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. Author manuscript; available in PMC: 2025 Jan 2.
Published in final edited form as: Surg Oncol Clin N Am. 2023 Jun 9;32(4):693–703. doi: 10.1016/j.soc.2023.05.003

Evidence-Based Strategies to Minimize the Likelihood of Axillary Lymph Node Dissection in Clinically Node-Positive Patients Following Neoadjuvant Chemotherapy

Ashley A Woodfin a, Abigail S Caudle b,*
PMCID: PMC11694792  NIHMSID: NIHMS2043061  PMID: 37714637

INTRODUCTION

The morbidity of axillary lymph node dissection (ALND) has been well studied, with lymphedema as the most concerning complication that can affect quality of life. Current literature quotes rates of lymphedema that range from 20% to 30% following ALND that can double with the addition of adjuvant nodal radiation.1–3 Although there are surgical techniques in development that may treat or prevent lymphedema in the future, understanding when extensive axillary surgery improves oncologic outcomes, and is thus necessary, is critical.1,4

ALND has historically been the standard of care for patients who present with clinically node-positive (cN1) breast cancer after neoadjuvant chemotherapy (NAC) despite the fact that many convert to pathologically node negative. As systemic therapy regimens have advanced in the neoadjuvant setting, we are now seeing higher rates of achieving pathologic complete response (pCR). For triple negative and Human Growth Factor Receptor 2 (HER21) cancers, this has been more significant with the addition of immunotherapy and HER2-targeted therapy achieving overall pCR rates of 45% to 65%,5–7 with an axillary pCR in up to 75% in these populations.8–10 Identifying the patients who have eradication of nodal disease is difficult without complete axillary clearance, so all patients were committed to this operation. However, there are multiple recent trials that have evaluated the accuracy of minimally invasive techniques to assess axillary response to chemotherapy. In the following article, we will discuss the current evidence on safely minimizing axillary surgery in cN 1 patients following NAC.

BACKGROUND

Sentinel Lymph Node Biopsy

Feasibility

Sentinel lymph node biopsy (SLNB) has been well established as technically feasible after NAC despite initial concerns that systemic therapy may lead to fibrosis in lymphatic channels that could affect drainage patterns. In upfront surgery, sentinel lymph node (SLN) detection rates now approach 100%,11–13 with similar rates seen in those patients who are clinically N0 (cN0) that undergo NAC when using dual tracer for the identification at the time of surgery. A single-center retrospective study out of MD Anderson Cancer Center (MDACC) demonstrated no significant difference in the detection rate when looking at patients with cN0 disease that underwent surgery first (99%) compared with those undergoing NAC followed by SLNB (97%) in a study population of more than 3700 patients.14 GANEA, a French multicenter prospective trial, demonstrated a similar SLN detection rate of 94.6% after NAC in those initially cN0, however, found that the detection dropped significantly in patients with initial cN1 dis- ease (81.5%).15

More recent studies including the SENTinel NeoAdjuvant (SENTINA), American College of Surgeons Oncology Group Z1071 (ACOSOG Z1071), and the Sentinel Node Biopsy After NeoAdjuvant Chemotherapy (SN FNAC) trials have included patient populations with cN1-N2 disease before NAC and reported identification rates between 80% and 93%.16–18 A variety of techniques for sentinel lymph node mapping was used in these studies, which may have affected the identification rates. The SENTINA study used radiocolloid alone in 61% of its population, and radiocolloid plus blue dye in 34%, and had the lowest reported SLN detection rate at 80%.16 Whereas the ACOSOG Z1071 trial used dual tracer in 79.1% of the population (4.1% using blue dye only, 16.8% with radiocolloid only) and found that detection rates of at least one SLN was slightly lower in those patients with cN2 disease versus cN1 disease (89.5% vs 92.9%, respectively).17 The SN FNAC trial also had a mix of single versus dual tracer use in their study population and reported a detection rate of 88%.18

Accuracy

In the setting of SLNB, the false-negative rate (FNR) is defined as the proportion of patients with residual nodal disease who had no metastases seen in sentinel nodes. Thus, relying on sentinel node pathologic condition alone would have understaged the extent of residual disease. Although there has been interest in minimally invasive techniques to assess axillary response to NAC, early studies showed an unacceptable FNR although they were primarily single-institutional, retrospective studies.

Three multiinstitutional, prospective registry trials were established to better evaluate the use of SLNB in cN 1 patients after completion of NAC. All 3 trials enrolled cN 1 patients who underwent NAC. At the time of surgery, enrolled patients underwent SLNB followed by completion ALND so that the pathologic condition of the sentinel nodes could be compared with that of the remaining nodes in order to determine the FNR. These 3 trials, SENTINA, ACOSOG Z1071, and the SN FNAC had striking similarities between the trials’ results both as to the accuracy of SLNB as well as technical factors that affect FNR. However, there were some key differences in study design.

SENTINA was a 4-armed study including patients with cN0, cN 1 that converted to cN0 after NAC, and those cN 1 that remained cN 1 after NAC. A unique aspect of this study included performing upfront SLNB on patients in the cN0 arm, with repeat SLNB following NAC in those with initial positive SLNB (arm B). This demonstrated repeat SLNB after NAC was not feasible (detection rate of only 60.8%) nor accurate (FNR 51.6%). When investigating initial SLNB accuracy after NAC, Arm C of the study contained 592 patients that converted from cN 1 to cN0 after NAC. SLNB after NAC performed had an FNR of 14.2%. However, it is notable that only 25% of those in Arm C underwent biopsy to verify nodal status before NAC,16 meaning a quarter of the patients in this cohort could have been cN0.

The ACOSOG Z1071 enrolled 756 patients with cT0–4, cN1–2, M0 breast cancer that underwent NAC, 663 of which were cN1 with ultimately evaluable disease receiving SLNB followed by completion ALND. After data analysis, the FNR of SLNB was calculated at 12.6%, similar to that up the SENTINA trial, and above the prespecified cutoff of 10%.17

SN FNAC included cT0–3, cN1–2, and M0-X receiving NAC. However, this study underwent unplanned interim analysis after the presentation of ACOSOG Z1071, at which point the trial was only at approximately 50% accrual. Considering the similar trial design and goals to ACOSOG Z1071, the study was ended early. The calculated SLNB FNR in this study with n 5 153 was 8.4%, furthermore an axillary PCR of 34.5% was reported.18

Dual tracer

The use of dual tracer refers to using 2 different techniques for sentinel lymph node mapping and identification, including use of a radiotracer such as Tc99 in addition to dye such as isosulfan or methylene blue. Single tracer technique has been shown effective in accurately identifying SLNs in cN0; however, multiple studies have shown that dual tracer technique is superior in cN 1 pts after NAC.14,16–18 All 3 large trials above demonstrated a decrease in the FNR when dual tracers were used: SENTINA 16% versus 9%.16 ACOSOG Z1071 20% versus 11%.17 SN FNAC 16% versus 5.2%.18

Number of sentinel lymph node resected

All 3 trials also demonstrated an inverse correlation between the number of SLN resected and FNR on subgroup analysis. In the SENTINA and ACOSOG Z1071 trials, resection of 3 or more nodes decreased the FNR to less than 10% (FNRs of 7% and 9%, respectively).16,17 Whereas in the SN FNAC trial, a resection of 2 or more nodes lowered the FNR to 4.9%.18

Immunohistochemistry

Use of immunohistochemistry (IHC) plays a significant role in the accuracy of SLNB in this patient population. In the SN FNAC study, all SLNs negative for metastases on hematoxylineosin stain (H&E) staining underwent IHC, and all nodal disease was considered positive including isolated tumor cells (ITCs) and micrometastases (<2 mm). Using H&E evaluation alone, the FNR would have been 13%. The addition of IHC reduced this to less than 10%.18 Once this data was published, the ACOSOG Z1071 did a central analysis of their nodal pathologic condition with IHC and also found a reduced FNR.19

Assessment of the clipped node

Finally, a subgroup of 170 patients in the ACOSOG Z1071 study had a clip placed in their biopsied positive node, even though this was not a mandatory part of the trial. The authors found analysis of the clipped node significant to the accuracy of the SLNB after NAC. It was reported that when the clipped node was retrieved as an SLN, the FNR dropped to 6.8% (CI: 1.9%–16.5%).20 See Table 1.

Table 1.

Feasibility and accuracy of sentinel lymph node biopsy after neoadjuvant chemotherapy

ACOSOG Z107117,19 SENTINA16 SN FNAC18
SLN Identification Rate 92.7% 80% 88%
False-negative rates:
Overall 12.6% 14.2% 13.4%
Single tracer 20.3% 16.0% 16%
Dual tracer 10.8% 8.6% 5.2%
Remove 1 SLN 31% 24.3% 18.2%
Remove 2 SLN 21.1% 18.5% >1 SLN – 4.9%
Remove 3 SLN 9.1% 7.3%
Immunohistochemistry 8.7% Not reported 8.4%
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Techniques to improve the false negative rate of sentinel lymph node biopsy

After review of the 3 large studies above, there are some take away points from sub-group analysis that suggest techniques to reduce the FNR.

  1. Use of dual tracer for SLN mapping

  2. Resecting 2 or more SLN

  3. Confirmatory testing with IHC on negative SLN

  4. Resection of previously biopsied node (clipped node)

Targeted axillary dissection

The data from the ACOSOG Z1071 trial showing an advantage to marking nodes after biopsy confirms the presence of metastatic disease led to the development of targeted axillary dissection (TAD). TAD consists of selectively localizing and removing the marked in node in addition to removing the sentinel nodes. The clipped node can be localized by a variety of techniques similar to localization techniques for the breast (ie, wire placement, magnetic localizer, radioactive seed, and reflector seed). This technique was demonstrated as feasible after NAC21 and shown to be beneficial in increasing the accuracy of axillary of the staging in patients with cN 1 disease after NAC.22

It is worth noting that the clipped node is not always a sentinel node, explaining why it needs to be localized to ensure resection. In the 141 patients that had a clipped node in the ACOSOG Z1071 trial with documented location at time of resection (either in SLNB specimen or in completion ALND [cALND] specimen), the clipped node was in the SLN in 107, and in the cALND specimen in 34, or approximately 24% of the time, which is consistent with current literature quoting rates 23% to 37%.20,22–24 This means that if relying only on lymphatic mapping and resection of the SLNs, the clipped node will be missed in approximately a quarter of patients.

The first study evaluating TAD as a surgical technique aimed to evaluate whether pathologic changes in the clipped node after NAC are reflective of the entire nodal basin and whether ensuring the removal of the clipped node in addition to SLNs improves the accuracy of axillary staging. They found that the evaluation of the clipped node alone resulted in an FNR of 4.2%, advocating that the clipped node is a valuable staging element. Evaluation of SLNB alone resulted in an FNR of 10.1%, whereas adding the evaluation of clipped node reduced the FNR to 1.4%. After an initial trial to establish the safety of TAD,21 they reported on 85 patients undergoing TAD showing an FNR of 2% (95% CI 0.05–10.7).22

SenTa

This was a German prospective, multicenter registry that included patients cT1–4, cN1, M0 who underwent NAC. The primary aim of this study was to explore the detection rate of SLNs, the clipped node, as well as TAD, and determine the FNR and negative predictive value (NPV) for each. With examination of the clipped node alone, the detection rate was 77.8% with an FNR of 7.2% and NPV of 92%. With TAD, the detection rate was 86.9%, FNR was 4.2%, and NPV was 93.9%.23 However, the successful replication of TAD in a nonselected multicenter trial validates the clinical feasibility and accuracy of TAD. Furthermore, SenTa 2 is a future study that is currently enrolling and investigating the accuracy of TAD in those patients presenting with 3 or more initially suspicious lymph nodes that convert to cN0 following NAC.

Radioactive iodine seed localization in the axilla combined with sentinel node

This was prospective, multicenter validation trial in cN 1 patients treated with NAC that demonstrates the replicability of TAD. Of note, in order to perform TAD in this study, they used their original MARI (Marking Axillary Lymph Nodes with Radioactive Iodine Seeds) technique placing I125 radioactive seeds in the positive node before NAC to guide resection of the biopsied node,25 at the time of definitive surgery. They reported a detection rate of the targeted node in 98% and FNR of 3.47% in a population of more than 200 patients.24 This is consistent with the findings of SenTa and the MDACC study, with future studies ongoing to examine outcomes and patient selection for TAD (Table 2).

Table 2.

Feasibility and accuracy of removing SLNs and marked nodes after neoadjuvant chemotherapy

Identification Rate False-Negative Rate
MD Anderson (TAD)22 Not reported 2%
SenTa (TAD)23 87% 4.2%
Netherlands (RISAS)24 98% 3.5%
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Future trials

The AXSANA (Axillary Surgery After NeoAdjuvant Treatment) European prospective multicenter cohort study from the European Breast Cancer Research Association of Surgical Trialists (EUBREAST) network is evaluating different surgical methods of axillary staging in cN 1 patients treated with NAC. Surgical management after NAC will be up to institutional/national standards and will evaluate SLNB, TAD, and ALND. The aim is to analyze the clinical landscape of axillary surgery in this patient population because there are currently discrepancies in technique and findings. Primary endpoints are invasive disease-free survival (DFS), axillary recurrence, health-related quality of life, and arm morbidity.26 The study is still accruing and has enrolled more than 300 patients. Similarly, GANEA-3, a French prospective, multicenter diagnostic study that will be assessing TAD, as well as breast tumor characteristics to predict axillary response after NAC. All enrolled patients will undergo TAD and completion ALND, with primary aim to help identify patients in whom ALND could be avoided.27

DISCUSSION

Oncologic Safety

Despite current literature on feasibility and accuracy of SLNB and TAD in cN 1 after NAC, we still do not have data on the oncologic outcomes. The hypothetical risk in leaving it behind chemoresistant disease is an area of concern when considering de-escalation of axillary surgery.

Residual Axillary Disease

Prognostically, low-volume axillary disease in the form of ITCs and micrometastases has been shown as similar to pN0 disease in upfront surgery.28,29 However, Wong and coauthors indicate that DFS and overall survival (OS) worsens with even low-volume residual axillary disease after NAC. They performed a single-institution retrospective review with median follow-up of 5.3 years to assess locoregional recurrence (LRR), DFS, and OS in cT1–4, N0–1 patients undergoing NAC. In addition, they reported an National Cancer Database (NCDB) query for cT1–3, N0–1 patients undergoing NAC with a mean follow-up of 3.7 years to assess OS. The population with ITCs after NAC had significantly poorer DFS at 5 years than ypN0 (73.5% vs 88.4%), and more- over, the 5-year DFS of those with micrometastases was comparable to that of pN1 (74.7% vs 69.5%). Analysis of the NCDB data from this study revealed ITCs with a 1.9-fold and micrometastases with a 2.2-fold increased risk of death compared with ypN0. In the cN1 cohort, the relative increase in mortality associated with residual ITCs was 81%, and 97% with micrometastases.30

A prospective registry out of Memorial Sloan Kettering Cancer Center (MSKCC), examining SLNB after NAC, found that low-volume residual axillary disease on SLNB in cN 1 patients after NAC was associated with high likelihood of non-SLN positivity on completion ALND. A total of 711 cancers were evaluated and 171 patients underwent completion ALND after positive SLNB (either on frozen section or on permanent pathologic condition). In this population, the presence of ITCs and micrometastases on SLNB was associated with additional non-SLN axillary disease in 17% and 64%, respectively,31 supporting the continued recommendation for completion ALND with low-volume residual axillary disease after NAC.

The OPBC-04/EUBREAST-06/OMA Study recently presented at SABCS in December 2022 has begun to examine the long-term outcomes of cN 1 after NAC that underwent limited axillary surgery. In this international multicenter study, the investigators collected data on axillary recurrence, LRR, and any invasive recurrence in patients that underwent either SLNB or TAD only after NAC and were ypN0. For the entire cohort, axillary recurrence was only 1.1%, LRR 3.1%, and any invasive recurrence 10% at 5 years.32 Furthermore, they found no difference in axillary recurrence rates at 2 years between the TAD and SLNB groups (0% vs 0.9%, respectively, P 5 .19).32 A retrospective study out of MSKCC also found that nodal recurrence was low in patients cN1 rendered cN0 after NAC undergoing SLNB alone. These patients had removal of at least 3 SLN using dual tracer, without targeted resection of the biopsied node, with a median follow-up of 40 months. Of 234 patients with at least 3 ypN0 SLN, only 1 (0.4%) had nodal recurrence (synchronous with local recurrence). Notably, this was in a patient that refused adjuvant radiation therapy.33 This further suggesting the safety of limited axillary surgery after NAC with pCR.

Axillary Radiation

Classically many cN 1 patients will receive adjuvant nodal irradiation (RNI) regardless of their response to chemotherapy. Currently, there are 2 large, ongoing studies that may support the future use of adjuvant RNI for possible axillary de-escalation over ALND in patients with residual nodal disease after NAC. NSABP B-51/RTOG 1304 is a randomized, phase 3 multicenter trial enrolling cT1–3, N1 patients that convert to pathologically node negative (ypN0 or ypN0(i1)) status determined by SLNB, TAD, or ALND after NAC. The study randomizes patients to either RNI or no RNI (breast conservation therapy [BCT] patients will still undergo whole breast irradiation). The primary endpoint is to determine if adjuvant radiation with RNI improves invasive recurrence-free interval, OS, and LRR with assessments at 3, 6, 12, and 24 months.34 The trial is now closed to enrollment and is currently following enrolled patients. Alliance A011202 is a complementary randomized, phase 3 multicenter noninferiority trial enrolling cT1–3, N1, M0 patients that receive NAC and have positive SLNB (ypN1mi and ypN1) identified at surgery. Enrolled patients with positive SLNB will be randomized to no further axillary surgery versus completion ALND. Both study groups will receive RNI. Primary endpoints of the trial include recurrence-free interval, LRR, and OS at 5 year follow-up.35 This study has also reached its enrollment target and is collecting outcomes data. Pending the results of this trial, it may justify the use of RNI in lieu of ALND for patients with residual axillary disease after NAC. These trials have the potential to impact locoregional therapy decisions after NAC in critical ways. However, ALND should still be performed when residual nodal disease is identified, no matter how small volume, until the trial results are published.

SUMMARY

In conclusion, axillary de-escalation following NAC in cN 1 patients is still an evolving subject matter as we determine how best to safely minimize axillary treatment. A voluntary survey distributed to members of the American Society of Breast Surgeons (response rate 21% of 3090, n 5 642) in 2017 found that use of SLNB after NAC in cN 1 patients increased after publication of SENTINA, ACOSOG Z1071, and SN FNAC. However, those not changing their practice to incorporate SLNB for this cohort cited concerns regarding the lack of outcome data and FNR as the biggest reasons.36

Overall, the National Comprehensive Cancer Network (NCCN) lists level 2B evidence for the omission of ALND in highly selected patients that convert to cN0 after NAC and undergo TAD with no residual disease. Furthermore, current NCCN guide- lines recommend clip placement in biopsied positive node before NAC in order to confirm the removal of that node at the time of surgery.37 However, the NCCN panel does note the FNR of SLNB can be reduced with the removal of more than 3 SLN, use of dual tracer for SLN mapping, and resection of the clipped node.37 Although many of the trials discussed focus on the accuracy of determining axillary response, there is very scarce data on oncologic outcomes.

This should be discussed with patients before considering minimizing axillary surgery so they understand where there is data to support the practice, and where there are gaps. Ongoing trials that will be reported in the future may help better clarify where de-escalation is appropriate and the impact.

Clinics care points.

  • SLNB is feasible in cN 1 after NAC, if done with techniques shown to reduce the FNR such as the use of dual tracer technique, removal of 2 or more nodes, and the use of IHC.

  • Performing TAD in cN 1 patients after NAC has consistently demonstrated an FNR less than that of SLNB alone.

  • Patient selection is important when considering axillary de-escalation. Patients presenting with extensive disease burden (cN2-N3) should be excluded from this approach since reported trials were limited to patients presenting with cN1 disease. Long-term outcomes of minimal axillary surgery are limited, but even low volume residual disease portends a poorer prognosis than ypN0.

  • Studies are still ongoing but in the future axillary radiation (XRT) may be a reasonable alternative to ALND in patients with residual nodal disease.

KeyPoints.

  • Sentinel lymph node biopsy (SLNB) is feasible in cN + after neoadjuvant chemotherapy (NAC), if done with dual tracer technique, removal of 2 or more nodes, and the use of immunohistochemistry.

  • Performing targeted axillary dissection in cN + patients after NAC has consistently demonstrated a false-negative rate below that of SLNB alone.

  • Patient selection is important for axillary de-escalation. Long-term outcomes on minimal axillary surgery are limited but even low-volume residual axillary disease portends poorer prognosis than ypN0.

FUNDING SOURCE

Cancer Center Support Grant (NCI Grant P30 CA016672).

Footnotes

DISCLOSURE

The authors have nothing to disclose.

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