphamide (TEC), epirubicin + cyclophosphamide-docetaxel (EC-T), and other regimens. Furthermore, in cN1, HER2-positive patients, those treated with dual-target anti-HER2 therapy (Herceptin + Pertuzumab) achieved a significantly higher rate of ypN0 compared to those treated with single-target therapy (Herceptin) (\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.01).\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eAmong patients with other clinical nodal status and tumor subtype, there was no statistically significant difference in the rates of ypN0 between those receiving different neoadjuvant regimens.\u003c/p\u003e\n\u003cp\u003eIn summary, our study found that among cN0, HR-positive patients, the TEC regimen was associated with a higher rate of ypN0 compared to the EC-T regimen, suggesting that SLNB omission might be more strongly recommended for patients treated with TEC. Furthermore, in cN1, HER2-positive patients, Herceptin + Pertuzumab therapy resulted in a higher rate of ypN0, indicating that ALND omission was more likely feasible in this group.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOverall, the cohort of newly diagnosed cN0-1 patients in this study underwent axillary surgery (including SLNB and/or ALND). Among these patients, 61.7% (659/1068) achieved ypN0 after NAS, suggesting that a proportion of patients did not benefit from axillary surgery and experienced reduced quality of life due to its side effects, thus potentially being candidates for de-escalated axillary surgery. Given the differences in initial axillary tumor burden and surgical approaches for newly diagnosed cN0 and cN1 patients, we conducted separate predictive analyses for these two groups. Patients were categorized into ypN0 and non-ypN0 groups to analyze the relationship between pre-surgical clinicopathological characteristics and ypN0 status, aiming to identify key factors guiding decisions regarding axillary surgery de-escalation and provide evidence to support clinical practice.\u003c/p\u003e\u003cp\u003eIn our study, the ypN0 rate was high in the newly diagnosed cN0 group (n\u0026thinsp;=\u0026thinsp;302) at 90.7% (274/302). Multivariate analysis revealed that rPR was a predictor of ypN0. Notably, all cN0 patients who achieved a rCR also achieved ypN0. This suggests that assessed by MRI or ultrasound, omission of SLNB can be considered in cN0 patients with a good response to NAS (rPR or rCR), which is consistent with the findings of van der Noordaa et al.\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e and Zhiqiang Shi et al\u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e. Furthermore, this study found that all patients with breast pCR in the newly diagnosed cN0 group achieved ypN0, aligning with previous reports\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e. This indicated that breast pCR is a strong predictor of ypN0. However, since breast pCR can typically only be confirmed post-surgically, radiological assessment of NAS efficacy is a more practical predictor for guiding axillary surgery decisions in clinical practice. Conversely, in multivariate analysis, higher clinical T stage (cT3-4) and ER positivity were associated with a lower ypN0 rate, suggesting that patients with these initial tumor biological characteristics may not be suitable candidates for SLNB omission. Numerous prior studies have reported that HER2-positive and TNBC subtypes are associated with higher ypN0 rates compared to HR-positive subtypes\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e, which may be related to the relatively lower sensitivity of ER-positive breast cancer patients to NAS. Additionally, the study by Zhiqiang Shi et al\u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e also confirmed that higher T stage is associated with a lower ypN0 rate. Our study identified key independent predictive factors, indicating that omitting SLNB may be a reasonable option for patients with specific initial tumor biological characteristics and a good response to NAS treatment. Ongoing prospective clinical trials, EUBREAST-01\u003csup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e and ASICS\u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e, are evaluating the safety of omitting SLNB in selected cN0 patients (T1-3, HER2-positive/TNBC with rCR on radiological assessment) after NAS, and their results will provide higher-level evidence regarding the feasibility of axillary surgery de-escalation in newly diagnosed cN0 patients.\u003c/p\u003e\u003cp\u003eIn newly diagnosed cN1 patients (n\u0026thinsp;=\u0026thinsp;766), a substantial proportion (50.3%, 385/766) achieved ypN0. Research by Giacomo Montagna, Andrea V. Barrio, and colleagues has demonstrated that axillary recurrence is a rare event when ALND is omitted in initially node-positive breast cancer patients\u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e. Although the accuracy of SLNB after NAS in initially node-positive disease has been debated (with reported identification rates (IR) of 87.6\u0026ndash;93.8% and false-negative rates (FNR) of 8.4\u0026ndash;14% \u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan additionalcitationids=\"CR30 CR31\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/sup\u003e), techniques such as dual tracer mapping, targeted axillary dissection (TAD), removal of \u0026ge;\u0026thinsp;3 nodes, and pathological evaluation with IHC have been shown to significantly improve accuracy\u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan additionalcitationids=\"CR34\" citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003e. Our results, identifying predictors of ypN0, contribute to the refinement of patient selection for SLNB post-NAS in the cN1 setting. Accurate identification of ypN0 predictors helps to further refine patient selection for SLNB. Based on this, multivariate analysis in this study found that in newly diagnosed cN1 patients, HER2 positivity, and achieving rPR or rCR were independent predictors of ypN0, and thus key predictive factors for guiding the omission of ALND. Regarding this finding, the higher ypN0 rate in HER2-positive patients may be attributed to the favorable effects of targeted therapy. Similar to the cN0 population, a good response to NAS assessed by MRI or ultrasound is also a key predictor for axillary de-escalation in cN1 patients. 83.2% of cN1 patients who achieved breast pCR also achieved ypN0, a proportion consistent with previous studies\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e. However, the inability to confirm breast pCR pre-surgically limits its practicality in axillary de-escalation decisions. Conversely, tumors located in the central quadrant, ER positivity, PR positivity and IBC-ST were associated with a lower ypN0 rate, suggesting caution when considering ALND omission in the presence of these features. In cN1 patients, many previous studies have also shown that HR-positive is associated with lower ypN0 rates, while HER2-positive and TNBC subtypes are associated with higher ypN0 rates\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/sup\u003e. Furthermore, there was a trend for lower ypN0 rates in unmarried or other marital status groups compared to married patients (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.084). In contrast, patients with Ki-67\u0026thinsp;\u0026ge;\u0026thinsp;30% exhibited a trend towards a higher ypN0 probability than those with Ki-67\u0026thinsp;\u0026lt;\u0026thinsp;30% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.094), which might be due to elevated Ki-67 values indicating vigorous cellular proliferation and thus potentially increased responsiveness to NAS. Regarding the impact of omitting ALND on prognosis, Sabrina Kahler-Ribeiro-Fontana et al. followed the oncological outcomes of initially node-positive patients who converted to clinical node-negative (ycN0) after NAS and underwent only SLNB, finding an axillary failure rate of only 1.8% with SLNB alone\u003csup\u003e[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/sup\u003e. Corrado Tinterri and colleagues categorized initially node-positive patients who converted to ycN0 after NAS based on the final axillary surgery performed (SLNB or ALND) and conducted long-term oncological outcome follow-up, finding that the SLNB group had better prognosis than the ALND group\u003csup\u003e[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]\u003c/sup\u003e. However, patients who underwent SLNB in this retrospective study were selected and had relatively less severe disease, so this conclusion requires further validation through more prospective randomized trials. In summary, while our study does not provide direct evidence on the long-term prognostic impact of axillary de-escalation treatment, it identified key independent predictors of achieving ypN0 in initially diagnosed cN1 patients with a good response to NAS, suggesting that substituting ALND with SLNB may be a reasonable option for carefully selected patients, providing evidence for future clinical trials.\u003c/p\u003e\u003cp\u003eFurthermore, we subsequently investigated whether the choice of specific NAS regimen further modulates ypN0 rates within key molecular-defined subgroups (TNBC, HER2-positive, and HR-positive subgroups). Our findings highlight potential subtype-specific optimal neoadjuvant regimens for achieving ypN0 and enabling surgical de-escalation. Specifically, in cN0, HR-positive patients, the TEC regimen was associated with a significantly higher ypN0 rate than the EC-T regimen, supporting the potential for SLNB omission with TEC. Furthermore, among cN1, HER2-positive patients, dual-target anti-HER2 therapy (Herceptin\u0026thinsp;+\u0026thinsp;Pertuzumab) resulted in a higher rate of ypN0, which suggests increased opportunity for ALND omission in this group. This finding strongly supports the superior efficacy of dual HER2 blockade not only for the primary tumor but also specifically for achieving axillary nodal clearance. Interestingly, our study did not detect statistically significant differences in ypN0 associated with different NAS regimens when examining combinations of other molecular subtypes and lymph node status. This lack of observed effect should be interpreted cautiously; the relatively recent widespread clinical adoption of platinum-based agents and the continuous emergence of novel drugs and potentially more potent neoadjuvant strategies necessitate ongoing, detailed, and systematic investigation into how specific regimen choices influence ypN0 rates across the full spectrum of breast cancer subtypes.\u003c/p\u003e\u003cp\u003eHowever, this study is subject to the limitations inherent in its retrospective, single-center design, including potential selection and information bias. Therefore, the proposed predictive schemes require validation in prospective, multi-center studies with long-term follow-up to confirm their oncologic safety and applicability to broader populations. Future research incorporating advancements in imaging, genomics, and systemic therapies may further refine patient selection, also allow selected patients with cN1 disease to omit SLNB, and potentially extend axillary de-escalation strategies to patients with higher baseline nodal burdens (cN2-3)\u003csup\u003e[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]\u003c/sup\u003e. In this study, a small number of patients did not undergo MRI examinations or completed only one MRI scan, and for these cases, the efficacy of neoadjuvant therapy was solely assessed using pre- and post-neoadjuvant ultrasound results. This was primarily attributed to objective factors such as the high cost of MRI examinations and data incompleteness stemming from the broad span of the study period. Although the sensitivity of axillary ultrasound after neoadjuvant chemotherapy (NAC) may be lower than that of MRI, potentially introducing an assessment bias, this represents an unavoidable limitation in real-world studies. Furthermore, as patients in our study did not undergo targeted axillary dissection (TAD), the impact on the cN1 group remains uncertain, whereas the results for the cN0 group were unaffected.\u003c/p\u003e\u003cp\u003eThis study, based on detailed real-world big data, identified predictors of ypN0 after neoadjuvant systemic therapy in newly diagnosed cN0 and cN1 patients. These factors can support clinical decisions regarding: (1) whether omission of SLNB can be considered in newly diagnosed cN0 patients after NAS; and (2) whether omission of ALND (performing only SLNB) can be considered in newly diagnosed cN1 patients after NAS. For newly diagnosed cN0-1 breast cancer patients undergoing NAS, the post-NAS radiological assessment is a critical factor in guiding axillary surgery decisions. Additionally, in newly diagnosed cN1 patients, HER2 positivity and higher Ki-67 expression were associated with a higher ypN0 rate, which may provide a basis for omitting ALND. Furthermore, we preliminarily explored the impact of specific neoadjuvant regimens on the ypN0 rate and the potential for axillary surgery omission, providing new insights and directions for selecting suitable candidates for axillary de-escalation therapy. In conclusion, this study highlights the importance of patient selection and evaluation in axillary de-escalation treatment, provides a framework for individualized axillary treatment strategies, and contributes to a deeper understanding of tumor biological characteristics, thereby allowing carefully selected patients with a good response to NAS who remain or convert to ycN0 status to avoid unnecessary axillary lymph node surgery, while ensuring adequate treatment for patients at higher risk of residual disease who would benefit from axillary surgery.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethics Committee of the First Affiliated Hospital of Xi\u0026rsquo;an Jiaotong University (Xi\u0026rsquo;an, China). As a retrospective study, informed consent of patients is not required. The research and data analyses comply with the current laws of the People\u0026rsquo;s Republic of China.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors have read and agreed with the content of the manuscript as well as its submission.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe acknowledge MSTATA software (https://www.mstata.com/) for its invaluable data analysis services, which facilitated the completion of Tables 2 and 3.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization, Yuhan Zhang, Guanqun Ge and Yu Ren; Data curation, Xiaoya Chen, Yi Pan and Zhihao Liu; Formal analysis, Yuhan Zhang and Xiaoya Chen; Funding acquisition, Bin Wang; Investigation, Yuhan Zhang, Lizhe Zhu and Xiaoya Chen; Methodology, Guanqun Ge and Bin Wang; Resources, Bin Wang; Software, Chenrong Zhang, Keyuan Du; Supervision, Bin Wang, Guanqun Ge and Yu Ren; Validation, Lizhe Zhu and Yuhan Zhang; Visualization, Yuhan Zhang, Xiaoya Chen and Yi Pan; Writing-original draft, Yuhan Zhang; Writing-review \u0026amp; editing, Yuhan Zhang.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was funded by National Natural Science Foundation of China (Grant No. 82172798 and 82472749) and Shaanxi Provincial Innovation Support Program (Grant No. 2022PT-24).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data used or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGENTILINI O D, BOTTERI E, SANGALLI C, et al. 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Therapeutic advances in medical oncology, 2021, 13: 1758835921996673.\u003c/li\u003e\n\u003cli\u003eREIMER T, GLASS A, BOTTERI E, et al. Avoiding Axillary Sentinel Lymph Node Biopsy after Neoadjuvant Systemic Therapy in Breast Cancer: Rationale for the Prospective, Multicentric EUBREAST-01 Trial s. Cancers (Basel), 2020, 12(12).\u003c/li\u003e\n\u003cli\u003eClinicaltrials.gov. Avoiding Sentinel Lymph Node Biopsy in Breast Cancer Patients After Neoadjuvant Chemotherapy (ASICS). https://clinicaltrials.gov/ct2/show/NCT04225858.\u003c/li\u003e\n\u003cli\u003eBARRIO A V, MONTAGNA G, MAMTANI A, et al. Nodal Recurrence in Patients With Node-Positive Breast Cancer Treated With Sentinel Node Biopsy Alone After Neoadjuvant Chemotherapy-A Rare Event s. JAMA Oncol, 2021, 7(12) : 1851\u0026ndash;5.\u003c/li\u003e\n\u003cli\u003eMONTAGNA G, MRDUTT M M, SUN S X, et al. Omission of Axillary Dissection Following Nodal Downstaging With Neoadjuvant Chemotherapy s. JAMA Oncol, 2024, 10(6) : 793\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eTEE S R, DEVANE L A, EVOY D, et al. Meta-analysis of sentinel lymph node biopsy after neoadjuvant chemotherapy in patients with initial biopsy-proven node-positive breast cancer s. The British journal of surgery, 2018, 105(12) : 1541\u0026ndash;52.\u003c/li\u003e\n\u003cli\u003eBOUGHEY J C, SUMAN V J, MITTENDORF E A, et al. Factors affecting sentinel lymph node identification rate after neoadjuvant chemotherapy for breast cancer patients enrolled in ACOSOG Z1071 (Alliance) s. Ann Surg, 2015, 261(3) : 547\u0026ndash;52.\u003c/li\u003e\n\u003cli\u003eBOILEAU J F, POIRIER B, BASIK M, et al. Sentinel node biopsy after neoadjuvant chemotherapy in biopsy-proven node-positive breast cancer: the SN FNAC study s. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2015, 33(3) : 258\u0026ndash;64.\u003c/li\u003e\n\u003cli\u003eBOUGHEY J C, BALLMAN K V, HUNT K K, et al. Axillary Ultrasound After Neoadjuvant Chemotherapy and Its Impact on Sentinel Lymph Node Surgery: Results From the American College of Surgeons Oncology Group Z1071 Trial (Alliance) s. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2015, 33(30) : 3386\u0026ndash;93.\u003c/li\u003e\n\u003cli\u003eGALIMBERTI V, RIBEIRO FONTANA S K, MAISONNEUVE P, et al. Sentinel node biopsy after neoadjuvant treatment in breast cancer: Five-year follow-up of patients with clinically node-negative or node-positive disease before treatment s. Eur J Surg Oncol, 2016, 42(3) : 361\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003ePILTIN M A, HOSKIN T L, DAY C N, et al. Oncologic Outcomes of Sentinel Lymph Node Surgery After Neoadjuvant Chemotherapy for Node-Positive Breast Cancer s. Ann Surg Oncol, 2020, 27(12) : 4795\u0026ndash;801.\u003c/li\u003e\n\u003cli\u003eCURIGLIANO G, BURSTEIN H J, WINER E P, et al. De-escalating and escalating treatments for early-stage breast cancer: the St. Gallen International Expert Consensus Conference on the Primary Therapy of Early Breast Cancer 2017 s. Ann Oncol, 2017, 28(8) : 1700\u0026ndash;12.\u003c/li\u003e\n\u003cli\u003eZHENG Q, YAN H, HE Y, et al. An ultrasound-based nomogram for predicting axillary node pathologic complete response after neoadjuvant chemotherapy in breast cancer: Modeling and external validation s. Cancer, 2024, 130(S8) : 1513\u0026ndash;23.\u003c/li\u003e\n\u003cli\u003eKAHLER-RIBEIRO-FONTANA S, PAGAN E, MAGNONI F, et al. Long-term standard sentinel node biopsy after neoadjuvant treatment in breast cancer: a single institution ten-year follow-up s. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology, 2021, 47(4) : 804\u0026ndash;12.\u003c/li\u003e\n\u003cli\u003eTINTERRI C, BARBIERI E, SAGONA A, et al. De-Escalation of Axillary Surgery in Clinically Node-Positive Breast Cancer Patients Treated with Neoadjuvant Therapy: Comparative Long-Term Outcomes of Sentinel Lymph Node Biopsy versus Axillary Lymph Node Dissection s. Cancers (Basel), 2024, 16(18).\u003c/li\u003e\n\u003cli\u003eCAPASSO K, MITRI S, ROLDAN-VASQUEZ E, et al. Axillary de-escalation after neoadjuvant chemotherapy for advanced lymph node involvement in breast cancer s. American journal of surgery, 2024, 236: 115893.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"breast cancer, neoadjuvant systemic therapy, de-escalation axillary treatment, cN0 and cN1 disease, retrospective study","lastPublishedDoi":"10.21203/rs.3.rs-8154244/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8154244/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eRecent advancements in breast cancer management have focused on de-escalating axillary surgery to minimize morbidity and improve quality of life, without compromising survival outcomes. Prior clinical trials have provided evidence supporting the use of less extensive axillary procedures in patients with favorable characteristics. However, research and evidence regarding optimal axillary lymph node surgical decisions after neoadjuvant systemic therapy (NAS) remain limited. Our study aimed to identify key factors in a real-world setting that predict the feasibility of omitting axillary surgery following NAS in clinically node negative (cN0) and clinically staged N1 (cN1) breast cancer.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe retrospectively analyzed 1068 clinical N0-1 breast cancer patients who received NAS followed by surgery. Univariable and multivariable logistic regression analyses were used to identify clinicopathological predictors for: (1) ypN0 after NAS in newly diagnosed cN0 patients, which could guide sentinel lymph node biopsy (SLNB) omission; and (2) ypN0 after NAS in newly diagnosed cN1 patients, which could guide axillary lymph node dissection (ALND) omission.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eIn newly diagnosed cN0 patients (n\u0026thinsp;=\u0026thinsp;302), 274 (90.7%) achieved ypN0. Achieving radiological partial response (rPR) after NAS (odds ratio (OR), 0.27; 95% CI, 0.11\u0026ndash;0.65; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003) was associated with a higher ypN0 rate, suggesting potential for SLNB omission. Conversely, higher clinical T stage (cT3-4) (OR, 3.06; 95% CI, 1.11\u0026ndash;8.39; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.030) and estrogen receptor (ER) positivity (OR, 3.94; 95% CI, 1.24\u0026ndash;12.54; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.020) were associated with a lower ypN0 rate, indicating a tendency towards retaining SLNB. In newly diagnosed cN1 patients (n\u0026thinsp;=\u0026thinsp;766), the ypN0 rate was 50.3% (385/766). Human epidermal growth factor receptor 2 (HER2) positivity (OR, 0.34; 95% CI, 0.25\u0026ndash;0.48; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), achieving rPR (OR, 0.38; 95% CI, 0.24\u0026ndash;0.59; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and achieving radiological complete response (rCR) (OR, 0.06; 95% CI, 0.02\u0026ndash;0.14; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) were associated with a higher ypN0 rate, potentially allowing for selective ALND omission. However, tumors located in the central quadrant (OR, 2.99; 95% CI, 1.05\u0026ndash;8.50; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.040), along with ER positivity (OR, 1.82; 95% CI, 1.16\u0026ndash;2.84; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009), progesterone receptor (PR) positivity (OR, 1.67; 95% CI, 1.08\u0026ndash;2.56; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.020) and invasive breast carcinoma of special type (IBC-ST) (OR, 2.76; 95% CI, 1.05\u0026ndash;7.22; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.039) were associated with a lower ypN0 rate, suggesting caution in omitting ALND.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eFor newly diagnosed cN0-1 breast cancer patients undergoing NAS, the post-NAS radiological assessment was a critical factor in guiding axillary surgical management decisions. Furthermore, in newly diagnosed cN1 patients, HER2 positivity was also associated with a higher ypN0 rate, which may inform the omission of ALND.\u003c/p\u003e","manuscriptTitle":"Axillary de-escalation after neoadjuvant systemic therapy in cN0-1 breast cancer patients","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-12 13:20:56","doi":"10.21203/rs.3.rs-8154244/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5ba98ec1-87d4-49ed-8327-6fc2ba17ce8b","owner":[],"postedDate":"December 12th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-01T00:24:46+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-12 13:20:56","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8154244","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8154244","identity":"rs-8154244","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}