Local recurrence in nipple-sparing mastectomy without intraoperative radiotherapy (IORT) in breast cancer

Introduction

Nipple-sparing mastectomy (NSM) is increasingly used in the treatment of breast cancer, particularly in patients with genetic mutations, large tumor-to-breast volume ratios, or multicentric lesions in whom breast-conserving surgery (BCS) is not feasible due to the risk of breast deformity. NSM preserves breast contour and symmetry, which are important for patient satisfaction and quality of life. Data from the NSABP B-06 trial demonstrated no significant difference in oncologic outcomes between patients treated with BCS plus radiation therapy (RT) and those undergoing mastectomy (1). However, BCS without RT resulted in higher recurrence rates, highlighting the role of RT in managing residual breast tissue (1,2).

Although NSM is a form of mastectomy, concerns remain regarding residual glandular tissue beneath the nipple-areolar complex (NAC), which may harbor microscopic disease and increase the risk of locoregional recurrence (LRR). RT has been proposed as a strategy to eradicate residual tissue in this area. For example, a large Milan cohort incorporating intraoperative radiotherapy (IORT) during NSM reported no NAC recurrences and only a 1.4% recurrence rate elsewhere (3).

Several studies have examined the role of preoperative or postoperative RT in NSM. Some suggest that NSM without RT achieves acceptable oncologic outcomes, whereas others advocate for RT because of concerns regarding microscopic residual disease (4). Due to conflicting results and the absence of level I evidence, no consensus or formal guidelines exist regarding RT after NSM (5).

In standard mastectomy, postmastectomy RT (PMRT) is recommended for patients with high-risk features such as ≥4 positive axillary lymph nodes, tumors ≥5 cm, T4 disease, or positive/close surgical margins (<0.1 cm) (6-9). However, not all patients meet these criteria. Furthermore, RT may increase complications, including impaired blood supply to the skin and NAC, fat necrosis, and capsular contracture, particularly in those undergoing reconstruction (10-16).

At present, there is no strong evidence to support routine RT after NSM, nor clear recommendations regarding optimal dose or technique. While adjuvant RT is the standard of care following lumpectomy, its role after NSM remains uncertain, particularly in the context of modern systemic therapies (5). Extrapolating PMRT indications from conventional mastectomy to NSM is problematic due to the unique anatomy and surgical technique of NSM, and the oncologic safety of the procedure continues to be debated.

The aim of this study was to evaluate local recurrence following NSM, comparing patients who received RT with those who did not, in a cohort treated without IORT. We present this article in accordance with the STROBE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-2026-0272/rc).

Methods

This study was a retrospective chart review of breast cancer patients who underwent NSM at the Breast and Endocrine Surgery Unit, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, between January 2007 and July 2021. Patients with missing information on RT or incomplete medical records were excluded from the analysis. Data collected included demographic characteristics, mammographic findings, pathological information, surgical details, treatment modalities, postoperative complications, and oncologic outcomes.

The primary objective of this study was to evaluate local and regional recurrence rates following NSM, comparing patients who received adjuvant RT with those who did not. Secondary objectives included assessing locoregional disease-free survival (LRDFS), disease-free survival (DFS), overall survival (OS), and identifying clinicopathological factors associated with the administration of RT as well as factors linked to recurrence in patients undergoing NSM.

Recurrence definitions were standardized as follows: local recurrence was defined as the reappearance of breast cancer in the ipsilateral skin, NAC, breast, or chest wall, measured from the date of surgery to the date of detection. Regional recurrence referred to metastasis to ipsilateral axillary, infraclavicular, or supraclavicular lymph nodes, whereas contralateral recurrence was defined as a newly diagnosed breast cancer in the contralateral breast. Distant recurrence was defined as metastatic disease at any site other than local or regional sites. LRDFS was calculated from diagnosis to the first local or regional recurrence, DFS from diagnosis to the first event of local recurrence, regional recurrence, contralateral breast cancer, distant metastasis, or a new primary breast cancer, and OS from diagnosis to death from any cause. Patients were followed with regular physical examinations, mammography, and annual breast ultrasound.

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of Mahidol University (COA No. MURA 2023/603). As this was a retrospective study involving review of existing medical records, individual informed consent was waived by the Institutional Review Board, given that the data collection did not expose patients to any additional risk, involved no intervention, and all patient information was handled with strict confidentiality.

Statistical analysis

Descriptive statistics were used to summarize clinicopathological characteristics. Continuous variables were compared using Student’s t-test or the Wilcoxon rank-sum test, depending on the distribution of the data. Categorical variables were analyzed using the Chi-squared test or Fisher’s exact test, as appropriate. Risk factors for recurrence were evaluated using univariate and multivariate Cox proportional hazards regression models, with results expressed as hazard ratios (HRs) and 95% confidence intervals (CIs). A P value <0.05 was considered statistically significant. All analyses were performed using STATA version 17 (StataCorp LLC, College Station, TX, USA).

Results

Patient and tumor characteristics

A total of 148 NSMs were analyzed, with 106 patients not receiving RT and 42 receiving RT. The cohort included 116 invasive carcinomas and 33 ductal carcinoma in situ (DCIS), with RT patients more likely to have invasive disease. Most patients were premenopausal (79.6%), and the mean age at diagnosis was 43 years; RT patients were younger than non-RT patients (39.9 vs. 44.6 years, P=0.002). The majority presented with T1–2 tumors (94.3%), node-negative status (64.1%), and estrogen receptor (ER)-positive disease (81.6%). Compared with the non-RT group, RT patients had higher rates of T3–4 tumors (11.9% vs. 3.1%, P<0.01), nodal involvement (85.4% vs. 16.3%, P<0.01), and lymphovascular invasion (65.8% vs. 22.9%, P<0.01). Tumor grade and lesion number were similar between groups. Positive margins occurred in 10 patients (6.8%), most of whom received RT (Table 1).

Treatments

Chemotherapy was administered to 91 patients (68.4%), more commonly in the RT group (100% vs. 55.3%, P<0.01). Among 21 human epidermal growth factor receptor 2 (HER2)-positive patients, 11 received trastuzumab. Endocrine therapy was given to 118 patients (83.1%), predominantly tamoxifen. Use of endocrine therapy and trastuzumab did not differ between groups (Table 1).

Breast reconstruction was mainly implant-based (43.9%), followed by autologous (34.9%) and combined autologous plus implant (21.2%), with no difference between groups. Whole-breast RT was delivered to 42 patients (28%). Complication rates—including skin flap necrosis, NAC necrosis, seroma, fat necrosis, and wound dehiscence—were comparable between groups (Table 1).

In univariate analysis, RT use was associated with invasive histology, T3 stage, nodal positivity, lymphovascular invasion, and positive margins; multivariate analysis confirmed nodal positivity and positive margins as significant predictors (Table 2).

Oncological outcomes

After a median follow-up of 72 months, 9 patients (6%) experienced LRR (median time 47 months). Due to the small number of events, independent risk factors could not be determined. RT did not significantly affect local or regional recurrence or overall mortality. Distant metastases were more frequent in RT patients. In the non-RT group, 8 patients (7.5%) experienced recurrence (7 local, 1 regional), whereas 1 patient (2.4%) in the RT group had a local recurrence. Distant metastases occurred in 9 patients (8.3%): 7 (6.9%) non-RT and 2 (28.6%) RT. One death occurred in the RT group (2.4%). Contralateral breast cancer developed in 5 patients (3.4%), with similar distribution between groups (Table 3).

At 10 years, OS was 100% in the non-RT group and 94.7% in the RT group (95% CI: 68.1–99.2%; P=0.08) (Figure 1). Ten-year DFS was 88.2% (95% CI: 78.0–93.9%) in the non-RT group and 97.6% (95% CI: 84.3–99.7%; P=0.24) in the RT group (Figure 2). No significant differences in recurrence or death were observed between groups (Table 3).

Figure 1 OS in the non-RT group and RT group. OS, overall survival; RT, radiation therapy.

Figure 2 DFS in the non-RT group and RT group. DFS, disease-free survival; RT, radiation therapy.

Discussion

NSM is increasingly used in the treatment of breast cancer, offering superior aesthetic results and improved psychosocial and sexual well-being compared to traditional mastectomy (17,18). Meta-analyses have confirmed the oncologic safety of NSM in appropriately selected patients, demonstrating high rates of locoregional control equivalent to skin-sparing mastectomy (SSM) (19). Current contraindications for NSM generally exclude patients with tumor involvement of the NAC, Paget’s disease, pathological nipple discharge, or inflammatory breast cancer (20).

Despite growing acceptance, concerns persist regarding residual breast tissue beneath the NAC. Unlike BCS, standard mastectomy typically involves complete removal of the breast and NAC. Current indications for PMRT focus on high-risk features (T3–4, ≥4 nodes), while the benefit for patients with 1–3 positive nodes remains controversial (8,21). Furthermore, the addition of RT to implant-based reconstruction is associated with increased risks of capsular contracture and reconstructive failure (22). To address residual tissue risks without full breast irradiation, some centers utilize IORT (3).

In our study, we evaluated the safety and oncologic outcomes of NSM without the addition of IORT. The results demonstrated a low rate of recurrence and OS outcomes comparable to large cohorts. Recurrence rates in our cohort (4.7% at 3 years; 7.4% at 5 years) align with findings from the Massachusetts General Hospital, which reported low recurrence rates without routine sub-NAC irradiation (23). Long-term follow-up data from large series, such as those by Galimberti et al., confirm that these favorable outcomes are durable over 10 years (4).

The majority of our patients were staged as T1–2N0–1 and received standard adjuvant therapies. Our findings suggest that adjuvant RT was not significantly associated with recurrence or survival outcomes, consistent with data from studies incorporating IORT (3,24). Patients receiving RT had higher-risk features; however, in multivariate analysis, RT itself was not an independent predictor. Instead, recurrence was driven by tumor multifocality. Tumor-to-nipple distance (TND) did not significantly affect local recurrence in our cohort. However, it was too small of number of recurrence in our cohort to make the conclusion (Table S1). While some studies suggest a rigid cutoff, recent data indicate that closer margins may be safe if the sub-areolar biopsy is negative (25,26). Most local recurrences in our study occurred away from the NAC, supporting the notion that NSM without sub-NAC irradiation is oncologically safe. This conclusion is further supported by analyses of the Surveillance, Epidemiology, and End Results (SEER) database, which affirm the survival equivalence of NSM compared to traditional mastectomy in a nationwide setting (27). Overall, our data support the safety of NSM performed without additional RT directed to the NAC area, when patients are selected based on current oncologic principles and receive standard postoperative care.

Several limitations should be acknowledged. First, this was a retrospective, single-institution analysis, which may limit generalizability. Second, missing data could have introduced bias and influenced recurrence and survival estimates. Third, the relatively small sample size reduced statistical power. Additionally, as this was not a randomized comparison, inherent selection bias affected which patients received RT. Finally, the study did not directly compare outcomes between patients receiving IORT, conventional RT, or no RT.

Future prospective studies with larger sample sizes and randomized designs are warranted to provide level I evidence regarding the role of RT—particularly IORT and targeted sub-NAC irradiation—in NSM. Such investigations will help clarify optimal treatment strategies and support evidence-based decision-making in clinical practice.

Conclusions

Based on our study, NSM without IORT is safe, and selective RT, guided solely by standard criteria such as tumor characteristics, lymph node involvement, and margin status, is safe and associated with a low rate of LRR.

Acknowledgments

Our abstract has been accepted for presentation at the 19^th St. Gallen International Breast Cancer Conference (SGBCC 2025), Vienna, Austria, taking place between the 12^th and 15^th of March 2025.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-2026-0272/rc

Data Sharing Statement: Available at https://gs.amegroups.com/article/view/10.21037/gs-2026-0272/dss

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2026-0272/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-2026-0272/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of Mahidol University (COA No. MURA 2023/603). As this was a retrospective study involving review of existing medical records, individual informed consent was waived by the Institutional Review Board, given that the data collection did not expose patients to any additional risk, involved no intervention, and all patient information was handled with strict confidentiality.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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