Expanding Eligibility for Targeted Axillary Dissection

The treatment of regional nodal disease in breast cancer has shifted to a biologically informed and response-adapted approach. Targeted axillary dissection (TAD) has been demonstrated to be a safe and feasible approach to patients with breast cancer who present with cN1 disease and who convert to ycN0 following neoadjuvant systemic chemotherapy (NAC). When the biopsy-proven positive node is marked at the time of diagnosis with a radiological clip and/or localizer, TAD (removal of the clipped node and use of dual tracer for sentinel lymph node biopsy (SLNB)) has a lower false-negative rate than SLNB without intentional removal of the clipped node.^1,2 However, the primary application of TAD has been for patients with a low nodal disease burden, defined as cN1 by pretreatment clinical assessment.^1,2 With recent advances in modern systemic therapy resulting in improved pathological complete response (pCR) rates after NAC,^3-6 we can now ask whether it might be reasonable to expand TAD to the treatment of patients with advanced nodal disease treated with NAC and rendered ycN0. That is, might we take a “treatment response approach” rather than an “anatomic extent of disease approach” to locoregional treatment?

In this edition of the Annals of Surgical Oncology, Lee et al. report on their prospective single-arm cohort trial that enrolled patients with cT1–4 breast cancer treated with NAC with either cN1 disease and ≥4 abnormal nodes or cN2 or N3 disease.⁷ All had a favorable clinical response on post-NAC imaging and subsequently underwent TAD followed by completion axillary lymph node dissection.⁷ While standard TAD requires removal of ≥3 nodes, including the clipped node to minimize the FNR,^1,2 the protocol only required removal of a minimimum of one SLN in addition to the clipped node. The study enrolled 55 patients, of whom 53 had a successful TAD, a technical success rate of 96%, and were evaluated for the study endpoint. Notably, among the 27 patients with residual nodal disease, TAD identified every case, yielding a false-negative rate (FNR) of 0%, a negative predictive value of 100%, and 100% diagnostic accuracy in identifying those patients who had a true pCR with TAD alone. Interestingly, the investigators found that the combination of SLNB plus retrieval of the clipped node (TAD) outperformed both SLNB alone (FNR 11.1%) and clipped node excision alone (FNR 18.5%) in this setting. The axillary pCR rate was 51%, and 60% of the cohort had hormone-receptor positive disease. While this data is compelling and provides pragmatic evidence favoring expansion of TAD to this population, caution is warranted as more evidence is required before incorporating this TAD eligibility expansion into standard surgical practice.

First, the sample size is modest, thus confidence intervals around the predicted estimates are wide and, as the authors appropriately acknowledge, a larger cohort could yield different estimates of diagnostic performance. Secondly, the population is somewhat heterogeneous in their initial nodal disease burden and tumor biology and perhaps confounded by the subjectivity in defining an abnormal axillary lymph node on imaging.⁸ Patients with cN1 disease in this cohort specifically required radiographic assessment to quantify the number of abnormal nodes to meet study inclusion, but it is unclear whether the study’s protocol defined specific parameters for classification. Similarly, for patients with cN3 disease, it is unclear whether patients underwent biopsies of abnormal nodes seen in non-axillary nodal basins or if the definition of cN3 disease was based on imaging findings alone. Furthermore, the protocol specified that included patients have a radiologic complete or partial response to treatment, but the latter was not defined. Particularly as immune checkpoint inhibitors are added to NAC regimens and may confound interpretation of post-treatment nodal imaging findings, specific criteria for defining a radiologic complete response are required.⁹

One data element that will be beneficial to report in future work is the specific number of abnormal axillary lymph nodes in those patients with cN2 and cN3 disease. Specifically for patients with cN3 disease, some may be categorized as cN3 based on abnormal internal mammary, supraclavicular, or infraclavicular lymph nodes rather than specifically having a high burden of axillary disease. While just under half of the cohort had cN3 (40%) disease, it is unclear what the specific axillary nodal disease burden was for these patients. For patients with cN3 disease and a single abnormal axillary node, one can argue that many are currently candidates for TAD after NAC, and for those who have cN2/3 disease and no abnormal axillary nodes, conventional axillary SLNB would likely be performed. Future study of the central question of how well TAD reflects the axillary nodal basin response after NAC might focus specifically on those patients with four or more abnormal axillary nodes on pretreatment imaging rather than the burden of disease in nonaxillary nodal basins.

In the modern era of multidisciplinary breast cancer treatment, accurate surgical axillary staging after NAC is critical not only for assessing residual disease to guide adjuvant systemic therapy planning,^10-12 but also for identifying patients with a nodal pCR who may be candidates for de-escalation of nodal radiation.¹³ The forthcoming results from the Alliance 11202 and TAXIS trials will clarify the role of completion ALND in patients with residual nodal disease after NAC.^14,15 While the single-arm study of Lee and colleagues was conducted in China, there are known racial and socioeconomic disparities in who receives NAC in the United States, which underscores the need for future trials to enroll diverse patient populations to determine the generalizability of potentially expanding TAD eligibility.^16,17

Ultimately the study was designed to test diagnostic accuracy, not the oncologic safety, of TAD in patients with advanced nodal disease. Accurate determination of residual axillary nodal disease burden after NAC is key in determining candidacy for additional potentially lifesaving systemic and locoregional therapies. While the data from Lee et al. demonstrated a 0% false-negative rate for TAD in this single-arm prospective study of 53 evaluable patients with advanced nodal disease,⁷ the decision to broadly de-escalate axillary surgery must be built on strong and replicable data not only on the diagnostic accuracy of TAD, but on key oncologic outcomes. In this way we can best determine whether surgical de-escalation might be achievable without compromising disease control and survival. The novel findings presented here support the rationale for a larger phase II trial with an appropriately powered and rigorously defined cohort to confirm these results and to assess oncologic outcomes.