Abstract
Background:
Various techniques exist to decrease the false negative rate (FNR) of axillary surgical staging post- neoadjuvant chemotherapy (NAC). While biopsy-proven positive lymph nodes (LNs) are often clipped prior to NAC, the value of clipped node localization is debated.
Methods:
We identified cT0–4c biopsy-proven cN+ breast cancer patients with a clipped LN treated with NAC and definitive surgery (9/2016–7/2024). Axillary staging procedure included sentinel lymph node (SLN) surgery or targeted axillary dissection (TAD). Frequency of the clipped node being a SLN and FNR of the clipped node versus all nodes removed during SLN surgery/TAD were determined.
Results:
Of 540 patients with 541 cN+ breasts with cancer, 456 patients had a positive LN clipped prior to NAC and underwent axillary surgical staging (404 TAD, 52 SLN surgery). The clipped node was retrieved in 93% of eligible patients (96% TAD vs 77% SLN surgery, p<0.001) and, if retrieved, was a SLN in 86% (85% TAD vs 92.5% SLN surgery, p=0.20). The median number of nodes retrieved was 4 for both SLN surgery and TAD. Among 204 patients with ypN+ disease who had the clipped node and additional non-clipped nodes removed, FNR of the clipped node was 5.4% and of SLNs was 4.9%.
Conclusion:
In a contemporary NAC cohort of cN+ patients, the clipped node was retrieved and was a SLN in most cases. When compared to all nodes removed during SLN surgery/TAD, the clipped node FNR was low, thus supporting the potential for limitation of axillary staging surgery to selective removal of the clipped node alone.
Keywords: Breast Cancer, Axillary Management, Clipped Node, Sentinel Lymph Node, Targeted Axillary Dissection, Axillary Dissection, Neoadjuvant Chemotherapy, De-escalation of Axillary Surgery
INTRODUCTION:
Axillary management in the setting of clinically node-positive breast cancer treated with neoadjuvant chemotherapy (NAC) has significantly changed over the past several decades. Historically, patients with clinically node-positive breast cancer required axillary lymph node dissection (ALND) regardless of their response to chemotherapy. With contemporary neoadjuvant systemic therapy paradigms, however, up to 70% of patients experience a nodal pathologic complete response.1 Sentinel lymph node (SLN) surgery in patients with biopsy-proven node-positive disease (cN+) who convert to having clinically node-negative disease after undergoing NAC (ycN0) has consequently become widely accepted. The use of SLN surgery is mostly based on data from four large prospective trials (i.e., ACOSOG Z1071, SENTinel NeoAdjuvant (SENTINA), Sentinel Node Biopsy Following Neoadjuvant Chemotherapy (SN FNAC), and GANEA2),2–5 among many additional studies in this realm. Cumulatively, these trials demonstrate high rates of SLN identification after NAC (80.1%–92.9%). While overall false negative rates (FNRs) of SLNs compared to ALND ranged between 11.9% and 14.2% in these studies, various techniques, such as dual tracer injection and a higher number of SLNs removed, have been shown to improve the FNR to more acceptable levels (4.9%–12%).
To further reduce the FNR of SLN surgery in the post-neoadjuvant population, additional approaches have been developed. The Netherlands Cancer Institute, for example, developed the Marking the Axilla with Radioactive Iodine (MARI) procedure,6 in which a radioactive seed is placed into the biopsy-proven positive LN prior to neoadjuvant systemic therapy with selective excision of only the single node with seed at time of surgery. The MARI procedure has a high identification rate of the marked LN (97%) and a FNR of 7% in feasibility studies when compared to results from completion ALND.7 Outcomes are also favorable with low recurrence rates and high disease-free and overall survival (OS).8
Similarly, targeted axillary dissection (TAD), developed by Caudle et. al,9 combines localization and excision of the biopsy-proven LN along with SLN surgery. This technique was based on the finding in ACOSOG Z1071 that the FNR of SLN surgery was lower when the clipped node was resected as one of the SLNs, even though the clipped node was identified at SLN surgery in 75% of cases.10 By localizing the clipped node, retrieval rates of the clipped node substantially increase, and FNRs conversely decrease.
Considering the favorable data regarding de-escalation of axillary staging, current National Comprehensive Cancer Network (NCCN) guidelines recommend that cN+ patients who convert to clinically node-negative after neoadjuvant systemic therapy (ycN0) undergo SLN surgery.11 Footnotes in the NCCN guidelines also state that if a positive LN is clipped, then every effort should be made to remove the clipped node at time of surgery. It is suggested that only the most suspicious node be marked and retrieved along with additional SLNs to reduce the FNR.
In support of these guidelines, recent publications confirm that unnecessary ALND is successfully avoided and that patients undergoing SLN surgery are experiencing favorable oncologic results. Piltin et. al12 demonstrated that 52.5% of patients who were selected for SLN surgery between 2009 and 2019 were spared ALND and experienced a similar two-year recurrence free survival to those undergoing ALND. Likewise, omission of ALND was demonstrated to have reasonable short-term oncologic outcomes in ISPY-2 trial patients with ypN0 or ypN+ disease between the years of 2011 and 2021.13
Given the ongoing evolution of axillary management in the setting of neoadjuvant systemic therapy, we sought to further characterize the role of the clipped node in a contemporary cohort of patients treated with NAC. By evaluating the axillary surgical staging procedures at our institution, the primary goals of our study were to calculate the frequency of clipped node retrieval and to see how often the clipped node is a SLN. We also assessed the sensitivity of the clipped node to identify residual nodal disease (ypN+) and calculated its FNR when compared to other LNs removed during SLN surgery/TAD.
METHODS:
With institutional review board approval, the breast surgery database at Mayo Clinic Rochester was utilized to identify consecutively treated patients, age 18 or greater, with cT0–4c, node-positive (cN1–3) breast cancer who were treated with NAC and subsequent axillary surgery. Surgery was performed at Mayo Clinic in Rochester, Minnesota, between the dates of 9/1/2016 and 7/31/2024.
Patients had to have biopsy-proven nodal disease with clip placement in the positive LN(s) prior to NAC to be included. There was no limit on the number of abnormal lymph nodes identified on pre-NAC imaging and/or the presence of matted nodal disease prior to treatment. Patients with occult primary breast disease or non-invasive disease but positive LNs (i.e., cT0 or cTis with cN1–3) were also included. Patients denying research authorization and those with distant metastases, recurrent ipsilateral breast cancer, and/or inflammatory breast cancer were excluded from the study. Demographic, clinicopathologic, treatment data, and oncologic outcomes were extracted from our surgical database and supplemented with review of the electronic medical record.
Clinical Nodal Category
At our institution, standardized workup of newly diagnosed invasive breast cancer includes axillary ultrasound evaluation with subsequent fine-needle aspiration (FNA) or core-needle biopsy of any sonographically abnormal-appearing lymph nodes, including those with a thickened cortex of 3 mm or greater. The most suspicious LN is biopsied if there is greater than one LN with concerning features. Clinical examination is also utilized to determine a patient’s clinical nodal status, particularly to ascertain if matted nodal disease is present (cN2) and/or if there is involvement of infraclavicular or supraclavicular lymph nodes.
Similarly, prior to NAC, most patients undergo bilateral breast MRIs, allowing for further assessment of regional lymph node basins, including axillary (levels I-III), internal mammary, infraclavicular, and supraclavicular lymph nodes.
Using the eighth edition of the American Joint Committee on Cancer (AJCC) staging for breast cancer, clinical nodal category was determined from these results and was subsequently recorded in the breast surgery database. For patients diagnosed and treated prior to 2018, the seventh edition of the AJCC staging system was used. It should be noted that there are no major differences for clinical nodal staging when the two AJCC editions are compared.14
Tumor Biology
Estrogen receptor (ER) and progesterone receptor (PR) status were evaluated as positive or negative, with positive defined at 1% or higher. Similarly, human epidermal growth factor receptor 2 (HER2) positivity was defined as 3+ staining by immunohistochemistry for the HER2 protein or gene amplification by fluorescence in situ hybridization.
Neoadjuvant Chemotherapy
The NAC regimens utilized were at the discretion of the treating provider and included standard chemotherapy regimens along with HER2-directed therapy, immunotherapy, and open clinical trials.
Axillary Surgery Details
Axillary surgery was defined as SLN surgery, TAD, or SLN surgery/TAD with a completion ALND (cALND). In our study, a TAD procedure was defined as localization and excision of the clipped LN in combination with SLN surgery. Clipped node localization technique was at the discretion of the operating surgeon and included preoperative placement of a radioactive seed or surgeon-performed intra-operative ultrasound for identification and resection of the clipped node. In those instances where intra-operative ultrasound was utilized for clip localization, a post-NAC axillary ultrasound was reviewed to ensure that the clip was still able to be visualized. A surgeon-directed ultrasound was also often performed during the surgical consult but was not mandated. Our institutional standard for node-positive patients undergoing TAD or SLN surgery after NAC is to use a dual tracer approach (i.e., radioactive colloid and either Lymphazurin or methylene blue dye). This standard, however, is not mandated. Patients who underwent a direct ALND and/or experienced failed SLN identification were excluded from the primary analysis cohort.
During an axillary surgical staging procedure (SLN surgery/TAD), both SLNs and non-SLNs are potentially removed. We defined a SLN as a LN that was blue, radioactive, and/or palpable.
Successful clip removal was determined by reviewing pathology reports, specifically the gross pathology description that notes the presence or absence of a clip, intra-operative specimen radiographs, and operative reports for the intra-operative description of nodes removed.
Primary Outcomes
There were three primary outcomes of our analysis. First, we wanted to calculate the frequency at which the clipped node was successfully retrieved during SLN surgery/TAD. Secondly, we wanted to see how often the clipped positive node was deemed a SLN. Finally, we sought to determine how often the clipped node provided accurate staging relative to the pathologic findings from all nodes removed during the axillary staging surgery (SLN surgery or TAD).
The FNR for the clipped node was estimated by comparing the pathologic status of the clipped node to the final pathologic status of all other LNs removed during SLN surgery/TAD. Patients were included in the FNR calculation only if they (1) had the clipped node retrieved during SLN surgery/TAD and (2) had at least one additional node removed during SLN surgery/TAD for comparison. The FNR was calculated, among those meeting the aforementioned criteria, as the fraction of pathologically positive (i.e., micro- or macrometastasis) specimens from SLN surgery or TAD where the clipped node was negative (a false negative relative to the pathological status of the entire SLN surgery/TAD procedure). We assessed the FNR by first counting isolated tumor cells (ITCs) in the clipped node as a negative result for the clipped node and also performed a sensitivity analysis to assess the impact if the ITCs in the clipped node were considered a positive result for the clipped node.
Similarly, and for comparison, we calculated the FNR for SLNs (which may or may not have included the clipped node) as the fraction of pathologically positive (i.e., micro- or macrometastasis) specimens from SLN surgery or TAD where all SLNs were negative (which could occur only if the clipped node was positive and was not a SLN). We also assessed whether the SLN FNR was impacted if ITCs in the SLNs were considered positive.
Secondary Outcomes
Given that a portion of our cohort underwent cALND after axillary staging, we reviewed the incidence at which this occurred. Final pathologic nodal status was defined as ypN0 if ypN0, ypN0(i-), or ypN0(i+) and as ypN+ if ypN1mi-ypN3. Oncologic outcomes, including axillary recurrences, overall survival (OS), breast-cancer specific survival (BCSS), freedom from recurrence, and recurrence-free survival (RFS), were assessed for the entire cohort and also stratified by final ypN status.
Statistical Analysis
Statistical analysis was performed using Kruskal-Wallis and chi-squared tests, as appropriate, to compare patients with SLN surgery versus TAD. The percentage of patients where the clipped node was a SLN and the sensitivity of the clipped node for correctly identifying ypN+ axillary staging procedures (comparing the clipped node result relative to the result from all nodes removed during SLN surgery/TAD) was estimated. The FNR was calculated as 1 – sensitivity and estimated with 95% confidence intervals (CI) calculated using the Wilson score method. An alpha level of < 0.05 was set to determine statistical significance.
Demographic and clinical features were also reported descriptively to characterize the sample using median (range or interquartile range (IQR)) for quantitative variables and frequency (percentage) for categorical variables. Oncologic outcomes were analyzed with the Kaplan-Meier method and log-rank tests. Analysis was performed using SAS® (Version 9.4, SAS® Institute Inc., Cary, NC, USA) and R software (https://www.R-project.org/, Version 4.3.1).
Results:
Between September 2016 and July 2024, we identified 540 patients with 541 cT0–4c, cN1–3 breasts with cancer meeting inclusion criteria. Seventy patients, including one breast from the patient with bilateral breast cancers, had an ALND without axillary staging and were excluded from the study. Of the remaining 471 patients, 15 patients failed SLN identification and thus underwent either an ALND (n = 14) or extended axillary sampling (n = 1; removal of clipped node plus four surrounding LNs). These 15 patients were excluded from the study. The final primary analysis sample included 456 patients with successful SLN identification who underwent SLN surgery or TAD (Figure 1).
Figure 1. Study Flow Diagram.
*Right breast of a patient with bilateral breast cancer was excluded since a direct ALND was performed. cN+, clinically node positive; s/p, status post; ALND, axillary lymph node dissection; SLN, sentinel lymph node; TAD, targeted axillary dissection
Cohort demographics and surgical treatments are listed in Table 1. The median age of our study cohort was 50 (range 23–85) years, and the median body mass index (BMI) was 27.6 (range 17.7–52.0). The predominant ethnicity and race in our study were not Hispanic or Latino (94.3%) and white (87.5%), respectively. The majority of patients presented with cT2 (48.7%) or cT3 (31.4%) and cN1 (86.4%) disease, and the most common tumor biology was ER+/HER2− disease (45.2%). At the time of surgery, 31.8% of patients were ypT0, and 46.3% had a complete pathologic nodal response (ypN0). The axillary staging procedure utilized was TAD in 404/456 (88.6%) patients, and SLN surgery in the remaining 52/456 (11.4%). There were no significant differences in demographics and/or tumor and nodal staging categories amongst patients undergoing TAD versus SLN surgery (Table 1, all p > 0.05).
Table 1:
Cohort Demographics
| Total (n=456) |
TAD (n=404) |
SLN Surgery (n=52) |
P-value | |
|---|---|---|---|---|
|
| ||||
| Age at Surgery, Median (Range) | 50.0 (23.0, 85.0) | 50.0 (23.0, 85.0) | 48.5 (28.0, 74.0) | 0.15451 |
| Ethnicity, n (%) | 0.13502 | |||
| Not Hispanic or Latino | 430 (94.3%) | 384 (95.0%) | 46 (88.5%) | |
| Hispanic or Latino | 19 (4.2%) | 15 (3.7%) | 4 (7.7%) | |
| Unknown | 7 (1.5%) | 5 (1.2%) | 2 (3.8%) | |
| Race, n (%) | 0.60902 | |||
| White | 399 (87.5%) | 356 (88.1%) | 43 (82.7%) | |
| Black | 18 (3.9%) | 16 (4.0%) | 2 (3.8%) | |
| Asian | 16 (3.5%) | 13 (3.2%) | 3 (5.8%) | |
| Other/Unknown | 23 (5.0%) | 19 (4.7%) | 4 (7.7%) | |
| BMI at Surgery, Median (Range) | 27.6 (17.7, 52.0) | 27.6 (17.7, 52.0) | 27.7 (18.8, 42.3) | 0.93101 |
| Clinical T Category, n (%) | 0.42132 | |||
| cT0 | 7 (1.5%) | 7 (1.7%) | 0 (0.0%) | |
| cT1 | 71 (15.6%) | 60 (14.9%) | 11 (21.2%) | |
| cT2 | 222 (48.7%) | 196 (48.5%) | 26 (50.0%) | |
| cT3 | 143 (31.4%) | 128 (31.7%) | 15 (28.8%) | |
| cT4 | 13 (2.9%) | 13 (3.2%) | 0 (0.0%) | |
| Clinical N Category, n (%) | 0.24222 | |||
| cN1 | 394 (86.4%) | 347 (85.9%) | 47 (90.4%) | |
| cN2 | 21 (4.6%) | 21 (5.2%) | 0 (0.0%) | |
| cN3 | 41 (9.0%) | 36 (8.9%) | 5 (9.6%) | |
| Pathologic T Category, n (%) | 0.36562 | |||
| ypT0 | 145 (31.8%) | 133 (32.9%) | 12 (23.1%) | |
| ypTis | 41 (9.0%) | 35 (8.7%) | 6 (11.5%) | |
| ypT1 | 158 (34.6%) | 137 (33.9%) | 21 (40.4%) | |
| ypT2 | 81 (17.8%) | 69 (17.1%) | 12 (23.1%) | |
| ypT3 | 26 (5.7%) | 25 (6.2%) | 1 (1.9%) | |
| ypT4 | 5 (1.1%) | 5 (1.2%) | 0 (0.0%) | |
| Pathologic N Category, n (%) | 0.80062 | |||
| ypN0 | 211 (46.3%) | 185 (45.8%) | 26 (50.0%) | |
| ypN1 | 166 (36.4%) | 147 (36.4%) | 19 (36.5%) | |
| ypN2 | 60 (13.2%) | 54 (13.4%) | 6 (11.5%) | |
| ypN3 | 19 (4.2%) | 18 (4.5%) | 1 (1.9%) | |
| Biologic Subtype, n (%) | 0.09252 | |||
| ER-/HER2+ | 63 (13.8%) | 56 (13.9%) | 7 (13.5%) | |
| ER+/HER2+ | 99 (21.7%) | 83 (20.5%) | 16 (30.8%) | |
| ER-/HER2- | 88 (19.3%) | 84 (20.8%) | 4 (7.7%) | |
| ER+/HER2- | 206 (45.2%) | 181 (44.8%) | 25 (48.1%) | |
Kruskal-Wallis p-value;
Chi-Square p-value
TAD, targeted axillary dissection; SLN, sentinel lymph node; BMI, body mass index; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2
The various types of breast surgeries performed included mastectomy (n = 96, 21.1%), mastectomy with immediate breast reconstruction (n = 223, 48.9%), and breast conserving surgery (n = 131, 28.7%). Six patients (1.3%) only underwent an axillary surgery procedure. There was no difference in the type of breast surgery performed between TAD and SLN surgery cohorts (p = 0.72).
Axillary Surgery Details
Details regarding axillary surgery and the clipped node are listed in Table 2. Although the overall use of dual tracer for SLN mapping was high (88.8%), its use was higher in TAD (90.1%) than in SLN surgery (78.8%, p=0.04, Table 2). The median number of LNs retrieved during an axillary staging procedure was 4 (IQR: 3–5) and was not significantly different between TAD and SLN surgery (p=0.05).
Table 2.
Axillary Surgery Details
| Total (n=456) |
TAD (n=404) |
SLN Surgery (n=52) |
P-value | |
|---|---|---|---|---|
|
| ||||
| Number of Nodes Retrieved During SLN Surgery/TAD, Median (IQR) | 4 (3, 5) | 4 (2, 5) | 4 (3, 5) | 0.05021 |
| Type of SLN Mapping Performed, n (%) | 0.04202 | |||
| Dual Tracer | 405 (88.8%) | 364 (90.1%) | 41 (78.8%) | |
| Radioactive Isotype Only | 50 (11.0%) | 39 (9.7%) | 11 (21.2%) | |
| Bye Dye Only | 1 (0.2%) | 1 (0.2%) | 0 (0.0%) | |
| Clipped Node Retrieved, n (%) | <.00012 | |||
| No | 30 (6.6%) | 18 (4.5%) | 12 (23.1%) | |
| Yes | 426 (93.4%) | 386 (95.5%) | 40 (76.9%) | |
| Clipped Node Retrieved During SLN Surgery/TAD is a SLN, n (%) | 0.19582 | |||
| No | 61/426 (14.3%) | 58/386 (15%) | 3/40 (7.5%) | |
| Yes | 365/426 (85.7%) | 328/386 (85%) | 37/40 (92.5%) | |
| Pathology of Clipped Node Retrieved During SLN Surgery/TAD, n (%) | 0.22272 | |||
| Negative | 182/426 (42.7%) | 168/386 (43.5%) | 15/40 (37.5%) | |
| ITCs only | 20/426 (4.7%) | 18/386 (4.7%) | 1/40 (2.5%) | |
| Micromets | 33/426 (7.7%) | 31/386 (8.0%) | 2/40 (5.0%) | |
| Macromets | 189/426 (44.4%) | 168/386 (43.5%) | 21/40 (52.5%) | |
| Unknown | 2/426 (0.5%) | 1/386 (0.3%) | 1/40 (2.5%) | |
Kruskal-Wallis p-value;
Chi-Square p-value
TAD, targeted axillary dissection; SLN, sentinel lymph node; ITCs, isolated tumor cells
In total, the clipped node was retrieved in 426 patients (93.4%) with successful SLN identification. Clip retrieval was higher in TAD than SLN surgery patients (95.5% vs 76.9%, p < 0.001). The retrieved clipped node was also a SLN (i.e., radioactive, blue, and/or palpable) in 365/426 patients (85.7%). This did not differ based on axillary staging procedure (85.0% TAD vs 92.5% SLN surgery, p=0.20).
Among the 426 patients with the clipped node retrieved, 394 (190 ypN0, 204 ypN+) had additional non-clipped nodes removed during the axillary staging procedure (i.e., SLN surgery or TAD). The clipped node was the only positive node removed during SLN surgery/TAD in 45.1% of cases when ITCs were not considered positive residual disease, and 44.8% when ITCs were considered positive residual disease. When comparing the pathology of the clipped node to that of the other nodes removed during SLN surgery/TAD, the FNR was 5.4% (95% CI: 3.0–9.4%). Similarly, when considering ITCs as positive residual disease, the FNR of the clipped node relative to SLN surgery/TAD findings was 4.9% (95% CI: 2.7–8.8%).
Of the 57 patients (34 ypN0, 23 ypN+) for whom the clipped node was not a SLN (i.e., not radioactive, blue, or palpable), and who had both the non-sentinel clipped node and at least one additional LN retrieved during SLN surgery/TAD, the non-sentinel clipped node was negative in 33, had ITCs only in 3, micromets in 5, and macromets in 16. Among the 21 patients with micromets or greater in the non-sentinel clipped node, 10/21 (47.6%) had negative non-clipped SLNs, while 11/21 (52.4%) had at least micrometastatic disease in the non-clipped SLNs. None of the patients had ITCs in the non-clipped SLNs, making the aforementioned numbers invariant to analysis of ITCs. Thus, the overall SLN FNR among 204 ypN+ patients was 4.9% (10/204, 95% CI: 2.7–8.8%) relative to findings from the entire axillary staging procedure (i.e., SLN surgery/TAD).
Clip Retrieval for TAD Techniques
Of 404 patients that had a TAD axillary staging procedure, 355 (87.9%) used a seed localized technique and 49 (12.1%) used intra-operative ultrasound. The clip retrieval rate was 386 (95.5%) overall and did not differ based on localization technique utilized (95.5% [339/355] seed localized vs 95.9% [47/49] intra-op ultrasound, p = 0.89).
Patients with Clipped Node Not Retrieved
In the 30 patients where the clipped node was not retrieved (18 TAD vs 12 SLN surgery patients), 20 were ypN0 with removal of a median of 5 nodes (range: 3–16 nodes) during SLN surgery/TAD and did not undergo cALND. The remaining 10 patients were ypN+, and cALND was performed in nine. Of those nine patients, the clipped node was identified in 88.9% of cALND specimens and was also positive in 87.5% of patients. For one patient with the clipped node retrieved during cALND, the pathology of the clipped node was unknown.
Completion ALND
One hundred and eighty-two patients underwent cALND after axillary staging. This included 4 ypN0 patients, 1 ypN0(i+) patient, and 177 ypN+ patients. Of those patients who were found to be ypN0 and ypN0(i+), the clipped node was identified and removed via TAD in 100% of cases. In the 4 ypN0 patients with cALND, the clipped node was negative in all patients on final pathology. A cALND was performed in these patients due to discordant intra-operative frozen pathology, and no additional nodal disease was identified on cALND. A single ypN0(i+) patient had a cALND with no higher stage nodal disease identified.
For patients ypN+ (ypN1mi-ypN1b), a cALND was omitted in 68/161 (42.2%) overall, including 60.7% (17/28) of ypN1mi and 38.3% (51/133) of ypN1a-b. All 84 patients with ypN1c or higher on SLN surgery underwent a cALND.
Oncologic Outcomes
The median follow-up for our cohort of 456 patients was 3.2 years, and did not differ between TAD and SLN surgery cohorts (p = 0.12). Two axillary recurrences were observed, both in patients who had successful retrieval of the clipped node. Patient 1 was diagnosed with cT1N1M0, ER−/PR−/HER2− invasive ductal carcinoma. After NAC, she underwent a left therapeutic mastectomy with TAD. Surgical pathology revealed that the clipped node was positive, as were two additional SLNs, thus a cALND was performed with eight additional positive LNs. Pathologic staging was ypT2N2aM0, and the patient received adjuvant post-mastectomy radiation with nodal irradiation, as well as adjuvant chemotherapy with capecitabine. Synchronous local, regional, and distance disease was diagnosed 15 months after surgery. Patient 2 was diagnosed with cT1N1M0, ER+/PR−/HER2+ invasive ductal carcinoma. She received NAC, including HER2-directed therapy with Herceptin and Perjeta, and then underwent breast conserving therapy with TAD. Surgical pathology revealed that the clipped node was negative, as were three additional SLNs, with final pathological staging of ypT0N0M0. She completed HER2-directed therapy and adjuvant radiation. She presented with synchronous local, regional, and distant disease 40 months following surgery.
Overall outcomes are noted in Table 3 and include the following first breast cancer-specific events: 2 axillary recurrences, 16 locoregional recurrences, 26 distant recurrences, and 15 disease-related deaths. All outcomes were worse in the ypN+ versus ypN0 patients (all p < 0.05, Table 3).
Table 3.
Overall Outcomes
| Total (n=456) |
ypN0 (n=211) |
ypN+ (n=245) |
P-value | |
|---|---|---|---|---|
|
| ||||
| Axillary Recurrence | 2 | 1 | 1 | |
| Length of Follow-Up, years, Median (Range) | 3.2 (0.2–8.4) | 3.3 (0.4–8.4) | 3.0 (0.2–8.0) | |
| Locoregional Recurrence, n | 16 | 3 | 13 | |
| Distant Recurrence, n | 26 | 7 | 19 | |
| Any Recurrence, n | 30 | 7 | 23 | |
| Death, n | 25 | 6 | 19 | |
| Death due to Breast Cancer, n | 15 | 3 | 12 | |
| Freedom from Locoregional Recurrence | 0.02 | |||
| 3-year estimate | 96.4% (94.5–98.4%) | 98.7% (97.0–100%) | 94.4% (91.2–97.7%) | |
| 5-year estimate | 94.9% (92.3–97.5%) | 97.8% (95.3–100%) | 92.2% (88.0–96.7%) | |
| Freedom from Distant Recurrence | 0.04 | |||
| 3-year estimate | 93.3% (90.7–95.9%) | 96.3% (93.4–99.3%) | 90.7% (86.6–94.9%) | |
| 5-year estimate | 92.3% (89.4–95.3%) | 95.4% (92.0–98.9%) | 89.6% (85.2–94.3%) | |
| Freedom from Any Recurrence | 0.008 | |||
| 3-year estimate | 92.8% (90.2–95.5%) | 96.4% (93.6–99.3%) | 89.7% (85.5–94.2%) | |
| 5-year estimate | 90.7% (87.5–94.1%) | 95.5% (92.1–98.9%) | 86.5% (81.3–92.2%) | |
| Overall Survival | ||||
| 3-year estimate | 95.1% (92.7–97.5%) | 97.5% (95.0–100%) | 93.0% (89.2–97.0%) | 0.01 |
| 5-year estimate | 92.2% (88.8–95.7%) | 96.6% (93.7–99.6%) | 88.1% (82.3–94.3%) | |
| Breast-Cancer Specific Survival | 0.03 | |||
| 3-year estimate | 96.4% (94.4–98.5%) | 98.1% (96.1–100%) | 94.9% (91.5–98.4%) | |
| 5-year estimate | 95.0% (92.2–97.9%) | 98.1% (96.1–100%) | 92.1% (87.1–97.3%) | |
| Recurrence Free Survival | 0.002 | |||
| 3-year estimate | 91.5% (88.6–94.4%) | 95.7% (92.6–98.9%) | 87.8% (83.3–92.6%) | |
| 5-year estimate | 87.9% (84.1–91.8%) | 93.9% (90.1–98.0%) | 82.5% (76.4–89.1%) | |
DISCUSSION:
In a contemporary cohort of over 500 node-positive patients treated with NAC and SLN surgery/TAD, we demonstrate that the clipped node provides reliable staging information and that the FNR of the clipped node is low and similar to that of SLN surgery/TAD. Retrieval rate of the clipped node is high with successful retrieval in 93.4% of patients.
When comparing axillary staging procedures, clipped node retrieval was higher in TAD (95.5%) than in SLN surgery (76.9%), which is expected given intentional localization of the clipped node during TAD procedures. The clip retrieval rate in our TAD cohort is in line with other reported experiences, ranging from 85 to 96%.15,16 For our SLN surgery cohort, clip retrieval was also consistent with published literature of SLN surgery prior to nodal localization, which showed that the clipped node was retrieved in 76–77% of cases after NAC.10,17 This is also similar to the rate of retrieval of the clipped node with SLN surgery in the absence of NAC.18 More recently, the MSKCC group reported 93% retrieval of the clipped node with SLN surgery when using a protocol that required dual tracer and removal of at least three SLNs.19
Beyond retrieval, the clipped node was specifically documented as a SLN (i.e., blue, radioactive, and/or palpable) in the majority (85.7%) of our study cohort. More specifically, the clipped node was a SLN in 85% of patients undergoing TAD and 92.5% of patients undergoing SLN surgery. These results are similar to other studies in which the clipped node is identified as a SLN in 77–88% of patients.9,17,19
Aside from these notable results, the most important aspect regarding the clipped node is the FNR relative to other nodes removed during SLN surgery/TAD. In our cohort, the FNR was 5.4%. Likewise, in those patients with ypN+ disease, pathology from SLN surgery/TAD accurately reflected the status of the axilla. Additionally, the non-sentinel clipped node was the only positive LN removed during SLN surgery/TAD in 47.6% of cases. These values highlight the continued significance of the clipped node in the setting of the post-neoadjuvant axilla, particularly in patients presenting with cN+ disease. The FNR calculated in our study, which is relative to the remainder of the SLN surgery/TAD specimen results, is also comparable to those FNR values previously reported for clipped nodes relative to findings on ALND, which range from 4.2 to 6.8%.10,17 While comparison to findings on cALND is the gold standard, our study uniquely presents the clipped node FNR compared to other nodes removed during SLN surgery/TAD. This distinction is important as the field is rapidly evolving and increasingly cALND is not being performed in patients with ypN+ disease found by SLN surgery/TAD. Data relative to findings on cALND will thus be less available going forward. The findings from this study highlight the reliability of retrieving only a single node, specifically the clipped node, as is done with the MARI procedure.7,8
Compared to the MARI procedure, however, our study supports an approach to removing only the clipped node that does somewhat differ. In the MARI procedure, a radioactive seed is placed into a biopsy-proven LN prior to NAC, which typically only lasts 18 weeks. Conversely, NAC regimens utilized in our patient population were much longer in duration. Despite these differences, retrieval rates of the MARI node are similar to that of the clipped node in our study when TAD was performed (97% and 95.5%, respectively), and the FNR is slightly higher than ours (7% vs 5.4%).7 These results are even more profound given that data collected for the MARI procedure involved a cohort size of 100, while our cohort includes 456 patients. Ultimately, the FNRs of the clipped node and SLN in our cohort are clinically comparable (5.4 vs 4.9%), highlighting that both techniques are acceptable oncologic options. Due to the similarity between these FNRs, however, the benefit of removing a single node should be further investigated.
In addition to a low FNR and high retrieval rate, the rate of axillary recurrence observed in our study population was 0.4%. At a median follow-up of 3.2 years, in fact, only two patients experienced axillary failure, and both were synchronous with local and distant disease. No isolated axillary recurrences were observed. Interestingly, both axillary recurrences were noted within patients who underwent TAD with successful clip retrieval, including one patient who underwent cALND. Our overall low recurrence rate is in accordance with recent literature demonstrating axillary recurrence rates ranging from 0 to 2% in cN+ patients who receive NAC and subsequently undergo TAD or SLN surgery.15,20–24 Although longer follow-up time is certainly needed, these results support the omission of ALND in patients with cN+ converted to ypN0 disease.
When considering additional strengths of our study, it is important to highlight that we included patients in which the clipped node was identified and retrieved under intra-operative ultrasound guidance, as well as traditional localization techniques, unlike other studies in which TAD is only performed via localization with a specific device (e.g., radioactive seed, wire, or Magseed). The inclusion of such patients allowed for a direct comparison of the two localization techniques, revealing that both techniques allow for high retrieval rates (95.5% seed localized vs 95.9% intra-op ultrasound) without a significant difference in results. To our knowledge, this is one of the only studies that has allowed for such conclusions to be drawn and, given concerns surrounding the additional cost and procedures needed when retrieving a clipped node, it suggests that intra-operative ultrasound may be a reasonable alternative to traditional localization techniques.
Despite these findings, there are several limitations with our study that must be considered. Firstly, this study was retrospective in its design and completed at a single institution, potentially limiting the generalizability of its results. Secondly, because of its retrospective design, there is the potential for selection bias in patients chosen to undergo certain axillary staging procedures (i.e., TAD vs SLN surgery) and the use of specific techniques for localization (e.g., intra-operative ultrasound vs radioactive seed placement). Similarly, the number of patients undergoing TAD versus SLN surgery was not equitable (404 vs 52), which makes comparison between the groups limited. Given our institution is a large academic center, there may also be selection bias in regard to the patients treated at our institution and the novel neoadjuvant regimens utilized. The NAC regimens received were at the discretion of the treating provider and were not standardized amongst our study cohort, though they do represent a truly contemporary population. Moreover, data on the number of suspicious lymph nodes identified on pre-NAC imaging and/or clinical exam was not available, thus we could not determine whether the FNR varied based on this factor. Similarly, as less than 5% of our cohort had cN2 disease, it is difficult to comment on the FNR of the clipped node in the cN2 disease setting. Likewise, there was quite a bit of variability in identifying and labeling SLNs amongst surgeons and pathologists. While various aspects of the electronic medical record were utilized to ascertain this information, there were times when we could not definitively say if the clipped node was a SLN. These factors taken together could potentially impact our findings.
We also recognize that our study population is heterogenous in nature with a mixture of ypN0 and ypN+ disease and that only select populations underwent a cALND. As such, when determining the FNR of the clipped node, the clipped node’s pathology could not be compared to that of the cALND specimen. Instead, the clipped node was compared to all other LNs removed during the axillary staging procedure (i.e., SLN surgery or TAD). The reported oncologic outcomes, while separated by ypN status, reflect a mixed population with respect to cALND as well.
Despite these limitations, our study provides important information on the role of the clipped node in a large, contemporary NAC cohort. With low rates of axillary failure and a FNR of 5.4% relative to SLN surgery/TAD, our study suggests that selective removal of the clipped node alone may be a plausible option for axillary staging in post-NAC patients. In addition to reliable nodal staging, exclusive removal of the clipped node may allow for decreased post-operative morbidity even as compared to SLN surgery/TAD where multiple nodes are removed for axillary surgical staging. Although a correlation between the number of lymph nodes removed and clinically observed lymphedema rates has not yet been demonstrated,25,26 patients with numerically more lymph nodes excised have been shown to have an increase in perceived lymphedema symptoms, as well as numbness.27 Thus, while data in this realm is currently not available, removing only one lymph node in an already high-risk population has the potential to improve overall quality of life.
Moreover, though foregoing clipping and localization of positive axillary lymph nodes may be deemed advantageous in regard to ease of procedure and decreased overall cost/time, our data demonstrates that the clipped node may be of particular benefit when additional sentinel lymph nodes cannot be identified, still providing insight into nodal response without completion ALND. Regardless of the benefits, the overarching concern with both SLN surgery and removing the single clipped node in the post-NAC axilla is the potential impact on adjuvant therapies, specifically inappropriate omission of nodal radiation or missed opportunity to escalate systemic treatment. While this concern is of oncologic importance, the low FNR in this study, of both clipped node retrieval and SLN surgery, contributes to a larger body of data suggesting that this overall risk is low.
In conclusion, our data supports the continued importance of the clipped node in assessing pathologic nodal response after neoadjuvant systemic treatment. Further investigation, however, is warranted before exclusive clipped node resection can be deemed an acceptable standard of care.
Figure 2. Clipped Node Retrieval.
The number of patients in whom the clipped node was retrieved and was deemed a SLN in TAD versus SLN surgery cohorts.
SLN, sentinel lymph node; TAD, targeted axillary dissection
Synopsis:
In a contemporary NAC cohort of cN+ patients, the clipped node was retrieved in 93% of cases and was a SLN in 86%. When compared to additional LNs removed during SLN surgery/TAD, the FNR of the clipped node was 5.4%.
Funding:
Funding of this research study was provided in part by the Mayo Clinic Breast Cancer Specialized Program of Research Excellence Grant (Grant No. P50CA116201).
Dr. Mrdutt is supported by the National Cancer Institute / Mayo Clinic Paul Calabresi Program in Clinical/Translational Research (K12 CA90628).
Dr. Boughey is supported by the W.H. Odell Professorship in Individualized Medicine.
Disclosures:
Dr. Judy Boughey receives research funding paid to her institution from Eli Lilly, SimBioSys and Quantum Lep Healthcare. She is on the DSMB for Cairns Surgical.
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