Axillary surgery after neoadjuvant therapy: rethinking completion axillary dissection for residual micrometastatic disease

The management of the axilla in breast cancer has undergone a profound transformation over the past two decades. While completion axillary lymph node dissection (cALND) was historically considered mandatory for any nodal involvement, several landmark trials—including ACOSOG Z0011, IBCSG 23-01, and AMAROS—demonstrated that routine cALND can be safely omitted in selected patients with limited nodal disease undergoing upfront surgery (1-3). However, the optimal management of residual micrometastatic nodal disease (ypN1mi) after neoadjuvant systemic therapy (NST) remains uncertain. In this context, the recently reported OPBC-07/microNAC study provides important new insights into whether completion of axillary dissection is necessary for patients with micrometastatic residual disease following NST.

The neoadjuvant setting introduces additional complexity. NST can substantially reduce nodal tumour burden, yet the clinical significance of residual micrometastatic disease—defined as tumour deposits measuring 0.2–2.0 mm—remains unclear. Unlike micrometastases detected at upfront surgery, ypN1mi represents residual disease persisting despite systemic therapy and may indicate treatment-resistant tumour biology. This has prompted ongoing debate regarding whether completion of axillary dissection remains necessary in this setting or whether de-escalation strategies used in upfront surgery can safely be extended to this population.

Two recent large studies provide important data addressing this question. Zhang et al. analysed the Surveillance, Epidemiology, and End Results (SEER) registry [2010–2021] and found no significant differences in overall survival (OS), disease-free survival (DFS), or breast cancer-specific survival (BCSS) between patients treated with sentinel lymph node biopsy (SLNB) alone versus SLNB plus cALND (4). Subgroup analyses should be interpreted cautiously. In the SEER analysis, a non-significant trend toward improved OS with SLNB alone was observed in the triple-negative breast cancer (TNBC) subgroup, whereas in the microNAC cohort a higher rate of axillary recurrence was reported among TNBC patients who did not undergo cALND. These findings should be interpreted carefully because the SEER analysis evaluated survival outcomes, whereas the microNAC study reported axillary recurrence. Given the small sample sizes and exploratory nature of these analyses, these observations should be considered hypothesis-generating rather than practice-changing, and further prospective evaluation is warranted.

Similar findings were reported in the international OPBC-07/microNAC cohort study by Montagna et al. (5). With a median follow-up of 3.1 years, axillary recurrence rates were similarly low regardless of whether patients underwent cALND (1.7% vs. 2.3%, P=0.92). Importantly, approximately 80% of patients received regional nodal irradiation (RNI), which likely contributed to excellent locoregional control. On multivariable analysis, cALND was not independently associated with reduced risk of axillary or invasive recurrence.

These findings align with accumulating evidence from other post-NST cohorts. Barrio et al. demonstrated that axillary recurrence after SLNB alone following NST is rare in patients with cN1 disease rendered clinically node-negative, provided adequate sentinel node retrieval is achieved (6). Similarly, results from more than 1,500 patients enrolled in the I-SPY2 trial showed that omission of cALND in selected patients was not associated with worse axillary recurrence, locoregional recurrence, distant recurrence-free survival, or event-free survival (7). Studies examining patients with isolated tumour cells [ypN0(i+)] have also reported very low axillary recurrence rates without routine cALND (8).

Advances in systemic therapy have also reshaped the clinical context in which axillary surgery decisions are made. Contemporary targeted therapies and immunotherapy have substantially improved outcomes across breast cancer subtypes, and the presence of residual disease—whether in the breast or axilla—often guides adjuvant treatment escalation. Consequently, the prognostic importance of residual nodal burden must increasingly be interpreted alongside tumour biology and systemic therapy response (9,10).

For example, antibody-drug conjugates such as trastuzumab deruxtecan have demonstrated improved invasive DFS compared with trastuzumab emtansine in patients with residual HER2-positive disease after neoadjuvant therapy (11). In hormone receptor–positive disease, CDK4/6 inhibitors such as abemaciclib have improved long-term outcomes in high-risk patients (12), while immune checkpoint inhibitors and PARP inhibitors provide additional therapeutic options in triple-negative and BRCA-mutated disease (13,14).

Axillary radiotherapy has emerged as an effective alternative to surgical clearance for regional disease control. The AMAROS trial demonstrated equivalent oncological outcomes between axillary radiotherapy and ALND with substantially lower morbidity (3). Extension of this principle to the post-neoadjuvant setting appears reasonable and may partly explain the low recurrence rates observed in contemporary observational studies.

Ongoing trials are also evaluating whether RNI can be safely de-escalated. The ATNEC trial, for example, is investigating whether axillary treatment can be safely omitted in patients with T1–3N1M0 breast cancer whose axillary nodes have converted to pathologically negative (ypN0) following neoadjuvant chemotherapy (15). Treatment decisions must also consider patient-specific factors, including the risk of lymphoedema associated with both ALND and radiotherapy. Some patients may prefer surgical management—particularly when immediate lymphatic reconstruction is available—to avoid potential radiotherapy-related complications. Similarly, in patients undergoing implant-based breast reconstruction, regional radiotherapy may increase the risk of reconstructive complications, highlighting the importance of multidisciplinary decision-making.

Targeted axillary dissection (TAD), which combines sentinel node biopsy with selective removal of a previously biopsied metastatic node after localisation, improves staging accuracy by ensuring retrieval of the originally involved node and has been shown to reduce false-negative rates compared with SLNB alone (16). However, current evidence does not clearly demonstrate superior oncological outcomes compared with SLNB, and long-term data remain limited. Accordingly, TAD may be considered a useful staging strategy when feasible, although its routine use remains an area of ongoing investigation.

Current guidelines reflect the evolving but still incomplete evidence base. The 2025 AGO Breast Commission no longer recommends routine cALND for ypN1mi, acknowledging that it rarely alters staging or treatment decisions (17). In contrast, National Comprehensive Cancer Network (NCCN), European Society for Medical Oncology (ESMO), and American Society of Clinical Oncology (ASCO) guidelines continue to recommend completion of axillary dissection for residual nodal disease after neoadjuvant therapy, including micrometastases, pending stronger prospective evidence.

The evolving position of the AGO Breast Commission is informed in part by emerging prospective data from the AXSANA study, a large multicentre cohort evaluating axillary management strategies after neoadjuvant therapy (18). Although long-term oncologic outcomes remain pending, early results suggest that axillary de-escalation strategies are increasingly adopted in carefully selected patients.

Several limitations should temper interpretation of the currently available data. Most studies supporting omission of cALND in ypN1mi are retrospective or registry-based analyses and therefore susceptible to selection bias and confounding by indication. In large database studies such as SEER, important clinical details—including radiotherapy fields, systemic therapy regimens, and surgical decision-making—are often incompletely captured. Similarly, the microNAC study represents a multicentre observational cohort with heterogeneous treatment approaches, including variability in radiotherapy use and systemic therapy protocols. In addition, follow-up remains relatively short for survival outcomes, particularly for hormone receptor-positive diseases where late recurrences are common.

Taken together, the available observational evidence suggests that routine cALND may represent unnecessary treatment for many patients with ypN1mi, particularly when effective systemic therapy and regional radiotherapy are delivered. However, the absence of prospective randomized trials specifically addressing this population means that definitive conclusions cannot yet be drawn.

In summary, emerging observational evidence suggests that omission of cALND may be feasible for selected patients with residual micrometastatic nodal disease after neoadjuvant therapy, particularly when effective systemic therapy and regional radiotherapy are administered. The OPBC-07/microNAC study contributes valuable contemporary data to this evolving discussion and highlights the feasibility of axillary de-escalation in appropriately selected patients. Real-world data indicate that multidisciplinary teams are already de-escalating axillary surgery, with only 39% of patients with clinically node-positive disease at diagnosis undergoing cALND after NST in contemporary cohorts (19). However, the current evidence base remains limited by retrospective study designs and relatively short follow-up. Ongoing prospective trials such as Alliance A011202 and TAXIS will be essential to determine the optimal management of residual nodal disease in this setting (20,21). Until such data matures, management of ypN1mi should be individualized within a multidisciplinary framework that considers tumour biology, response to systemic therapy, radiotherapy plans, reconstructive considerations, and patient preferences.

AI statement: this article adheres to the TITAN Guidelines 2025 for transparent reporting and governance of artificial intelligence use in surgical research (22).

Acknowledgments

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