A Retrospective Multi-Center Cohort Study Investigating Safety of Sentinel Lymph Node Biopsy for Axillary Staging in Clinical T3-4c Breast Cancer

A Retrospective Multi-Center Cohort Study Investigating Safety of Sentinel Lymph Node Biopsy for Axillary Staging in Clinical T3-4c Breast Cancer | 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 A Retrospective Multi-Center Cohort Study Investigating Safety of Sentinel Lymph Node Biopsy for Axillary Staging in Clinical T3-4c Breast Cancer Sayaka Kuba, Yasuaki Sagara, Ph.D Hiroshi Yano, Shigeto Maeda, and 31 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6315783/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 01 Aug, 2025 Read the published version in Breast Cancer → Version 1 posted 5 You are reading this latest preprint version Abstract Background Sentinel lymph node biopsy (SLNB) has become a standard procedure for patients with breast cancer (BC) without clinically evident axillary metastasis. However, its role in cT3-4cN0 BC remains underexplored, leading to uncertainty regarding its safety. Methods This retrospective, multicenter observational study included patients with cT3-4cN0M0 BC who underwent radical surgery between 2006 and 2016. Patients were divided into an SLNB group, which included those who underwent SLNB exclusively and ALND after SLNB, and an ALND group, which included those who underwent ALND exclusively. Inverse probability treatment weighting was applied to balance the patient characteristics, with recurrence-free survival (RFS) as the primary endpoint. Results The study included 930 patients: 716 in the SLNB group and 214 in the ALND group. The ALND group had a higher proportion of patients diagnosed earlier, more T4 tumors, and more frequent use of neoadjuvant chemotherapy. During a median follow-up period of 89 months, 176 RFS events and 51 loco-regional recurrence events occurred. After adjusting for confounding factors, no significant difference was found in 10-year RFS between the groups (74.2% versus 79.2%). Adjusted hazard ratios for RFS did not differ between the groups, even when stratified by tumor stage (cT3, cT4) or neoadjuvant chemotherapy. No significant differences were observed between the SLNB and ALND groups in loco-regional recurrence rate (LRR), with 10-year LRR rates of 93.1% and 90.8%, respectively. Conclusions SLNB was a safe axillary staging method for patients with cT3-4cN0M0 BC and does not impact RFS or LRR negatively when compared with ALND. Breast cancer Sentinel lymph node biopsy Axillary lymph node dissection Recurrence-free survival Loco-regional recurrence rate Figures Figure 1 Figure 2 Figure 3 Introduction Breast cancer (BC) is the most commonly diagnosed cancer in women after non-melanoma skin cancer [1, 2]. Axillary lymph node dissection (ALND), the standard procedure for early-stage BC, is associated with adverse effects such as pain, numbness, muscle weakness, and lymphedema, which impair leisure activities and sports [3]. Some clinical trials have reported no significant differences in overall survival (OS), disease-free survival, and regional control between sentinel lymph node biopsy (SLNB) and ALND in patients with clinically node-negative BC [4–6]. Compared with the ALND group, the SLNB group experienced less pain, improved arm mobility, and reduced hospitalization costs [7–10]. Consequently, SLNB has become the standard approach for axillary staging in patients with clinically node-negative BC. Most SLNB trials focused on patients with cT1, with inclusion criteria limited to cT2 or smaller tumors. Several studies have explored SLNB in a small number of cT3 and 4 cases; however, data on patients who underwent neo-adjuvant chemotherapy (NAC) remain insufficient [11, 12]. The 2016 American Society Clinical Oncology (ASCO) clinical practice guidelines recommend against performing SLNB in these patients [13]. In contrast, the European Society of Medical Oncology and the Japanese Breast Cancer Society clinical practice guidelines do not restrict SLNB based on tumor size in cN0 cases, resulting in differing policies across regions [14, 15]. Patients with cT3-4 and clinically node-negative BC are not uncommon, making the clinical decision whether to proceed with SLNB or ALND critical. Recently, research using real-world data (RWD) has gained considerable attention [16]. While RWD has inherent biases and limitations, addressing these conceptually can provide several advantages. RWD offers insights into patient populations and treatment outcomes in routine clinical settings, making findings more generalizable. Additionally, RWD facilitates long-term outcomes analysis, which is often unfeasible in traditional clinical trials with limited follow-up. Given the challenges to prospectively verify whether ALND can be omitted for axillary staging using SLNB in patients with cT3-4N0, this study aimed to conduct a retrospective study comparing SLNB and ALND without SLNB in patients with cT3-4 and node-negative BC. Methods Selection and description of participants This retrospective, multicenter observational study included patients with cT3-4cN0M0 BC who underwent surgery between 2006 and 2016. Patients who received NAC or primary surgery were eligible. Of these, cases that did not meet the following exclusion criteria were extracted and collected from the database for each center. Exclusion criteria included: 1) patients who did not undergo SLNB or ALND, 2) cases where ALND was omitted in positive sentinel lymph node (SLN), 3) metachronous BC, excluding non-invasive ductal BC, and 4) simultaneously diagnosed with contralateral BC and cT3-4cN0, excluding non-invasive ductal BC. The SLNB group was defined as cases where only SLNB was performed and those where SLNB was followed by ALND. Patients who underwent ALND after SLNB included those with metastasis in the SLN and those who underwent ALND due to an undetectable SLN. In the SLNB group, non-identifiable SLN cases were defined as those who underwent ALND following SLNB, but post-operative pathological examination revealed no lymph node metastasis. Cases where ALND was performed from the beginning were classified as the ALND group. Among the clinical and pathological factors, age, menopausal status, tumor size, clinical T stage, estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2) status, and histological grade were assessed before the initiation of drug therapy, while vascular invasion and the number of lymph node metastases were evaluated from the surgical specimens. This study was approved by the Ethics Committee of the Nagasaki University Hospital Clinical Research, Nagasaki, Japan (approval number, 22071102) on July 12, 2022. The data were collected up to January 31, 2024. The study utilized an opt-out method for informed consent, where participants were informed about the study via a publicly available overview on the web and given the opportunity to decline participation. Data collection and measurements Data were collected from three groups: SLNB only, SLNB followed by ALND, and ALND without SLNB. The primary end-point was recurrence-free survival (RFS), defined as the time from surgery to invasive disease (ipsilateral breast, chest wall, loco-regional lymph nodes, or distant site) and death from any cause, as defined by the standardized efficacy end-point criteria [17]. The secondary end-points included OS, defined as the time from surgery to death from any cause; loco-regional recurrence rate (LRR), defined as the occurrence of invasive disease (ipsilateral breast, chest wall, or loco-regional lymph nodes) after surgery; and subgroup analysis, including cT3/4, NAC, and pN0. Statistics To account for factors influencing the choice of surgical procedure (ALND vs. SLNB), propensity scores were generated using the following covariates: year of diagnosis, age, cT3/T4 a-c, pretreatment tumor size, grade, ER status, PgR status, HER2 status, and the presence or absence of NAC. Comparative analysis was performed using three methods: (1) an unadjusted analysis that did not account for baseline patient characteristics, (2) the stabilized inverse probability of treatment weighting (sIPTW), the primary analysis, to balance baseline characteristics between treatment groups, and control for confounders, and (3) overlap weighting (OW) as a sensitivity analysis. In adjusting for patient characteristics, cases with missing values were excluded, and a complete case analysis was performed. Kaplan–Meier curves were generated to estimate RFS, and the log-rank test was used to compare survival rates between the groups. Statistical significance was determined using a two-sided alpha level of 5%. Hazard ratios (HRs) for RFS were calculated using Cox regression models, adjusting for propensity scores and postoperative findings, including radiation therapy, adjuvant chemotherapy, endocrine therapy, vascular invasion, number of pathological lymph node metastases, and surgical margin (doubly robust methods). The 95% confidence intervals (CIs) and p-values were also calculated. Subgroup analyses were conducted to examine how HRs varied across different categories, including cT3/T4 a-c, pN-/N+, Grade 1–2/3, ER-positive/negative, HER2-positive/negative, and presence or absence of NAC. Results Patients In total, 964 patients were enrolled, with 34 excluded (Supporting Fig. 1 ). The final cohort included 930 patients: 214 in the ALND group and 716 in the SLNB group. Additionally, 680 patients (73%) underwent computed tomography or positron emission tomography-computed tomography, 627 patients (67%) underwent magnetic resonance imaging, and 56 (6%) did not undergo either of the procedures but were evaluated for axillary staging before treatment using only ultrasound. The median number of lymph nodes excised was 3 (interquartile range [IQR]: 1–9) in the SLNB group and 14 (IQR: 9–18) in the ALND group. In the unadjusted cohort, more patients were diagnosed in earlier years in the ALND group than in the SLNB group. Conversely, the SLNB group had higher proportions of cT3 cases (SLNB vs. ALND: 71% vs. 43%) and histological grade 1 cases (39% vs. 22%) than the ALND group. Regarding receptor status, ER-positive and PgR-positive cases were more common in the SLNB group than in the ALND group (ER-positive 79% vs. 72%, PgR-positive 65% vs. 58%). In contrast, HER2-positive cases were more common in the ALND group than in the SLNB group (20% vs. 29%). NAC and mastectomy were more common in the ALND group than in the SLNB group (NAC 28% vs. 53%, mastectomy 79% vs. 88%) (Table 1 ). Patient characteristics were generally balanced after sIPTW analyses (absolute standard mean differences for sIPTW was 0.005). After sIPTW, the median follow-up was 82.5 months (IQR: 40.8–124 months) and 83 months (IQR: 60–118 months) in the ALND and SLNB groups, respectively. In the SLNB group, the SLN identification rate was 93.9% (672/716). Table 1 Patient characteristics Unadjusted cohort Cohort after sIPTW ALND N = 214 SLNB N = 716 Standardized difference ALND N = 555 SLNB N = 553 Standardized difference Year of diagnosis, n (%) 2005–2008 68 (32) 95 (13) 0.198 86 (16) 89 (16) 0.006 2009–2012 89 (42) 254 (35) 0.103 181 (33) 182 (33) 0.002 2013–2016 57 (27) 367 (51) 0.301 288 (51) 282 (51) 0.009 Age (years), n (%) ≤ 40 18 (8) 75 (10) 0.020 51 (9) 54 (10) 0.006 > 40–69 154 (72) 494 (69) 0.008 409 (74) 384 (69) 0.043 > 69 42 (20) 147 (21) 0.012 95 (17) 115 (21) 0.036 Menopausal status, n (%) Men 0 (0) 4 (0.6) 0.010 0 (0) 6 (1) 0.011 Postmenopausal 145 (69) 428 (61) 0.097 350 (63) 349 (63) 0.001 Premenopausal 65 (31) 275 (39) 0.088 205 (37) 198 (36) 0.011 Missing 4 9 - - - Median tumor size b 55 (36–70) 58 (50–70) 0.018 55 (43–70) 55 (37–65) 0.039 Clinical T stage, n (%) 3 91 (43) 508 (71) 0.258 325 (59) 320 (58) 0.006 4a 4 (1.9) 17 (2.4) 0.013 11 (2) 18 (3) 0.011 4b 115 (54) 185 (26) 0.250 212 (38) 209 (38) 0.004 4c 4 (1.9) 6 (0.8) 0.021 7 (1) 6 (1) 0.001 Subtype, n (%) ER-positive, n (%) 155 (72) 565 (79) 0.098 470 (85) 451 (82) 0.030 PgR positive, n (%) 125 (58) 463 (65) 0.096 358 (64) 376 (68) 0.035 HER2 positive, n (%) 62 (29) 140 (20) 0.112 129 (23) 107 (19) 0.039 Operation method of breast, n (%) Partial mastectomy 26 (12) 151 (21) 0.109 73(13) 145(26) 0.130 Mastectomy 188 (88) 565 (79) 0.109 482(87) 408(74) 0.130 Histological grade, n (%) 1 37 (22) 204 (39) 0.171 200 (36) 206 (37) 0.012 2 75 (45) 200 (38) 0.074 196 (35) 213 (39) 0.033 3 53 (32) 121 (23) 0.096 159 (29) 134 (24) 0.045 Missing 49 191 - - - Vascular invasion, n (%) 99 (48) 224 (33) 0.169 326 (59) 191 (35) 0.241 Missing 6 39 - - - Number of lymph node metastasis, n (%) 0 138 (64) 457 (64) 0.019 289 (52) 369 (67) 0.148 1–3 44 (21) 192 (27) 0.039 128 (23) 143 (26) 0.028 4 or more 32 (15) 65 (9.1) 0.058 138 (25) 41 (7) 0.175 Missing 0 2 - - - Adjuvant endocrine therapy, n (%) 141 (66) 525 (73) 0.105 374(67) 418(76) 0.083 Missing 0 1 Neo-adjuvant chemotherapy, n (%) 113 (53) 198 (28) 0.240 183 (33) 188 (34) 0.010 pCR, n (%) 9 (8.0) 33 (17) 0.048 6 (3) 14 (7) 0.040 Perioperative chemotherapy, n (%) 160 (75) 431 (60) 0.016 257(46) 192(35) 0.116 Missing 0 2 Radiation therapy, n (%) 85 (40) 268 (38) 0.003 269 (48) 235 (43) 0.058 Missing 1 4 - - - # y.o. (IQR), b mm (IQR) ALND, axillary lymph node dissection; SLNB, sentinel lymph node biopsy; ER, estrogen receptor; PgR, progesterone receptor; HER, human epidermal growth factor receptor; pCR, pathologic complete response; sIPTW, stabilized inverse probability of treatment weighting RFS between the SLNB and ALND groups During follow-up, 176 RFS events were observed, with details of recurrence sites shown in (Table 2 ). In the unadjusted analysis of the full cohort (n = 930), patients in the ALND group had significantly shorter RFS than those in the SLNB group, with 10-year RFS rates of 72.7% (95% CI, 66.5–79.6) vs. 79.6% (95% CI, 76.1–83.3) (HR 0.70 [95% CI, 0.50–0.99]; P = 0.003; Fig. 1 a). After sIPTW adjustment, the RFS for the ALND vs. SLNB groups at 10 years was 74.2% (95% CI, 63.7–86.4) vs. 79.2% (95% CI, 74.3–84.4), respectively. The HR of SLNB to ALND was 0.80 (95% CI, 0.44–1.44; P = 0.37; Fig. 1 b). Subgroup analysis after sIPTW revealed no significant differences between SLNB and ALND groups, whether based on cT3 or cT4 cases (Fig. 1 c, d). Among patients with pN0, no significant differences were noted between the SLNB (true SLNB without axillary dissection) and ALND groups (Fig. 2 ). In all other subgroup analyses, including those considering NAC presence, no significant differences in RFS were found between the SLNB and ALND groups (Fig. 2 ). Regarding sensitivity analysis by OW adjustment, the 10-year RFS rates for the ALND vs. SLNB were 74.9% vs. 79.4%, respectively (Supporting Fig. 2 a). The HR of SLNB to ALNB was 0.79 (95% CI, 0.47–1.31; P = 0.27;), similar to the results of the sIPTW analysis. Table 2 Number of recurrences by site and deaths. ALND (N = 214) SLNB (N = 716) Invasive ipsilateral breast tumor recurrence, n (%) 1 (0.5) 11 (2) Ipsilateral ductal carcinoma in situ, n (%) 0 2 (0.3) Invasive ipsilateral tumor recurrence in chest wall, n (%) 6 (3) 14 (2) Nodal recurrence in ipsilateral axilla, n (%) 4 (2) 19 (3) Nodal recurrence in ipsilateral supraclavicular or internal mammary regions, n (%) 4 (2) 12 (2) Distant recurrence, n (%) 41 (19) 80 (11) All-cause death, n (%) 41 (19) 69 (10) Death from breast cancer, n (%) 31 (14) 42 (6) ALND, Axillary lymph node dissection; SLNB, Sentinel lymph node biopsy LRR and OS between the SLNB and ALND groups During follow-up, 51 LRRs (18%) were observed (Table 2 ). In the unadjusted analysis, no significant difference in LRR was observed between the ALND and SLNB groups, with 10-year LRR rates of 93.5% (95% CI, 89.6–97.6) and 93.6% (95% CI, 91.5–95.7), respectively. The HR of SLNB to ALNB was 1.14 (95% CI; 0.57–2.27; Fig. 3 a). Similarly, after sIPTW, no significant differences in LRR were observed between the ALND and SLNB groups (Fig. 3 b), with 10-year LRR rates of 90.8% (95% CI, 83.3–99.1) vs. 93.1% (95% CI, 89.9–96.5), respectively. The HR of SLNB to ALNB was 0.71 (95% CI: 0.30–1.7, Fig. 3 b). No significant difference was observed between SLNB and ALND groups when categorized based on cT3 and cT4, respectively (Supporting Fig. 3 a, b). Regarding sensitivity analysis by OW adjustment, the LRR rate at 10 years was 92.0% vs. 93.0%, respectively, for ALND vs. SLNB groups. The HR of SLNB to ALNB was 0.77 (95% CI: 0.32 to 1.83; Supporting Fig. 2 b). In total, 110 OS events (18%) were observed (Table 2 ). In the unadjusted analysis, the median OS was significantly shorter in the ALND group than in the SLNB group. The 10-year OS rates were 79.1% (95% CI, 73.2–85.4) for the ALND group and 87.6% (95% CI, 84.6–90.7) for the SLNB group. The HR of SLNB to ALNB was 0.57 (95% CI, 0.37–0.87; P < 0.0001; Supporting Fig. 4a). After sIPTW adjustment, the 10-year OS rate for ALND vs. SLNB groups was 81.1% (95% CI, 71.8–91.6) vs. 89.0% (95% CI, 85.2–92.9), respectively. The HR of SLNB to ALNB was 0.56 (95% CI, 0.31–1.04; Supporting Fig. 4b). No significant differences in OS were observed between the groups when stratified by cT3 or cT4 (Supporting Fig. 4c, d). Regarding sensitivity analysis by OW adjustment, the OS at 10 years was 80.3% vs. 89.4%, respectively, for the ALND vs. SLNB groups. The HR of SLNB to ALNB was 0.53 (95% CI, 0.29–0.97; Supporting Fig. 2 c). Discussion This multicenter retrospective study compared RFS, OS, and LRR between patients with cT3-4cN0 BC who underwent SLNB and ALND. Before adjusting for patient characteristics, the ALND group exhibited a higher prevalence of poor prognostic factors than the SLNB group, with worse RFS and OS. After adjustment using sIPTW or OW, no significant differences in RFS, OS, and LRR were observed between the SLNB and ALND groups in the overall patient population or all subgroups, including cT3 and cT4 cases. No randomized controlled trials have directly compared SLNB and ALND for cT3-4 BC, using SLNB for cT3-4cN0 BC controversial [13, 18]. In a small prospective cohort study of 41 cases of cT3N0, the false-negative rate of SLNB was 3%, indicating good performance [19]. A single-center observational study of 73 patients with cT3 and T4b BC who underwent SLNB reported that 60.3% were negative for macrometastasis, with no ipsilateral axillary local recurrence observed during a median follow-up of 45 months [6]. This study is a single-center, small-sample research with a short study period; however, local control of cT3 and cT4b BC with SLNB was favorable. Li et al. analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database, focusing on patients with cT3-4c BC who underwent surgery [7]. Of these, 864 patients (432 from the SLNB group and 432 from the ALND group) were selected using propensity score matching, and no significant differences in OS or breast cancer-specific survival (BCSS) were observed between SLNB and ALND groups. OS and BCSS were similar in both groups overall and across subgroup analysis; however, RFS and LRR rates were not assessed. This study had some limitations, including defining whether SLNB or ALND was performed based on the number of removed lymph nodes and not adjusting for factors such as chemotherapy timing (neo-adjuvant or adjuvant), tumor grade, and preoperative tumor size. These results align with prior reports, showing no significant difference in RFS or OS between the ALND and SLNB groups. Furthermore, no significant difference was observed in LRR between the two groups, with both groups achieving favorable outcomes, with the 10-year LRR exceeding 90%. However, Kaplan–Meier curves indicated that even after adjusting for patient backgrounds using the sIPTW method, OS was somewhat worse in the ALND group compared with the SLNB group. Before adjustment, RFS and OS were significantly worse in the ALND group, suggesting that physicians may select ALND for patients with poorer prognoses, even in cN0 cases. We adjusted for potential prognostic factors between the two groups; however, latent factors were not fully accounted for. For instance, the pathological complete response rate was low in both groups in this study, owing to locally advanced BC; however, NAC response was not adjusted. Even in cT3-4cN0 cases, the LRR was low regardless of whether SLNB or ALND was performed, with few recurrence events observed. In this study, the cT3-4c cohort comprised patients who underwent either upfront surgery or NAC. Significant differences in patient and tumor characteristics likely existed between these two groups. Notably, the study focuses on patients with cN0, where the selection of SLNB or ALND after NAC appears unrelated to the axillary lymph nodes' treatment response. Nevertheless, differences in baseline patient characteristics between the groups must be considered. Before adjusting for these characteristics, the ALND group included a higher proportion of patients who received NAC. However, after applying the sIPTW, the standardized difference between the groups was reduced to 0.01, indicating successful adjustment. Subgroup analyses aligned with the overall findings, showing no significant differences between SLNB and ALND groups within both the NAC and non-NAC populations. For cN0 BC, axillary staging with SLNB is recommended, even after NAC [14,15]. In 127 cases of cT3cN0 BC treated with NAC, the false-negative rate for SNLB was 9.6%, slightly worse than previously reported results [29]. Furthermore, high false-negative rates have been reported in node-positive cases before NAC [21–24]. In this study, most cases underwent axillary staging with multiple imaging studies before treatment, which may contribute to the high SLN identification rate of 93.9% and low LRR. Studies have reported on the omission of ALND in patients with cT3-4 and 1 or 2 SLN metastases, as investigated in the “extended” ACOSOG Z0011 trial. In a cohort of cT3-4cN0 with 1–2 SLN metastases using data from the West German Breast Cancer Study, the proportion of patients undergoing ALND decreased between 2008 and 2015, regardless of whether they underwent mastectomy or lumpectomy [25]. However, some reports have indicated that non-SLN metastases were observed in 46.9% of cT3 cases and 58.1% of cT4 cases, suggesting that these cases should be carefully evaluated [25]. In the SENOMAC trial, a randomized controlled trial investigating the omission of ALND for SLN metastases (1 or 2 nodes) in cT1-3cN0 BC, non-inferiority of omitting ALND was demonstrated. However, this trial included only 73 cT3 cases in the SLNB group (5.5%) and 74 cT3 cases in the ALND group (6.1%) [26]. Therefore, the validity of performing SLNB and omitting ALND for positive metastases in cT3 cases has not been fully clarified. This study has some limitations. First, sIPTW and OW were employed to adjust for baseline and clinical patient characteristics; however, accounting for unobserved variables using these techniques alone was impossible. Second, this study included patients between 2006 and 2016 to ensure a sufficient observation period; however, some of these cases may not align with current standard perioperative drug therapies, such as abemaciclib, trastuzumab, pertuzumab, and pembrolizumab. Third, this was a multicenter retrospective study; however, the sample size was too small for analysis based on BC subtypes. After adjustment using sIPTW, the study included more samples than several previous reports on cT1-2N0 SLNB, but it did not reach the sample size of the NSABP B-32 trial, which may result in reduced power [3–5]. Despite these limitations, this study covered a long observation period, extracted cases from the databases of each facility, and added the necessary information, allowing us to collect detailed patient background characteristics. Furthermore, this study examined an important endpoint, local and regional lymph node recurrence, and revealed no significant difference between the ALND and SLNB groups. Conclusions In conclusion, these findings suggest that compared with ALND, SLNB is a safe option for axillary staging in cT3-4cN0 without negatively impacting RFS, OS, and LRR. This finding supports the potential expansion of SLNB to higher stages of BC, pending further prospective studies to confirm these results and assess long-term outcomes. Declarations Author contributions: The study design and concept were developed by SK, YS, and SM. Statistical analysis was performed by HY. SK, YS, SM, TS, YK, MH, SA, ET, TS, HB, KA, NI, SM, MY, MH, MO, TS, MI, TN, TH, MT, KT, GK, MT, NH-S, KK, KT, KY, MK, CY, YT made substantial contributions to data acquisition. All authors contributed to the interpretation of the results. The first draft was written by SK, and all authors participated in revising it critically for important intellectual content. All authors approved the version of the manuscript. Data availability statement: The datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request. Funding statement: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Acknowledgments : The authors thank the Editage Group (https://www.editage.com/) for editing the draft of this manuscript Conflict of interest disclosure: The authors have no conflict of interest disclosures to disclose. Ethics approval statement: This study was approved by the Ethics Committee of the Nagasaki University Hospital Clinical Research, Nagasaki, Japan (approval number, 22071102) on July 12, 2022. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study formal consent is not required. Patient consent statement: The study utilized an opt-out method for informed consent, where participants were informed about the study via a publicly available overview on the web and given the opportunity to decline participation. Permission to reproduce material from other sources: Not applicable References Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. Global Burden of Disease Cancer Collaboration; Fitzmaurice C, Abate D, Abbasi N, Abbastabar H, Abd-Allah F, Abdel-Rahman O, et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2017: a systematic analysis for the global burden of disease study. JAMA Oncol . 2019;5(12):1749–1768. Ververs JM, Roumen RM, Vingerhoets AJ, Vreugdenhil G, Coebergh JW, Crommelin MA, et al. Risk, severity and predictors of physical and psychological morbidity after axillary lymph node dissection for breast cancer. Eur J Cancer . 2001;37(8):991–999. Veronesi U, Paganelli G, Viale G, Luini A, Zurrida S, Galimberti V, et al. Sentinel-lymph-node biopsy as a staging procedure in breast cancer: update of a randomised controlled study. Lancet Oncol . 2006;7(12):983–990. Krag DN, Anderson SJ, Julian TB, Brown AM, Harlow SP, Costantino JP, et al. Sentinel-lymph-node resection compared with conventional axillary-lymph-node dissection in clinically node-negative patients with breast cancer: overall survival findings from the NSABP B-32 randomised phase 3 trial. Lancet Oncol . 2010;11(10):927–933. Canavese G, Catturich A, Vecchio C, Tomei D, Gipponi M, Villa G, et al. Sentinel node biopsy compared with complete axillary dissection for staging early breast cancer with clinically negative lymph nodes: results of randomized trial. Ann Oncol . 2009;20(6):1001–1007. Land SR, Kopec JA, Julian TB, Brown AM, Anderson SJ, Krag DN, et al. Patient-reported outcomes in sentinel node-negative adjuvant breast cancer patients receiving sentinel-node biopsy or axillary dissection: National Surgical Adjuvant Breast and Bowel Project phase III protocol B-32. J Clin Oncol . 2010;28(5):3929–3936. Purushotham AD, Upponi S, Klevesath MB, Bobrow L, Millar K, Myles JP, et al: Morbidity after sentinel lymph node biopsy in primary breast cancer: results from a randomized controlled trial. J Clin Oncol . 2005;23(19):4312–4321. Mansel RE, Fallowfield L, Kissin M, Goyal A, Newcombe RG, Dixon JM, et al. Randomized multicenter trial of sentinel node biopsy versus standard axillary treatment in operable breast cancer: the ALMANAC Trial. J Natl Cancer Inst . 2006;98(9):599–609. Che Bakri NA, Kwasnicki RM, Khan N, Ghandour O, Lee A, Grant Y, et al. Impact of axillary lymph node dissection and sentinel lymph node biopsy on upper limb morbidity in breast cancer patients: a systematic review and meta-analysis. Ann Surg . 2023;277(4):572–580. de Oliveira-Junior I, Nahas EAP, Cherem AC, Nahas-Neto J, Vieira RADC. Sentinel lymph node biopsy in T3 and T4b breast cancer patients: analysis in a tertiary Cancer Hospital and systematic literature review. Breast Care (Basel) . 2021;16(1):27–35. Li P, Yang C, Zhang J, Chen Y, Zhang X, Liang M, et al. Survival after sentinel lymph node biopsy compared with axillary lymph node dissection for female patients with T3-4c breast cancer. Oncologist . 2023;28(8):e591–e599, 2023. Lyman GH, Somerfield MR, Bosserman LD, Perkins CL, Weaver DL, Giuliano AE. Sentinel lymph node biopsy for patients with early-stage breast cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2017;35(5):561–564. Sakai T, Kutomi G, Shien T, Asaga S, Aruga T, Ishitobi M, et al. The Japanese Breast Cancer Society Clinical Practice Guidelines for surgical treatment of breast cancer, 2022 edition. Breast Cancer . 2024;31(1):1–7. Loibl S, André F, Bachelot T, Barrios CH, Bergh J, Burstein HJ, et al. Early breast cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol . 2024;35(2):159–182. Ramsey SD, Onar-Thomas A, Wheeler SB. Real-world database studies in oncology: a call for standards. J Clin Oncol . 2024;42(9):977–980. Tolaney SM, Garrett-Mayer E, White J, Blinder VS, Foster JC, Amiri-Kordestani L, Hwang ES, et al. Updated Standardized Definitions for Efficacy End Points (STEEP) in Adjuvant Breast Cancer Clinical Trials: STEEP Version 2.0. J Clin Oncol . 2021;39(24):2720–2731. Kaufmann M, Morrow M, von Minckwitz G, Harris JR. Locoregional treatment of primary breast cancer: consensus recommendations from an International Expert Panel. Cancer . 2010;116(5):1184–1191. Chung MH, Ye W, Giuliano AE. Role for sentinel lymph node dissection in the management of large (> or = 5 cm) invasive breast cancer. Ann Surg Oncol . 2001;8(9):688–692. Yu JC, Hsu GC, Hsieh CB, Yu CP, Chao TY. Role of sentinel lymphadenectomy combined with intraoperative ultrasound in the assessment of locally advanced breast cancer after neoadjuvant chemotherapy. Ann Surg Oncol . 2007;14(1):174–180. Mamounas EP, Brown A, Anderson S, Smith R, Julian T, Miller B, et al. Sentinel node biopsy after neoadjuvant chemotherapy in breast cancer: results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol . 2005;23(12):2694–2702. Boileau 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):258–264. Kuehn 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):609–618. Boughey 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):1455–1461. Riedel F, Heil J, Feisst M, Moderow M, von Au A, Domschke C, et al. Analyzing non-sentinel axillary metastases in patients with T3-T4 cN0 early breast cancer and tumor-involved sentinel lymph nodes undergoing breast-conserving therapy or mastectomy. Breast Cancer Res Treat . 2020;184(2):627–636. de Boniface J, Filtenborg Tvedskov T, Rydén L, Szulkin R, Reimer T, Kühn T, et al. Omitting axillary dissection in breast cancer with sentinel-node metastases. N Engl J Med . 2024;390(13):1163–1175. Supplementary Files Supportinginformation.docx Cite Share Download PDF Status: Published Journal Publication published 01 Aug, 2025 Read the published version in Breast Cancer → Version 1 posted Editorial decision: Major Revision 25 Apr, 2025 Reviewers agreed at journal 30 Mar, 2025 Reviewers invited by journal 30 Mar, 2025 Editor assigned by journal 27 Mar, 2025 First submitted to journal 26 Mar, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6315783","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":435936547,"identity":"e49bb89d-c661-4ae0-8ab0-a16d4477c49f","order_by":0,"name":"Sayaka 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00:44:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6315783/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6315783/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s12282-025-01749-9","type":"published","date":"2025-08-01T16:13:03+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":82053862,"identity":"65aad465-7d6e-4dc2-84f1-540b6531cfa4","added_by":"auto","created_at":"2025-05-06 10:17:05","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":85677,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curves of recurrence-free survival. a. Unadjusted analysis, b. after stabilized inverse probability of treatment weighting (sIPTW), c. by cT3 and d. T4a-c.\u003c/p\u003e\n\u003cp\u003eALND, axillary lymph node dissection; CI, confidence interval; SLNB, sentinel lymph node biopsy\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6315783/v1/9f6eb440248c623aae778bcf.jpg"},{"id":82055614,"identity":"d6284153-e808-457a-b47e-4a96a9b97ab0","added_by":"auto","created_at":"2025-05-06 10:25:05","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":89170,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of recurrence-free survival by subgroup after stabilized inverse probability of treatment weighting (sIPTW).\u003c/p\u003e\n\u003cp\u003eALND, axillary lymph node dissection; HER2, HER, human epidermal growth factor receptor 2; NAC, neoadjuvant chemotherapy; SLNB, sentinel lymph node biopsy\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6315783/v1/f1e07c10380d30f0e57d3a74.jpg"},{"id":82053864,"identity":"4a96d65b-875c-46ae-8e81-223c9ee9e8d8","added_by":"auto","created_at":"2025-05-06 10:17:05","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":758804,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curves of loco-regional recurrence rate. a. Unadjusted analysis, b. Patient background adjusted for the stabilized inverse probability of treatment weighting (sIPTW) method.\u003c/p\u003e\n\u003cp\u003eALND, axillary lymph node dissection; CI, confidence interval; SLNB, sentinel lymph node biopsy\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6315783/v1/94656c5bdf6794fbbe68c98e.jpg"},{"id":88268835,"identity":"4d39768e-715e-4b74-8069-200b690210c8","added_by":"auto","created_at":"2025-08-04 16:52:29","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1924876,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6315783/v1/6278181a-06c1-4516-8ec6-f692752d9ec5.pdf"},{"id":82053874,"identity":"fda04dd0-fcd9-4756-9695-c44a22fa9a3e","added_by":"auto","created_at":"2025-05-06 10:17:05","extension":"docx","order_by":9,"title":"","display":"","copyAsset":false,"role":"supplement","size":399524,"visible":true,"origin":"","legend":"","description":"","filename":"Supportinginformation.docx","url":"https://assets-eu.researchsquare.com/files/rs-6315783/v1/48ea126e59df9a881d298c41.docx"}],"financialInterests":"","formattedTitle":"A Retrospective Multi-Center Cohort Study Investigating Safety of Sentinel Lymph Node Biopsy for Axillary Staging in Clinical T3-4c Breast Cancer","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBreast cancer (BC) is the most commonly diagnosed cancer in women after non-melanoma skin cancer [1, 2]. Axillary lymph node dissection (ALND), the standard procedure for early-stage BC, is associated with adverse effects such as pain, numbness, muscle weakness, and lymphedema, which impair leisure activities and sports [3]. Some clinical trials have reported no significant differences in overall survival (OS), disease-free survival, and regional control between sentinel lymph node biopsy (SLNB) and ALND in patients with clinically node-negative BC [4\u0026ndash;6]. Compared with the ALND group, the SLNB group experienced less pain, improved arm mobility, and reduced hospitalization costs [7\u0026ndash;10]. Consequently, SLNB has become the standard approach for axillary staging in patients with clinically node-negative BC.\u003c/p\u003e \u003cp\u003eMost SLNB trials focused on patients with cT1, with inclusion criteria limited to cT2 or smaller tumors. Several studies have explored SLNB in a small number of cT3 and 4 cases; however, data on patients who underwent neo-adjuvant chemotherapy (NAC) remain insufficient [11, 12]. The 2016 American Society Clinical Oncology (ASCO) clinical practice guidelines recommend against performing SLNB in these patients [13]. In contrast, the European Society of Medical Oncology and the Japanese Breast Cancer Society clinical practice guidelines do not restrict SLNB based on tumor size in cN0 cases, resulting in differing policies across regions [14, 15]. Patients with cT3-4 and clinically node-negative BC are not uncommon, making the clinical decision whether to proceed with SLNB or ALND critical.\u003c/p\u003e \u003cp\u003eRecently, research using real-world data (RWD) has gained considerable attention [16]. While RWD has inherent biases and limitations, addressing these conceptually can provide several advantages. RWD offers insights into patient populations and treatment outcomes in routine clinical settings, making findings more generalizable. Additionally, RWD facilitates long-term outcomes analysis, which is often unfeasible in traditional clinical trials with limited follow-up. Given the challenges to prospectively verify whether ALND can be omitted for axillary staging using SLNB in patients with cT3-4N0, this study aimed to conduct a retrospective study comparing SLNB and ALND without SLNB in patients with cT3-4 and node-negative BC.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSelection and description of participants\u003c/h2\u003e \u003cp\u003eThis retrospective, multicenter observational study included patients with cT3-4cN0M0 BC who underwent surgery between 2006 and 2016. Patients who received NAC or primary surgery were eligible. Of these, cases that did not meet the following exclusion criteria were extracted and collected from the database for each center. Exclusion criteria included: 1) patients who did not undergo SLNB or ALND, 2) cases where ALND was omitted in positive sentinel lymph node (SLN), 3) metachronous BC, excluding non-invasive ductal BC, and 4) simultaneously diagnosed with contralateral BC and cT3-4cN0, excluding non-invasive ductal BC. The SLNB group was defined as cases where only SLNB was performed and those where SLNB was followed by ALND. Patients who underwent ALND after SLNB included those with metastasis in the SLN and those who underwent ALND due to an undetectable SLN. In the SLNB group, non-identifiable SLN cases were defined as those who underwent ALND following SLNB, but post-operative pathological examination revealed no lymph node metastasis. Cases where ALND was performed from the beginning were classified as the ALND group. Among the clinical and pathological factors, age, menopausal status, tumor size, clinical T stage, estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2) status, and histological grade were assessed before the initiation of drug therapy, while vascular invasion and the number of lymph node metastases were evaluated from the surgical specimens. This study was approved by the Ethics Committee of the Nagasaki University Hospital Clinical Research, Nagasaki, Japan (approval number, 22071102) on July 12, 2022. The data were collected up to January 31, 2024. The study utilized an opt-out method for informed consent, where participants were informed about the study via a publicly available overview on the web and given the opportunity to decline participation.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData collection and measurements\u003c/h3\u003e\n\u003cp\u003eData were collected from three groups: SLNB only, SLNB followed by ALND, and ALND without SLNB. The primary end-point was recurrence-free survival (RFS), defined as the time from surgery to invasive disease (ipsilateral breast, chest wall, loco-regional lymph nodes, or distant site) and death from any cause, as defined by the standardized efficacy end-point criteria [17]. The secondary end-points included OS, defined as the time from surgery to death from any cause; loco-regional recurrence rate (LRR), defined as the occurrence of invasive disease (ipsilateral breast, chest wall, or loco-regional lymph nodes) after surgery; and subgroup analysis, including cT3/4, NAC, and pN0.\u003c/p\u003e\n\u003ch3\u003eStatistics\u003c/h3\u003e\n\u003cp\u003eTo account for factors influencing the choice of surgical procedure (ALND vs. SLNB), propensity scores were generated using the following covariates: year of diagnosis, age, cT3/T4 a-c, pretreatment tumor size, grade, ER status, PgR status, HER2 status, and the presence or absence of NAC. Comparative analysis was performed using three methods: (1) an unadjusted analysis that did not account for baseline patient characteristics, (2) the stabilized inverse probability of treatment weighting (sIPTW), the primary analysis, to balance baseline characteristics between treatment groups, and control for confounders, and (3) overlap weighting (OW) as a sensitivity analysis. In adjusting for patient characteristics, cases with missing values were excluded, and a complete case analysis was performed. Kaplan\u0026ndash;Meier curves were generated to estimate RFS, and the log-rank test was used to compare survival rates between the groups. Statistical significance was determined using a two-sided alpha level of 5%. Hazard ratios (HRs) for RFS were calculated using Cox regression models, adjusting for propensity scores and postoperative findings, including radiation therapy, adjuvant chemotherapy, endocrine therapy, vascular invasion, number of pathological lymph node metastases, and surgical margin (doubly robust methods). The 95% confidence intervals (CIs) and p-values were also calculated. Subgroup analyses were conducted to examine how HRs varied across different categories, including cT3/T4 a-c, pN-/N+, Grade 1\u0026ndash;2/3, ER-positive/negative, HER2-positive/negative, and presence or absence of NAC.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eIn total, 964 patients were enrolled, with 34 excluded (Supporting Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The final cohort included 930 patients: 214 in the ALND group and 716 in the SLNB group. Additionally, 680 patients (73%) underwent computed tomography or positron emission tomography-computed tomography, 627 patients (67%) underwent magnetic resonance imaging, and 56 (6%) did not undergo either of the procedures but were evaluated for axillary staging before treatment using only ultrasound. The median number of lymph nodes excised was 3 (interquartile range [IQR]: 1\u0026ndash;9) in the SLNB group and 14 (IQR: 9\u0026ndash;18) in the ALND group. In the unadjusted cohort, more patients were diagnosed in earlier years in the ALND group than in the SLNB group. Conversely, the SLNB group had higher proportions of cT3 cases (SLNB vs. ALND: 71% vs. 43%) and histological grade 1 cases (39% vs. 22%) than the ALND group. Regarding receptor status, ER-positive and PgR-positive cases were more common in the SLNB group than in the ALND group (ER-positive 79% vs. 72%, PgR-positive 65% vs. 58%). In contrast, HER2-positive cases were more common in the ALND group than in the SLNB group (20% vs. 29%). NAC and mastectomy were more common in the ALND group than in the SLNB group (NAC 28% vs. 53%, mastectomy 79% vs. 88%) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Patient characteristics were generally balanced after sIPTW analyses (absolute standard mean differences for sIPTW was 0.005). After sIPTW, the median follow-up was 82.5 months (IQR: 40.8\u0026ndash;124 months) and 83 months (IQR: 60\u0026ndash;118 months) in the ALND and SLNB groups, respectively. In the SLNB group, the SLN identification rate was 93.9% (672/716).\u003c/p\u003e \u003cp\u003e \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\u003ePatient characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\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 \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eUnadjusted cohort\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003eCohort after sIPTW\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\u003eALND\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;214\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSLNB\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;716\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eStandardized difference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eALND\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;555\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSLNB\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;553\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eStandardized difference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003eYear of diagnosis, n (%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2005\u0026ndash;2008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e68 (32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95 (13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.198\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e86 (16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e89 (16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.006\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2009\u0026ndash;2012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e89 (42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e254 (35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.103\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e181 (33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e182 (33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2013\u0026ndash;2016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e57 (27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e367 (51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.301\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e288 (51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e282 (51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003eAge (years), n (%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026le;\u0026thinsp;40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e75 (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e51 (9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e54 (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.006\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;40\u0026ndash;69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e154 (72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e494 (69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e409 (74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e384 (69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.043\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42 (20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e147 (21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e95 (17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e115 (21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.036\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003eMenopausal status, n (%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (0.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.010\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6 (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.011\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePostmenopausal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e145 (69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e428 (61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.097\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e350 (63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e349 (63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePremenopausal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e65 (31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e275 (39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.088\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e205 (37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e198 (36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.011\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian tumor size \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e55\u003c/p\u003e \u003cp\u003e(36\u0026ndash;70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e58\u003c/p\u003e \u003cp\u003e(50\u0026ndash;70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e55\u003c/p\u003e \u003cp\u003e(43\u0026ndash;70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e55\u003c/p\u003e \u003cp\u003e(37\u0026ndash;65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.039\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003eClinical T stage, n (%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e91 (43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e508 (71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.258\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e325 (59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e320 (58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.006\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (1.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (2.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.013\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11 (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e18 (3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.011\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4b\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e115 (54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e185 (26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.250\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e212 (38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e209 (38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4c\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (1.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (0.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7 (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6 (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003eSubtype, n (%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eER-positive, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e155 (72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e565 (79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.098\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e470 (85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e451 (82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.030\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePgR positive, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e125 (58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e463 (65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.096\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e358 (64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e376 (68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.035\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHER2 positive, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62 (29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e140 (20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.112\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e129 (23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e107 (19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.039\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003eOperation method of breast, n (%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePartial mastectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26 (12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e151 (21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.109\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e73(13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e145(26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.130\u003c/p\u003e \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\u003e188 (88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e565 (79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.109\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e482(87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e408(74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.130\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003eHistological grade, n (%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37 (22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e204 (39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.171\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e200 (36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e206 (37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e75 (45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e200 (38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.074\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e196 (35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e213 (39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.033\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53 (32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e121 (23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.096\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e159 (29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e134 (24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.045\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e191\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVascular invasion, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e99 (48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e224 (33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.169\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e326 (59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e191 (35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.241\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003eNumber of lymph node metastasis, n (%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e138 (64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e457 (64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e289 (52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e369 (67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.148\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u0026ndash;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44 (21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e192 (27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.039\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e128 (23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e143 (26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.028\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4 or more\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32 (15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65 (9.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.058\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e138 (25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e41 (7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.175\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdjuvant endocrine therapy, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e141 (66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e525 (73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.105\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e374(67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e418(76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.083\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\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 \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeo-adjuvant chemotherapy, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e113 (53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e198 (28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.240\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e183 (33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e188 (34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.010\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epCR, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (8.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33 (17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.048\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6 (3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e14 (7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.040\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePerioperative chemotherapy, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e160 (75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e431 (60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e257(46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e192(35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.116\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\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 \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRadiation therapy, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e85 (40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e268 (38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e269 (48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e235 (43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.058\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003csup\u003e#\u003c/sup\u003e y.o. (IQR), \u003csup\u003eb\u003c/sup\u003e mm (IQR)\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eALND, axillary lymph node dissection; SLNB, sentinel lymph node biopsy; ER, estrogen receptor; PgR, progesterone receptor; HER, human epidermal growth factor receptor; pCR, pathologic complete response; sIPTW, stabilized inverse probability of treatment weighting\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eRFS between the SLNB and ALND groups\u003c/h2\u003e \u003cp\u003eDuring follow-up, 176 RFS events were observed, with details of recurrence sites shown in (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). In the unadjusted analysis of the full cohort (n\u0026thinsp;=\u0026thinsp;930), patients in the ALND group had significantly shorter RFS than those in the SLNB group, with 10-year RFS rates of 72.7% (95% CI, 66.5\u0026ndash;79.6) vs. 79.6% (95% CI, 76.1\u0026ndash;83.3) (HR 0.70 [95% CI, 0.50\u0026ndash;0.99]; P\u0026thinsp;=\u0026thinsp;0.003; Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). After sIPTW adjustment, the RFS for the ALND vs. SLNB groups at 10 years was 74.2% (95% CI, 63.7\u0026ndash;86.4) vs. 79.2% (95% CI, 74.3\u0026ndash;84.4), respectively. The HR of SLNB to ALND was 0.80 (95% CI, 0.44\u0026ndash;1.44; P\u0026thinsp;=\u0026thinsp;0.37; Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb). Subgroup analysis after sIPTW revealed no significant differences between SLNB and ALND groups, whether based on cT3 or cT4 cases (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec, d). Among patients with pN0, no significant differences were noted between the SLNB (true SLNB without axillary dissection) and ALND groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). In all other subgroup analyses, including those considering NAC presence, no significant differences in RFS were found between the SLNB and ALND groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Regarding sensitivity analysis by OW adjustment, the 10-year RFS rates for the ALND vs. SLNB were 74.9% vs. 79.4%, respectively (Supporting Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). The HR of SLNB to ALNB was 0.79 (95% CI, 0.47\u0026ndash;1.31; P\u0026thinsp;=\u0026thinsp;0.27;), similar to the results of the sIPTW analysis.\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\u003eNumber of recurrences by site and deaths.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eALND\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;214)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSLNB\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;716)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInvasive ipsilateral breast tumor recurrence, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIpsilateral ductal carcinoma in situ, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (0.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInvasive ipsilateral tumor recurrence in chest wall, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNodal recurrence in ipsilateral axilla, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 (3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNodal recurrence in ipsilateral supraclavicular or\u003c/p\u003e \u003cp\u003einternal mammary regions, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDistant recurrence, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41 (19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e80 (11)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAll-cause death, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41 (19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e69 (10)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDeath from breast cancer, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31 (14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42 (6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eALND, Axillary lymph node dissection; SLNB, Sentinel lymph node biopsy\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eLRR and OS between the SLNB and ALND groups\u003c/h3\u003e\n\u003cp\u003eDuring follow-up, 51 LRRs (18%) were observed (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). In the unadjusted analysis, no significant difference in LRR was observed between the ALND and SLNB groups, with 10-year LRR rates of 93.5% (95% CI, 89.6\u0026ndash;97.6) and 93.6% (95% CI, 91.5\u0026ndash;95.7), respectively. The HR of SLNB to ALNB was 1.14 (95% CI; 0.57\u0026ndash;2.27; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea). Similarly, after sIPTW, no significant differences in LRR were observed between the ALND and SLNB groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb), with 10-year LRR rates of 90.8% (95% CI, 83.3\u0026ndash;99.1) vs. 93.1% (95% CI, 89.9\u0026ndash;96.5), respectively. The HR of SLNB to ALNB was 0.71 (95% CI: 0.30\u0026ndash;1.7, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb). No significant difference was observed between SLNB and ALND groups when categorized based on cT3 and cT4, respectively (Supporting Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea, b). Regarding sensitivity analysis by OW adjustment, the LRR rate at 10 years was 92.0% vs. 93.0%, respectively, for ALND vs. SLNB groups. The HR of SLNB to ALNB was 0.77 (95% CI: 0.32 to 1.83; Supporting Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn total, 110 OS events (18%) were observed (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). In the unadjusted analysis, the median OS was significantly shorter in the ALND group than in the SLNB group. The 10-year OS rates were 79.1% (95% CI, 73.2\u0026ndash;85.4) for the ALND group and 87.6% (95% CI, 84.6\u0026ndash;90.7) for the SLNB group. The HR of SLNB to ALNB was 0.57 (95% CI, 0.37\u0026ndash;0.87; P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; Supporting Fig.\u0026nbsp;4a). After sIPTW adjustment, the 10-year OS rate for ALND vs. SLNB groups was 81.1% (95% CI, 71.8\u0026ndash;91.6) vs. 89.0% (95% CI, 85.2\u0026ndash;92.9), respectively. The HR of SLNB to ALNB was 0.56 (95% CI, 0.31\u0026ndash;1.04; Supporting Fig.\u0026nbsp;4b). No significant differences in OS were observed between the groups when stratified by cT3 or cT4 (Supporting Fig.\u0026nbsp;4c, d). Regarding sensitivity analysis by OW adjustment, the OS at 10 years was 80.3% vs. 89.4%, respectively, for the ALND vs. SLNB groups. The HR of SLNB to ALNB was 0.53 (95% CI, 0.29\u0026ndash;0.97; Supporting Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis multicenter retrospective study compared RFS, OS, and LRR between patients with cT3-4cN0 BC who underwent SLNB and ALND. Before adjusting for patient characteristics, the ALND group exhibited a higher prevalence of poor prognostic factors than the SLNB group, with worse RFS and OS. After adjustment using sIPTW or OW, no significant differences in RFS, OS, and LRR were observed between the SLNB and ALND groups in the overall patient population or all subgroups, including cT3 and cT4 cases.\u003c/p\u003e \u003cp\u003eNo randomized controlled trials have directly compared SLNB and ALND for cT3-4 BC, using SLNB for cT3-4cN0 BC controversial [13, 18]. In a small prospective cohort study of 41 cases of cT3N0, the false-negative rate of SLNB was 3%, indicating good performance [19]. A single-center observational study of 73 patients with cT3 and T4b BC who underwent SLNB reported that 60.3% were negative for macrometastasis, with no ipsilateral axillary local recurrence observed during a median follow-up of 45 months [6]. This study is a single-center, small-sample research with a short study period; however, local control of cT3 and cT4b BC with SLNB was favorable. Li et al. analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database, focusing on patients with cT3-4c BC who underwent surgery [7]. Of these, 864 patients (432 from the SLNB group and 432 from the ALND group) were selected using propensity score matching, and no significant differences in OS or breast cancer-specific survival (BCSS) were observed between SLNB and ALND groups. OS and BCSS were similar in both groups overall and across subgroup analysis; however, RFS and LRR rates were not assessed. This study had some limitations, including defining whether SLNB or ALND was performed based on the number of removed lymph nodes and not adjusting for factors such as chemotherapy timing (neo-adjuvant or adjuvant), tumor grade, and preoperative tumor size.\u003c/p\u003e \u003cp\u003eThese results align with prior reports, showing no significant difference in RFS or OS between the ALND and SLNB groups. Furthermore, no significant difference was observed in LRR between the two groups, with both groups achieving favorable outcomes, with the 10-year LRR exceeding 90%. However, Kaplan\u0026ndash;Meier curves indicated that even after adjusting for patient backgrounds using the sIPTW method, OS was somewhat worse in the ALND group compared with the SLNB group. Before adjustment, RFS and OS were significantly worse in the ALND group, suggesting that physicians may select ALND for patients with poorer prognoses, even in cN0 cases. We adjusted for potential prognostic factors between the two groups; however, latent factors were not fully accounted for. For instance, the pathological complete response rate was low in both groups in this study, owing to locally advanced BC; however, NAC response was not adjusted. Even in cT3-4cN0 cases, the LRR was low regardless of whether SLNB or ALND was performed, with few recurrence events observed.\u003c/p\u003e \u003cp\u003eIn this study, the cT3-4c cohort comprised patients who underwent either upfront surgery or NAC. Significant differences in patient and tumor characteristics likely existed between these two groups. Notably, the study focuses on patients with cN0, where the selection of SLNB or ALND after NAC appears unrelated to the axillary lymph nodes' treatment response. Nevertheless, differences in baseline patient characteristics between the groups must be considered. Before adjusting for these characteristics, the ALND group included a higher proportion of patients who received NAC. However, after applying the sIPTW, the standardized difference between the groups was reduced to 0.01, indicating successful adjustment. Subgroup analyses aligned with the overall findings, showing no significant differences between SLNB and ALND groups within both the NAC and non-NAC populations. For cN0 BC, axillary staging with SLNB is recommended, even after NAC [14,15]. In 127 cases of cT3cN0 BC treated with NAC, the false-negative rate for SNLB was 9.6%, slightly worse than previously reported results [29]. Furthermore, high false-negative rates have been reported in node-positive cases before NAC [21\u0026ndash;24]. In this study, most cases underwent axillary staging with multiple imaging studies before treatment, which may contribute to the high SLN identification rate of 93.9% and low LRR.\u003c/p\u003e \u003cp\u003eStudies have reported on the omission of ALND in patients with cT3-4 and 1 or 2 SLN metastases, as investigated in the \u0026ldquo;extended\u0026rdquo; ACOSOG Z0011 trial. In a cohort of cT3-4cN0 with 1\u0026ndash;2 SLN metastases using data from the West German Breast Cancer Study, the proportion of patients undergoing ALND decreased between 2008 and 2015, regardless of whether they underwent mastectomy or lumpectomy [25]. However, some reports have indicated that non-SLN metastases were observed in 46.9% of cT3 cases and 58.1% of cT4 cases, suggesting that these cases should be carefully evaluated [25]. In the SENOMAC trial, a randomized controlled trial investigating the omission of ALND for SLN metastases (1 or 2 nodes) in cT1-3cN0 BC, non-inferiority of omitting ALND was demonstrated. However, this trial included only 73 cT3 cases in the SLNB group (5.5%) and 74 cT3 cases in the ALND group (6.1%) [26]. Therefore, the validity of performing SLNB and omitting ALND for positive metastases in cT3 cases has not been fully clarified.\u003c/p\u003e \u003cp\u003eThis study has some limitations. First, sIPTW and OW were employed to adjust for baseline and clinical patient characteristics; however, accounting for unobserved variables using these techniques alone was impossible. Second, this study included patients between 2006 and 2016 to ensure a sufficient observation period; however, some of these cases may not align with current standard perioperative drug therapies, such as abemaciclib, trastuzumab, pertuzumab, and pembrolizumab. Third, this was a multicenter retrospective study; however, the sample size was too small for analysis based on BC subtypes. After adjustment using sIPTW, the study included more samples than several previous reports on cT1-2N0 SLNB, but it did not reach the sample size of the NSABP B-32 trial, which may result in reduced power [3\u0026ndash;5]. Despite these limitations, this study covered a long observation period, extracted cases from the databases of each facility, and added the necessary information, allowing us to collect detailed patient background characteristics. Furthermore, this study examined an important endpoint, local and regional lymph node recurrence, and revealed no significant difference between the ALND and SLNB groups.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, these findings suggest that compared with ALND, SLNB is a safe option for axillary staging in cT3-4cN0 without negatively impacting RFS, OS, and LRR. This finding supports the potential expansion of SLNB to higher stages of BC, pending further prospective studies to confirm these results and assess long-term outcomes.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study design and concept were developed by SK, YS, and SM. Statistical analysis was performed by HY. SK, YS, SM, TS, YK, MH, SA, ET, TS, HB, KA, NI, SM, MY, MH, MO, TS, MI, TN, TH, MT, KT, GK, MT, NH-S, KK, KT, KY, MK, CY, YT made substantial contributions to data acquisition. All authors contributed to the interpretation of the results. The first draft was written by SK, and all authors participated in revising it critically for important intellectual content. All authors approved the version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement:\u0026nbsp;\u003c/strong\u003eThe datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding statement:\u003c/strong\u003e This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003e The authors thank the Editage Group (https://www.editage.com/) for editing the draft of this manuscript\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest disclosure:\u003c/strong\u003e The authors have no conflict of interest disclosures to disclose.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval statement:\u0026nbsp;\u003c/strong\u003eThis study was approved by the Ethics Committee of the Nagasaki University Hospital Clinical Research, Nagasaki, Japan (approval number, 22071102) on July 12, 2022. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study formal consent is not required.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatient consent statement:\u0026nbsp;\u003c/strong\u003eThe study utilized an opt-out method for informed consent, where participants were informed about the study via a publicly available overview on the web and given the opportunity to decline participation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePermission to reproduce material from other sources:\u0026nbsp;\u003c/strong\u003eNot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. \u003cem\u003eCA Cancer J Clin.\u003c/em\u003e 2018;68(6):394\u0026ndash;424.\u003c/li\u003e\n\u003cli\u003eGlobal Burden of Disease Cancer Collaboration; Fitzmaurice C, Abate D, Abbasi N, Abbastabar H, Abd-Allah F, Abdel-Rahman O, et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2017: a systematic analysis for the global burden of disease study. \u003cem\u003eJAMA Oncol\u003c/em\u003e. 2019;5(12):1749\u0026ndash;1768.\u003c/li\u003e\n\u003cli\u003eVervers JM, Roumen RM, Vingerhoets AJ, Vreugdenhil G, Coebergh JW, Crommelin MA, et al. Risk, severity and predictors of physical and psychological morbidity after axillary lymph node dissection for breast cancer. \u003cem\u003eEur J Cancer\u003c/em\u003e. 2001;37(8):991\u0026ndash;999.\u003c/li\u003e\n\u003cli\u003eVeronesi U, Paganelli G, Viale G, Luini A, Zurrida S, Galimberti V, et al. Sentinel-lymph-node biopsy as a staging procedure in breast cancer: update of a randomised controlled study. \u003cem\u003eLancet Oncol\u003c/em\u003e. 2006;7(12):983\u0026ndash;990.\u003c/li\u003e\n\u003cli\u003eKrag DN, Anderson SJ, Julian TB, Brown AM, Harlow SP, Costantino JP, et al. Sentinel-lymph-node resection compared with conventional axillary-lymph-node dissection in clinically node-negative patients with breast cancer: overall survival findings from the NSABP B-32 randomised phase 3 trial. \u003cem\u003eLancet Oncol\u003c/em\u003e. 2010;11(10):927\u0026ndash;933.\u003c/li\u003e\n\u003cli\u003eCanavese G, Catturich A, Vecchio C, Tomei D, Gipponi M, Villa G, et al. Sentinel node biopsy compared with complete axillary dissection for staging early breast cancer with clinically negative lymph nodes: results of randomized trial. \u003cem\u003eAnn Oncol\u003c/em\u003e. 2009;20(6):1001\u0026ndash;1007.\u003c/li\u003e\n\u003cli\u003eLand SR, Kopec JA, Julian TB, Brown AM, Anderson SJ, Krag DN, et al. Patient-reported outcomes in sentinel node-negative adjuvant breast cancer patients receiving sentinel-node biopsy or axillary dissection: National Surgical Adjuvant Breast and Bowel Project phase III protocol B-32. \u003cem\u003eJ Clin Oncol\u003c/em\u003e. 2010;28(5):3929\u0026ndash;3936.\u003c/li\u003e\n\u003cli\u003ePurushotham AD, Upponi S, Klevesath MB, Bobrow L, Millar K, Myles JP, et al: Morbidity after sentinel lymph node biopsy in primary breast cancer: results from a randomized controlled trial. \u003cem\u003eJ Clin Oncol\u003c/em\u003e. 2005;23(19):4312\u0026ndash;4321.\u003c/li\u003e\n\u003cli\u003eMansel RE, Fallowfield L, Kissin M, Goyal A, Newcombe RG, Dixon JM, et al. Randomized multicenter trial of sentinel node biopsy versus standard axillary treatment in operable breast cancer: the ALMANAC Trial. \u003cem\u003eJ Natl Cancer Inst\u003c/em\u003e. 2006;98(9):599\u0026ndash;609.\u003c/li\u003e\n\u003cli\u003eChe Bakri NA, Kwasnicki RM, Khan N, Ghandour O, Lee A, Grant Y, et al. Impact of axillary lymph node dissection and sentinel lymph node biopsy on upper limb morbidity in breast cancer patients: a systematic review and meta-analysis. \u003cem\u003eAnn Surg\u003c/em\u003e. 2023;277(4):572\u0026ndash;580.\u003c/li\u003e\n\u003cli\u003ede Oliveira-Junior I, Nahas EAP, Cherem AC, Nahas-Neto J, Vieira RADC. Sentinel lymph node biopsy in T3 and T4b breast cancer patients: analysis in a tertiary Cancer Hospital and systematic literature review. \u003cem\u003eBreast Care (Basel)\u003c/em\u003e. 2021;16(1):27\u0026ndash;35.\u003c/li\u003e\n\u003cli\u003eLi P, Yang C, Zhang J, Chen Y, Zhang X, Liang M, et al. Survival after sentinel lymph node biopsy compared with axillary lymph node dissection for female patients with T3-4c breast cancer. \u003cem\u003eOncologist\u003c/em\u003e. 2023;28(8):e591\u0026ndash;e599, 2023.\u003c/li\u003e\n\u003cli\u003eLyman GH, Somerfield MR, Bosserman LD, Perkins CL, Weaver DL, Giuliano AE. Sentinel lymph node biopsy for patients with early-stage breast cancer: American Society of Clinical Oncology clinical practice guideline update. \u003cem\u003eJ Clin Oncol.\u003c/em\u003e 2017;35(5):561\u0026ndash;564.\u003c/li\u003e\n\u003cli\u003eSakai T, Kutomi G, Shien T, Asaga S, Aruga T, Ishitobi M, et al. The Japanese Breast Cancer Society Clinical Practice Guidelines for surgical treatment of breast cancer, 2022 edition. \u003cem\u003eBreast Cancer\u003c/em\u003e. 2024;31(1):1\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eLoibl S, Andr\u0026eacute; F, Bachelot T, Barrios CH, Bergh J, Burstein HJ, et al. Early breast cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. \u003cem\u003eAnn Oncol\u003c/em\u003e. 2024;35(2):159\u0026ndash;182.\u003c/li\u003e\n\u003cli\u003eRamsey SD, Onar-Thomas A, Wheeler SB. Real-world database studies in oncology: a call for standards. \u003cem\u003eJ Clin Oncol\u003c/em\u003e. 2024;42(9):977\u0026ndash;980.\u003c/li\u003e\n\u003cli\u003eTolaney SM, Garrett-Mayer E, White J, Blinder VS, Foster JC, Amiri-Kordestani L, Hwang ES, et al. Updated Standardized Definitions for Efficacy End Points (STEEP) in Adjuvant Breast Cancer Clinical Trials: STEEP Version 2.0. \u003cem\u003eJ Clin Oncol\u003c/em\u003e. 2021;39(24):2720\u0026ndash;2731.\u003c/li\u003e\n\u003cli\u003eKaufmann M, Morrow M, von Minckwitz G, Harris JR. Locoregional treatment of primary breast cancer: consensus recommendations from an International Expert Panel. \u003cem\u003eCancer\u003c/em\u003e. 2010;116(5):1184\u0026ndash;1191.\u003c/li\u003e\n\u003cli\u003eChung MH, Ye W, Giuliano AE. Role for sentinel lymph node dissection in the management of large (\u0026gt;\u0026thinsp;or =\u0026thinsp;5 cm) invasive breast cancer. \u003cem\u003eAnn Surg Oncol\u003c/em\u003e. 2001;8(9):688\u0026ndash;692.\u003c/li\u003e\n\u003cli\u003eYu JC, Hsu GC, Hsieh CB, Yu CP, Chao TY. Role of sentinel lymphadenectomy combined with intraoperative ultrasound in the assessment of locally advanced breast cancer after neoadjuvant chemotherapy. \u003cem\u003eAnn Surg Oncol\u003c/em\u003e. 2007;14(1):174\u0026ndash;180.\u003c/li\u003e\n\u003cli\u003eMamounas EP, Brown A, Anderson S, Smith R, Julian T, Miller B, et al. Sentinel node biopsy after neoadjuvant chemotherapy in breast cancer: results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. \u003cem\u003eJ Clin Oncol\u003c/em\u003e. 2005;23(12):2694\u0026ndash;2702.\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. \u003cem\u003eJ Clin Oncol\u003c/em\u003e. 2015;33(3):258\u0026ndash;264.\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. \u003cem\u003eLancet Oncol.\u003c/em\u003e 2013;14(7):609\u0026ndash;618.\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. \u003cem\u003eJAMA\u003c/em\u003e. 2013;310(14):1455\u0026ndash;1461.\u003c/li\u003e\n\u003cli\u003eRiedel F, Heil J, Feisst M, Moderow M, von Au A, Domschke C, et al. Analyzing non-sentinel axillary metastases in patients with T3-T4 cN0 early breast cancer and tumor-involved sentinel lymph nodes undergoing breast-conserving therapy or mastectomy. \u003cem\u003eBreast Cancer Res Treat\u003c/em\u003e. 2020;184(2):627\u0026ndash;636.\u003c/li\u003e\n\u003cli\u003ede Boniface J, Filtenborg Tvedskov T, Ryd\u0026eacute;n L, Szulkin R, Reimer T, K\u0026uuml;hn T, et al. Omitting axillary dissection in breast cancer with sentinel-node metastases. \u003cem\u003eN Engl J Med\u003c/em\u003e. 2024;390(13):1163\u0026ndash;1175.\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":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"breast-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"brca","sideBox":"Learn more about [Breast Cancer](http://link.springer.com/journal/12282)","snPcode":"12282","submissionUrl":"https://www.editorialmanager.com/brca/default2.aspx","title":"Breast Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Breast cancer, Sentinel lymph node biopsy, Axillary lymph node dissection, Recurrence-free survival, Loco-regional recurrence rate","lastPublishedDoi":"10.21203/rs.3.rs-6315783/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6315783/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eSentinel lymph node biopsy (SLNB) has become a standard procedure for patients with breast cancer (BC) without clinically evident axillary metastasis. However, its role in cT3-4cN0 BC remains underexplored, leading to uncertainty regarding its safety.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis retrospective, multicenter observational study included patients with cT3-4cN0M0 BC who underwent radical surgery between 2006 and 2016. Patients were divided into an SLNB group, which included those who underwent SLNB exclusively and ALND after SLNB, and an ALND group, which included those who underwent ALND exclusively. Inverse probability treatment weighting was applied to balance the patient characteristics, with recurrence-free survival (RFS) as the primary endpoint.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe study included 930 patients: 716 in the SLNB group and 214 in the ALND group. The ALND group had a higher proportion of patients diagnosed earlier, more T4 tumors, and more frequent use of neoadjuvant chemotherapy. During a median follow-up period of 89 months, 176 RFS events and 51 loco-regional recurrence events occurred. After adjusting for confounding factors, no significant difference was found in 10-year RFS between the groups (74.2% versus 79.2%). Adjusted hazard ratios for RFS did not differ between the groups, even when stratified by tumor stage (cT3, cT4) or neoadjuvant chemotherapy. No significant differences were observed between the SLNB and ALND groups in loco-regional recurrence rate (LRR), with 10-year LRR rates of 93.1% and 90.8%, respectively.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eSLNB was a safe axillary staging method for patients with cT3-4cN0M0 BC and does not impact RFS or LRR negatively when compared with ALND.\u003c/p\u003e","manuscriptTitle":"A Retrospective Multi-Center Cohort Study Investigating Safety of Sentinel Lymph Node Biopsy for Axillary Staging in Clinical T3-4c Breast Cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-06 10:17:01","doi":"10.21203/rs.3.rs-6315783/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major Revision","date":"2025-04-25T23:14:56+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-03-30T22:57:29+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-03-30T14:14:41+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-03-27T06:46:13+00:00","index":"","fulltext":""},{"type":"submitted","content":"Breast Cancer","date":"2025-03-27T02:32:40+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"breast-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"brca","sideBox":"Learn more about [Breast Cancer](http://link.springer.com/journal/12282)","snPcode":"12282","submissionUrl":"https://www.editorialmanager.com/brca/default2.aspx","title":"Breast Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"8e176471-9996-4bb0-85ce-1ec948e40b54","owner":[],"postedDate":"May 6th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-08-04T16:48:26+00:00","versionOfRecord":{"articleIdentity":"rs-6315783","link":"https://doi.org/10.1007/s12282-025-01749-9","journal":{"identity":"breast-cancer","isVorOnly":false,"title":"Breast Cancer"},"publishedOn":"2025-08-01 16:13:03","publishedOnDateReadable":"August 1st, 2025"},"versionCreatedAt":"2025-05-06 10:17:01","video":"","vorDoi":"10.1007/s12282-025-01749-9","vorDoiUrl":"https://doi.org/10.1007/s12282-025-01749-9","workflowStages":[]},"version":"v1","identity":"rs-6315783","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6315783","identity":"rs-6315783","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}