Axillary management in patients with sentinel lymph node micrometastases following neoadjuvant systemic therapy: a call for de-escalation

Introduction

The management of the axilla in breast cancer patients following neoadjuvant systemic therapy (NST) has evolved considerably in recent years. There is increasing recognition that extensive axillary surgery may not improve survival but contributes significantly to morbidity, including lymphedema, neuropathic pain, and impaired shoulder function—complications that adversely affect long-term quality of life.

Shin et al. (1) reported a 24.2% incidence of non-sentinel lymph node (non-SLN) metastases in patients with SLN micrometastasis (SLNmi) following NST, recommending axillary lymph node dissection (ALND) as the standard management. However, an expanding body of real-world and clinical trial evidence supports a more conservative, evidence-based, and patient-centered approach to axillary management that may be both safe and appropriate.

Limitations of intraoperative sentinel node assessment post-NST

Frozen section (FS) analysis of SLNs after NST has limited sensitivity for detecting SLNmi and isolated tumor cells, with reported rates below 80% (2,3). In Shin et al.’s study, 17% of SLNmi cases were upstaged to macrometastases on paraffin sections, highlighting the limitations of FS alone. However, only 6% of patients with SLNmi had non-SLN macrometastases, suggesting that routine ALND may overtreat 94% of such patients, exposing them to unnecessary morbidity without a clear oncological benefit.

Prognostic implications of SLNmis

In patients undergoing upfront surgery, SLNmi is associated with a slightly increased risk of additional axillary disease and a modestly worse prognosis compared to node-negative status (2). However, this risk must be balanced against the morbidity associated with ALND and therefore the latter is safely omitted in patients found to have SLNmi (2). In the context of NST, SLNmi is a negative prognostic factor significantly associated with additional non-SLN metastases, while ypN1mi does not influence the prognosis compared to ypN0 (4).

Modern systemic therapies increasingly determine prognosis, as evidenced by the CREATE-X (capecitabine for residual cancer as adjuvant therapy), KATHERINE (adjuvant trastuzumab emtansine vs. trastuzumab), and monarchE (abemaciclib combined with endocrine therapy) trials, which demonstrated that the benefits of adjuvant agents [capecitabine, trastuzumab emtansine (T-DM1), abemaciclib] were independent of residual axillary disease burden (5,6).

Axillary radiotherapy (ART) versus completion ALND

Multiple studies have shown that ART provides equivalent regional control to ALND, with reduced morbidity. Chun et al. (7) found no significant differences in oncologic outcomes between sentinel lymph node biopsy (SLNB) alone and ALND in selected post-NST patients. The AMAROS trial (8) and IBCSG 23-01 trial (9) further demonstrated that ART can safely replace ALND in SLN-positive patients undergoing primary surgery or presenting with SLNmi.

Extending these findings to post-NST care, the I-SPY2 trial (10) reported no increase in axillary or distant recurrence when ALND was omitted in patients with either ypN0 or ypN+ disease.

The Oncoplastic Breast Consortium-05/ICARO cohort study (11), which included patients from 62 centers in 18 countries, found that axillary recurrence following omission of ALND in patients with ypN0(i+) status was rare, supporting the safety of a de-escalated approach.

A multicenter retrospective study involving 1,144 patients across 25 centers in 11 countries showed 5-year axillary, locoregional, and invasive recurrence rates of 1.0%, 2.7%, and 10%, respectively. Notably, the 3-year cumulative incidence of axillary recurrence did not significantly differ between targeted axillary dissection (TAD) and SLNB (0.5% vs. 0.8%; P=0.55) (12).

At the 2025 Society of Surgical Oncology meeting, Montagna et al. presented data showing that SLNB and TAD were comparable to ALND in terms of overall survival, disease-free survival, and locoregional recurrence among patients with residual micrometastatic nodal disease post-NST, suggesting that ALND may not be necessary for all ypN1mi cases (13).

Biological rationale for de-escalation

Current understanding of metastasis highlights systemic dissemination via circulating tumor cells (CTCs) and cancer stem cells (14,15)—processes that are unlikely to be influenced by local surgery. Therefore, the presence of SLNmi may serve more as a biomarker for systemic therapy intensification than as a rationale for ALND. This supports a shift toward biologically driven, less invasive approaches.

The role of TAD post-NST

A major limitation of Shin et al.’s study is the omission of TAD in 93% of their node-positive cohort. Current best practice includes marking biopsy-proven positive nodes before NST and performing TAD post-treatment to optimize staging accuracy. Our recent pooled analysis revealed that omitting marked lymph node biopsy (MLNB) leads to axillary under staging in 15.2% of patients (16). TAD improves staging precision, reduces overtreatment, and supports individualized treatment planning.

Implications for clinical practice

Patients with SLNmi following NST should be evaluated in a multidisciplinary setting, considering response to NST, tumor biology (e.g., receptor status, genomic risk), systemic therapy received, radiotherapy plans, comorbidities, and patient preferences. For many—particularly those with favorable tumor biology and good treatment response—ART offers a safe, effective alternative to ALND, achieving disease control while minimizing morbidity. These insights reflect a broader paradigm shift toward personalized and de-escalated locoregional therapy.

Conclusions

SLNmi after NST is associated with an increased risk of residual nodal disease, but routine ALND likely represents overtreatment for the majority. With the effectiveness of systemic therapy, the safety of ART, and the morbidity of ALND, a conservative surgical approach is increasingly justified. The results of the Alliance A011202 trial are anticipated to offer important insights into the role of axillary radiation in managing breast cancer with residual disease following neoadjuvant chemotherapy. These findings may prompt a shift in clinical practice, potentially allowing select patients with residual nodal disease to avoid more extensive axillary surgery (17). Until then, individualized, evidence-based approaches that prioritize oncologic safety and quality of life are warranted—reserving ALND only when the benefits clearly outweigh the risks.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was a standard submission to the journal. The article has undergone external peer review.

Peer Review File: Available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-15/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-15/coif). K.M. serves as an unpaid editorial board member of Translational Breast Cancer Research from May 2025 to June 2027. K.M. is a fractional shareholder of Datar Genetics’ stock. K.M. has received honoraria for offering academic and clinical advice to Merit Medical and QMedical corporations. Furthermore, he owns shares in HCA Healthcare UK. The other author has 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.

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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