{"paper_id":"43a96355-9596-4fbf-a5e6-912eccc5f87a","body_text":"Re-evaluating the Role of Regional Nodal Irradiation for Node‐Negative Breast Cancer in the Modern Therapy Era: A Matched Cohort Analysis of EORTC 22922/10925 | 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 Re-evaluating the Role of Regional Nodal Irradiation for Node‐Negative Breast Cancer in the Modern Therapy Era: A Matched Cohort Analysis of EORTC 22922/10925 Yajuan Chu, Xiaofang Wang, Xiaomeng Zhang, Li Zhang, Jin Meng, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7351544/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: While early breast cancer patients with node-negative disease generally exhibit a favorable prognosis and do not routinely require regional nodal irradiation (RNI), the EORTC 22922/10925 trial demonstrated that comprehensive nodal irradiation could potentially improve survival in selected N0 patients. To further investigate this paradigm, we applied the EORTC 22922/10925 trial criteria to a contemporary cohort of node-negative patients and evaluated their long-term outcomes. Methods: We retrospectively analyzed 2567 consecutive female patients with pT1–3N0 breast cancer who underwent curative surgery between January 2005 and December 2014. Among these, 1302 patients met the eligibility criteria of the EORTC 22922/10925 trial. Clinicopathologic characteristics, treatment details, and follow-up data were systematically collected. Primary endpoints included disease-free survival (DFS), local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), locoregional recurrence–free survival (LRRFS), distant metastasis–free survival (DMFS), breast cancer recurrence–free survival (BCRFS), overall survival (OS), and breast cancer–specific survival (BCSS). Results: The EORTC-matched cohort demonstrated high 8.3-year survival: LRRFS 96.4%, DMFS 93.6%, DFS 90.0%, and OS 95.2%. In the overall cohort, non-RNI patients achieved 97.1% 8.3-year and 96.7% 10-year LRRFS. Multivariate analysis confirmed age ≤ 40 years and tumor size > 2.5 cm as independent LRRFS risk factors (both P < 0.05). Although high-risk patients (1–2 factors) had significantly lower LRRFS than low-risk patients (0 factors), their absolute outcomes remained favorable (95.0% at 8.3 years and 94.4% at 10 years). Conclusion: Patients with pT1–3N0 breast cancer receiving modern systemic therapy have excellent survival and low locoregional recurrence rates, both in the EORTC 22922/10925-matched cohort and overall. Despite higher risks associated with young age and larger tumors, absolute recurrence rates remain low, suggesting that routine RNI can be safely omitted in these patients. breast cancer radiotherapy node negative EORTC 22922/10925 survival Figures Figure 1 Figure 2 Introduction Historically, early-stage breast cancer patients with pathological node-negative (pN0) at diagnosis have exhibited a low rate of long-term locoregional recurrence (LRR)—less than 5% at 10 years [ 1 ] . Consequently, postmastectomy radiation therapy (PMRT) or regional nodal irradiation (RNI) after breast-conserving surgery (BCS) is not routinely recommended for N0 patients [ 2 ] . In recent years, however, studies such as EORTC 22922/10925 [ 3 ] and MA20 [ 4 ] , in which a subset of participants had pN0 disease, have indicated that RNI may improve survival outcomes. Nevertheless, the concept of comprehensive radiation therapy (RT) for N0 patients has not been widely adopted in clinical practice. One possible reason is that the inclusion of participants from mixed disease stages may not accurately represent a puro N0 group. Moreover, the widespread use of modern systemic treatment—including chemotherapy, endocrine therapy, and targeted therapy—have further improve survival, potentially diminishing the incremental value of RT. In addition, the SUPREMO trial reported favorable survival outcomes with omission of RNI in intermediate-risk patients, indicating that radiotherapy could be omitted [ 5 ] . Therefore, in this study, we matched our study populations according to the eligibility criteria of the EORTC 22922/10925 trial and report the survival outcome of this cohort. Furthermore, we refined the risk factors among patients with N0 disease and provided treatment options. Material and methods Patients and study design This retrospective cohort study included female patients diagnosed with pathologic stage T1–3N0 breast cancer who underwent either BCS or mastectomy at Fudan University Shanghai Cancer Center between January 2005 and December 2014. A total of 3,380 patients were initially identified from the institutional database. Patients meeting any of the following criteria were excluded: previous history of malignant tumors (n = 102), serious nonmalignant diseases (n = 66), age > 75 years (n = 56), receipt of neoadjuvant systemic therapy (n = 238), BCS without whole-breast radiotherapy (WBRT) (n = 61), or a follow-up period of less than 6 months (n = 290). After applying these criteria, the remaining 2567 patients included in the final analysis. Among these, 1302 patients met the inclusion criteria of the EORTC 22922/10925 trial, which required (1) age of ≤ 75 years, (2) unilateral breast cancer, (3) histologically confirmed adenocarcinoma, and (4) node-negative disease with tumors located in the medial or central region of the breast. Ethical approval for this study was obtained from the Ethics Committee and Institutional Review Board of our institution. Date collection Clinicopathologic characteristics, treatment details, and follow-up data were extracted from the institutional electronic medical records. Clinicopathologic factors included age at diagnosis, type of surgical procedure, laterality, tumor location, tumor size, histological subtype and grade, status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal receptor 2 (HER2) status, Ki-67 index, and lymphovascular invasion (LVI). Treatment variables including adjuvant chemotherapy regimens, endocrine therapy, anti-HER2 targeted therapy, and RT details were reviewed. Biomarker assessment ER and PR status were assessed using immunohistochemistry (IHC), with a threshold of at least 1% positive nuclear staining in tumor cells used to define receptor positivity [ 6 ] . Hormone receptor (HR) status was classified as HR-positive if ER and/or PR were positive, and as HR-negative if both receptors were negative. HER2 status was determined using IHC and/or fluorescence in situ hybridization (FISH). Tumors were considered HER2-positive if IHC score was 3 + or if IHC was 2 + with confirmed gene amplification by FISH (HER2/CEP17 ratio ≥ 2.0), and HER2-negative if the IHC score was 0–1 + or if the score was 2 + without amplification by FISH [ 7 ] . Treatment All patients underwent either BCS or mastectomy with pathologically confirmed negative surgical margins. Sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND) was performed based on clinical and intraoperative indications. Adjuvant chemotherapy was administered in accordance with prevailing international guidelines at the time of diagnosis, taking tumor biology and pathological staging into account. Patients undergoing BCS received WBRT, typically consisting of 50 Gy in 25 fractions followed by a tumor bed boost of 10 Gy in 5 fractions. PMRT was selectively administered at the discretion of the treating radiation oncologist, particularly in patients with pT3 tumors, and was delivered to the chest wall at a dose of 50 Gy in 25 fractions. RNI, including irradiation of the supraclavicular (SCV), infraclavicular (ICV), and internal mammary (IMN) nodes, was not routinely incorporated into either WBRT or PMRT plans. Radiotherapy employed either three-dimensional conformal radiotherapy (3DCRT) or simplified intensity-modulated radiotherapy (sIMRT), depending on anatomical and dosimetric considerations. Endocrine therapy was administered to HR-positive patients and anti-HER2 therapy was administered to HER2-positive patients according to contemporary treatment guidelines. Outcome definitions and endpoints LRR was defined as clinically, radiologically, or pathologically confirmed tumor recurrence within the ipsilateral breast/chest wall (CW) or regional lymph nodes (axillary, infraclavicular, supraclavicular, or internal mammary). Distant metastasis (DM) was defined as recurrence beyond locoregional sites. The primary endpoint of this study was LRR-free survival (LRRFS), defined as the time from surgery to the first documented LRR. Secondary endpoints included disease-free survival (DFS), local recurrence (LR)-free survival (LRFS), regional recurrence (RR)-free survival (RRFS), DM-free survival (DMFS), breast cancer recurrence-free survival (BCRFS), overall survival (OS) and breast cancer-specific survival (BCSS). DFS was defined as the time from surgery to LRR, DM, second breast cancer, or death from any cause; LRFS as the time from surgery to the first LR; RRFS as the time from surgery to the first RR; DMFS as the time from surgery to DM or death from any cause; BCRFS as the time from surgery to the occurrence of LRR, DM, secondary ipsilateral breast cancer, or breast cancer-related death; OS as the time from surgery to death from any cause; and BCSS as the time from surgery to death attributable to breast cancer. Statistical analysis Categorical variables were compared using Pearson’s chi-square (χ²) test. Survival outcomes, including DFS, LRRFS, LRFS, RRFS, DMFS, BCRFS, OS and BCSS, were estimated using the Kaplan–Meier method and compared between groups using the two-sided log-rank test. Univariate and multivariate analyses were performed using Cox proportional hazards regression models to identify independent prognostic factors. Based on the identified high-risk prognostic factors, the entire cohort were classified into risk groups. All statistical analyses were performed using SPSS version 26.0, and a two-sided p-value < 0.05 was considered statistically significant. Results The cohort meeting the inclusion criteria of the EORTC 22922/10925 trial (n = 1302) Patient and treatment characteristics In this cohort, the median age was 51 years (range, 20–75 years). Mastectomy was performed in 91.6% (n = 1192) of patients, compared with 8.4% (n = 110) who received breast-conserving surgery (BCS). SLNB was performed for 34.1% of patients, with ALND for the remainder. The median size of invasive tumor was 2.0 cm (range, 0.1–6.5 cm), with 98.2% (n = 1278) classified as T1-2 tumors. Histological grades were primarily grade 2 (51.8%) or 3 (29.0%), together accounting for 80.8% of cases. HR-positive tumor expression was found in 73.5% of patients (n = 957), and HER2-positive expression in 24.9% (n = 324). Systemic chemotherapy was administered to 72.4% of patients (n = 943). Nearly all recipients (n = 930) completed 4–8 cycles of postoperative chemotherapy, predominantly using anthracycline- and/or taxanes-based regimens. All patients undergoing BCS received WBRT; only 20 patients who underwent mastectomy received CW irradiation. Among HER2-positive patients, 135 (41.7%) received adjuvant anti-HER2 therapy. 97.8% (n = 936) of HR-positive cases received endocrine therapy (Table 1). Survival outcomes During a median follow-up of 8.3 years (range, 0.5–16.9 years), 106 patients experienced any recurrence: 23 with isolated LRR, 61 with isolated DM, and 22 with concurrent LRR and DM. Among patients with LRR, recurrences were local only in 25 patients (1.9%), regional only in 16 patients (1.2%), and both local and regional in 4 patients (0.3%) (Table 2). By the last follow-up, 84 patients had died, including 63 from breast cancer. At 8.3 and 10 years, the survival estimates (%) were: LRFS: 97.6/97.0, RRFS: 98.5/98.3, LRRFS: 96.4/95.7, DMFS: 93.6/92.5, DFS: 90.0/87.5, BCRFS: 91.6/90.3, OS: 95.2 /92.7, and BCSS: 95.9/94.2 (Fig. 1A-H). The entire cohort (n = 2567) Patient and treatment characteristics The distribution of clinicopathological features did not differ significantly between this group and the subset meeting the EORTC 22922/10925 inclusion criteria (Table 1). Overall, 49.3% of patients (n = 1265) had outer quadrant tumors, compared to 50.7% (n = 1302) with central or medial quadrant tumors. 85.2% of patients underwent mastectomy, and 14.8% received BCS. Of the mastectomy cohort, 2.0% (n = 44) received CW irradiation, while none received RNI. 74.6% of patients received chemotherapy. Of the 540 HER2-positive patients, 38.3% (n = 207) received adjuvant anti-HER2 therapy (primarily trastuzumab-based). Separately, 97.3% (n = 1838) of HR-positive patients received endocrine therapy. Survival outcomes After a median follow-up of 8.3 years (range, 0.5–16.9 years), recurrences occurred in 189 patients, including 41 with isolated LRR, 111 with isolated DM, and 37 with concurrent LRR and DM (Table 2). The most common recurrence site was the CW or breast alone (n = 39; 1.5%), followed by regional lymph nodes alone (n = 31; 1.2%), and combined LRR (n = 8, 0.3%). Among RRs, the SCV/ICV nodes were most frequently involved, then the ALN and IMN (Table 2). During follow-up, a total of 173 deaths occurred, 124 (71.7%) of which were breast cancer-related. The estimated 8.3- and 10-year rates of LRFS, RRFS, LRRFS, and DMFS were 98.2%/97.9%, 98.6%/98.5%, 97.1%/96.7%, and 94.1%/93.1%, respectively. The 8.3- and 10-year rates of DFS, BCRFS, OS, and BCSS were 91.1%/89.0%, 92.7%/91.4%, 94.7%/92.7%, and 95.4%/94.2%, respectively (Fig. 1A-H). Risk factors The associations between clinicopathological variables and survivals are summarized in Table 3. In univariate analysis, age ≤ 40 years (p = 0.015) and tumor size > 2.5cm (p = 0.020) were correlated with poorer LRRFS. Moreover, age ≤ 40 years, tumor size > 2.5cm and HR-negative status were associated with worse DFS and BCRFS. Multivariate analysis confirmed that age ≤ 40 years (HR, 1.845; 95% CI, 1.107–3.075; p = 0.019) and tumor size > 2.5cm (HR, 1.808; 95% CI, 1.109–2.947; p = 0.017) were independent predictors of poorer LRRFS. Furthermore, age ≤ 40 years, tumor size > 2.5 cm, and HR-negative status remained independently associated with a shorter DFS and BCRFS. Other clinicopathological variables, including laterality, location, histological grade, HER2 status, Ki67 index, and LVI, showed no significant association with LRRFS, DFS, or BCRFS (Table 3). Outcomes of Risk Groups The cohort was stratified into low-risk (no factors; n = 1726, 67.2%) and high-risk (≥ 1 factor; n = 841, 32.8%) groups based on LRRFS-associated risk factors. Kaplan–Meier analysis showed significantly higher 8.3-year (98.1% vs. 95.0%) and 10-year (97.8% vs. 94.4%) LRRFS rates in low-risk versus high-risk patients (p < 0.001) (Fig. 2). Discussion Patients with pN0 breast cancer are typically classified as having early-staged disease, and experience favorable prognoses with standard therapies. For pN0 disease, current guidelines restrict RT primarily to WBRT following BCS and chest wall irradiation after mastectomy in cases with tumors > 5cm; RNI is not routinely administrated. However, recent large-scale studies have challenged this paradigm. The MA.20 trial [ 4 ] demonstrated improved 10-year DFS with RNI versus WBRT alone (82.0% vs. 77.0%, p = 0.01). Yet these findings have limited applicability to a truly pN0 populations, as only 9.7% of the cohort had pN0 disease. Similarly, the EORTC 22922/10925 trial [ 3 ] (15.7-year follow-up) showed comprehensive RNI reduced any breast recurrence (24.5% vs. 27.1%, p = 0.024), and breast cancer mortality (16.0% vs. 19.8%, p = 0.0055), though without significant improvements in DFS, DMFS or OS. Key limitations for extrapolating these findings to pN0 disease include cohort heterogeneity (only 44.4% node-negative), unvalidated medial/central tumor location criteria, and limited contemporary systemic therapies (e.g., only 29.6% received endocrine therapy; no targeted agents). In the present study, we applied the EORTC 22922/10925 trial eligibility criteria to a pure pN0 cohort to analyze the survival outcomes. Within the matched cohort, the estimated 10-year rates were 95.7% for LRRFS, 92.5% for DMFS, 90.3% for BCRFS, 87.5% for DFS, 94.2% for BCSS and 92.7% for OS. These outcomes were comparable with those reported in the 10-year result of the EORTC 22922/10925 trial [ 8 ] , which showed the following rates for RNI vs. no RNI groups: DFS 72.1% vs. 69.1%, DMFS 78.0% vs. 75.0%, OS 82.3% vs. 80.7%, and BCM 12.5% vs. 14.4%. Among patients with outer quadrant breast tumors, the 8.3-year LRRFS (p = 0.147), DFS (p = 0.095), DMFS (p = 0.150), BCRFS (p = 0.089), BCSS (p = 0.800) and OS (p = 0.925) did not differ significantly from those observed in the EORTC 22922/10925-matched cohort. For the N0 cohort meeting the EORTC 22922/10925 criteria, the LRR rate remained below 4% at 8.3 years and 5% at 10 years without RNI, confirming a low risk of LRR. Additionally, primary tumor quadrant was not identified as a significant prognostic factor for survival outcomes. We analyzed survival outcomes in our entire cohort of 2567 patients. The 8.3-year and 10-year LRFS, RRFS, LRRFS, DMFS, DFS, BCRFS, OS, and BCSS were 98.2%/97.9%, 98.6%/98.5%, 97.1%/96.7%, 94.1%/93.1%, 91.1%/89.0%, 92.7%/91.4%, 94.7%/92.7%, and 95.4%/94.2%, respectively. These results demonstrate excellent long-term survival, with 10-year rates exceeding 89% across all endpoints, and are comparable to those reported in historical studies of similarly early-stage breast cancer patients. For instance, Leonardi et al. [ 9 ] reported 10-year LRR rate of 8.8% (equivalent to 91.2% LRRFS) in a cohort of 1281 pT1-2N0 patients, while Abi-Raad et al. [ 10 ] documented a 10-year LRR rate of 5.2% (equivalent to 94.8% LRRFS) in 1188 node-negative patients. Other studies in pT1-2N0 cohorts reported 10-year LRR rates ranging from 3.0–3.7% (equivalent to 96.3% -97.0% LRRFS), with corresponding 5-year RR and all-cause mortality rates of 1.3% and 4.4%, respectively [ 11 ] [ 12 , 13 ] . Given the favorable locoregional control in pN0 breast cancer, a major clinical challenge is identifying high-risk patients who might benefit from RT. Studies have stratified patients into prognostic groups based on risk factors. For example, Luo et al. [ 14 ] identified tumor size, ER status, histologic grade and LVI as significant predictors of LRR. In the high-risk patients (those with 3–4 risk factors), PMRT significantly reduced the 5-year rates of LRR (1.2% vs. 9.5%, p = 0.021), DM (2.6% vs. 10.4%, p = 0.006), and BCM (1.5% vs. 7.9%, p = 0.002). Conversely, PMRT provided no significant benefit in the low-risk group (patients with 0–2 risk factors). Similarly, Leonardi MC et al [ 9 ] found that young age (< 35 years), LVI, and elevated Ki-67 (≥ 20%) predicted worse LRR in 1281 pT1-2N0 patients treated with mastectomy without PMRT. Among those with ≥ 2 risk factors, the 10-year LRR rate exceeded 15%, suggesting PMRT might be considered for this subgroup. Abi-Raad et al. [ 10 ] found tumor size, margin status, age, systemic therapy, and LVI to be independent predictors of LRR in 1136 pN0 patients. Those with ≥ 3 risk factors had a ~ 20% LRR rate, supporting consideration of PMRT for this group. Peng et al.'s [ 15 ] meta-analysis identified young age, positive LVI, high histologic grade, HER2 positivity, premenopausal status, and positive surgical margins as risk factors of LRR in pT1-2N0 patients after mastectomy. Given these findings, prospective trials are warranted to define the role of PMRT in this high-risk population. Finally, Jwa E et al. [ 13 ] analyzed 307 pT1-2N0 patients who did not receive PMRT and identified age < 50 years and the absence of adjuvant chemotherapy as independent risk factors for LRR. Based on these factors, the study reported 5-year LRRFS rates of 100% (no risk factors), 96.4% (one risk factor), and 86.7% (two risk factors), suggesting PMRT may benefit patients under 50 years or not receiving adjuvant chemotherapy. In our study, age ≤ 40 years and tumor size > 2.5 cm were identified as independent prognostic factors for LRRFS. Patients in the high-risk group (1–2 factors) had significantly worse LRRFS than the low‐risk group (0 factors) (p = 0.001) Notably, even high‐risk patients exhibited 8.3‐year and 10‐year LRR rates of only 5.0% and 5.6%, respectively, dramatically lower than the historically reported 15–20% LRR rates. These favorable outcomes may be attributed to advancements in surgical techniques with meticulous margin control and consistent application of standardized systemic treatments per contemporary guidelines. Notably, even among high-risk patients, the 5‐year and 10‐year LRR rates were remarkably low. Given the marginal absolute benefit against potential treatment-related toxicities, RT could likely be omitted safely in pT1-2N0 patients receiving contemporary systemic therapy. In the randomized SUPREMO trial, RNI was uniformly omitted across all enrolled patients (pT1-2N1 or pT2-3N0), with pN0 cases representing 25.1% (n = 402) of the cohort. At the 2024 SABCS meeting, 10-year follow-up results from the trial revealed comparable outcomes between non-CW-irradiated and CW-irradiated groups: LR 2.5% vs. 1.1% (p = 0.04); RR 4.5% vs. 2.7% (p = 0.06); DM 20.8% vs. 21.8% (p = 0.60, DFS 24.5% vs. 23.8% (p = 0.70)), and mortality18.1% vs. 18.6% (p = 0.79). Critically, no survival differences emerged in pN0 subgroup analyses. Although a clinically insignificant reduction in 10-year LR rate (an absolute difference of only 1.4%) was observed, the overall low recurrence rates (LR + RR < 7%) led the SUPREMO investigators to conclude that omitting irradiation is justifiable, particular for pN0 patients [ 5 ] . Molecular subtype, defined clinically by IHC assessment of HR status (ER/PR), HER2 status, and Ki67 index, guides prognosis and therapeutic decisions in breast cancer. Consistent with prior studies [ 9 , 10 , 17 – 20 ] , neither HR nor HER2 status predicted LRRFS in our cohort, whether assessed individually or as biological subtypes. The EBCTCG meta-analysis demonstrated that endocrine therapy substantially reduces recurrence risk in ER-positive early-stage breast cancer, independent of nodal status [ 21 ] . In our cohort, 97.3% of HR-positive patients underwent endocrine therapy. Moreover, HR-positive status independently predicted improved DFS and BCRFS, validating prior reports [ 9 ] . Due to historical anti-HER2 drug unavailability and economic barriers, only 38.3% of HER2‐positive patients (207/540) received targeted therapy. Although prior studies confirm survival benefits from Trastuzumab +/- Pertuzumab in pN0 disease [ 22 – 25 ] . Our HER2-positive cohort showed no significant improvement with anti-HER2 therapy, likely due to limited statistical power from the subgroup size. Routine use of anti‐HER2 agents may further improve survival outcomes in pN0 patients beyond those observed in this study. This study, among the largest survival analyses in pT1-3N0 breast cancer, refined the risk factors for N0 disease, reported stratified survival outcomes with treatment suggestions. However, a key limitation is that no patients received nodal irradiation, preventing assessment of its potential survival benefit in high-risk subgroups. Conclusion This study demonstrates favorable survival outcomes for pT1-3N0 breast cancer patients treated with surgery and contemporary systemic therapy. While the EORTC 22922/10925 criteria failed to effectively identify high-risk patients within this pN0 cohort, our analysis identified ≤ 40 years and tumor size > 2.5cm as independent prognostic factors of LRRFS. Patients classified as high-risk group (1–2 factors) had significantly worse LRRFS than low-risk patients (0 factors). Notably, even high-risk patients achieved excellent long-term LRRFS. These findings suggest that the omitting radiotherapy may be considered for such patients receiving standard systemic treatment. Declarations Conflict of interest The authors declare no conflicts of interest. Ethical Approval The ethical consent of this study was not required. Funding This work was no Funding to support. Author Contribution Conception and design: Jinli Ma, Collection and assembly of data: Yajuan Chu, Xiaofang Wang, Data analysis and interpretation: Yajuan Chu, and Jinli Ma, Manuscript writing: All authors, Final approval of manuscript: All authors References Early Breast Cancer Trialists' Collaborative Group. Electronic address bocoau. Reductions in recurrence in women with early breast cancer entering clinical trials between 1990 and 2009: a pooled analysis of 155 746 women in 151 trials. Lancet. 2024;404(10461):1407–18. Kolarova I, Melichar B, Sirak I, Vanasek J, Petera J, Horackova K, et al. The Role of Adjuvant Radiotherapy in the Treatment of Breast Cancer. Curr Oncol. 2024;31(3):1207–20. Poortmans PM, Weltens C, Fortpied C, Kirkove C, Peignaux-Casasnovas K, Budach V, et al. Internal mammary and medial supraclavicular lymph node chain irradiation in stage I-III breast cancer (EORTC 22922/10925): 15-year results of a randomised, phase 3 trial. Lancet Oncol. 2020;21(12):1602–10. Whelan TJ, Olivotto IA, Levine MN. Regional Nodal Irradiation in Early-Stage Breast Cancer. N Engl J Med. 2015;373(19):1878–9. Kunkler I. Does postmastectomy radiotherapy in 'intermediate-risk' breast cancer impact overall survival? 10 year results of the BIG 2–04 MRC randomized trial on behalf of the SUPREMO trial investigators. SAN ANTONIO BREAST CANCER SYMPOSIUM ; 2024. Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, et al. American Society of Clinical Oncology/College Of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol. 2010;28(16):2784–95. Wolff AC, Hammond MEH, Allison KH, Harvey BE, Mangu PB, Bartlett JMS, et al. Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. J Clin Oncol. 2018;36(20):2105–22. Poortmans PM, Collette S, Kirkove C, Van Limbergen E, Budach V, Struikmans H, et al. Internal Mammary and Medial Supraclavicular Irradiation in Breast Cancer. N Engl J Med. 2015;373(4):317–27. Leonardi MC, Scognamiglio IR, Maisonneuve P, Dicuonzo S, Rojas DP, Zerella MA, et al. Mastectomy alone for pT1-2 pN0-1 breast cancer patients: when postmastectomy radiotherapy is indicated. Breast Cancer Res Treat. 2021;188(2):511–24. Abi-Raad R, Boutrus R, Wang R, Niemierko A, Macdonald S, Smith B, et al. Patterns and risk factors of locoregional recurrence in T1-T2 node negative breast cancer patients treated with mastectomy: implications for postmastectomy radiotherapy. Int J Radiat Oncol Biol Phys. 2011;81(3):e151–157. van Steenhoven JEC, Kuijer A, van Maaren MC, Roos M, Elias SG, van Diest PJ, et al. Quantifying the Mitigating Effects of Whole-Breast Radiotherapy and Systemic Treatments on Regional Recurrence Incidence Among Breast Cancer Patients. Ann Surg Oncol. 2020;27(9):3402–11. Zhao X, Tang Y, Wang S, Yang Y, Fang H, Wang J, et al. Locoregional recurrence patterns in women with breast cancer who have not undergone post-mastectomy radiotherapy. Radiat Oncol. 2020;15(1):212. Jwa E, Shin KH, Lim HW, Jung SY, Lee S, Kang HS, et al. Identification of Risk Factors for Locoregional Recurrence in Breast Cancer Patients with Nodal Stage N0 and N1: Who Could Benefit from Post-Mastectomy Radiotherapy? PLoS ONE. 2015;10(12):e0145463. Luo C, Zhong X, Fan Y, Wang C, Wang Y, Luo T. The effect of postmastectomy radiation therapy on high-risk patients with T1-2N0 breast cancer. Breast. 2021;60:1–5. Peng G, Zhou Z, Jiang M, Yang F. Can a subgroup at high risk for LRR be identified from T1-2 breast cancer with negative lymph nodes after mastectomy? A meta-analysis. Biosci Rep 2019, 39(9). Mamounas EP, Bandos H, White JR, Julian TB, Khan AJ, Shaitelman SF, et al. Omitting Regional Nodal Irradiation after Response to Neoadjuvant Chemotherapy. N Engl J Med. 2025;392(21):2113–24. Truong PT, Sadek BT, Lesperance MF, Alexander CS, Shenouda M, Raad RA, et al. Is biological subtype prognostic of locoregional recurrence risk in women with pT1-2N0 breast cancer treated with mastectomy? Int J Radiat Oncol Biol Phys. 2014;88(1):57–64. Selz J, Stevens D, Jouanneau L, Labib A, Le Scodan R. Prognostic value of molecular subtypes, ki67 expression and impact of postmastectomy radiation therapy in breast cancer patients with negative lymph nodes after mastectomy. Int J Radiat Oncol Biol Phys. 2012;84(5):1123–32. Yildirim E, Berberoglu U. Can a subgroup of node-negative breast carcinoma patients with T1-2 tumor who may benefit from postmastectomy radiotherapy be identified? Int J Radiat Oncol Biol Phys. 2007;68(4):1024–9. Sharma R, Bedrosian I, Lucci A, Hwang RF, Rourke LL, Qiao W, et al. Present-day locoregional control in patients with t1 or t2 breast cancer with 0 and 1 to 3 positive lymph nodes after mastectomy without radiotherapy. Ann Surg Oncol. 2010;17(11):2899–908. Early Breast Cancer Trialists', Collaborative G, Davies C, Godwin J, Gray R, Clarke M, Cutter D, et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. 2011;378(9793):771–84. Tolaney SM, Tarantino P, Graham N, Tayob N, Pare L, Villacampa G, et al. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer: final 10-year analysis of the open-label, single-arm, phase 2 APT trial. Lancet Oncol. 2023;24(3):273–85. Perez EA, Romond EH, Suman VJ, Jeong JH, Sledge G, Geyer CE Jr., et al. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol. 2014;32(33):3744–52. Cameron D, Piccart-Gebhart MJ, Gelber RD, Procter M, Goldhirsch A, de Azambuja E, et al. 11 years' follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial. Lancet. 2017;389(10075):1195–205. Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011;365(14):1273–83. Tables Tables 1 to 3 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files tables.pptx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-7351544\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":true,\"archivedVersions\":[],\"articleType\":\"Research Article\",\"associatedPublications\":[],\"authors\":[{\"id\":504331557,\"identity\":\"69cdde49-082f-463c-ab54-40c863c3d303\",\"order_by\":0,\"name\":\"Yajuan Chu\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Minhang Branch, Fudan University Shanghai Cancer Center\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Yajuan\",\"middleName\":\"\",\"lastName\":\"Chu\",\"suffix\":\"\"},{\"id\":504331558,\"identity\":\"ce0a8c34-7acb-492b-8cb3-3727e3e2fe14\",\"order_by\":1,\"name\":\"Xiaofang Wang\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Fudan University Shanghai Cancer Center\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Xiaofang\",\"middleName\":\"\",\"lastName\":\"Wang\",\"suffix\":\"\"},{\"id\":504331559,\"identity\":\"d7a4b4ec-d9b7-4d74-b40d-87e9c09de355\",\"order_by\":2,\"name\":\"Xiaomeng Zhang\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Fudan University Shanghai Cancer Center\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Xiaomeng\",\"middleName\":\"\",\"lastName\":\"Zhang\",\"suffix\":\"\"},{\"id\":504331560,\"identity\":\"ba887ee2-e25a-4f7d-8154-91da315034fd\",\"order_by\":3,\"name\":\"Li Zhang\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Fudan University Shanghai Cancer Center\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Li\",\"middleName\":\"\",\"lastName\":\"Zhang\",\"suffix\":\"\"},{\"id\":504331561,\"identity\":\"6559f465-8b29-4d89-9664-d4d2d4edf536\",\"order_by\":4,\"name\":\"Jin Meng\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Fudan University Shanghai Cancer Center\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Jin\",\"middleName\":\"\",\"lastName\":\"Meng\",\"suffix\":\"\"},{\"id\":504331562,\"identity\":\"c23b9d58-b90d-47c9-867b-7eaeae403009\",\"order_by\":5,\"name\":\"Wei Shi\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Fudan University Shanghai Cancer Center\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Wei\",\"middleName\":\"\",\"lastName\":\"Shi\",\"suffix\":\"\"},{\"id\":504331563,\"identity\":\"19009720-257c-4bd4-b0a8-71a41c126021\",\"order_by\":6,\"name\":\"Xingxing Chen\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Fudan University Shanghai Cancer Center\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Xingxing\",\"middleName\":\"\",\"lastName\":\"Chen\",\"suffix\":\"\"},{\"id\":504331564,\"identity\":\"531678df-17fd-4181-9441-535fe2747555\",\"order_by\":7,\"name\":\"Zhaozhi 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Zhang\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Fudan University Shanghai Cancer Center\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Zhen\",\"middleName\":\"\",\"lastName\":\"Zhang\",\"suffix\":\"\"},{\"id\":504331568,\"identity\":\"e333541a-5164-453b-bbee-44bb2e59855a\",\"order_by\":11,\"name\":\"Zhimin Shao\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Fudan University Shanghai Cancer Center\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Zhimin\",\"middleName\":\"\",\"lastName\":\"Shao\",\"suffix\":\"\"},{\"id\":504331569,\"identity\":\"008501ed-6d18-4524-8611-6ba6a745751c\",\"order_by\":12,\"name\":\"Xiaomao Guo\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Fudan University Shanghai Cancer Center\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Xiaomao\",\"middleName\":\"\",\"lastName\":\"Guo\",\"suffix\":\"\"},{\"id\":504331570,\"identity\":\"ee5fdef6-817d-458f-940c-6bd04557a032\",\"order_by\":13,\"name\":\"Jinli Ma\",\"email\":\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAy0lEQVRIiWNgGAWjYJACgwQGCx5+EOsBkEOsFgkeyQYGxoYEYrUAgQSDwQFitei2H2AoeLhDQsb4eI/5g4QKG2MG9sNHN+DTYnYmgcEg8YwEj9mZM4YNCWfSzBh40tJu4NVyIP+DQWIbUMuNHMOGxLbDNgwgNl4t5x8wgLUYzyBay40EiBYDCYgWMyK0QG2ROHOscAbQL8ZsBP1yPoHN8GebjT1/e/OGDx8qbAz72Q8fw6sFCNhQo4KNgHIQYH5AhKJRMApGwSgYyQAAEGBGvbNi9t0AAAAASUVORK5CYII=\",\"orcid\":\"\",\"institution\":\"Fudan University Shanghai Cancer Center\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"Jinli\",\"middleName\":\"\",\"lastName\":\"Ma\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2025-08-12 05:23:28\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-7351544/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-7351544/v1\",\"draftVersion\":[],\"editorialEvents\":[],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":90305681,\"identity\":\"3e360d57-354f-4cda-91be-2612228ee40a\",\"added_by\":\"auto\",\"created_at\":\"2025-09-01 09:24:19\",\"extension\":\"png\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":1043876,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eSee image above for figure legend.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Figure1.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7351544/v1/6f56108b8930870a2ffa51dd.png\"},{\"id\":90305699,\"identity\":\"88a459d2-966d-4994-a373-140e16eccb38\",\"added_by\":\"auto\",\"created_at\":\"2025-09-01 09:24:24\",\"extension\":\"png\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":230974,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eSee image above for figure legend.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Figure2.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7351544/v1/869e52ab24f847daf3caa4a2.png\"},{\"id\":98626260,\"identity\":\"e1222452-d827-41ce-b0bd-a99dc5aa886a\",\"added_by\":\"auto\",\"created_at\":\"2025-12-19 17:09:39\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":2157030,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7351544/v1/991c2aaa-c265-4204-8f21-8883974bf3b3.pdf\"},{\"id\":90305712,\"identity\":\"d0dfae79-9d9d-4d75-a654-09141ff96bf0\",\"added_by\":\"auto\",\"created_at\":\"2025-09-01 09:24:25\",\"extension\":\"pptx\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":69447,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"tables.pptx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7351544/v1/362567a8b9594ff51b5141d5.pptx\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"Re-evaluating the Role of Regional Nodal Irradiation for Node‐Negative Breast Cancer in the Modern Therapy Era: A Matched Cohort Analysis of EORTC 22922/10925\",\"fulltext\":[{\"header\":\"Introduction\",\"content\":\"\\u003cp\\u003eHistorically, early-stage breast cancer patients with pathological node-negative (pN0) at diagnosis have exhibited a low rate of long-term locoregional recurrence (LRR)\\u0026mdash;less than 5% at 10 years\\u003csup\\u003e[\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e]\\u003c/sup\\u003e. Consequently, postmastectomy radiation therapy (PMRT) or regional nodal irradiation (RNI) after breast-conserving surgery (BCS) is not routinely recommended for N0 patients\\u003csup\\u003e[\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e]\\u003c/sup\\u003e. In recent years, however, studies such as EORTC 22922/10925\\u003csup\\u003e[\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e]\\u003c/sup\\u003e and MA20\\u003csup\\u003e[\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e]\\u003c/sup\\u003e, in which a subset of participants had pN0 disease, have indicated that RNI may improve survival outcomes. Nevertheless, the concept of comprehensive radiation therapy (RT) for N0 patients has not been widely adopted in clinical practice. One possible reason is that the inclusion of participants from mixed disease stages may not accurately represent a puro N0 group. Moreover, the widespread use of modern systemic treatment\\u0026mdash;including chemotherapy, endocrine therapy, and targeted therapy\\u0026mdash;have further improve survival, potentially diminishing the incremental value of RT. In addition, the SUPREMO trial reported favorable survival outcomes with omission of RNI in intermediate-risk patients, indicating that radiotherapy could be omitted\\u003csup\\u003e[\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e]\\u003c/sup\\u003e. Therefore, in this study, we matched our study populations according to the eligibility criteria of the EORTC 22922/10925 trial and report the survival outcome of this cohort. Furthermore, we refined the risk factors among patients with N0 disease and provided treatment options.\\u003c/p\\u003e\"},{\"header\":\"Material and methods\",\"content\":\"\\u003cdiv id=\\\"Sec3\\\" class=\\\"Section2\\\"\\u003e\\u003ch2\\u003ePatients and study design\\u003c/h2\\u003e\\u003cp\\u003eThis retrospective cohort study included female patients diagnosed with pathologic stage T1\\u0026ndash;3N0 breast cancer who underwent either BCS or mastectomy at Fudan University Shanghai Cancer Center between January 2005 and December 2014. A total of 3,380 patients were initially identified from the institutional database. Patients meeting any of the following criteria were excluded: previous history of malignant tumors (n\\u0026thinsp;=\\u0026thinsp;102), serious nonmalignant diseases (n\\u0026thinsp;=\\u0026thinsp;66), age\\u0026thinsp;\\u0026gt;\\u0026thinsp;75 years (n\\u0026thinsp;=\\u0026thinsp;56), receipt of neoadjuvant systemic therapy (n\\u0026thinsp;=\\u0026thinsp;238), BCS without whole-breast radiotherapy (WBRT) (n\\u0026thinsp;=\\u0026thinsp;61), or a follow-up period of less than 6 months (n\\u0026thinsp;=\\u0026thinsp;290). After applying these criteria, the remaining 2567 patients included in the final analysis. Among these, 1302 patients met the inclusion criteria of the EORTC 22922/10925 trial, which required (1) age of \\u0026le;\\u0026thinsp;75 years, (2) unilateral breast cancer, (3) histologically confirmed adenocarcinoma, and (4) node-negative disease with tumors located in the medial or central region of the breast. Ethical approval for this study was obtained from the Ethics Committee and Institutional Review Board of our institution.\\u003c/p\\u003e\\u003c/div\\u003e\\n\\u003ch3\\u003eDate collection\\u003c/h3\\u003e\\n\\u003cp\\u003eClinicopathologic characteristics, treatment details, and follow-up data were extracted from the institutional electronic medical records. Clinicopathologic factors included age at diagnosis, type of surgical procedure, laterality, tumor location, tumor size, histological subtype and grade, status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal receptor 2 (HER2) status, Ki-67 index, and lymphovascular invasion (LVI). Treatment variables including adjuvant chemotherapy regimens, endocrine therapy, anti-HER2 targeted therapy, and RT details were reviewed.\\u003c/p\\u003e\\n\\u003ch3\\u003eBiomarker assessment\\u003c/h3\\u003e\\n\\u003cp\\u003eER and PR status were assessed using immunohistochemistry (IHC), with a threshold of at least 1% positive nuclear staining in tumor cells used to define receptor positivity\\u003csup\\u003e[\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e]\\u003c/sup\\u003e. Hormone receptor (HR) status was classified as HR-positive if ER and/or PR were positive, and as HR-negative if both receptors were negative. HER2 status was determined using IHC and/or fluorescence in situ hybridization (FISH). Tumors were considered HER2-positive if IHC score was 3\\u0026thinsp;+\\u0026thinsp;or if IHC was 2\\u0026thinsp;+\\u0026thinsp;with confirmed gene amplification by FISH (HER2/CEP17 ratio\\u0026thinsp;\\u0026ge;\\u0026thinsp;2.0), and HER2-negative if the IHC score was 0\\u0026ndash;1\\u0026thinsp;+\\u0026thinsp;or if the score was 2\\u0026thinsp;+\\u0026thinsp;without amplification by FISH\\u003csup\\u003e[\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e]\\u003c/sup\\u003e.\\u003c/p\\u003e\\n\\u003ch3\\u003eTreatment\\u003c/h3\\u003e\\n\\u003cp\\u003eAll patients underwent either BCS or mastectomy with pathologically confirmed negative surgical margins. Sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND) was performed based on clinical and intraoperative indications. Adjuvant chemotherapy was administered in accordance with prevailing international guidelines at the time of diagnosis, taking tumor biology and pathological staging into account.\\u003c/p\\u003e\\u003cp\\u003ePatients undergoing BCS received WBRT, typically consisting of 50 Gy in 25 fractions followed by a tumor bed boost of 10 Gy in 5 fractions. PMRT was selectively administered at the discretion of the treating radiation oncologist, particularly in patients with pT3 tumors, and was delivered to the chest wall at a dose of 50 Gy in 25 fractions. RNI, including irradiation of the supraclavicular (SCV), infraclavicular (ICV), and internal mammary (IMN) nodes, was not routinely incorporated into either WBRT or PMRT plans. Radiotherapy employed either three-dimensional conformal radiotherapy (3DCRT) or simplified intensity-modulated radiotherapy (sIMRT), depending on anatomical and dosimetric considerations. Endocrine therapy was administered to HR-positive patients and anti-HER2 therapy was administered to HER2-positive patients according to contemporary treatment guidelines.\\u003c/p\\u003e\\n\\u003ch3\\u003eOutcome definitions and endpoints\\u003c/h3\\u003e\\n\\u003cp\\u003eLRR was defined as clinically, radiologically, or pathologically confirmed tumor recurrence within the ipsilateral breast/chest wall (CW) or regional lymph nodes (axillary, infraclavicular, supraclavicular, or internal mammary). Distant metastasis (DM) was defined as recurrence beyond locoregional sites.\\u003c/p\\u003e\\u003cp\\u003eThe primary endpoint of this study was LRR-free survival (LRRFS), defined as the time from surgery to the first documented LRR. Secondary endpoints included disease-free survival (DFS), local recurrence (LR)-free survival (LRFS), regional recurrence (RR)-free survival (RRFS), DM-free survival (DMFS), breast cancer recurrence-free survival (BCRFS), overall survival (OS) and breast cancer-specific survival (BCSS). DFS was defined as the time from surgery to LRR, DM, second breast cancer, or death from any cause; LRFS as the time from surgery to the first LR; RRFS as the time from surgery to the first RR; DMFS as the time from surgery to DM or death from any cause; BCRFS as the time from surgery to the occurrence of LRR, DM, secondary ipsilateral breast cancer, or breast cancer-related death; OS as the time from surgery to death from any cause; and BCSS as the time from surgery to death attributable to breast cancer.\\u003c/p\\u003e\\u003cdiv id=\\\"Sec8\\\" class=\\\"Section2\\\"\\u003e\\u003ch2\\u003eStatistical analysis\\u003c/h2\\u003e\\u003cp\\u003eCategorical variables were compared using Pearson\\u0026rsquo;s chi-square (χ\\u0026sup2;) test. Survival outcomes, including DFS, LRRFS, LRFS, RRFS, DMFS, BCRFS, OS and BCSS, were estimated using the Kaplan\\u0026ndash;Meier method and compared between groups using the two-sided log-rank test. Univariate and multivariate analyses were performed using Cox proportional hazards regression models to identify independent prognostic factors. Based on the identified high-risk prognostic factors, the entire cohort were classified into risk groups. All statistical analyses were performed using SPSS version 26.0, and a two-sided p-value\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05 was considered statistically significant.\\u003c/p\\u003e\\u003c/div\\u003e\"},{\"header\":\"Results\",\"content\":\"\\u003cdiv id=\\\"Sec10\\\" class=\\\"Section2\\\"\\u003e\\u003ch2\\u003eThe cohort meeting the inclusion criteria of the EORTC 22922/10925 trial (n\\u0026thinsp;=\\u0026thinsp;1302)\\u003c/h2\\u003e\\u003cdiv id=\\\"Sec11\\\" class=\\\"Section3\\\"\\u003e\\u003ch2\\u003ePatient and treatment characteristics\\u003c/h2\\u003e\\u003cp\\u003eIn this cohort, the median age was 51 years (range, 20\\u0026ndash;75 years). Mastectomy was performed in 91.6% (n\\u0026thinsp;=\\u0026thinsp;1192) of patients, compared with 8.4% (n\\u0026thinsp;=\\u0026thinsp;110) who received breast-conserving surgery (BCS). SLNB was performed for 34.1% of patients, with ALND for the remainder. The median size of invasive tumor was 2.0 cm (range, 0.1\\u0026ndash;6.5 cm), with 98.2% (n\\u0026thinsp;=\\u0026thinsp;1278) classified as T1-2 tumors. Histological grades were primarily grade 2 (51.8%) or 3 (29.0%), together accounting for 80.8% of cases. HR-positive tumor expression was found in 73.5% of patients (n\\u0026thinsp;=\\u0026thinsp;957), and HER2-positive expression in 24.9% (n\\u0026thinsp;=\\u0026thinsp;324). Systemic chemotherapy was administered to 72.4% of patients (n\\u0026thinsp;=\\u0026thinsp;943). Nearly all recipients (n\\u0026thinsp;=\\u0026thinsp;930) completed 4\\u0026ndash;8 cycles of postoperative chemotherapy, predominantly using anthracycline- and/or taxanes-based regimens. All patients undergoing BCS received WBRT; only 20 patients who underwent mastectomy received CW irradiation. Among HER2-positive patients, 135 (41.7%) received adjuvant anti-HER2 therapy. 97.8% (n\\u0026thinsp;=\\u0026thinsp;936) of HR-positive cases received endocrine therapy (Table\\u0026nbsp;1).\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv id=\\\"Sec12\\\" class=\\\"Section2\\\"\\u003e\\u003ch2\\u003eSurvival outcomes\\u003c/h2\\u003e\\u003cp\\u003eDuring a median follow-up of 8.3 years (range, 0.5\\u0026ndash;16.9 years), 106 patients experienced any recurrence: 23 with isolated LRR, 61 with isolated DM, and 22 with concurrent LRR and DM. Among patients with LRR, recurrences were local only in 25 patients (1.9%), regional only in 16 patients (1.2%), and both local and regional in 4 patients (0.3%) (Table\\u0026nbsp;2). By the last follow-up, 84 patients had died, including 63 from breast cancer. At 8.3 and 10 years, the survival estimates (%) were: LRFS: 97.6/97.0, RRFS: 98.5/98.3, LRRFS: 96.4/95.7, DMFS: 93.6/92.5, DFS: 90.0/87.5, BCRFS: 91.6/90.3, OS: 95.2 /92.7, and BCSS: 95.9/94.2 (Fig.\\u0026nbsp;1A-H).\\u003c/p\\u003e\\u003c/div\\u003e\\u003cdiv id=\\\"Sec13\\\" class=\\\"Section2\\\"\\u003e\\u003ch2\\u003eThe entire cohort (n\\u0026thinsp;=\\u0026thinsp;2567)\\u003c/h2\\u003e\\u003cdiv id=\\\"Sec14\\\" class=\\\"Section3\\\"\\u003e\\u003ch2\\u003ePatient and treatment characteristics\\u003c/h2\\u003e\\u003cp\\u003eThe distribution of clinicopathological features did not differ significantly between this group and the subset meeting the EORTC 22922/10925 inclusion criteria (Table\\u0026nbsp;1). Overall, 49.3% of patients (n\\u0026thinsp;=\\u0026thinsp;1265) had outer quadrant tumors, compared to 50.7% (n\\u0026thinsp;=\\u0026thinsp;1302) with central or medial quadrant tumors. 85.2% of patients underwent mastectomy, and 14.8% received BCS. Of the mastectomy cohort, 2.0% (n\\u0026thinsp;=\\u0026thinsp;44) received CW irradiation, while none received RNI. 74.6% of patients received chemotherapy. Of the 540 HER2-positive patients, 38.3% (n\\u0026thinsp;=\\u0026thinsp;207) received adjuvant anti-HER2 therapy (primarily trastuzumab-based). Separately, 97.3% (n\\u0026thinsp;=\\u0026thinsp;1838) of HR-positive patients received endocrine therapy.\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv id=\\\"Sec15\\\" class=\\\"Section2\\\"\\u003e\\u003ch2\\u003eSurvival outcomes\\u003c/h2\\u003e\\u003cp\\u003eAfter a median follow-up of 8.3 years (range, 0.5\\u0026ndash;16.9 years), recurrences occurred in 189 patients, including 41 with isolated LRR, 111 with isolated DM, and 37 with concurrent LRR and DM (Table\\u0026nbsp;2). The most common recurrence site was the CW or breast alone (n\\u0026thinsp;=\\u0026thinsp;39; 1.5%), followed by regional lymph nodes alone (n\\u0026thinsp;=\\u0026thinsp;31; 1.2%), and combined LRR (n\\u0026thinsp;=\\u0026thinsp;8, 0.3%). Among RRs, the SCV/ICV nodes were most frequently involved, then the ALN and IMN (Table\\u0026nbsp;2).\\u003c/p\\u003e\\u003cp\\u003eDuring follow-up, a total of 173 deaths occurred, 124 (71.7%) of which were breast cancer-related. The estimated 8.3- and 10-year rates of LRFS, RRFS, LRRFS, and DMFS were 98.2%/97.9%, 98.6%/98.5%, 97.1%/96.7%, and 94.1%/93.1%, respectively. The 8.3- and 10-year rates of DFS, BCRFS, OS, and BCSS were 91.1%/89.0%, 92.7%/91.4%, 94.7%/92.7%, and 95.4%/94.2%, respectively (Fig.\\u0026nbsp;1A-H).\\u003c/p\\u003e\\u003c/div\\u003e\\u003cdiv id=\\\"Sec16\\\" class=\\\"Section2\\\"\\u003e\\u003ch2\\u003eRisk factors\\u003c/h2\\u003e\\u003cp\\u003eThe associations between clinicopathological variables and survivals are summarized in Table\\u0026nbsp;3. In univariate analysis, age\\u0026thinsp;\\u0026le;\\u0026thinsp;40 years (p\\u0026thinsp;=\\u0026thinsp;0.015) and tumor size\\u0026thinsp;\\u0026gt;\\u0026thinsp;2.5cm (p\\u0026thinsp;=\\u0026thinsp;0.020) were correlated with poorer LRRFS. Moreover, age\\u0026thinsp;\\u0026le;\\u0026thinsp;40 years, tumor size\\u0026thinsp;\\u0026gt;\\u0026thinsp;2.5cm and HR-negative status were associated with worse DFS and BCRFS.\\u003c/p\\u003e\\u003cp\\u003eMultivariate analysis confirmed that age\\u0026thinsp;\\u0026le;\\u0026thinsp;40 years (HR, 1.845; 95% CI, 1.107\\u0026ndash;3.075; p\\u0026thinsp;=\\u0026thinsp;0.019) and tumor size\\u0026thinsp;\\u0026gt;\\u0026thinsp;2.5cm (HR, 1.808; 95% CI, 1.109\\u0026ndash;2.947; p\\u0026thinsp;=\\u0026thinsp;0.017) were independent predictors of poorer LRRFS. Furthermore, age\\u0026thinsp;\\u0026le;\\u0026thinsp;40 years, tumor size\\u0026thinsp;\\u0026gt;\\u0026thinsp;2.5 cm, and HR-negative status remained independently associated with a shorter DFS and BCRFS. Other clinicopathological variables, including laterality, location, histological grade, HER2 status, Ki67 index, and LVI, showed no significant association with LRRFS, DFS, or BCRFS (Table\\u0026nbsp;3).\\u003c/p\\u003e\\u003c/div\\u003e\\u003cdiv id=\\\"Sec17\\\" class=\\\"Section2\\\"\\u003e\\u003ch2\\u003eOutcomes of Risk Groups\\u003c/h2\\u003e\\u003cp\\u003eThe cohort was stratified into low-risk (no factors; n\\u0026thinsp;=\\u0026thinsp;1726, 67.2%) and high-risk (\\u0026ge;\\u0026thinsp;1 factor; n\\u0026thinsp;=\\u0026thinsp;841, 32.8%) groups based on LRRFS-associated risk factors. Kaplan\\u0026ndash;Meier analysis showed significantly higher 8.3-year (98.1% vs. 95.0%) and 10-year (97.8% vs. 94.4%) LRRFS rates in low-risk versus high-risk patients (p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001) (Fig.\\u0026nbsp;2).\\u003c/p\\u003e\\u003c/div\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cp\\u003ePatients with pN0 breast cancer are typically classified as having early-staged disease, and experience favorable prognoses with standard therapies. For pN0 disease, current guidelines restrict RT primarily to WBRT following BCS and chest wall irradiation after mastectomy in cases with tumors\\u0026thinsp;\\u0026gt;\\u0026thinsp;5cm; RNI is not routinely administrated. However, recent large-scale studies have challenged this paradigm. The MA.20 trial\\u003csup\\u003e[\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e]\\u003c/sup\\u003e demonstrated improved 10-year DFS with RNI versus WBRT alone (82.0% vs. 77.0%, p\\u0026thinsp;=\\u0026thinsp;0.01). Yet these findings have limited applicability to a truly pN0 populations, as only 9.7% of the cohort had pN0 disease. Similarly, the EORTC 22922/10925 trial\\u003csup\\u003e[\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e]\\u003c/sup\\u003e (15.7-year follow-up) showed comprehensive RNI reduced any breast recurrence (24.5% vs. 27.1%, p\\u0026thinsp;=\\u0026thinsp;0.024), and breast cancer mortality (16.0% vs. 19.8%, p\\u0026thinsp;=\\u0026thinsp;0.0055), though without significant improvements in DFS, DMFS or OS. Key limitations for extrapolating these findings to pN0 disease include cohort heterogeneity (only 44.4% node-negative), unvalidated medial/central tumor location criteria, and limited contemporary systemic therapies (e.g., only 29.6% received endocrine therapy; no targeted agents). In the present study, we applied the EORTC 22922/10925 trial eligibility criteria to a pure pN0 cohort to analyze the survival outcomes.\\u003c/p\\u003e\\u003cp\\u003eWithin the matched cohort, the estimated 10-year rates were 95.7% for LRRFS, 92.5% for DMFS, 90.3% for BCRFS, 87.5% for DFS, 94.2% for BCSS and 92.7% for OS. These outcomes were comparable with those reported in the 10-year result of the EORTC 22922/10925 trial\\u003csup\\u003e[\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e]\\u003c/sup\\u003e, which showed the following rates for RNI vs. no RNI groups: DFS 72.1% vs. 69.1%, DMFS 78.0% vs. 75.0%, OS 82.3% vs. 80.7%, and BCM 12.5% vs. 14.4%.\\u003c/p\\u003e\\u003cp\\u003eAmong patients with outer quadrant breast tumors, the 8.3-year LRRFS (p\\u0026thinsp;=\\u0026thinsp;0.147), DFS (p\\u0026thinsp;=\\u0026thinsp;0.095), DMFS (p\\u0026thinsp;=\\u0026thinsp;0.150), BCRFS (p\\u0026thinsp;=\\u0026thinsp;0.089), BCSS (p\\u0026thinsp;=\\u0026thinsp;0.800) and OS (p\\u0026thinsp;=\\u0026thinsp;0.925) did not differ significantly from those observed in the EORTC 22922/10925-matched cohort. For the N0 cohort meeting the EORTC 22922/10925 criteria, the LRR rate remained below 4% at 8.3 years and 5% at 10 years without RNI, confirming a low risk of LRR. Additionally, primary tumor quadrant was not identified as a significant prognostic factor for survival outcomes.\\u003c/p\\u003e\\u003cp\\u003eWe analyzed survival outcomes in our entire cohort of 2567 patients. The 8.3-year and 10-year LRFS, RRFS, LRRFS, DMFS, DFS, BCRFS, OS, and BCSS were 98.2%/97.9%, 98.6%/98.5%, 97.1%/96.7%, 94.1%/93.1%, 91.1%/89.0%, 92.7%/91.4%, 94.7%/92.7%, and 95.4%/94.2%, respectively. These results demonstrate excellent long-term survival, with 10-year rates exceeding 89% across all endpoints, and are comparable to those reported in historical studies of similarly early-stage breast cancer patients. For instance, Leonardi et al.\\u003csup\\u003e[\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e]\\u003c/sup\\u003e reported 10-year LRR rate of 8.8% (equivalent to 91.2% LRRFS) in a cohort of 1281 pT1-2N0 patients, while Abi-Raad et al.\\u003csup\\u003e[\\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e]\\u003c/sup\\u003e documented a 10-year LRR rate of 5.2% (equivalent to 94.8% LRRFS) in 1188 node-negative patients. Other studies in pT1-2N0 cohorts reported 10-year LRR rates ranging from 3.0\\u0026ndash;3.7% (equivalent to 96.3% -97.0% LRRFS), with corresponding 5-year RR and all-cause mortality rates of 1.3% and 4.4%, respectively\\u003csup\\u003e[\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e] [\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e]\\u003c/sup\\u003e.\\u003c/p\\u003e\\u003cp\\u003eGiven the favorable locoregional control in pN0 breast cancer, a major clinical challenge is identifying high-risk patients who might benefit from RT. Studies have stratified patients into prognostic groups based on risk factors. For example, Luo et al.\\u003csup\\u003e[\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e]\\u003c/sup\\u003e identified tumor size, ER status, histologic grade and LVI as significant predictors of LRR. In the high-risk patients (those with 3\\u0026ndash;4 risk factors), PMRT significantly reduced the 5-year rates of LRR (1.2% vs. 9.5%, p\\u0026thinsp;=\\u0026thinsp;0.021), DM (2.6% vs. 10.4%, p\\u0026thinsp;=\\u0026thinsp;0.006), and BCM (1.5% vs. 7.9%, p\\u0026thinsp;=\\u0026thinsp;0.002). Conversely, PMRT provided no significant benefit in the low-risk group (patients with 0\\u0026ndash;2 risk factors). Similarly, Leonardi MC et al\\u003csup\\u003e[\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e]\\u003c/sup\\u003e found that young age (\\u0026lt;\\u0026thinsp;35 years), LVI, and elevated Ki-67 (\\u0026ge;\\u0026thinsp;20%) predicted worse LRR in 1281 pT1-2N0 patients treated with mastectomy without PMRT. Among those with \\u0026ge;\\u0026thinsp;2 risk factors, the 10-year LRR rate exceeded 15%, suggesting PMRT might be considered for this subgroup. Abi-Raad et al.\\u003csup\\u003e[\\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e]\\u003c/sup\\u003e found tumor size, margin status, age, systemic therapy, and LVI to be independent predictors of LRR in 1136 pN0 patients. Those with \\u0026ge;\\u0026thinsp;3 risk factors had a\\u0026thinsp;~\\u0026thinsp;20% LRR rate, supporting consideration of PMRT for this group. Peng et al.'s \\u003csup\\u003e[\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e]\\u003c/sup\\u003e meta-analysis identified young age, positive LVI, high histologic grade, HER2 positivity, premenopausal status, and positive surgical margins as risk factors of LRR in pT1-2N0 patients after mastectomy. Given these findings, prospective trials are warranted to define the role of PMRT in this high-risk population. Finally, Jwa E et al.\\u003csup\\u003e[\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e]\\u003c/sup\\u003e analyzed 307 pT1-2N0 patients who did not receive PMRT and identified age\\u0026thinsp;\\u0026lt;\\u0026thinsp;50 years and the absence of adjuvant chemotherapy as independent risk factors for LRR. Based on these factors, the study reported 5-year LRRFS rates of 100% (no risk factors), 96.4% (one risk factor), and 86.7% (two risk factors), suggesting PMRT may benefit patients under 50 years or not receiving adjuvant chemotherapy. In our study, age\\u0026thinsp;\\u0026le;\\u0026thinsp;40 years and tumor size\\u0026thinsp;\\u0026gt;\\u0026thinsp;2.5 cm were identified as independent prognostic factors for LRRFS. Patients in the high-risk group (1\\u0026ndash;2 factors) had significantly worse LRRFS than the low‐risk group (0 factors) (p\\u0026thinsp;=\\u0026thinsp;0.001) Notably, even high‐risk patients exhibited 8.3‐year and 10‐year LRR rates of only 5.0% and 5.6%, respectively, dramatically lower than the historically reported 15\\u0026ndash;20% LRR rates. These favorable outcomes may be attributed to advancements in surgical techniques with meticulous margin control and consistent application of standardized systemic treatments per contemporary guidelines.\\u003c/p\\u003e\\u003cp\\u003eNotably, even among high-risk patients, the 5‐year and 10‐year LRR rates were remarkably low. Given the marginal absolute benefit against potential treatment-related toxicities, RT could likely be omitted safely in pT1-2N0 patients receiving contemporary systemic therapy. In the randomized SUPREMO trial, RNI was uniformly omitted across all enrolled patients (pT1-2N1 or pT2-3N0), with pN0 cases representing 25.1% (n\\u0026thinsp;=\\u0026thinsp;402) of the cohort. At the 2024 SABCS meeting, 10-year follow-up results from the trial revealed comparable outcomes between non-CW-irradiated and CW-irradiated groups: LR 2.5% vs. 1.1% (p\\u0026thinsp;=\\u0026thinsp;0.04); RR 4.5% vs. 2.7% (p\\u0026thinsp;=\\u0026thinsp;0.06); DM 20.8% vs. 21.8% (p\\u0026thinsp;=\\u0026thinsp;0.60, DFS 24.5% vs. 23.8% (p\\u0026thinsp;=\\u0026thinsp;0.70)), and mortality18.1% vs. 18.6% (p\\u0026thinsp;=\\u0026thinsp;0.79). Critically, no survival differences emerged in pN0 subgroup analyses. Although a clinically insignificant reduction in 10-year LR rate (an absolute difference of only 1.4%) was observed, the overall low recurrence rates (LR\\u0026thinsp;+\\u0026thinsp;RR\\u0026thinsp;\\u0026lt;\\u0026thinsp;7%) led the SUPREMO investigators to conclude that omitting irradiation is justifiable, particular for pN0 patients\\u003csup\\u003e[\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e]\\u003c/sup\\u003e.\\u003c/p\\u003e\\u003cp\\u003eMolecular subtype, defined clinically by IHC assessment of HR status (ER/PR), HER2 status, and Ki67 index, guides prognosis and therapeutic decisions in breast cancer. Consistent with prior studies\\u003csup\\u003e[\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e, \\u003cspan additionalcitationids=\\\"CR18 CR19\\\" citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e]\\u003c/sup\\u003e, neither HR nor HER2 status predicted LRRFS in our cohort, whether assessed individually or as biological subtypes. The EBCTCG meta-analysis demonstrated that endocrine therapy substantially reduces recurrence risk in ER-positive early-stage breast cancer, independent of nodal status\\u003csup\\u003e[\\u003cspan citationid=\\\"CR21\\\" class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e]\\u003c/sup\\u003e. In our cohort, 97.3% of HR-positive patients underwent endocrine therapy. Moreover, HR-positive status independently predicted improved DFS and BCRFS, validating prior reports\\u003csup\\u003e[\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e]\\u003c/sup\\u003e. Due to historical anti-HER2 drug unavailability and economic barriers, only 38.3% of HER2‐positive patients (207/540) received targeted therapy. Although prior studies confirm survival benefits from Trastuzumab +/- Pertuzumab in pN0 disease\\u003csup\\u003e[\\u003cspan additionalcitationids=\\\"CR23 CR24\\\" citationid=\\\"CR22\\\" class=\\\"CitationRef\\\"\\u003e22\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR25\\\" class=\\\"CitationRef\\\"\\u003e25\\u003c/span\\u003e]\\u003c/sup\\u003e. Our HER2-positive cohort showed no significant improvement with anti-HER2 therapy, likely due to limited statistical power from the subgroup size. Routine use of anti‐HER2 agents may further improve survival outcomes in pN0 patients beyond those observed in this study.\\u003c/p\\u003e\\u003cp\\u003eThis study, among the largest survival analyses in pT1-3N0 breast cancer, refined the risk factors for N0 disease, reported stratified survival outcomes with treatment suggestions. However, a key limitation is that no patients received nodal irradiation, preventing assessment of its potential survival benefit in high-risk subgroups.\\u003c/p\\u003e\"},{\"header\":\"Conclusion\",\"content\":\"\\u003cp\\u003eThis study demonstrates favorable survival outcomes for pT1-3N0 breast cancer patients treated with surgery and contemporary systemic therapy. While the EORTC 22922/10925 criteria failed to effectively identify high-risk patients within this pN0 cohort, our analysis identified\\u0026thinsp;\\u0026le;\\u0026thinsp;40 years and tumor size\\u0026thinsp;\\u0026gt;\\u0026thinsp;2.5cm as independent prognostic factors of LRRFS. Patients classified as high-risk group (1\\u0026ndash;2 factors) had significantly worse LRRFS than low-risk patients (0 factors). Notably, even high-risk patients achieved excellent long-term LRRFS. These findings suggest that the omitting radiotherapy may be considered for such patients receiving standard systemic treatment.\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e\\u003ch2\\u003eConflict of interest\\u003c/h2\\u003e\\u003cp\\u003eThe authors declare no conflicts of interest.\\u003c/p\\u003e\\u003c/p\\u003e\\u003cp\\u003e\\u003ch2\\u003eEthical Approval\\u003c/h2\\u003e\\u003cp\\u003eThe ethical consent of this study was not required.\\u003c/p\\u003e\\u003c/p\\u003e\\u003ch2\\u003eFunding\\u003c/h2\\u003e\\u003cp\\u003eThis work was no Funding to support.\\u003c/p\\u003e\\u003ch2\\u003eAuthor Contribution\\u003c/h2\\u003e\\u003cp\\u003eConception and design: Jinli Ma, Collection and assembly of data: Yajuan Chu, Xiaofang Wang, Data analysis and interpretation: Yajuan Chu, and Jinli Ma, Manuscript writing: All authors, Final approval of manuscript: All authors\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\u003cli\\u003e\\u003cspan\\u003eEarly Breast Cancer Trialists' Collaborative Group. Electronic address bocoau. Reductions in recurrence in women with early breast cancer entering clinical trials between 1990 and 2009: a pooled analysis of 155 746 women in 151 trials. Lancet. 2024;404(10461):1407\\u0026ndash;18.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eKolarova I, Melichar B, Sirak I, Vanasek J, Petera J, Horackova K, et al. The Role of Adjuvant Radiotherapy in the Treatment of Breast Cancer. Curr Oncol. 2024;31(3):1207\\u0026ndash;20.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003ePoortmans PM, Weltens C, Fortpied C, Kirkove C, Peignaux-Casasnovas K, Budach V, et al. Internal mammary and medial supraclavicular lymph node chain irradiation in stage I-III breast cancer (EORTC 22922/10925): 15-year results of a randomised, phase 3 trial. Lancet Oncol. 2020;21(12):1602\\u0026ndash;10.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eWhelan TJ, Olivotto IA, Levine MN. Regional Nodal Irradiation in Early-Stage Breast Cancer. N Engl J Med. 2015;373(19):1878\\u0026ndash;9.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eKunkler I. Does postmastectomy radiotherapy in 'intermediate-risk' breast cancer impact overall survival? 10 year results of the BIG 2\\u0026ndash;04 MRC randomized trial on behalf of the SUPREMO trial investigators. \\u003cem\\u003eSAN ANTONIO BREAST CANCER SYMPOSIUM\\u003c/em\\u003e; 2024.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eHammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, et al. American Society of Clinical Oncology/College Of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol. 2010;28(16):2784\\u0026ndash;95.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eWolff AC, Hammond MEH, Allison KH, Harvey BE, Mangu PB, Bartlett JMS, et al. Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. J Clin Oncol. 2018;36(20):2105\\u0026ndash;22.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003ePoortmans PM, Collette S, Kirkove C, Van Limbergen E, Budach V, Struikmans H, et al. Internal Mammary and Medial Supraclavicular Irradiation in Breast Cancer. N Engl J Med. 2015;373(4):317\\u0026ndash;27.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eLeonardi MC, Scognamiglio IR, Maisonneuve P, Dicuonzo S, Rojas DP, Zerella MA, et al. Mastectomy alone for pT1-2 pN0-1 breast cancer patients: when postmastectomy radiotherapy is indicated. Breast Cancer Res Treat. 2021;188(2):511\\u0026ndash;24.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eAbi-Raad R, Boutrus R, Wang R, Niemierko A, Macdonald S, Smith B, et al. Patterns and risk factors of locoregional recurrence in T1-T2 node negative breast cancer patients treated with mastectomy: implications for postmastectomy radiotherapy. Int J Radiat Oncol Biol Phys. 2011;81(3):e151\\u0026ndash;157.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003evan Steenhoven JEC, Kuijer A, van Maaren MC, Roos M, Elias SG, van Diest PJ, et al. Quantifying the Mitigating Effects of Whole-Breast Radiotherapy and Systemic Treatments on Regional Recurrence Incidence Among Breast Cancer Patients. Ann Surg Oncol. 2020;27(9):3402\\u0026ndash;11.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eZhao X, Tang Y, Wang S, Yang Y, Fang H, Wang J, et al. Locoregional recurrence patterns in women with breast cancer who have not undergone post-mastectomy radiotherapy. Radiat Oncol. 2020;15(1):212.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eJwa E, Shin KH, Lim HW, Jung SY, Lee S, Kang HS, et al. Identification of Risk Factors for Locoregional Recurrence in Breast Cancer Patients with Nodal Stage N0 and N1: Who Could Benefit from Post-Mastectomy Radiotherapy? PLoS ONE. 2015;10(12):e0145463.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eLuo C, Zhong X, Fan Y, Wang C, Wang Y, Luo T. The effect of postmastectomy radiation therapy on high-risk patients with T1-2N0 breast cancer. Breast. 2021;60:1\\u0026ndash;5.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003ePeng G, Zhou Z, Jiang M, Yang F. Can a subgroup at high risk for LRR be identified from T1-2 breast cancer with negative lymph nodes after mastectomy? A meta-analysis. Biosci Rep 2019, 39(9).\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eMamounas EP, Bandos H, White JR, Julian TB, Khan AJ, Shaitelman SF, et al. Omitting Regional Nodal Irradiation after Response to Neoadjuvant Chemotherapy. N Engl J Med. 2025;392(21):2113\\u0026ndash;24.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eTruong PT, Sadek BT, Lesperance MF, Alexander CS, Shenouda M, Raad RA, et al. Is biological subtype prognostic of locoregional recurrence risk in women with pT1-2N0 breast cancer treated with mastectomy? Int J Radiat Oncol Biol Phys. 2014;88(1):57\\u0026ndash;64.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eSelz J, Stevens D, Jouanneau L, Labib A, Le Scodan R. Prognostic value of molecular subtypes, ki67 expression and impact of postmastectomy radiation therapy in breast cancer patients with negative lymph nodes after mastectomy. Int J Radiat Oncol Biol Phys. 2012;84(5):1123\\u0026ndash;32.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eYildirim E, Berberoglu U. Can a subgroup of node-negative breast carcinoma patients with T1-2 tumor who may benefit from postmastectomy radiotherapy be identified? Int J Radiat Oncol Biol Phys. 2007;68(4):1024\\u0026ndash;9.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eSharma R, Bedrosian I, Lucci A, Hwang RF, Rourke LL, Qiao W, et al. Present-day locoregional control in patients with t1 or t2 breast cancer with 0 and 1 to 3 positive lymph nodes after mastectomy without radiotherapy. Ann Surg Oncol. 2010;17(11):2899\\u0026ndash;908.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eEarly Breast Cancer Trialists', Collaborative G, Davies C, Godwin J, Gray R, Clarke M, Cutter D, et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. 2011;378(9793):771\\u0026ndash;84.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eTolaney SM, Tarantino P, Graham N, Tayob N, Pare L, Villacampa G, et al. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer: final 10-year analysis of the open-label, single-arm, phase 2 APT trial. Lancet Oncol. 2023;24(3):273\\u0026ndash;85.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003ePerez EA, Romond EH, Suman VJ, Jeong JH, Sledge G, Geyer CE Jr., et al. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol. 2014;32(33):3744\\u0026ndash;52.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eCameron D, Piccart-Gebhart MJ, Gelber RD, Procter M, Goldhirsch A, de Azambuja E, et al. 11 years' follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial. Lancet. 2017;389(10075):1195\\u0026ndash;205.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eSlamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011;365(14):1273\\u0026ndash;83.\\u003c/span\\u003e\\u003c/li\\u003e\\u003c/ol\\u003e\"},{\"header\":\"Tables\",\"content\":\"\\u003cp\\u003eTables 1 to 3 are available in the Supplementary Files section.\\u003c/p\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":true,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":false,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true},\"keywords\":\"breast cancer, radiotherapy, node negative, EORTC 22922/10925, survival\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-7351544/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-7351544/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003ch2\\u003eBackground:\\u003c/h2\\u003e\\u003cp\\u003eWhile early breast cancer patients with node-negative disease generally exhibit a favorable prognosis and do not routinely require regional nodal irradiation (RNI), the EORTC 22922/10925 trial demonstrated that comprehensive nodal irradiation could potentially improve survival in selected N0 patients. To further investigate this paradigm, we applied the EORTC 22922/10925 trial criteria to a contemporary cohort of node-negative patients and evaluated their long-term outcomes.\\u003c/p\\u003e\\u003ch2\\u003eMethods:\\u003c/h2\\u003e\\u003cp\\u003eWe retrospectively analyzed 2567 consecutive female patients with pT1\\u0026ndash;3N0 breast cancer who underwent curative surgery between January 2005 and December 2014. Among these, 1302 patients met the eligibility criteria of the EORTC 22922/10925 trial. Clinicopathologic characteristics, treatment details, and follow-up data were systematically collected. Primary endpoints included disease-free survival (DFS), local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), locoregional recurrence\\u0026ndash;free survival (LRRFS), distant metastasis\\u0026ndash;free survival (DMFS), breast cancer recurrence\\u0026ndash;free survival (BCRFS), overall survival (OS), and breast cancer\\u0026ndash;specific survival (BCSS).\\u003c/p\\u003e\\u003ch2\\u003eResults:\\u003c/h2\\u003e\\u003cp\\u003eThe EORTC-matched cohort demonstrated high 8.3-year survival: LRRFS 96.4%, DMFS 93.6%, DFS 90.0%, and OS 95.2%. In the overall cohort, non-RNI patients achieved 97.1% 8.3-year and 96.7% 10-year LRRFS. Multivariate analysis confirmed age\\u0026thinsp;\\u0026le;\\u0026thinsp;40 years and tumor size\\u0026thinsp;\\u0026gt;\\u0026thinsp;2.5 cm as independent LRRFS risk factors (both P\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05). Although high-risk patients (1\\u0026ndash;2 factors) had significantly lower LRRFS than low-risk patients (0 factors), their absolute outcomes remained favorable (95.0% at 8.3 years and 94.4% at 10 years).\\u003c/p\\u003e\\u003ch2\\u003eConclusion:\\u003c/h2\\u003e\\u003cp\\u003ePatients with pT1\\u0026ndash;3N0 breast cancer receiving modern systemic therapy have excellent survival and low locoregional recurrence rates, both in the EORTC 22922/10925-matched cohort and overall. Despite higher risks associated with young age and larger tumors, absolute recurrence rates remain low, suggesting that routine RNI can be safely omitted in these patients.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Re-evaluating the Role of Regional Nodal Irradiation for Node‐Negative Breast Cancer in the Modern Therapy Era: A Matched Cohort Analysis of EORTC 22922/10925\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2025-09-01 09:23:44\",\"doi\":\"10.21203/rs.3.rs-7351544/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"bf2bebc4-2ab5-4733-9d79-1463da4ea172\",\"owner\":[],\"postedDate\":\"September 1st, 2025\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"posted\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2025-12-18T23:23:25+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2025-09-01 09:23:44\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-7351544\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-7351544\",\"identity\":\"rs-7351544\",\"version\":[\"v1\"]},\"buildId\":\"8U1c8b4HqxoKbykW_rLl7\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}