Targeted axillary dissection versus sentinel lymph node biopsy after neoadjuvant chemotherapy: are we underestimating the clinical significance of staging accuracy?

Abdulla and colleagues present a timely systematic review and meta-analysis comparing sentinel lymph node biopsy (SLNB) with targeted axillary dissection (TAD) for patients with initially node-positive breast cancer downstaged to ycN0 following neoadjuvant chemotherapy, reporting equivalent axillary recurrence and overall survival (OS) but a modestly worse 3-year disease-free survival (DFS) with SLNB compared with TAD [odds ratio (OR) 1.53; 95% confidence interval (CI): 1.11–2.12; P=0.01] (1). Their work reinforces the evolving paradigm of axillary de-escalation and contributes important outcome data to a field that has largely focused on diagnostic accuracy. However, several limitations warrant careful consideration when interpreting these findings and their applicability to clinical practice.

The DFS signal: interpreting clinical relevance with caution

While the authors appropriately note that the observed DFS difference may reflect confounding, the finding merits careful consideration. Accurate axillary staging after neoadjuvant therapy plays an important role in guiding adjuvant systemic (2-5) and radiotherapy (6) decisions. It is therefore biologically plausible that differences in staging accuracy could influence downstream treatment pathways and, potentially, clinical outcomes.

The observation that SLNB was associated with inferior DFS compared with TAD may be consistent with this rationale; however, this relationship should be interpreted cautiously, as the available data do not establish a direct causal link. Our previously published systematic review demonstrated that TAD is more accurate than SLNB alone in staging the axilla after neoadjuvant chemotherapy (7). In that analysis of 17 studies encompassing 1,358 TAD procedures using wire-free localisation technologies, omission of marked lymph node biopsy would have resulted in under-staging in 15.2% of cases, compared with 5.4% if SLNB were omitted (P<0.001).

Although these findings provide a potential mechanistic explanation for differences in outcomes, they should be regarded as hypothesis-generating rather than definitive evidence of causation. Furthermore, the absence of these contemporary accuracy data in the current meta-analysis limits the contextual interpretation of the DFS findings.

Interpreting the OS signal

The pooled analysis did not demonstrate a statistically significant difference in 3-year OS (OR 2.12; 95% CI: 0.59–7.55; P=0.25). While the numerical difference in events may be of interest, it should be interpreted with caution given the small number of events and limited follow-up. Importantly, lack of statistical significance should not be equated with equivalence, but neither does it establish a clinically meaningful difference.

Longer follow-up will be required to determine whether any divergence in survival outcomes emerges over time.

Inadequate follow-up for meaningful survival interpretation

The median follow-up of 34 months (range, 25–42 months) represents an important limitation. Hormone receptor-positive, HER2-negative disease constituted a substantial proportion of the cohort, and in this subgroup, late recurrences beyond 5 years are well recognised.

Accordingly, 3-year OS is an insensitive endpoint for assessing long-term outcomes, and the current data should not be interpreted as establishing equivalence between SLNB and TAD. The potential impact of staging accuracy on systemic therapy escalation, radiotherapy decisions, and late recurrence risk remains uncertain and requires longer-term evaluation.

Radiotherapy as a potential confounder

Approximately 90% of patients received regional nodal irradiation (RNI), although details regarding indications, target volumes, and dosing were limited. Radiotherapy may mitigate the impact of residual nodal disease and could therefore attenuate observable differences between surgical approaches.

As such, similar rates of axillary recurrence may reflect treatment compensation rather than true equivalence of surgical staging strategies. This consideration may become increasingly relevant as evolving evidence, including NSABP B-51, informs potential de-escalation of radiotherapy in selected patients (8).

Heterogeneity and limited biological stratification

The inclusion of biologically heterogeneous subtypes limits the interpretability of pooled outcomes. The clinical implications of staging accuracy may differ across hormone receptor-positive, HER2-positive, and triple-negative disease (9), yet subgroup analyses were limited.

Without consistent stratification by tumour biology, it remains challenging to determine which patient populations may derive the greatest benefit from different staging approaches.

Reconsidering clinical equipoise

The authors suggest that equipoise remains between SLNB and TAD; however, their findings also demonstrate a statistically significant difference in DFS favouring TAD. While this observation is noteworthy, it should be interpreted in the context of the limitations outlined above, including potential confounding and short follow-up.

Taken together with existing evidence demonstrating differences in staging accuracy, these data highlight areas of uncertainty rather than definitively resolving the question of equivalence. Further prospective studies are required to clarify whether differences in staging translate into meaningful long-term clinical benefit.

Conclusions

This meta-analysis supports the short-term oncologic safety of both SLNB and TAD in the context of contemporary multidisciplinary care, including widespread use of RNI. However, limitations including short follow-up, heterogeneity, and incomplete characterization of adjuvant therapies warrant cautious interpretation.

The observed differences in DFS, together with known differences in staging accuracy, suggest that further investigation is needed to better define the clinical significance of these findings. Future studies with longer follow-up and improved biological stratification will be essential to inform optimal axillary management strategies.

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-2026-1-0006/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-2026-1-0006/coif). K.M. serves as an unpaid editorial board member of Translational Breast Cancer Research from May 2025 to June 2027. K.M. reports a research grant from the Breast Cancer Charity; consulting fees from QMedical and Sebbin; honoraria from Merit Medical and QMedical Corporations; and holds stocks in HCA Healthcare, Datar Genetics, and OncoBotanica. 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/.

References

1. Abdulla HA, McGarry J, Kaczorowska R, et al. Oncologic Outcomes of Sentinel Lymph Node Biopsy Versus Targeted Axillary Dissection for Node-Positive Breast Cancer Patients After Neoadjuvant Chemotherapy: A Systematic Review and Meta-Analysis. Ann Surg Oncol 2026;33:4453-62. [Crossref] [PubMed]
2. Loibl S, Park YH, Shao Z, et al. Trastuzumab Deruxtecan in Residual HER2-Positive Early Breast Cancer. N Engl J Med 2026;394:845-57. [Crossref] [PubMed]
3. Masuda N, Lee SJ, Ohtani S, et al. Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy. N Engl J Med 2017;376:2147-59. [Crossref] [PubMed]
4. Johnston S, Martin M, O'Shaughnessy J, et al. Overall survival with abemaciclib in early breast cancer. Ann Oncol 2026;37:155-65. [Crossref] [PubMed]
5. Ganz PA, Bandos H, Španić T, et al. Patient-Reported Outcomes in OlympiA: A Phase III, Randomized, Placebo-Controlled Trial of Adjuvant Olaparib in gBRCA1/2 Mutations and High-Risk Human Epidermal Growth Factor Receptor 2-Negative Early Breast Cancer. J Clin Oncol 2024;42:1288-300. [Crossref] [PubMed]
6. Mokbel K, Oner M. Translating NSABP B-51 findings into practice: rethinking regional nodal irradiation in breast cancer. Transl Cancer Res 2025;14:7472-7. [Crossref] [PubMed]
7. Varghese J, Patani N, Wazir U, et al. Wire-Free Targeted Axillary Dissection: A Pooled Analysis of 1300+ Cases Post-Neoadjuvant Systemic Therapy in Node-Positive Early Breast Cancer. Cancers (Basel) 2024;16:2172. [Crossref] [PubMed]
8. Mamounas EP, Bandos H, White JR, et al. Omitting Regional Nodal Irradiation after Response to Neoadjuvant Chemotherapy. N Engl J Med 2025;392:2113-24. [Crossref] [PubMed]
9. Schmid P, Cortes J, Dent R, et al. Overall Survival with Pembrolizumab in Early-Stage Triple-Negative Breast Cancer. N Engl J Med 2024;391:1981-91. [Crossref] [PubMed]