Micrometastases in axillary lymph nodes in breast cancer, post-neoadjuvant systemic therapy

Micrometastases in axillary lymph nodes in breast cancer, post-neoadjuvant systemic therapy | 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 Micrometastases in axillary lymph nodes in breast cancer, post-neoadjuvant systemic therapy Janghee Lee, Seho Park, Soong June Bae, Junghwan Ji, Dooreh Kim, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4381795/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 31 Jul, 2024 Read the published version in Breast Cancer Research → Version 1 posted 9 You are reading this latest preprint version Abstract Introduction: The significance of minimal residual axillary disease, specifically micrometastases, following neoadjuvant systemic therapy (NST) remains largely unexplored. Our study aimed to elucidate the prognostic implications of micrometastases in axillary and sentinel lymph nodes following NST. Methods This retrospective study analyzed primary breast cancer patients who underwent surgery after NST from September 2006 through February 2018. All patients received axillary lymph node dissection (ALND), either with or without sentinel lymph node biopsy. Recurrence-free survival (RFS)-associated variables were identified using a multivariate Cox proportional hazard model. Results Of the 978 patients examined, 438 (44.8%) exhibited no pathologic lymph node involvement (ypN0) after NST, while 89 (9.1%) had micrometastases (ypNmi). Multivariate analysis revealed no significant association between ypNmi and RFS in patients post-NST (hazard ratio [HR], 1.02; 95% confidence interval [CI], 0.42–2.49; P = 0.958). Notably, over half of the patients with sentinel lymph node micrometastases (SLNmi) had additional metastases, nearly triple that of SLN-negative patients ( P < 0.001). Furthermore, SLNmi patients experienced significantly worse RFS compared to SLN-negative patients (HR, 2.23; 95% CI, 1.12–4.46; P = 0.023). Additional metastases in SLNmi were more prevalent in patients with larger residual breast disease greater than 20 mm, HR-positive/HER2-negative subtype, and low Ki-67 LI (< 14%). Conclusions While ypNmi does not influence the prognosis compared to ypN0, SLNmi emerges as a significant negative prognostic factor and a robust predictor of additional metastases. Hence, additional ALND may be warranted to confirm axillary nodal status in patients with SLNmi. breast cancer neoadjuvant systemic therapy micrometastases axillary lymph node sentinel lymph node Figures Figure 1 Figure 2 Figure 3 Introduction The prognostic importance of axillary lymph node (LN) metastases in breast cancer has been well established [ 1 ]. Traditionally, axillary lymph node dissection (ALND) served as the standard surgical treatment of invasive breast cancer until the 1990s [ 2 ]. Since then, sentinel lymph node biopsy (SLNB) has emerged as a viable alternative, offering an accurate prediction of axillary nodal status while mitigating the higher morbidity rates associated with ALND [ 3 , 4 ]. Nodal status evaluation involves the consideration of metastatic LN size and quantity. The 2002 guidelines introduced micrometastases (0.2mm < metastatic size ≤ 2.0mm) as distinct categories [ 5 ]. Subsequent studies suggested that micrometastases were not correlated with prognosis, and additional ALND did not significantly enhance locoregional recurrence (LRR) and survival rates in patients presenting with sentinel lymph node micrometastases (SLNmi) in adjuvant settings [ 6 – 9 ]. In the neoadjuvant context, patients with clinically lymph node-positive (cN+) status underwent ALND, independent of their neoadjuvant systemic therapy (NST) response [ 10 ]. However, recent trends advocate the judicious avoidance of ALND in patients who transition to clinically lymph node-negative status post-systemic therapy, especially in the absence of metastases in a sufficient number (≥ 3) of sentinel lymph node (SLN)s [ 11 – 13 ]. Previous research on minimal residual axillary disease, particularly micrometastases, after NST has been limited. Consequently, ALND persists as the standard treatment for patients with SLNmi [ 14 ]. This study aims to investigate the significance of pathologic lymph node-micrometastases (ypNmi) following NST, in comparison to pathologic lymph node-negative (ypN0) or macrometastases (ypN+). We further explore the prognostic implications of SLNmi for the prediction of axillary LN status and survival outcomes. Methods Study populations We conducted a retrospective review of primary breast cancer patients from the registries of Gangnam Severance Hospital and Severance Hospital, who underwent surgery following NST between September 2006 and February 2018. These patients were clinically diagnosed with stage II or III breast cancer and underwent ALND, with or without SLNB. Exclusion criteria comprised of patients who had upfront surgery, underwent only SLNB, or presented with de novo stage IV disease. Our study adhered to Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. The institutional review boards (IRB) granted study protocol approval (approval number: 3-2023-0214). The retrospective study design warranted a waiver for the requirement of written informed consent by the IRB. Assessment of axillary nodal status The initial axillary nodal status was evaluated using ultrasonography and breast magnetic resonance imaging (MRI). Fine needle aspiration biopsy (FNAB) was conducted on patients where necessary. Patients with metastatic LN revealed by FNAB were categorized as cN+. Furthermore, we classified unconfirmed axillary LN metastases as cN + if ultrasonography or breast MRI indicated a strong suspicion of metastasis. We defined metastatic LNs with a size range between > 0.2 mm and ≤ 2 mm as ypNmi, regardless of the metastatic LN count. LNs exceeding 2 mm were classified as ypN+, and the pathologic lymph node (ypN) stage was assigned based on the number of LNs, inclusive of micrometastases. Moreover, isolated tumor cells measuring ≤ 0.2 mm were classified as ypN0, in accordance with guideline [ 15 ]. SLNB and ALND procedures SLNB was performed using single or dual tracers. For the single tracer technique, Technetium 99, a radioactive substance, was administered periareolarly prior to surgery, and SLNs were identified intraoperatively via a gamma detection system (Neoprobe®). The dual tracer method employed both an isosulfan blue dye and Technetium 99 concurrently. The choice of SLNB technique was contingent upon the surgeon’s discretion. SLNs were categorized as one or multiple, and any LN identified by either or both methods was defined as SLN. LNs resected during SLNB without tracer signal were not classified as SLNs. ALND was characterized by the removal of all LNs in axillary levels I and II. Patients documented to have undergone ALND in surgical records were primarily selected from our registry. Among them, those with fewer than 10 LNs were excluded, based on the assumption that a competent ALND necessitated the removal of 10 or more LNs as defined in previous studies [ 16 – 18 ]. Statistical analysis Statistical analyses were conducted using SPSS version 25.0 (IBM Inc., Armonk, NY, USA) and GraphPad Prism, version 9 (GraphPad Software). Differences between groups were assessed using the chi-square test for categorical data and one-way ANOVA for continuous variables, subsequent to confirmation by Levene’s test for equality of variances. The primary outcome was recurrence-free survival (RFS), while overall survival (OS) was analyzed as the secondary outcome. RFS was defined as the interval from breast cancer diagnosis to the initial recurrence, including LRR, distant metastasis, or any cause of death. OS was defined as the duration from breast cancer diagnosis to death from any cause. Kaplan-Meier survival estimations were implemented for RFS and OS, and survival curve group disparities were examined via the log-rank test. Variables associated with RFS and OS were ascertained using a multivariate Cox proportional hazard model, with hazard ratio (HR) and corresponding 95% confidence intervals (CI). The analysis of risk factors for additional metastases in SLNmi patients was performed using a binary logistic regression model. All statistical tests were two-sided, and a p value < 0.05 was considered statistically significant. Results Figure 1 depicts the distribution of axillary surgical procedures among the patients enrolled in our study. Out of the initial 1,642 participants, 664 were excluded due to an inadequate number of axillary LNs or insufficient metastatic LN information. Consequently, 978 patients were analyzed, with a median follow-up duration of 73 months (range, 4-176 months). Among them, 465 (47.5%) patients underwent ALND alone, without SLNB, while 513 (52.5%) patients had SLNB prior to ALND. Baseline characteristics Only 89 (9.1%) patients presented with axillary LN micrometastases. In contrast, 438 (44.8%) had no metastases, and 451 (46.1%) exhibited macrometastases after NST. Table 1 summarizes the clinicopathologic characteristics and differences across these three groups. Among the evaluated cohort, 927 (94.8%) patients were cN + pre-chemotherapy. A significant correlation was observed between pathologic tumor size and axillary nodal status. More than half of the patients with ypN0 achieved a breast pathologic complete response (pCR), while this proportion was significantly lower in the ypN + group (7.3%). The rate of breast pCR in patients with ypNmi was 29.2%, lower than that in the ypN0 group, but higher than in the ypN + group. Moreover, the quantity of dissected LNs was marginally higher in ypN + patients ( P = 0.003). The proportion of estrogen receptor (ER)-positive or human epidermal growth factor receptor 2 (HER2)-negative tumors was found to be considerably higher in the ypNmi and ypN + groups compared to the ypN0 group. The Ki-67 labeling index (LI) was negatively correlated with ypN status. Notably, more patients in the ypNmi and ypN + groups received adjuvant radiotherapy compared to the ypN0 group. Table 1 Baseline characteristics of all patients All Patients (%) Patients with ypN0 (%) Patients with ypNmi (%) Patients with ypN+ (%) P value Total 978 (100) 438 (44.8) 89 (9.1) 451 (46.1) Age at diagnosis, average (range) 48.5 (20–79) 48.6 (26–79) 47.1 (28–75) 48.8 (20–75) 0.296 Clinical nodal status, initial 0.061 Negative 51 (5.2) 31 (7.3) 3 (3.4) 17 (3.8) Positive 927 (94.8) 407 (92.9) 86 (96.6) 434 (96.2) Breast surgery < 0.001 BCS 369 (37.7) 198 (45.2) 40 (44.9) 131 (29.0) Mastectomy 609 (62.3) 240 (54.8) 49 (55.1) 320 (71.0) Pathologic tumor size (mm) 50 43 (4.4) 7 (1.6) 0 (0) 36 (8.0) Number of dissected LNs, average (range) 16.7 (10–60) 16.0 (10–38) 16.1 (10–31) 17.4 (10–60) 0.003 ER < 0.001 Positive 572 (58.5) 186 (42.5) 60 (67.4) 326 (72.3) Negative 406 (41.5) 252 (57.5) 29 (32.6) 125 (27.7) PR < 0.001 Positive 431 (44.1) 122 (28.3) 50 (56.2) 259 (57.4) Negative 547 (55.9) 316 (72.1) 39 (43.8) 192 (42.6) HER2 < 0.001 Negative 638 (65.2) 237 (54.1) 63 (70.8) 338 (74.9) Positive 340 (34.8) 201 (45.9) 26 (29.2) 113 (25.1) Ki-67 LI, % < 0.001 <14 370 (37.8) 112 (25.6) 39 (43.8) 219 (48.6) ≥14 438 (44.8) 224 (51.1) 38 (42.7) 176 (39.0) Unknown 170 (17.4) 102 (23.3) 12 (13.5) 56 (12.4) Radiotherapy 0.015 Not performed 78 (8.0) 47 (10.7) 4 (4.5) 27 (6.0) Performed 900 (92.0) 391 (89.3) 85 (95.5) 424 (94.0) BCS, breast-conserving surgery; pCR, pathologic complete response; LN, lymph node; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth receptor 2; LI, labelling index Survival outcome according to pathologic nodal status following NST The collective 5-year RFS for all patients was 82%. Broken down by group, the 5year RFS for ypN0, ypNmi, and ypN + patients were 89%, 87.6%, and 74.1% respectively. Throughout the follow-up period, a total of 183 patients experienced 217 recurrent events. These recurrences manifested as locoregional in 11 patients, systemic in 138 patients, and combined locoregional and systemic in 34 patients. Out of the total patient pool, 85 deaths occurred with a 5-year OS rate of 92.7%. Among the deceased, 70 patients succumbed to breast cancer recurrence, while 15 deaths were attributed to other causes. The Kaplan-Meier survival curve indicated that patients classified as ypN + demonstrated significantly inferior RFS compared to ypN0 and ypNmi patients (eFigure 1A; ypN0 vs. ypN+: P < 0.001; ypNmi vs. ypN+: P = 0.008). However, no statistically significant difference was observed in recurrence and survival rates between ypN0 and ypNmi groups ( P = 0.455). Furthermore, multivariate Cox regression hazard modeling failed to establish ypNmi as a significant prognostic factor of RFS in patients undergoing NST (Table 2 , HR, 1.70; 95% CI, 0.90–3.22; P = 0.104). Factors including macrometastases, large pathological tumor size, high Ki-67 LI (≥ 14%), and lack of radiotherapy were associated with an increased risk of RFS. In terms of OS, the Kaplan-Meier survival curve also indicated a worse prognosis for ypN + patients compared to ypN0 or ypNmi patients (eFigure 1B; ypN0 vs. ypN+: P < 0.001; ypNmi vs. ypN+: P = 0.035). Multivariate analysis continued to highlight macrometastases as a risk factor for OS, whereas micrometastases did not impact survival outcomes (eTable 1; ypNmi: HR, 1.61; 95% CI, 0.52–4.98; P = 0.409; ypN+: HR, 2.88; 95% CI, 1.47–5.66; P = 0.002). Table 2 Uni- and multivariate analysis of RFS in patients with NST Univariate analysis Multivariate analysis HR (95% CI) P value HR (95% CI) P value Pathologic nodal status ypN0 Ref. ** Ref. ypNmi 1.26 (0.70–2.26) 0.448 1.70 (0.90–3.22) 0.104 ypN+ 2.60 (1.89–3.58) < 0.001 2.81 (1.85–4.27) < 0.001 Age at diagnosis * 1.00 (0.99–1.02) 0.885 Breast surgery BCS Ref. Ref. Mastectomy 1.66 (1.21–2.28) 0.002 1.01 (0.70–1.46) 0.964 Pathologic tumor size, mm Breast pCR Ref. Ref. 0–20 1.81 (1.17–2.80) 0.007 1.85 (1.05–3.25) 0.033 20–50 3.96 (2.53–6.20) < 0.001 3.12 (1.71–5.68) 50 8.31 (4.79–14.43) < 0.001 5.75 (2.85–11.59) < 0.001 Number of dissected LNs * 1.02 (1.00-1.04) 0.099 ER Positive Ref. Ref. Negative 1.59 (1.21–2.11) 0.001 1.50 (0.95–2.37) 0.084 PR Positive Ref. Ref. Negative 1.36 (1.02–1.81) 0.035 1.37 (0.86–2.18) 0.191 HER2 Negative Ref. Positive 0.76 (0.56–1.03) 0.079 Ki-67 LI, % <14 Ref. Ref. ≥14 1.78 (1.28–2.47) 0.001 1.83 (1.29–2.61) 0.001 Radiotherapy Not performed Ref. Performed 0.62 (0.40–0.95) 0.029 0.55 (0.33–0.91) 0.021 * Continuous variable ** Reference value RFS, recurrence free survival; NST, neoadjuvant systemic therapy; HR, hazard ratio; CI, confidence interval; BCS, breast-conserving surgery; pCR, pathologic complete response; LN, lymph node; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth receptor 2; LI, labelling index Significance of micrometastases in SLNs Further analyses were conducted on patients who underwent SLNB preceding ALND. Of these patients, 296 (57.7%) were SLN-negative, while 47 (9.2%) exhibited SLNmi (Fig. 2 ). No significant difference was observed in the average number of removed SLNs between these groups (eTable 2). Patients in the SLNmi category demonstrated larger pathological tumor sizes, higher ER positivity rates, and lower Ki-67 LI compared to SLN-negative patients. Over half of SLNmi patients were identified with additional metastases in non-SLNs, nearly a three-fold increase compared to SLN-negative patients (Fig. 2 ; P < 0.001). Moreover, 29.8% of SLNmi patients were categorized as ypN+. The 5-year RFS rates for SLN-negative and SLNmi patients were 89.5% and 76.6% respectively. Notably, SLNmi patients had a significantly poorer RFS than SLN-negative patients in the Kaplan-Meier survival analysis (Fig. 3 ; P = 0.023). In the multivariate analysis, SLNmi emerged as a poor prognostic factor for RFS (Table 3 ; HR, 2.23; 95% CI, 1.12–4.46; P = 0.023). Nonetheless, no significant differences were found in OS between SLN-negative and SLNmi patients (eFigure 2 and eTable 3). Table 3 Uni and multivariate analysis of the effect of SLN-micrometastases on RFS Univariate analysis Multivariate analysis HR (95% CI) P value HR (95% CI) P value SLN Negative Ref. ** Ref. Micrometastases 2.11 (1.09–4.07) 0.026 2.23 (1.12–4.46) 0.023 Age at diagnosis * 0.99 (0.96–1.02) 0.466 Breast surgery BCS Ref. Mastectomy 1.13 (0.63–2.01) 0.689 Pathologic tumor size, mm Breast pCR Ref. Ref. 0–20 2.76 (1.23–6.20) 0.014 3.33 (1.31–8.42) 0.011 20–50 5.39 (2.26–12.86) 50 38.57 (7.97-186.66) < 0.001 39.48 (7.54-206.74) < 0.001 ER Positive Ref. Ref. Negative 1.81 (1.01–3.25) 0.045 1.55 (0.79–3.05) 0.203 PR Positive Ref. Negative 1.43 (0.77–2.64) 0.260 HER2 Negative Ref. Positive 0.77 (0.41–1.47) 0.431 Ki-67 LI, % <14 Ref. Ref. ≥14 2.40 (1.18–4.91) 0.016 2.58 (1.17–5.68) 0.019 Radiotherapy No Ref. Yes 1.73 (0.53–5.60) 0.363 * Continuous variable ** Reference value SLN, sentinel lymph node; RFS, recurrence free survival; HR, hazard ratio; CI, confidence interval; BCS, breast-conserving surgery; pCR, pathologic complete response; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth receptor 2; LI, labelling index Risk factors associated with additional metastases in SLNmi patients Risk factors associated with additional metastases in SLNmi patients were investigated. Additional metastases were more prevalent in patients with pathological tumor size > 20 mm, ER-positive/HER2-negative subtype, and a low Ki-67 LI (< 14%) (eTable 4). Notably, 30.0% (3 out of 10) and 18.2% (2 out of 11) of patients with additional metastases had HER2-overexpressing and triple-negative breast cancer (TNBC) subtypes, respectively, whereas 73.1% (19 out of 26) of ER-positive/HER2-negative patients demonstrated additional metastases (eTable 5). In the presence of SLNmi, ER-positive/HER2-negative subtype had a significantly higher rate of additional metastases compared to other subtypes ( P = 0.003). Conversely, no significant difference was observed in the incidence of additional metastases among patients with SLNmi, irrespective of subtype ( P = 0.079). Discussion Our study showed that patients with ypN0 and ypNmi had comparable RFS and OS outcomes, while those with ypN + had a negative impact on oncologic outcomes. Notably, axillary LN status could not be accurately ascertained solely by the micrometastases of SLN. Instances of SLNmi often coincided with additional LN metastases and correlated with worse RFS compared to patients who were SLN-negative. Consequently, our findings suggest that axillary staging via ALND in patients with SLNmi should be considered following NST. The association between residual axillary disease and prognosis is well-documented [ 19 – 21 ]. We hypothesized the existence of a subgroup of patients who might exhibit a more favorable prognosis, even in the presence of residual axillary tumor burden, such as micrometastases. Our findings substantiate this, demonstrating that patients with ypNmi have a more favorable prognosis compared to those with ypN+, and their oncologic outcomes are on par with those of ypN0. Prior to our investigation, only two retrospective studies, to the best of our knowledge, examined residual nodal burden. Nijinatten et al. studied prognosis as a function of metastatic LN size in a single institution [ 22 ], in which all patients were cN + and 3.8% of patients were classified as ypNitc/mi. They reported a similar prognosis for ypNitc/mi and ypN0 patients, superior to that of ypN + patients. Our results align with these findings within a similar patient population, despite a higher ypNmi percentage (9.1%) in our study. Conversely, Wong et al. contended that post-NST patients with isolated tumor cells or micrometastases had a worse prognosis than those with ypN0 in both a single institution cohort and the National Cancer Database (NCDB) [ 23 ]. They reported ypNmi rates of 9.1% and 4.7% in their respective cohorts. However, their study included patients who underwent SLNB without ALND in survival analysis. In contrast, our study exclusively enrolled patients who had 10 or more axillary LNs dissected to optimally evaluate axillary nodal status. SLNB is a valuable intraoperative tool for predicting axillary LN metastases, though it is observed to yield higher rates of false negatives in NST patients compared to those in a primary surgical setting [ 24 , 25 ]. The SENTINA trial demonstrated a FNR of 18.5% when two SLNs were removed, despite clinical conversion to node negativity post-NST [ 11 ]. In our cohort, the mean number of removed SLNs was 2.62, resulting in an elevated FNR of 23.8%. Furthermore, we noted that 17.9% of SLN-negative patients had verifiable axillary LN metastases. Our findings indicate a substantially higher incidence of additional metastases in patients with SLNmi relative to those with SLN-negative results. Prior to our investigation, Moo et al. documented that 64% of SLNmi patients exhibited non-SLN metastases, a significantly higher figure than the 17% observed in SLN-negative patients [ 26 ]. Our study corroborated these findings, revealing additional metastases in 51.1% of SLNmi patients, 58.3% of which were macrometastases. However, in the adjuvant setting, specifically within the American College of Surgeons Oncology Group Z0011 trial, the incidence of additional metastases among SLNmi was considerably lower, at roughly ten percent [ 27 ]. This discrepancy suggests a heightened likelihood of additional metastases in NST patients with SLNmi compared to those in the adjuvant setting. In a novel discovery, we also found that SLNmi patients exhibited lower RFS rates than SLN-negative patients. Collectively, these findings suggest the necessity of ALND in patients with SLNmi following NST. In the analysis of risk factors linked to additional metastases in SLNmi patients, a correlation was observed with pathological tumor size exceeding ypT2, ER-positive/HER2-negative subtype, and low Ki-67 LI (≤ 14%). These findings can be contextualized within the sphere of NST responsiveness. It is well established that ER-positive/HER2-negative tumors present a lower overall response rate [ 28 , 29 ]. Additionally, low levels of Ki-67 LI associated with reduced pCR rates [ 30 , 31 ]. Consequently, it can be inferred that SLNB accuracy is interrelated with NST response, and SLNmi is more likely to exhibit additional metastases in patients demonstrating a suboptimal response to chemotherapy. One limitation of this study includes the potential selection bias stemming from its retrospective design. However, we were able to source relatively uniform and reliable clinicopathological data from two institutions and endeavored to accurately evaluate the axillary nodal status. Nonetheless, we were unable to consider the clinical nodal status as determined by imaging modalities. Future studies combining SLNB results with chemotherapy response evaluations via imaging examination in SLNmi cases may be necessary, as some studies suggest that the accuracy of axillary nodal status prediction can be enhanced when imaging examination results are integrated with SLNB outcomes [ 32 ]. In conclusion, ypNmi does not significantly impact patient prognosis when compared with ypN0, although ypN + is correlated with a notably worse survival outcome. However, SLNmi is an adverse prognostic indicator and a critical predictor of additional metastases, particularly in patients with a poor NST response. As such, additional ALND should be considered for verifying axillary nodal status in patients presenting with SLNmi. Abbreviations LN, lymph node; ALND, axillary lymph node dissection; SLNB, sentinel lymph node biopsy; LRR, locoregional recurrence; SLNmi, sentinel lymph node micrometastases; cN+, clinically lymph node-positive; NST, neoadjuvant systemic therapy; SLN, sentinel lymph node; ypNmi; pathologic lymph node-micrometastases; ypN0, pathologic lymph node-negative; ypN+, pathologic lymph node-macrometastases; IRB, institutional review boards; MRI, magnetic resonance imaging; FNAB, fine needle aspiration biopsy; ypN, pathologic lymph node; RFS, recurrence-free survival; OS, overall survival; HR, hazard ratio; CI, confidence intervals; pCR; pathologic complete response; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; LI, labeling index; BCS, breast-conserving surgery; PR, progesterone receptor Declarations Ethics approval and consent to participate Our study adhered to Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. The institutional review boards granted study protocol approval (approval number: 3-2023-0214). The retrospective study design warranted a waiver for the requirement of written informed consent by the institutional review boards. Consent for publication Not applicable Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request Competing interests The authors declare that they have no competing interests Funding None Authors’ contributions JL and JJ (Joon Jeong) conceptualized and designed the study, JL, SP, SJB, JJ (Junghwan Ji), DK and JYK performed the data curation, JL and SJB performed statistical analysis, JL, SP and SGA interpreted the data, JL drafted the manuscript, JJ (Joon Jeong) critically revised the manuscript, HSP, SGA, SIK, BWP and JJ (Joon Jeong) supervised parts of the study. All authors have read and agreed to the published version of the manuscript. 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Meric F, Mirza NQ, Buzdar AU, Hunt KK, Ames FC, Ross MI, et al. Prognostic implications of pathological lymph node status after preoperative chemotherapy for operable T3N0M0 breast cancer. Ann Surg Oncol. 2000;7(6):435-40. Hennessy BT, Hortobagyi GN, Rouzier R, Kuerer H, Sneige N, Buzdar AU, et al. Outcome after pathologic complete eradication of cytologically proven breast cancer axillary node metastases following primary chemotherapy. J Clin Oncol. 2005;23(36):9304-11. Mougalian SS, Hernandez M, Lei X, Lynch S, Kuerer HM, Symmans WF, et al. Ten-Year Outcomes of Patients With Breast Cancer With Cytologically Confirmed Axillary Lymph Node Metastases and Pathologic Complete Response After Primary Systemic Chemotherapy. JAMA Oncol. 2016;2(4):508-16. van Nijnatten TJ, Simons JM, Moossdorff M, de Munck L, Lobbes MB, van der Pol CC, et al. Prognosis of residual axillary disease after neoadjuvant chemotherapy in clinically node-positive breast cancer patients: isolated tumor cells and micrometastases carry a better prognosis than macrometastases. Breast Cancer Res Treat. 2017;163(1):159-66. Wong SM, Almana N, Choi J, Hu J, Gagnon H, Natsuhara K, et al. Prognostic Significance of Residual Axillary Nodal Micrometastases and Isolated Tumor Cells After Neoadjuvant Chemotherapy for Breast Cancer. Ann Surg Oncol. 2019;26(11):3502-9. Akay CL, Albarracin C, Torstenson T, Bassett R, Mittendorf EA, Yi M, et al. Factors impacting the accuracy of intra-operative evaluation of sentinel lymph nodes in breast cancer. Breast J. 2018;24(1):28-34. Gimbergues P, Dauplat MM, Durando X, Abrial C, Le Bouedec G, Mouret-Reynier MA, et al. Intraoperative imprint cytology examination of sentinel lymph nodes after neoadjuvant chemotherapy in breast cancer patients. Ann Surg Oncol. 2010;17(8):2132-7. Moo TA, Edelweiss M, Hajiyeva S, Stempel M, Raiss M, Zabor EC, et al. Is Low-Volume Disease in the Sentinel Node After Neoadjuvant Chemotherapy an Indication for Axillary Dissection? Ann Surg Oncol. 2018;25(6):1488-94. Giuliano AE, Ballman K, McCall L, Beitsch P, Whitworth PW, Blumencranz P, et al. Locoregional Recurrence After Sentinel Lymph Node Dissection With or Without Axillary Dissection in Patients With Sentinel Lymph Node Metastases: Long-term Follow-up From the American College of Surgeons Oncology Group (Alliance) ACOSOG Z0011 Randomized Trial. Ann Surg. 2016;264(3):413-20. Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014;384(9938):164-72. Haque W, Verma V, Hatch S, Suzanne Klimberg V, Brian Butler E, Teh BS. Response rates and pathologic complete response by breast cancer molecular subtype following neoadjuvant chemotherapy. Breast Cancer Res Treat. 2018;170(3):559-67. Tao M, Chen S, Zhang X, Zhou Q. Ki-67 labeling index is a predictive marker for a pathological complete response to neoadjuvant chemotherapy in breast cancer: A meta-analysis. Medicine (Baltimore). 2017;96(51):e9384. Inwald EC, Klinkhammer-Schalke M, Hofstädter F, Zeman F, Koller M, Gerstenhauer M, et al. Ki-67 is a prognostic parameter in breast cancer patients: results of a large population-based cohort of a cancer registry. Breast Cancer Res Treat. 2013;139(2):539-52. Morency D, Dumitra S, Parvez E, Martel K, Basik M, Robidoux A, et al. Axillary Lymph Node Ultrasound Following Neoadjuvant Chemotherapy in Biopsy-Proven Node-Positive Breast Cancer: Results from the SN FNAC Study. Ann Surg Oncol. 2019;26(13):4337-45. Additional Declarations No competing interests reported. Supplementary Files NeomicrometastasesSupplementarymaterialsBCR.docx Cite Share Download PDF Status: Published Journal Publication published 31 Jul, 2024 Read the published version in Breast Cancer Research → Version 1 posted Editorial decision: Revision requested 23 Jun, 2024 Reviews received at journal 02 Jun, 2024 Reviews received at journal 17 May, 2024 Reviewers agreed at journal 15 May, 2024 Reviewers agreed at journal 14 May, 2024 Reviewers invited by journal 13 May, 2024 Editor assigned by journal 09 May, 2024 Submission checks completed at journal 08 May, 2024 First submitted to journal 07 May, 2024 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. 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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-4381795","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":302348130,"identity":"a30d487d-880e-451e-b61f-595bf891f334","order_by":0,"name":"Janghee Lee","email":"","orcid":"","institution":"Hallym University Dongtan Sacred Heart Hospital","correspondingAuthor":false,"prefix":"","firstName":"Janghee","middleName":"","lastName":"Lee","suffix":""},{"id":302348131,"identity":"8c251e4e-41cb-47b0-a12e-f9540c71ba5d","order_by":1,"name":"Seho Park","email":"","orcid":"","institution":"Severance Hospital","correspondingAuthor":false,"prefix":"","firstName":"Seho","middleName":"","lastName":"Park","suffix":""},{"id":302348132,"identity":"84cbc303-b1bf-4754-9d83-bf8b68f24a46","order_by":2,"name":"Soong June Bae","email":"","orcid":"","institution":"Gangnam Severance Hospital","correspondingAuthor":false,"prefix":"","firstName":"Soong","middleName":"June","lastName":"Bae","suffix":""},{"id":302348133,"identity":"495f1b90-4da9-4041-a8f9-8a8438f9193d","order_by":3,"name":"Junghwan Ji","email":"","orcid":"","institution":"Gangnam Severance Hospital","correspondingAuthor":false,"prefix":"","firstName":"Junghwan","middleName":"","lastName":"Ji","suffix":""},{"id":302348134,"identity":"613a2ff7-b0a8-4031-b87a-f425e0e447f3","order_by":4,"name":"Dooreh Kim","email":"","orcid":"","institution":"Seoul St. Mary's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Dooreh","middleName":"","lastName":"Kim","suffix":""},{"id":302348135,"identity":"6fbef8b4-21fc-4d40-83dd-a9b7915ed6d3","order_by":5,"name":"Jee Ye Kim","email":"","orcid":"","institution":"Severance Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jee","middleName":"Ye","lastName":"Kim","suffix":""},{"id":302348136,"identity":"012abfdc-92a6-4ec9-8c0d-204070d01966","order_by":6,"name":"Hyung Seok Park","email":"","orcid":"","institution":"Severance Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hyung","middleName":"Seok","lastName":"Park","suffix":""},{"id":302348137,"identity":"fac86826-9923-430d-827a-8dcb12172795","order_by":7,"name":"Sung Gwe Ahn","email":"","orcid":"","institution":"Gangnam Severance Hospital","correspondingAuthor":false,"prefix":"","firstName":"Sung","middleName":"Gwe","lastName":"Ahn","suffix":""},{"id":302348138,"identity":"97e22c5b-6c00-4483-9a9d-fb6acf4caac1","order_by":8,"name":"Seung Il Kim","email":"","orcid":"","institution":"Severance Hospital","correspondingAuthor":false,"prefix":"","firstName":"Seung","middleName":"Il","lastName":"Kim","suffix":""},{"id":302348139,"identity":"1b236896-9d00-4923-85b4-5f55a55043cf","order_by":9,"name":"Byeong-Woo Park","email":"","orcid":"","institution":"Severance Hospital","correspondingAuthor":false,"prefix":"","firstName":"Byeong-Woo","middleName":"","lastName":"Park","suffix":""},{"id":302348140,"identity":"60a1daf5-40d3-41fb-abe2-81fcb6e051d3","order_by":10,"name":"Joon Jeong","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAvklEQVRIiWNgGAWjYHCCBAMgIcfAwEOiFmOStIBBYgPRWuT9Dzwo+FBxJ33DjdzDHxhq7AhrMbyRkGA448yz3A038tIkGI4lE6FlBkOCMW/bYaCWHDMGBrYDRGjpPwDWkm5wI8f4A8M/IrTIMySAtSQAtRhIMLYRocVAAuyXw4Yzz7wxk0jsI8Iv8v1n0gw+VByW5zsOdNiHb0SEmMEBnjRQVDIogJyUQFgD0JYG9sMPIAxilI+CUTAKRsGIBAA7TD5t7gDrYwAAAABJRU5ErkJggg==","orcid":"","institution":"Gangnam Severance Hospital","correspondingAuthor":true,"prefix":"","firstName":"Joon","middleName":"","lastName":"Jeong","suffix":""}],"badges":[],"createdAt":"2024-05-07 09:16:41","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4381795/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4381795/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13058-024-01874-x","type":"published","date":"2024-07-31T15:57:02+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":56621970,"identity":"d884cf83-24f0-42cd-953b-e68936203e1d","added_by":"auto","created_at":"2024-05-16 18:12:47","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":175119,"visible":true,"origin":"","legend":"\u003cp\u003eConsort diagram of enrolled patients\u003c/p\u003e\n\u003cp\u003eNST, neoadjuvant systemic therapy; ALND, axillary lymph node dissection; LN, lymph node; SLNB, sentinel lymph node biopsy\u003c/p\u003e","description":"","filename":"NeomicrometastasesFigure1BCR.png","url":"https://assets-eu.researchsquare.com/files/rs-4381795/v1/960c999a1d0580c5ebd577e6.png"},{"id":56621974,"identity":"2b11cc93-3ffd-4e30-95c3-019c76b8d2dd","added_by":"auto","created_at":"2024-05-16 18:12:47","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":164358,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of additional metastases in non-SLN between SLN-negative and SLN-micrometastases (\u003cem\u003eP \u003c/em\u003e\u0026lt; 0.001)\u003c/p\u003e\n\u003cp\u003eSLN, sentinel lymph node\u003c/p\u003e","description":"","filename":"NeomicrometastasesFigure2BCR.png","url":"https://assets-eu.researchsquare.com/files/rs-4381795/v1/1930a1e90dd130331aa42f33.png"},{"id":56621971,"identity":"2350a5d3-366f-426c-aea9-03729c533e80","added_by":"auto","created_at":"2024-05-16 18:12:47","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":57159,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier survival curve for RFS of SLN-negative and SLN-micrometastases (\u003cem\u003eP \u003c/em\u003e= 0.023)\u003c/p\u003e\n\u003cp\u003eRFS, recurrence-free survival; SLN, sentinel lymph node\u003c/p\u003e","description":"","filename":"NeomicrometastasesFigure3BCR.png","url":"https://assets-eu.researchsquare.com/files/rs-4381795/v1/9219af94a572a718a6c566a2.png"},{"id":61793355,"identity":"5bcd6ae3-ad2d-45e0-826d-ffefbfb6668d","added_by":"auto","created_at":"2024-08-05 16:11:28","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1141663,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4381795/v1/6adca254-db90-4a13-970f-8de90947411a.pdf"},{"id":56621973,"identity":"95699c85-a049-4594-bff0-fe6538e53994","added_by":"auto","created_at":"2024-05-16 18:12:47","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":564633,"visible":true,"origin":"","legend":"","description":"","filename":"NeomicrometastasesSupplementarymaterialsBCR.docx","url":"https://assets-eu.researchsquare.com/files/rs-4381795/v1/c552df10a68ecc55e6d92342.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Micrometastases in axillary lymph nodes in breast cancer, post-neoadjuvant systemic therapy","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe prognostic importance of axillary lymph node (LN) metastases in breast cancer has been well established [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Traditionally, axillary lymph node dissection (ALND) served as the standard surgical treatment of invasive breast cancer until the 1990s [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Since then, sentinel lymph node biopsy (SLNB) has emerged as a viable alternative, offering an accurate prediction of axillary nodal status while mitigating the higher morbidity rates associated with ALND [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNodal status evaluation involves the consideration of metastatic LN size and quantity. The 2002 guidelines introduced micrometastases (0.2mm\u0026thinsp;\u0026lt;\u0026thinsp;metastatic size\u0026thinsp;\u0026le;\u0026thinsp;2.0mm) as distinct categories [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Subsequent studies suggested that micrometastases were not correlated with prognosis, and additional ALND did not significantly enhance locoregional recurrence (LRR) and survival rates in patients presenting with sentinel lymph node micrometastases (SLNmi) in adjuvant settings [\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn the neoadjuvant context, patients with clinically lymph node-positive (cN+) status underwent ALND, independent of their neoadjuvant systemic therapy (NST) response [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. However, recent trends advocate the judicious avoidance of ALND in patients who transition to clinically lymph node-negative status post-systemic therapy, especially in the absence of metastases in a sufficient number (\u0026ge;\u0026thinsp;3) of sentinel lymph node (SLN)s [\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePrevious research on minimal residual axillary disease, particularly micrometastases, after NST has been limited. Consequently, ALND persists as the standard treatment for patients with SLNmi [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. This study aims to investigate the significance of pathologic lymph node-micrometastases (ypNmi) following NST, in comparison to pathologic lymph node-negative (ypN0) or macrometastases (ypN+). We further explore the prognostic implications of SLNmi for the prediction of axillary LN status and survival outcomes.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy populations\u003c/h2\u003e \u003cp\u003eWe conducted a retrospective review of primary breast cancer patients from the registries of Gangnam Severance Hospital and Severance Hospital, who underwent surgery following NST between September 2006 and February 2018. These patients were clinically diagnosed with stage II or III breast cancer and underwent ALND, with or without SLNB. Exclusion criteria comprised of patients who had upfront surgery, underwent only SLNB, or presented with de novo stage IV disease.\u003c/p\u003e \u003cp\u003e Our study adhered to Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. The institutional review boards (IRB) granted study protocol approval (approval number: 3-2023-0214). The retrospective study design warranted a waiver for the requirement of written informed consent by the IRB.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eAssessment of axillary nodal status\u003c/h2\u003e \u003cp\u003eThe initial axillary nodal status was evaluated using ultrasonography and breast magnetic resonance imaging (MRI). Fine needle aspiration biopsy (FNAB) was conducted on patients where necessary. Patients with metastatic LN revealed by FNAB were categorized as cN+. Furthermore, we classified unconfirmed axillary LN metastases as cN\u0026thinsp;+\u0026thinsp;if ultrasonography or breast MRI indicated a strong suspicion of metastasis.\u003c/p\u003e \u003cp\u003eWe defined metastatic LNs with a size range between \u0026gt;\u0026thinsp;0.2 mm and \u0026le;\u0026thinsp;2 mm as ypNmi, regardless of the metastatic LN count. LNs exceeding 2 mm were classified as ypN+, and the pathologic lymph node (ypN) stage was assigned based on the number of LNs, inclusive of micrometastases. Moreover, isolated tumor cells measuring\u0026thinsp;\u0026le;\u0026thinsp;0.2 mm were classified as ypN0, in accordance with guideline [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eSLNB and ALND procedures\u003c/h2\u003e \u003cp\u003eSLNB was performed using single or dual tracers. For the single tracer technique, Technetium 99, a radioactive substance, was administered periareolarly prior to surgery, and SLNs were identified intraoperatively via a gamma detection system (Neoprobe\u0026reg;). The dual tracer method employed both an isosulfan blue dye and Technetium 99 concurrently. The choice of SLNB technique was contingent upon the surgeon\u0026rsquo;s discretion. SLNs were categorized as one or multiple, and any LN identified by either or both methods was defined as SLN. LNs resected during SLNB without tracer signal were not classified as SLNs.\u003c/p\u003e \u003cp\u003eALND was characterized by the removal of all LNs in axillary levels I and II. Patients documented to have undergone ALND in surgical records were primarily selected from our registry. Among them, those with fewer than 10 LNs were excluded, based on the assumption that a competent ALND necessitated the removal of 10 or more LNs as defined in previous studies [\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eStatistical analyses were conducted using SPSS version 25.0 (IBM Inc., Armonk, NY, USA) and GraphPad Prism, version 9 (GraphPad Software). Differences between groups were assessed using the chi-square test for categorical data and one-way ANOVA for continuous variables, subsequent to confirmation by Levene\u0026rsquo;s test for equality of variances. The primary outcome was recurrence-free survival (RFS), while overall survival (OS) was analyzed as the secondary outcome. RFS was defined as the interval from breast cancer diagnosis to the initial recurrence, including LRR, distant metastasis, or any cause of death. OS was defined as the duration from breast cancer diagnosis to death from any cause. Kaplan-Meier survival estimations were implemented for RFS and OS, and survival curve group disparities were examined via the log-rank test. Variables associated with RFS and OS were ascertained using a multivariate Cox proportional hazard model, with hazard ratio (HR) and corresponding 95% confidence intervals (CI). The analysis of risk factors for additional metastases in SLNmi patients was performed using a binary logistic regression model. All statistical tests were two-sided, and a \u003cem\u003ep\u003c/em\u003e value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eFigure \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e depicts the distribution of axillary surgical procedures among the patients enrolled in our study. Out of the initial 1,642 participants, 664 were excluded due to an inadequate number of axillary LNs or insufficient metastatic LN information. Consequently, 978 patients were analyzed, with a median follow-up duration of 73 months (range, 4-176 months). Among them, 465 (47.5%) patients underwent ALND alone, without SLNB, while 513 (52.5%) patients had SLNB prior to ALND.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eBaseline characteristics\u003c/h2\u003e \u003cp\u003eOnly 89 (9.1%) patients presented with axillary LN micrometastases. In contrast, 438 (44.8%) had no metastases, and 451 (46.1%) exhibited macrometastases after NST. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e summarizes the clinicopathologic characteristics and differences across these three groups. Among the evaluated cohort, 927 (94.8%) patients were cN\u0026thinsp;+\u0026thinsp;pre-chemotherapy. A significant correlation was observed between pathologic tumor size and axillary nodal status. More than half of the patients with ypN0 achieved a breast pathologic complete response (pCR), while this proportion was significantly lower in the ypN\u0026thinsp;+\u0026thinsp;group (7.3%). The rate of breast pCR in patients with ypNmi was 29.2%, lower than that in the ypN0 group, but higher than in the ypN\u0026thinsp;+\u0026thinsp;group. Moreover, the quantity of dissected LNs was marginally higher in ypN\u0026thinsp;+\u0026thinsp;patients (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003). The proportion of estrogen receptor (ER)-positive or human epidermal growth factor receptor 2 (HER2)-negative tumors was found to be considerably higher in the ypNmi and ypN\u0026thinsp;+\u0026thinsp;groups compared to the ypN0 group. The Ki-67 labeling index (LI) was negatively correlated with ypN status. Notably, more patients in the ypNmi and ypN\u0026thinsp;+\u0026thinsp;groups received adjuvant radiotherapy compared to the ypN0 group.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of all patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll Patients (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePatients with ypN0 (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePatients with ypNmi (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePatients with ypN+ (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e978 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e438 (44.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e89 (9.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e451 (46.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at diagnosis, average (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e48.5 (20\u0026ndash;79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e48.6 (26\u0026ndash;79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e47.1 (28\u0026ndash;75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e48.8 (20\u0026ndash;75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.296\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical nodal status, initial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.061\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e51 (5.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31 (7.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (3.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e17 (3.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e927 (94.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e407 (92.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e86 (96.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e434 (96.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBreast surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBCS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e369 (37.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e198 (45.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e40 (44.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e131 (29.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMastectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e609 (62.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e240 (54.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e49 (55.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e320 (71.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePathologic tumor size (mm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBreast pCR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e283 (28.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e224 (51.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26 (29.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e33 (7.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u0026ndash;20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e458 (46.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e169 (38.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e49 (55.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e240 (53.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e20\u0026ndash;50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e194 (19.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e38 (8.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14 (15.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e142 (31.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e43 (4.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7 (1.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e36 (8.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of dissected LNs, average (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16.7 (10\u0026ndash;60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16.0 (10\u0026ndash;38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16.1 (10\u0026ndash;31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e17.4 (10\u0026ndash;60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eER\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e572 (58.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e186 (42.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e60 (67.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e326 (72.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e406 (41.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e252 (57.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29 (32.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e125 (27.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e431 (44.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e122 (28.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e50 (56.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e259 (57.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e547 (55.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e316 (72.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e39 (43.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e192 (42.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHER2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e638 (65.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e237 (54.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e63 (70.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e338 (74.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e340 (34.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e201 (45.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26 (29.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e113 (25.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKi-67 LI, %\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e370 (37.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e112 (25.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e39 (43.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e219 (48.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e438 (44.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e224 (51.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e38 (42.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e176 (39.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e170 (17.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e102 (23.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (13.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e56 (12.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRadiotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.015\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNot performed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e78 (8.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e47 (10.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (4.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e27 (6.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePerformed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e900 (92.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e391 (89.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e85 (95.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e424 (94.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eBCS, breast-conserving surgery; pCR, pathologic complete response; LN, lymph node; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth receptor 2; LI, labelling index\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eSurvival outcome according to pathologic nodal status following NST\u003c/h2\u003e \u003cp\u003eThe collective 5-year RFS for all patients was 82%. Broken down by group, the 5year RFS for ypN0, ypNmi, and ypN\u0026thinsp;+\u0026thinsp;patients were 89%, 87.6%, and 74.1% respectively. Throughout the follow-up period, a total of 183 patients experienced 217 recurrent events. These recurrences manifested as locoregional in 11 patients, systemic in 138 patients, and combined locoregional and systemic in 34 patients. Out of the total patient pool, 85 deaths occurred with a 5-year OS rate of 92.7%. Among the deceased, 70 patients succumbed to breast cancer recurrence, while 15 deaths were attributed to other causes.\u003c/p\u003e \u003cp\u003eThe Kaplan-Meier survival curve indicated that patients classified as ypN\u0026thinsp;+\u0026thinsp;demonstrated significantly inferior RFS compared to ypN0 and ypNmi patients (eFigure 1A; ypN0 vs. ypN+: \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; ypNmi vs. ypN+: \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.008). However, no statistically significant difference was observed in recurrence and survival rates between ypN0 and ypNmi groups (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.455). Furthermore, multivariate Cox regression hazard modeling failed to establish ypNmi as a significant prognostic factor of RFS in patients undergoing NST (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, HR, 1.70; 95% CI, 0.90\u0026ndash;3.22; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.104). Factors including macrometastases, large pathological tumor size, high Ki-67 LI (\u0026ge;\u0026thinsp;14%), and lack of radiotherapy were associated with an increased risk of RFS. In terms of OS, the Kaplan-Meier survival curve also indicated a worse prognosis for ypN\u0026thinsp;+\u0026thinsp;patients compared to ypN0 or ypNmi patients (eFigure 1B; ypN0 vs. ypN+: \u003cem\u003eP\u0026thinsp;\u0026lt;\u003c/em\u003e\u0026thinsp;0.001; ypNmi vs. ypN+: \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.035). Multivariate analysis continued to highlight macrometastases as a risk factor for OS, whereas micrometastases did not impact survival outcomes (eTable 1; ypNmi: HR, 1.61; 95% CI, 0.52\u0026ndash;4.98; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.409; ypN+: HR, 2.88; 95% CI, 1.47\u0026ndash;5.66; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUni- and multivariate analysis of RFS in patients with NST\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnivariate analysis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMultivariate analysis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePathologic nodal status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eypN0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRef.\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eypNmi\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.26 (0.70\u0026ndash;2.26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.448\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.70 (0.90\u0026ndash;3.22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.104\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eypN+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.60 (1.89\u0026ndash;3.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.81 (1.85\u0026ndash;4.27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at diagnosis\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.00 (0.99\u0026ndash;1.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.885\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBreast surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBCS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMastectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.66 (1.21\u0026ndash;2.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.01 (0.70\u0026ndash;1.46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.964\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePathologic tumor size, mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBreast pCR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u0026ndash;20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.81 (1.17\u0026ndash;2.80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.007\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.85 (1.05\u0026ndash;3.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.033\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e20\u0026ndash;50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.96 (2.53\u0026ndash;6.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.12 (1.71\u0026ndash;5.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.31 (4.79\u0026ndash;14.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5.75 (2.85\u0026ndash;11.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of dissected LNs\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.02 (1.00-1.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.099\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eER\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.59 (1.21\u0026ndash;2.11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.50 (0.95\u0026ndash;2.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.084\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.36 (1.02\u0026ndash;1.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.035\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.37 (0.86\u0026ndash;2.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.191\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHER2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.76 (0.56\u0026ndash;1.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.079\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKi-67 LI, %\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.78 (1.28\u0026ndash;2.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.83 (1.29\u0026ndash;2.61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRadiotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNot performed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePerformed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.62 (0.40\u0026ndash;0.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.029\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.55 (0.33\u0026ndash;0.91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.021\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003e*\u003c/sup\u003eContinuous variable\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003e**\u003c/sup\u003eReference value\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eRFS, recurrence free survival; NST, neoadjuvant systemic therapy; HR, hazard ratio; CI, confidence interval; BCS, breast-conserving surgery; pCR, pathologic complete response; LN, lymph node; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth receptor 2; LI, labelling index\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eSignificance of micrometastases in SLNs\u003c/h2\u003e \u003cp\u003eFurther analyses were conducted on patients who underwent SLNB preceding ALND. Of these patients, 296 (57.7%) were SLN-negative, while 47 (9.2%) exhibited SLNmi (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). No significant difference was observed in the average number of removed SLNs between these groups (eTable 2). Patients in the SLNmi category demonstrated larger pathological tumor sizes, higher ER positivity rates, and lower Ki-67 LI compared to SLN-negative patients. Over half of SLNmi patients were identified with additional metastases in non-SLNs, nearly a three-fold increase compared to SLN-negative patients (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Moreover, 29.8% of SLNmi patients were categorized as ypN+. The 5-year RFS rates for SLN-negative and SLNmi patients were 89.5% and 76.6% respectively. Notably, SLNmi patients had a significantly poorer RFS than SLN-negative patients in the Kaplan-Meier survival analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.023). In the multivariate analysis, SLNmi emerged as a poor prognostic factor for RFS (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e; HR, 2.23; 95% CI, 1.12\u0026ndash;4.46; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.023). Nonetheless, no significant differences were found in OS between SLN-negative and SLNmi patients (eFigure 2 and eTable 3).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUni and multivariate analysis of the effect of SLN-micrometastases on RFS\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnivariate analysis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eMultivariate analysis\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSLN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRef.\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMicrometastases\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.11 (1.09\u0026ndash;4.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.026\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.23 (1.12\u0026ndash;4.46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.023\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at diagnosis\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.99 (0.96\u0026ndash;1.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.466\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBreast surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBCS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMastectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.13 (0.63\u0026ndash;2.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.689\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePathologic tumor size, mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBreast pCR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u0026ndash;20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.76 (1.23\u0026ndash;6.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.33 (1.31\u0026ndash;8.42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.011\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e20\u0026ndash;50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.39 (2.26\u0026ndash;12.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5.63 (2.11\u0026ndash;15.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38.57 (7.97-186.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e39.48 (7.54-206.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eER\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.81 (1.01\u0026ndash;3.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.045\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.55 (0.79\u0026ndash;3.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.203\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.43 (0.77\u0026ndash;2.64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.260\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHER2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.77 (0.41\u0026ndash;1.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.431\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKi-67 LI, %\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.40 (1.18\u0026ndash;4.91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.58 (1.17\u0026ndash;5.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.019\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRadiotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRef.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.73 (0.53\u0026ndash;5.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.363\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003e*\u003c/sup\u003eContinuous variable\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003e**\u003c/sup\u003eReference value\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eSLN, sentinel lymph node; RFS, recurrence free survival; HR, hazard ratio; CI, confidence interval; BCS, breast-conserving surgery; pCR, pathologic complete response; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth receptor 2; LI, labelling index\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eRisk factors associated with additional metastases in SLNmi patients\u003c/h2\u003e \u003cp\u003eRisk factors associated with additional metastases in SLNmi patients were investigated. Additional metastases were more prevalent in patients with pathological tumor size\u0026thinsp;\u0026gt;\u0026thinsp;20 mm, ER-positive/HER2-negative subtype, and a low Ki-67 LI (\u0026lt;\u0026thinsp;14%) (eTable 4). Notably, 30.0% (3 out of 10) and 18.2% (2 out of 11) of patients with additional metastases had HER2-overexpressing and triple-negative breast cancer (TNBC) subtypes, respectively, whereas 73.1% (19 out of 26) of ER-positive/HER2-negative patients demonstrated additional metastases (eTable 5). In the presence of SLNmi, ER-positive/HER2-negative subtype had a significantly higher rate of additional metastases compared to other subtypes (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003). Conversely, no significant difference was observed in the incidence of additional metastases among patients with SLNmi, irrespective of subtype (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.079).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur study showed that patients with ypN0 and ypNmi had comparable RFS and OS outcomes, while those with ypN\u0026thinsp;+\u0026thinsp;had a negative impact on oncologic outcomes. Notably, axillary LN status could not be accurately ascertained solely by the micrometastases of SLN. Instances of SLNmi often coincided with additional LN metastases and correlated with worse RFS compared to patients who were SLN-negative. Consequently, our findings suggest that axillary staging via ALND in patients with SLNmi should be considered following NST.\u003c/p\u003e \u003cp\u003eThe association between residual axillary disease and prognosis is well-documented [\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. We hypothesized the existence of a subgroup of patients who might exhibit a more favorable prognosis, even in the presence of residual axillary tumor burden, such as micrometastases. Our findings substantiate this, demonstrating that patients with ypNmi have a more favorable prognosis compared to those with ypN+, and their oncologic outcomes are on par with those of ypN0. Prior to our investigation, only two retrospective studies, to the best of our knowledge, examined residual nodal burden. Nijinatten et al. studied prognosis as a function of metastatic LN size in a single institution [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], in which all patients were cN\u0026thinsp;+\u0026thinsp;and 3.8% of patients were classified as ypNitc/mi. They reported a similar prognosis for ypNitc/mi and ypN0 patients, superior to that of ypN\u0026thinsp;+\u0026thinsp;patients. Our results align with these findings within a similar patient population, despite a higher ypNmi percentage (9.1%) in our study. Conversely, Wong et al. contended that post-NST patients with isolated tumor cells or micrometastases had a worse prognosis than those with ypN0 in both a single institution cohort and the National Cancer Database (NCDB) [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. They reported ypNmi rates of 9.1% and 4.7% in their respective cohorts. However, their study included patients who underwent SLNB without ALND in survival analysis. In contrast, our study exclusively enrolled patients who had 10 or more axillary LNs dissected to optimally evaluate axillary nodal status.\u003c/p\u003e \u003cp\u003eSLNB is a valuable intraoperative tool for predicting axillary LN metastases, though it is observed to yield higher rates of false negatives in NST patients compared to those in a primary surgical setting [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. The SENTINA trial demonstrated a FNR of 18.5% when two SLNs were removed, despite clinical conversion to node negativity post-NST [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In our cohort, the mean number of removed SLNs was 2.62, resulting in an elevated FNR of 23.8%. Furthermore, we noted that 17.9% of SLN-negative patients had verifiable axillary LN metastases.\u003c/p\u003e \u003cp\u003eOur findings indicate a substantially higher incidence of additional metastases in patients with SLNmi relative to those with SLN-negative results. Prior to our investigation, Moo et al. documented that 64% of SLNmi patients exhibited non-SLN metastases, a significantly higher figure than the 17% observed in SLN-negative patients [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Our study corroborated these findings, revealing additional metastases in 51.1% of SLNmi patients, 58.3% of which were macrometastases. However, in the adjuvant setting, specifically within the American College of Surgeons Oncology Group Z0011 trial, the incidence of additional metastases among SLNmi was considerably lower, at roughly ten percent [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. This discrepancy suggests a heightened likelihood of additional metastases in NST patients with SLNmi compared to those in the adjuvant setting. In a novel discovery, we also found that SLNmi patients exhibited lower RFS rates than SLN-negative patients. Collectively, these findings suggest the necessity of ALND in patients with SLNmi following NST.\u003c/p\u003e \u003cp\u003eIn the analysis of risk factors linked to additional metastases in SLNmi patients, a correlation was observed with pathological tumor size exceeding ypT2, ER-positive/HER2-negative subtype, and low Ki-67 LI (\u0026le;\u0026thinsp;14%). These findings can be contextualized within the sphere of NST responsiveness. It is well established that ER-positive/HER2-negative tumors present a lower overall response rate [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Additionally, low levels of Ki-67 LI associated with reduced pCR rates [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Consequently, it can be inferred that SLNB accuracy is interrelated with NST response, and SLNmi is more likely to exhibit additional metastases in patients demonstrating a suboptimal response to chemotherapy.\u003c/p\u003e \u003cp\u003eOne limitation of this study includes the potential selection bias stemming from its retrospective design. However, we were able to source relatively uniform and reliable clinicopathological data from two institutions and endeavored to accurately evaluate the axillary nodal status. Nonetheless, we were unable to consider the clinical nodal status as determined by imaging modalities. Future studies combining SLNB results with chemotherapy response evaluations via imaging examination in SLNmi cases may be necessary, as some studies suggest that the accuracy of axillary nodal status prediction can be enhanced when imaging examination results are integrated with SLNB outcomes [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn conclusion, ypNmi does not significantly impact patient prognosis when compared with ypN0, although ypN\u0026thinsp;+\u0026thinsp;is correlated with a notably worse survival outcome. However, SLNmi is an adverse prognostic indicator and a critical predictor of additional metastases, particularly in patients with a poor NST response. As such, additional ALND should be considered for verifying axillary nodal status in patients presenting with SLNmi.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eLN, lymph node; ALND, axillary lymph node dissection; SLNB, sentinel lymph node biopsy; LRR, locoregional recurrence; SLNmi, sentinel lymph node micrometastases; cN+, clinically lymph node-positive; NST, neoadjuvant systemic therapy; SLN, sentinel lymph node; ypNmi; pathologic lymph node-micrometastases; ypN0, pathologic lymph node-negative; ypN+, pathologic lymph node-macrometastases; IRB, institutional review boards; MRI, magnetic resonance imaging; FNAB, fine needle aspiration biopsy; ypN, pathologic lymph node; RFS, recurrence-free survival; OS, overall survival; HR, hazard ratio; CI, confidence intervals; pCR; pathologic complete response; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; LI, labeling index; BCS, breast-conserving surgery; PR, progesterone receptor\u003c/p\u003e\n"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur study adhered to Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. The institutional review boards granted study protocol approval (approval number: 3-2023-0214). The retrospective study design warranted a waiver for the requirement of written informed consent by the institutional review boards.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJL and JJ (Joon Jeong) conceptualized and designed the study, JL, SP, SJB, JJ (Junghwan Ji), DK\u0026nbsp;and JYK performed the data curation, JL and SJB performed statistical analysis, JL, SP and SGA interpreted the data, JL drafted the manuscript, JJ (Joon Jeong) critically revised the manuscript,\u0026nbsp;HSP, SGA, SIK, BWP and JJ (Joon Jeong) supervised parts of the study. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank ESSAYREVIEW (www.essayreview.co.kr) for English language editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eCarter CL, Allen C, Henson DE. Relation of tumor size, lymph node status, and survival in 24,740 breast cancer cases. Cancer. 1989;63(1):181-7.\u003c/li\u003e\n\u003cli\u003eMurley R. Axillary dissection in primary breast cancer. BMJ : British Medical Journal. 1991;302(6776):590-1.\u003c/li\u003e\n\u003cli\u003eHladiuk M, Huchcroft S, Temple W, Schnurr BE. Arm function after axillary dissection for breast cancer: a pilot study to provide parameter estimates. J Surg Oncol. 1992;50(1):47-52.\u003c/li\u003e\n\u003cli\u003eIvens D, Hoe AL, Podd TJ, Hamilton CR, Taylor I, Royle GT. Assessment of morbidity from complete axillary dissection. Br J Cancer. 1992;66(1):136-8.\u003c/li\u003e\n\u003cli\u003eBreast. In: Greene FL, Page DL, Fleming ID, Fritz AG, Balch CM, Haller DG, et al., editors. AJCC Cancer Staging Manual. New York, NY: Springer New York; 2002. p. 223-40.\u003c/li\u003e\n\u003cli\u003eGalimberti V, Cole BF, Viale G, Veronesi P, Vicini E, Intra M, et al. Axillary dissection versus no axillary dissection in patients with breast cancer and sentinel-node micrometastases (IBCSG 23-01): 10-year follow-up of a randomised, controlled phase 3 trial. Lancet Oncol. 2018;19(10):1385-93.\u003c/li\u003e\n\u003cli\u003eTjan-Heijnen VC, Buit P, de Widt-Evert LM, Ruers TJ, Beex LV. 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J Natl Compr Canc Netw. 2016;14(3):324-54.\u003c/li\u003e\n\u003cli\u003eKuehn T, Bauerfeind I, Fehm T, Fleige B, Hausschild M, Helms G, et al. Sentinel-lymph-node biopsy in patients with breast cancer before and after neoadjuvant chemotherapy (SENTINA): a prospective, multicentre cohort study. Lancet Oncol. 2013;14(7):609-18.\u003c/li\u003e\n\u003cli\u003eBoileau JF, Poirier B, Basik M, Holloway CM, Gaboury L, Sideris L, et al. Sentinel node biopsy after neoadjuvant chemotherapy in biopsy-proven node-positive breast cancer: the SN FNAC study. J Clin Oncol. 2015;33(3):258-64.\u003c/li\u003e\n\u003cli\u003eBoughey JC, Suman VJ, Mittendorf EA, Ahrendt GM, Wilke LG, Taback B, et al. Sentinel lymph node surgery after neoadjuvant chemotherapy in patients with node-positive breast cancer: the ACOSOG Z1071 (Alliance) clinical trial. Jama. 2013;310(14):1455-61.\u003c/li\u003e\n\u003cli\u003eOsorio-Silla I, G\u0026oacute;mez Valdazo A, S\u0026aacute;nchez M\u0026eacute;ndez JI, York E, D\u0026iacute;az-Almir\u0026oacute;n M, G\u0026oacute;mez Ram\u0026iacute;rez J, et al. Is it always necessary to perform an axillary lymph node dissection after neoadjuvant chemotherapy for breast cancer? Ann R Coll Surg Engl. 2019;101(3):186-92.\u003c/li\u003e\n\u003cli\u003eGradishar WJ, Anderson BO, Abraham J, Aft R, Agnese D, Allison KH, et al. Breast Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2020;18(4):452-78.\u003c/li\u003e\n\u003cli\u003eMathiesen O, Carl J, Bonderup O, Panduro J. Axillary sampling and the risk of erroneous staging of breast cancer. An analysis of 960 consecutive patients. Acta Oncol. 1990;29(6):721-5.\u003c/li\u003e\n\u003cli\u003eAxelsson CK, Mouridsen HT, Zedeler K. Axillary dissection of level I and II lymph nodes is important in breast cancer classification. The Danish Breast Cancer Cooperative Group (DBCG). Eur J Cancer. 1992;28a(8-9):1415-8.\u003c/li\u003e\n\u003cli\u003eRecht A, Houlihan MJ. Axillary lymph nodes and breast cancer: a review. Cancer. 1995;76(9):1491-512.\u003c/li\u003e\n\u003cli\u003eMeric F, Mirza NQ, Buzdar AU, Hunt KK, Ames FC, Ross MI, et al. Prognostic implications of pathological lymph node status after preoperative chemotherapy for operable T3N0M0 breast cancer. Ann Surg Oncol. 2000;7(6):435-40.\u003c/li\u003e\n\u003cli\u003eHennessy BT, Hortobagyi GN, Rouzier R, Kuerer H, Sneige N, Buzdar AU, et al. Outcome after pathologic complete eradication of cytologically proven breast cancer axillary node metastases following primary chemotherapy. J Clin Oncol. 2005;23(36):9304-11.\u003c/li\u003e\n\u003cli\u003eMougalian SS, Hernandez M, Lei X, Lynch S, Kuerer HM, Symmans WF, et al. Ten-Year Outcomes of Patients With Breast Cancer With Cytologically Confirmed Axillary Lymph Node Metastases and Pathologic Complete Response After Primary Systemic Chemotherapy. JAMA Oncol. 2016;2(4):508-16.\u003c/li\u003e\n\u003cli\u003evan Nijnatten TJ, Simons JM, Moossdorff M, de Munck L, Lobbes MB, van der Pol CC, et al. Prognosis of residual axillary disease after neoadjuvant chemotherapy in clinically node-positive breast cancer patients: isolated tumor cells and micrometastases carry a better prognosis than macrometastases. Breast Cancer Res Treat. 2017;163(1):159-66.\u003c/li\u003e\n\u003cli\u003eWong SM, Almana N, Choi J, Hu J, Gagnon H, Natsuhara K, et al. Prognostic Significance of Residual Axillary Nodal Micrometastases and Isolated Tumor Cells After Neoadjuvant Chemotherapy for Breast Cancer. Ann Surg Oncol. 2019;26(11):3502-9.\u003c/li\u003e\n\u003cli\u003eAkay CL, Albarracin C, Torstenson T, Bassett R, Mittendorf EA, Yi M, et al. Factors impacting the accuracy of intra-operative evaluation of sentinel lymph nodes in breast cancer. Breast J. 2018;24(1):28-34.\u003c/li\u003e\n\u003cli\u003eGimbergues P, Dauplat MM, Durando X, Abrial C, Le Bouedec G, Mouret-Reynier MA, et al. Intraoperative imprint cytology examination of sentinel lymph nodes after neoadjuvant chemotherapy in breast cancer patients. Ann Surg Oncol. 2010;17(8):2132-7.\u003c/li\u003e\n\u003cli\u003eMoo TA, Edelweiss M, Hajiyeva S, Stempel M, Raiss M, Zabor EC, et al. Is Low-Volume Disease in the Sentinel Node After Neoadjuvant Chemotherapy an Indication for Axillary Dissection? Ann Surg Oncol. 2018;25(6):1488-94.\u003c/li\u003e\n\u003cli\u003eGiuliano AE, Ballman K, McCall L, Beitsch P, Whitworth PW, Blumencranz P, et al. Locoregional Recurrence After Sentinel Lymph Node Dissection With or Without Axillary Dissection in Patients With Sentinel Lymph Node Metastases: Long-term Follow-up From the American College of Surgeons Oncology Group (Alliance) ACOSOG Z0011 Randomized Trial. Ann Surg. 2016;264(3):413-20.\u003c/li\u003e\n\u003cli\u003eCortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014;384(9938):164-72.\u003c/li\u003e\n\u003cli\u003eHaque W, Verma V, Hatch S, Suzanne Klimberg V, Brian Butler E, Teh BS. Response rates and pathologic complete response by breast cancer molecular subtype following neoadjuvant chemotherapy. Breast Cancer Res Treat. 2018;170(3):559-67.\u003c/li\u003e\n\u003cli\u003eTao M, Chen S, Zhang X, Zhou Q. Ki-67 labeling index is a predictive marker for a pathological complete response to neoadjuvant chemotherapy in breast cancer: A meta-analysis. Medicine (Baltimore). 2017;96(51):e9384.\u003c/li\u003e\n\u003cli\u003eInwald EC, Klinkhammer-Schalke M, Hofst\u0026auml;dter F, Zeman F, Koller M, Gerstenhauer M, et al. Ki-67 is a prognostic parameter in breast cancer patients: results of a large population-based cohort of a cancer registry. Breast Cancer Res Treat. 2013;139(2):539-52.\u003c/li\u003e\n\u003cli\u003eMorency D, Dumitra S, Parvez E, Martel K, Basik M, Robidoux A, et al. Axillary Lymph Node Ultrasound Following Neoadjuvant Chemotherapy in Biopsy-Proven Node-Positive Breast Cancer: Results from the SN FNAC Study. Ann Surg Oncol. 2019;26(13):4337-45.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"breast-cancer-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"brcr","sideBox":"Learn more about [Breast Cancer Research](http://breast-cancer-research.biomedcentral.com)","snPcode":"13058","submissionUrl":"https://submission.nature.com/new-submission/13058/3","title":"Breast Cancer Research","twitterHandle":"@BCRJournal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"breast cancer, neoadjuvant systemic therapy, micrometastases, axillary lymph node, sentinel lymph node","lastPublishedDoi":"10.21203/rs.3.rs-4381795/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4381795/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eIntroduction:\u003c/h2\u003e \u003cp\u003eThe significance of minimal residual axillary disease, specifically micrometastases, following neoadjuvant systemic therapy (NST) remains largely unexplored. Our study aimed to elucidate the prognostic implications of micrometastases in axillary and sentinel lymph nodes following NST.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis retrospective study analyzed primary breast cancer patients who underwent surgery after NST from September 2006 through February 2018. All patients received axillary lymph node dissection (ALND), either with or without sentinel lymph node biopsy. Recurrence-free survival (RFS)-associated variables were identified using a multivariate Cox proportional hazard model.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eOf the 978 patients examined, 438 (44.8%) exhibited no pathologic lymph node involvement (ypN0) after NST, while 89 (9.1%) had micrometastases (ypNmi). Multivariate analysis revealed no significant association between ypNmi and RFS in patients post-NST (hazard ratio [HR], 1.02; 95% confidence interval [CI], 0.42\u0026ndash;2.49; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.958). Notably, over half of the patients with sentinel lymph node micrometastases (SLNmi) had additional metastases, nearly triple that of SLN-negative patients (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Furthermore, SLNmi patients experienced significantly worse RFS compared to SLN-negative patients (HR, 2.23; 95% CI, 1.12\u0026ndash;4.46; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.023). Additional metastases in SLNmi were more prevalent in patients with larger residual breast disease greater than 20 mm, HR-positive/HER2-negative subtype, and low Ki-67 LI (\u0026lt;\u0026thinsp;14%).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eWhile ypNmi does not influence the prognosis compared to ypN0, SLNmi emerges as a significant negative prognostic factor and a robust predictor of additional metastases. Hence, additional ALND may be warranted to confirm axillary nodal status in patients with SLNmi.\u003c/p\u003e","manuscriptTitle":"Micrometastases in axillary lymph nodes in breast cancer, post-neoadjuvant systemic therapy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-16 18:12:42","doi":"10.21203/rs.3.rs-4381795/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-06-23T09:30:12+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-06-02T17:29:55+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-05-17T19:33:06+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"233269315165393976269833953469559215639","date":"2024-05-15T19:29:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"249760232623587698460936479249751135959","date":"2024-05-14T12:32:43+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-05-13T18:54:50+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-05-09T05:33:42+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-05-08T23:32:13+00:00","index":"","fulltext":""},{"type":"submitted","content":"Breast Cancer Research","date":"2024-05-07T09:00:38+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"breast-cancer-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"brcr","sideBox":"Learn more about [Breast Cancer Research](http://breast-cancer-research.biomedcentral.com)","snPcode":"13058","submissionUrl":"https://submission.nature.com/new-submission/13058/3","title":"Breast Cancer Research","twitterHandle":"@BCRJournal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4c734fbf-920c-4166-b2cc-5cfe29497b80","owner":[],"postedDate":"May 16th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-08-05T15:59:53+00:00","versionOfRecord":{"articleIdentity":"rs-4381795","link":"https://doi.org/10.1186/s13058-024-01874-x","journal":{"identity":"breast-cancer-research","isVorOnly":false,"title":"Breast Cancer Research"},"publishedOn":"2024-07-31 15:57:02","publishedOnDateReadable":"July 31st, 2024"},"versionCreatedAt":"2024-05-16 18:12:42","video":"","vorDoi":"10.1186/s13058-024-01874-x","vorDoiUrl":"https://doi.org/10.1186/s13058-024-01874-x","workflowStages":[]},"version":"v1","identity":"rs-4381795","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4381795","identity":"rs-4381795","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}