Impact of Imaging-Guided Localization on Performance of Tailored Axillary Surgery in Patients with Clinically Node-Positive Breast Cancer: Prospective Cohort Study Within TAXIS (OPBC-03, SAKK 23/16, IBCSG 57-18, ABCSG-53, GBG 101)

Background Tailored axillary surgery (TAS) is a novel surgical concept for clinical node-positive breast cancer. It consists of the removal of the sentinel lymph nodes (LNs), as well as palpably suspicious nodes. The TAS technique can be utilized in both the upfront and neoadjuvant chemotherapy (NACT) setting. This study assessed whether/how imaging-guided localization (IGL) influenced TAS. Patients and Methods This was a prospective observational cohort study preplanned in the randomized phase-III OPBC-03/TAXIS trial. IGL was performed at the surgeon’s discretion for targeted removal of LNs during TAS. Immediate back-up axillary lymph node dissection (ALND) followed TAS according to TAXIS randomization. Results Five-hundred patients were included from 44 breast centers in six countries, 151 (30.2%) of whom underwent NACT. IGL was performed in 84.4% of all patients, with significant variation by country (77.6–100%, p < 0.001). No difference in the median number of removed (5 vs. 4, p = 0.3) and positive (2 vs. 2, p = 0.6) LNs by use of IGL was noted. The number of LNs removed during TAS with IGL remained stable over time (p = 0.8), but decreased significantly without IGL, from six (IQR 4–6) in 2019 to four (IQR 3–4) in 2022 (p = 0.015). An ALND was performed in 249 patients, removing another 12 (IQR 9–17) LNs, in which a median number of 1 (IQR 0–4) was positive. There was no significant difference in residual nodal disease after TAS with or without IGL (68.0% vs. 57.6%, p = 0.2). Conclusions IGL did not significantly change either the performance of TAS or the volume of residual nodal tumor burden. Trial registration: ClinicalTrials.gov Identifier: NCT03513614. Supplementary Information The online version contains supplementary material available at 10.1245/s10434-023-14404-4.

Axillary surgery has changed remarkably over the last decades.][12][13][14][15][16] Imaging-guided localization (IGL) of the clipped node was introduced to increase the likelihood of clip removal. 17he lowest FNR was achieved when IGL was added to the SLN biopsy, a procedure called targeted axillary dissection (TAD). 10,11An ALND remains standard in those patients with residual nodal disease after NACT, and in those with palpable axillary disease in the upfront surgical setting. 18,19n the ongoing, international, multicenter phase III OPBC-03/TAXIS trial (SAKK 23/16 / IBCSG 57-18 / ABCSG-53 / GBG 101; ClinicalTrials.govidentifier: NCT03513614), patients with clinically node-positive breast cancer undergo tailored axillary surgery (TAS) before being randomized to receive ALND or axillary radiotherapy (ART) in the setting of extended regional nodal irradiation. 201][22][23] This prospective cohort study was pre-planned after 500 randomized patients to investigate the impact of IGL on the performance of TAS in patients with clinically node-positive breast cancer.

PATIENTS AND METHODS
This prospective study was preplanned within the randomized controlled international phase-III TAXIS trial (OPBC-03/SAKK 23/16/IBCSG 57-18/ABCSG-53/GBG 101; ClinicalTrials.govIdentifier: NCT03513614).Patients ≥ 18 years of age with histologically or cytologically proven node-positive breast cancer and adequate condition for breast cancer surgery were included.Node-positive disease was detected by palpation or imaging at the time of initial diagnosis.Clip placement in the biopsy-proven positive lymph node was required.Patients were included in both the upfront surgery setting and after NACT in case of residual nodal disease, which was confirmed by either intraoperative frozen section analysis or final histopathology.Patients with stage IV, cN3c or cN2b breast cancer, contralateral or other tumor malignancy within 3 years, prior axillary surgery (except SLN procedure), or prior axillary radiotherapy were considered ineligible.Furthermore, patients with nodal pCR, absence of clip in the specimen radiography, palpable disease left behind in the axilla after TAS, or no SLN identified in the axilla were excluded from randomization.This study was pre-planned after 500 patients were randomized (one-third of the total sample size) in the TAXIS trial.It was planned to gain relevant insight into the impact of IGL on performance of the pragmatic concept of TAS.Patients were treated from August 2018 to June 2022.Data extraction was performed after data cleaning on 30 September 2022.
This study was approved by the local ethics committees and performed in accordance with the requirements of the national regulatory authorities.Written informed consent was obtained from all patients.The study is reported according to the STROBE guidelines (Supplementary Table S1). 24

Imaging-Guided Localization (IGL)
Before surgery, the most suspicious axillary node on imaging or palpation was biopsied via core needle biopsy or aspirated with a fine needle according to study-site specific standards and clipped.The clipping was performed at diagnosis or after receiving the pathology report confirming nodal disease.Images of the biopsy and clip placement were documented, e.g., by ultrasound (US).The IGL of the clipped and sampled node was optional, and performance was at the discretion of the surgeon.IGL of radiologically suspicious nodes, in addition to the clipped node, was neither mandatory nor prohibited.Any imaging technology was allowed for IGL, including US, computed tomography (CT), and magnetic resonance imaging (MRI).Any method was allowed for localization of the clipped node, such as the use of wire, iodine-125 or magnetic seeds, radioguided occult lesion localization (ROLL), or a tattoo.Specimen radiography was performed on all removed lymph nodes as measure of surgical quality assurance.If the clip was not documented in the specimen radiography, the patient was not randomized in the TAXIS trial and accordingly, was not included in this study.

Treatment
The TAS procedure was defined by palpation-guided selective removal of clipped and biopsy proven nodes, SLNs, and removal of all palpably suspicious findings.The sequence of the individual steps, however, was left to the discretion of the surgeon.TAS was designed to turn a clinically node-positive axilla into a clinically negative axilla by removing all palpably obvious disease.TAS could not reflect a procedure as standardized as ALND, because it was designed to de-escalate axillary surgery in a personalized fashion.Therefore, we expected that the pragmatic concept of TAS would result in some degree of intersurgeon variability.During the SLN procedure that was performed according to local standard practice, all nodes that were either blue (blue dye), hot (technetium Tc 99m), fluorescent (indocyanine green), or magnetic (superparamagnetic iron oxide particles) were removed.Dual-tracer mapping was recommended.Patients in the control group of the TAXIS trial underwent TAS followed by back-up ALND after intraoperative randomization in the upfront surgery setting or in case of residual nodal disease when confirmed by intraoperative frozen section analysis.In case of late confirmation of residual disease on final histopathology, randomization was delayed accordingly for a few days.ALND was performed at the discretion of the treating surgeon according to the pragmatic TAXIS trial design and typically cleared levels I and II.A full level III dissection above and medial to the pectoralis minor muscle was only recommended when there was gross nodal disease detected by palpation or imaging.In the experimental arm, patients received TAS followed by axillary radiotherapy (ART).All patients underwent adjuvant whole-breast irradiation after breast-conserving surgery and chest-wall irradiation after mastectomy.While patients in the ALND group received regional nodal irradiation excluding the dissected axilla as a target volume, patients in the ART group received regional nodal irradiation including the axilla.

Pathologic and Radiologic Evaluation
Pathologic evaluation was not centralized and performed according to the lymph node processing protocol at the local pathology department, thereby adhering to the principles of pragmatism. 25,26Nodal pathologic complete response was defined as absence of any nodal disease after NACT, including isolated tumor cells, which, however, were classified as ypN0(i+) according to TNM staging. 27Systemic radiologic staging was performed within two months before registration.Repeat staging after NACT was optional.Residual suspicious lymph nodes detected by imaging performed for radiotherapy treatment planning or restaging before the end of adjuvant treatment neither demanded nor prohibited take back surgery for completion ALND or selective removal of these nodes or an additional radiotherapy boost.

Endpoints
The primary endpoint was the rate of IGL, defined as attempt to selectively localize the clipped node under imaging guidance.Secondary endpoints assessed IGL use by country, year, palpable versus non-palpable disease, and type of clip.Further endpoints investigated the impact of IGL during TAS on number of removed lymph nodes and positive lymph nodes, as well as size of removed lymph node metastasis and rate of residual nodal disease removed during immediate back-up ALND that followed TAS according to the 1:1 randomization in the main TAXIS trial.

Statistical Analyses
Continuous endpoints were summarized using median and interquartile range (IQR).To assess the influence of covariables, linear regression models were applied that adjusted for potential confounders including upfront surgery versus NACT setting, palpable versus nonpalpable disease, tumor receptor subtype, grade, age, year, and country.Categorical endpoints were summarized using frequency counts and percentages and compared between subgroups of interest using Fisher's exact test.To assess the influence of covariables on binary variables, logistic regression models were applied.Two-tailed tests with a significance level of 0.05 were used.No adjustment was made for multiple testing and all analyses are considered exploratory.Missing values are reported in Tables 1, 2, 3, and 5.All analyses were performed using R (version 4.2.1).Impact of Imaging-Guided Localization on …

DISCUSSION
This is the first prospective study investigating the role of IGL in TAS for clinically node-positive breast cancer in patients undergoing upfront surgery or NACT with residual nodal disease.While IGL was frequently used, it had no impact on the number of positive or negative lymph nodes removed and residual nodal disease after TAS, with two-thirds of patients having at least one additional positive lymph node.Without use of IGL, the number of nodes removed during TAS decreased over the study period, suggesting that surgeons went through a learning curve and sampled fewer nodes at later time points.The study was, however, not designed to assess whether this small difference in number of nodes removed over time was clinically relevant.However, due to the limited impact of IGL on all other performance characteristics of TAS, we conclude that IGL is not a key element of TAS.
TAS consists of palpation-guided selective removal of obvious nodal disease, thereby tailoring the extent of axillary surgery to the extent of axillary disease.It further includes the SLN procedure to reduce the volume of microscopic disease, while IGL of clipped or suspicious nodes is optional. 21The underlying hypotheses are that ART can cure microscopic disease left behind in the axilla after TAS in both the neoadjuvant and adjuvant setting, and that the combination of TAS with ART is less harmful for patients compared with standard ALND in the context of extended regional nodal irradiation.Therefore, the new concept of TAS combines several established surgical techniques that are commonly used to stage the axilla in the adjuvant and neoadjuvant setting.While there is no new surgical technique per se involved in TAS, the novel concept is to use a targeted and limited approach to the axilla to treat cancer by selectively removing it, not to rule it out, as is the goal of TAD or the SLN procedure when used in today's practice.In the adjuvant setting, the main difference between TAS and the SLN procedure is that TAS allows IGL of nodes, and that the selective removal of palpably suspicious disease is a regular key component.Currently, since palpable disease is the main contraindication to the SLN procedure when used for staging purposes, it is rarely encountered.In the neoadjuvant setting, the main difference between the therapeutic concept of TAS, which serves as final surgical treatment of residual nodal disease, and the diagnostic concept of TAD is that the latter by definition requires IGL and is routinely followed by ALND in case of residual nodal disease.
When planning this study, we were interested to see how the pragmatic concept of TAS would be translated into clinical practice at the participating TAXIS study sites.Therefore, we extensively documented key aspects of TAS including details on preoperative workup (e.g., type of clips and imaging) and the intervention (e.g., number of lymph nodes removed, SLN-and localization techniques).Indeed, significant variation by country was observed.In Switzerland, for example, IGL was omitted in one-quarter of patients, whereas in Austria, Germany, and Hungary, IGL was used in almost all cases (Table 3).International expansion of study sites is currently ongoing.The prespecified evaluation of TAS after randomization of the total TAXIS sample size of 1500 patients will therefore further broaden its global applicability.When use of IGL was attempted, it was successfully performed in 98%.This was not depending on type of clip used (Table 4).However, patients with failed clip removal showed the lowest IGL success rate, suggesting that failed IGL may have increased the risk of missing the targeted node.In our cohort, the clipped node corresponded to an SLN in 74.4% of patients, a finding similar to data published by Kuemmel et al., in which the SLN and targeted lymph node were identical in 64.8%. 13Interestingly, IGL was also frequently used for upfront surgery of palpable disease, which reflects the popularity of IGL at some study sites.A prior TAXIS substudy was prespecified after the first 200 patients were randomized and included all details on the 96 patients who were excluded from the TAXIS trial, totaling 296 registered patients. 21It showed that the clip removal rate was 94.3% and the false-negative rate of TAS in patients undergoing completion ALND was 1.8%.Since the present substudy focused on use of IGL and its impact on TAS in the first 500 randomized patients, data collection on the 250 excluded patients was limited, and hence, no falsenegative rate of TAS could be evaluated.However, since other relevant performance characteristics of TAS remained almost identical, such as the clip removal rate of 94.9%, we have no reason to assume that any of the key findings of the initial substudy have changed after expansion of the patient population.
To the authors' knowledge, TAXIS is the only RCT addressing the omission of ALND in patients with palpable disease who undergo upfront surgery to date.9][30] We expect that further RCTs will soon be developed to investigate the omission of ALND during upfront surgery in light of the results of the RxPONDER and Mindact trials that questioned the routine use of chemotherapy in all patients with luminal node-positive breast cancer. 31,32n the neoadjuvant setting, the only RCT besides TAXIS to investigate omission of ALND for residual nodal disease after NACT is the Alliance A011202 trial (NCT01901094).While we eagerly await the primary analysis of this trial, ALND remains standard care, apart from, perhaps, the lowest volume of residual nodal disease, where ART may be considered on an individual basis. 184][35] Recently, an analysis from the MARI trial, including also patients with residual nodal disease, showed a 3-year axillary recurrence-free interval of 98.2%.Residual disease in the MARI-node independently predicted disease recurrence in multivariable analysis.In this trial, four of five axillary recurrences occurred in patients with residual nodal triple-negative disease and the corresponding 3-year axillary recurrence rate was 3.4%. 36We purposefully refrained from performing intrinsic subtypespecific analyses of IGL in TAS for the present substudy due to the limited sample size of non-HR+/HER2− breast cancer (n = 103).However, we prespecified the corresponding subgroup analyses in the TAXIS substudy that is planned to assess the performance of TAS after the full TAXIS sample size of 1500 patients is reached.Therefore, the relevance of finding positive nodes in the majority of patients after TAS with 29.3% of patients undergoing ALND having ≥ 4 additional positive nodes, currently remains unclear.Hence, we recommend waiting for oncologic outcome analysis of TAXIS before adopting the much less radical approach of TAS in clinical practice.

Limitation
This was a prospective observational cohort study embedded in a randomized trial, and IGL was used at the discretion of the surgeon.While IGL was a standard component of TAS in most countries, it was selectively used in Switzerland, where most patients were included.Particularly, the comparison group with no IGL remained rather small (n = 78).While we adjusted for multiple confounders including upfront surgery versus NACT setting, palpable versus nonpalpable disease, and tumor receptor subtype in Impact of Imaging-Guided Localization on … multivariable analyses, residual confounding by unknown factors cannot be excluded.

CONCLUSIONS
TAS targeted positive nodes with or without IGL.IGL proved to be feasible inasmuch as it could be successfully performed in almost all cases, irrespective of type of clip and localization method.However, IGL did not significantly change the performance of TAS, which left ≥ 2 positive nodes behind in 47.6% of patients.

TABLE 5
Characteristics of tailored axillary surgery by use of IGL IQR interquartile range, TAS tailored axillary surgery, ALND axillary lymph node dissection, NA not applicable a Nodes with isolated tumor cells are counted as positive *Fourteen patients had neoadjuvant therapy other than chemotherapy, three of which underwent ALND **Nine patients for whom IGL was unknown are not shown here, six of which underwent ALND ***Six patients for whom IGL was unknown are not shown here, four of which underwent ALND ****For three patients the number of removed and additional positive lymph nodes was

TABLE 1
Patient and tumor characteristics 3/3; MRI 100%, 3/3).The success of IGL did not depend on type of clip (Table4).The type of clips used in excluded patients are presented in TableS2.The clip removal rate in all registered patients was 94.9% (712/750).In 74.(103/128), and was considered to have successfully localized the target node in 95.1% (98/103) of these patients.There was no difference in any number of nodes removed by TAS with or without IGL, neither total[5 (IQR 3-8)

Table 5 ]
. In multivariable linear regression models controlling for confounding variables, the effect of IGL on the number of total as well as positive nodes removed remained nonsignificant (Supplementary TableS3).However, while the number of nodes removed during TAS with IGL remained stable over time [5 (IQR 3-8 in 2019 and 5 (IQR 3-8) in 2022, p = 0.8], it decreased significantly without IGL, from 6 (IQR 4-6) in 2019 to 4 (IQR 3-4) in 2022 (p = 0.015).The difference in the number of nodes removed by use of IGL was not statistically significant at any time point, neither in 2019 (p = 0.6), nor in

TABLE 3
Patient and tumor characteristics by use of imaging-guide localization