Updates in Surgical Management of the Axilla

Axillary management of patients with breast cancer such as sentinel lymph node biopsy have evolved substantially over the past 30 years.

The surgical management of the axilla has evolved significantly over time, shifting from axillary lymph node dissection (ALND) for all patients toward more limited axillary surgery, largely due to improvements in systemic therapy and radiotherapy (RT) techniques. Randomized trials established the safety of sentinel lymph node biopsy (SLNB) for axillary staging in patients with early-stage clinically node-negative (cN0) breast cancer with pathologically negative nodes or limited SLN metastases who are undergoing breast-conserving surgery (BCS).^1-3 Results of the recently published randomized SENOMAC trial (NCT02240472) confirmed the safety of ALND omission in a broader cohort of patients with cN0 and 1 or 2 positive SLNs, including patients treated with mastectomy, those with tumors larger than 5 cm, and those with microscopic extracapsular extension in the SLN.⁴ Neoadjuvant chemotherapy (NAC) also has emerged as a method for axillary downstaging in patients with clinically node-positive (cN+) breast cancer, allowing patients whose disease became cN0 with NAC to undergo SLNB and avoid ALND if a nodal pathologic complete response (pCR) is achieved^5-8; studies have demonstrated low rates of nodal recurrence with this approach.^9,10

Currently, there is interest in omitting axillary surgery altogether for patients with low-risk early-stage breast cancer. Results from the recently published SOUND trial (NCT02167490) demonstrated no difference in distant disease–free survival at 5 years in those treated with SLNB compared with those treated without SLNB.¹¹ Importantly, as axillary surgery is being de-escalated, oncologists have raised concerns about missing potential candidates for CDK 4/6 inhibition without accurate nodal staging. Safe surgical de-
escalation and avoidance of axillary overtreatment are key priorities in the modern era, with the understanding that tumor biology, not nodal status, determines prognosis and treatment. However, there remain subsets of patients for whom ALND is still indicated outside of a clinical trial, including patients with residual micro- or macrometastases in the SLN after NAC, and many patients with cN+ breast cancer and palpably abnormal nodes who have up-front surgery. Here we review recent updates and ongoing controversies in the surgical management of the axilla, and the impact of surgical de-escalation on systemic therapy recommendations.

Up-Front Surgery

Management of Positive SLN in cN0 Patients After Mastectomy

It is well-established that ALND may be safely omitted for patients with early-stage cN0 who have limited SLN metastases and undergo BCS and RT; this results in a lower risk of lymphedema. The phase 3 ACOSOG Z0011 trial (NCT00003855) and the EORTC 10981-22023 phase 3 AMAROS randomized trial (NCT00014612) included patients with T1 to T2 cN0 disease and 1 or 2 positive SLNs. It demonstrated equivalent disease-free survival and 10-year axillary recurrence rates of less than 2% with or without ALND.² Similar findings were observed at the 8-year follow-up of the OTOASOR trial, conducted by the National Institute of Oncology in Budapest, Hungary, of patients with tumors less than or equal to 3 cm or smaller and patients with cN0 disease who were randomly assigned to axillary RT (n = 230) or ALND (n = 244).¹² The majority of patients in these early trials underwent BCS. All patients enrolled in the ACOSOG Z0011 trial had BCS, and those with mastectomy comprised a small minority in the AMAROS (18%) and OTOASOR (16%) trials, with a collective sample size of 322 patients, which likely contributed to the slower adoption of this approach for patients with mastectomy. However, the more recent SENOMAC trial (NCT02240472), which enrolled patients with T1 to T3 cN0 with 1 or 2 positive SLNs, included a larger proportion of those who had a mastectomy (n = 920) and has similarly confirmed the safety of omission of ALND among patients for whom postmastectomy radiotherapy (PMRT) is indicated.⁴

Unlike those undergoing BCS, patients undergoing up-front mastectomy pose a unique challenge—namely, the lack of consensus on indications for PMRT/regional nodal irradiation (RNI). The demonstration of improved local control and distant disease-free survival with nodal irradiation among patients who underwent mastectomy with 1 to 3 positive SLNs has resulted in the increasing use of PMRT in this population,^13-15 despite controversy regarding the benefit of treatment in patients with N1 disease who otherwise have low-risk tumor characteristics. Although many countries recommend PMRT for any positive node, panelists at the 2023 St. Gallen International Breast Cancer Conference varied significantly in their recommendations for PMRT in patients with 1 to 3 positive nodes, depending on the number of positive nodes and the receptor status.¹⁶ Due to the lack of consensus, historically, immediate ALND was standard for patients undergoing up-front mastectomy with any SLN macrometastasis on frozen section evaluation. This reflexive approach has resulted in more than 50% of patients with cN0 SLN metastasis receiving both ALND and PMRT; many of those with 1 or 2 positive SLNs would have been adequately treated with PMRT alone.^17-19

Treatment with ALND combined with PMRT causes significant morbidity, with lymphedema and arm complications reported in up to 32% of patients who undergo both therapies.^12,20,21 Although this is justified in patients with a heavy nodal burden (3 or more positive nodes), it likely represents overtreatment in patients with 1 or 2 positive SLNs, for whom 1 axillary treatment would suffice. Avoidance of overtreatment may be facilitated by omitting the SLN frozen section, which would defer axillary treatment decision-making until the final pathology is known. In a study of 2207 patients with cT1-3N0 disease who underwent up-front mastectomy from 2018 to 2020 at Memorial Sloan Kettering Cancer Center (MSKCC) in New York, New York, 12% (n = 267) had 1 or more positive SLNs, and only 6% (n = 126) would have required a completion ALND because of 3 or more positive SLNs or 1 or 2 positive SLNs not meeting PMRT criteria, had frozen section been deferred.¹⁷ A similar study by Kantor et al²¹ evaluated 560 patients with cT1-2N0, of whom 121 had 1 or 2 positive SLNs, finding that omission of intraoperative SLN evaluation in this subset resulted in fewer patients having ALND (7.6% when frozen section evaluation was omitted vs 23.8% when frozen was performed), and the combination of ALND and PMRT (8.9% vs 40.5%, respectively). Overall, among 79 patients with 1 or 2 positive SLNs who had frozen section omitted, 84% were spared ALND.²¹ In 2022, we adopted a policy of omitting routine frozen section for patients with cT1-3N0 having up-front mastectomy at MSKCC: In the subsequent 2 years, only 5% of patients with cN0 have undergone completion ALND, and 88% of patients with 1 or 2 positive SLNs, who were postoperatively confirmed to meet PMRT criteria, have been spared ALND by avoidance of reflexive ALND for any positive SLN.²² Collectively, these findings demonstrate that deferring SLN frozen section in patients with cN0 having up-front mastectomy reduces axillary overtreatment and allows for multidisciplinary discussion regarding the need for PMRT.

Although minimizing extensive axillary treatment for limited nodal metastases is an important treatment goal, there is no evidence to support the absence of any axillary treatment for the undissected axilla in patients who underwent mastectomy with SLN macrometastases. Despite this lack of evidence, data from a National Cancer Database study from 2018 showed that among 4033 patients with 1 or 2 SLN micrometastases who received a mastectomy, 17% had no additional axillary treatment; outcomes were not reported.²³ Ongoing randomized trials are evaluating whether both ALND and RT can be omitted in select patients with SLN macrometastases (Table 1).

Table 1

Management of cN+ HR+/HER2− Breast Cancer

Unlike patients presenting with cN0 breast cancer, the standard of care for axillary management in patients with palpable cN+ disease having up-front surgery is ALND. Patients with mobile ipsilateral adenopathy (cN1) disease may be offered neoadjuvant therapy in hopes of achieving a nodal pCR, which would permit the omission of ALND. However, among those with hormone receptor–positive, HER2-negative (HR+/HER2–) disease, rates of nodal pCR are low (< 21%),^9,24 resulting in high rates of ALND (~80%) after neoadjuvant treatment.⁹ In addition, results from the phase 3 RxPONDER trial (NCT01272037) confirmed that genomic profiling identifies a subset of patients with node-positive HR+/HER2− disease who do not benefit from chemotherapy, further making neoadjuvant therapy a suboptimal choice for many such patients.²⁵

Currently, ALND remains standard for patients with cN+ disease having up-front surgery due to a presumptive heavier nodal burden. However, a single-institution retrospective analysis of
180 patients with cT1-3N1 HR+/HER2− tumors found that 50% to 60% have only 1 or 2 positive lymph nodes at up-front surgery,²⁶ similar to the ACOSOG Z0011 and AMAROS trial populations, and could therefore potentially avoid ALND if SLNB were feasible in this population. SLNB feasibility was evaluated in a prospective single-arm study (NCT04854005) opened at MSKCC in 2021. Patients with T1 to T2 cN1 HR+/HER2− breast cancer with preoperative ultrasound suggestive of limited nodal disease were enrolled,²⁷ with the study completing accrual in late 2024; results are forthcoming. Similarly, the ongoing European randomized TAXIS trial (NCT03513614) is enrolling patients with cN+ disease who are undergoing up-front surgery or neoadjuvant therapy; all patients undergo tailored axillary surgery (consisting of SLNB and selective removal of clinically suspicious nodes) and are subsequently randomly assigned to axillary RT vs ALND and RT, with results expected in 2029.²⁸ Both trials, if successful, would address an unmet need for surgical de-escalation in patients with cN+ disease having up-front surgery.

Omission of Sentinel Node Biopsy in cN0 Postmenopausal HR+/HER2− Breast Cancer

In patients with luminal cancers, systemic therapy decisions were historically based on tumor size, tumor grade, and, importantly, nodal status. In the modern era, decisions regarding the need for chemotherapy in patients with HR+/HER2− breast cancer are increasingly based on tumor biology and, specifically, genomic assays. Results from the randomized TAILORx(NCT00310180) and RxPONDER trials demonstrated no benefit from systemic chemotherapy for patients who are node-negative or postmenopausal node-positive with 1 to 3 positive nodes, respectively, and who have a recurrence score of 25 or less.^25,29 The decreased reliance on nodal status in postmenopausal patients with HR+/HER2− breast cancer raised the question of whether SLNB could be omitted in this patient subset. Omission of SLNB could be considered in patients with cN0 early-stage breast cancer if the likelihood of identifying 4 or more positive nodes is infrequent. Early retrospective studies of patients with cN0 report a low frequency of pN2-3 disease, ranging from 2% to 4%.^30-32 In a more recent retrospective evaluation by Lee et al³³ of postmenopausal women with cT1 to T2N0 breast cancer treated from 2006 to 2016, more than 3 positive nodes were identified in only 3.5% of 2639 patients with HR+/HER2− disease, highlighting the rarity of heavy nodal burden in this population and suggesting that SLNB would rarely impact chemotherapy recommendations.

The omission of SLNB has been standard practice among women older than 70 years with early-stage cT1N0 HR+/HER2− breast cancer and was incorporated into the Society of Surgical Oncology Choosing Wisely recommendations in 2016. This was based on studies demonstrating no difference in disease recurrence or overall survival with the omission of axillary staging in this subset.^34,35 More recent evidence suggests that this practice may be expanded to the majority of postmenopausal patients who are postmenopausal with HR+/HER2− early-stage invasive breast cancer. The SOUND trial enrolled 1405 women with cT1N0 tumors with a negative axillary ultrasound undergoing BCS who were randomly assigned to no axillary surgery (n = 697) or SLNB (n = 708). The majority of patients were postmenopausal (78%) and had HR+/HER2− breast cancer (88%). Approximately 98% of patients received RT, and there was no difference between groups with respect to receipt of endocrine therapy or chemotherapy. There was no difference in 5-year distant disease-free survival with SLNB (97.7%) vs without SLNB (98%; log-rank P = .67). Importantly, axillary recurrence occurred in 0.4% of patients in both study groups at 5 years (P = .91), despite the finding of positive axillary nodes in 13.7% of patients randomly assigned to SLNB, with 0.6% having 4 or more positive nodes.¹¹ Early reports from the trial (NCT02466737), which randomly assigned 5502 eligible patients with cT1-2N0 breast cancer undergoing BCS and RT with a negative axillary ultrasound 4:1 to SLNB vs no axillary surgery, found metastasis in 4 or more nodes in only 0.3% (n = 12/4124) of patients randomly assigned to SLNB, and reported non-inferiority of omission of axillary staging as compared to SLNB after median follow-up of 6 years.^36,37 

Additional randomized trials of SLNB omission in patients with early-stage breast cancer include the BOOG 2013-08 (NCT02271828), NAUTILUS (NCT04303715), and SOAPET trials (NCT04072653) (Table 2). While the results of these ongoing studies are awaited, data from the SOUND trial suggest that SLNB may be safely omitted among patients who are postmenopausal with cT1N0 HR+/HER2− breast cancer with a negative axillary ultrasound undergoing BCS. In addition, both SOUND and INSEMA demonstrated that identification of 4 or more positive nodes was rare (0.3%-0.6%) in these low-risk populations, suggesting that SLNB omission would not alter chemotherapy recommendations. Accordingly, in April 2024, our service at MSKCC adopted a policy of SLNB omission in patients with cT1N0 HR+/HER2− breast cancer (grade 1 to 2 disease) undergoing BCS and a negative preoperative axillary ultrasound, with plans to prospectively follow this cohort for evaluation of long-term outcomes.

Table 2

Neoadjuvant Therapy

Use of Targeted Axillary Dissection vs SLNB After NAC

Patients with clinically node-positive disease treated with NAC may undergo SLNB and avoid ALND if a nodal pCR is achieved. SLNB was confirmed as feasible in this setting in multiple prospective trials with identification rates of more than 80% and false-negative rates of less than 10% with dual-tracer lymphatic mapping and retrieval of 3 or more SLNs.^5-8 More recently, targeted axillary dissection was developed, which includes axillary staging with SLNB combined with targeted excision of the biopsy-
proven clipped node, with a reported false-negative rate ranging from 2% to 4%.^38,39 Although debate continues regarding the optimal axillary staging technique in patients with cN1 post NAC, several retrospective studies have demonstrated low rates of nodal recurrence in patients who achieve nodal pCR and are treated with SLNB alone, ranging from 0% to 1.6%. Until recently, there were limited data on the oncologic safety of targeted axillary dissection despite multiple studies demonstrating low false-negative rates with this technique. Investigators in a recent multicenter retrospective study from the Oncoplastic Breast Consortium evaluated 1144 patients with cN1/2/3 breast cancer treated with NAC and compared outcomes between patients with lymph node status after neoadjuvant therapy N0 treated with SLNB vs targeted axillary dissection. Overall, 666 patients had SLNB with dual-tracer mapping and retrieval of 3 or more SLNs, and 478 received targeted axillary dissection with no difference in 3-year rates of axillary recurrence (0.8%, SLNB; 0.5%, TAD; P = .55), confirming that at short-term follow-up, both techniques were oncologically equivalent.⁸ The ongoing nonrandomized observational AXSANA trial (NCT04373655) is comparing outcomes among patients with cN+ disease who are treated with various axillary staging techniques post NAC, including targeted axillary dissection, SLNB, targeted lymph node biopsy (removal of the biopsy-proven positive node), and ALND. It will provide prospective data on invasive disease-free survival (iDFS) and axillary recurrence with these different techniques.⁴⁰

Management of Residual
Disease in SLNs, Including ITCs

Although ALND may be safely omitted for patients with cN+ disease who achieve a nodal pCR after NAC, the presence of residual nodal disease in the SLNs warrants ALND due to a high residual nodal burden among those with potentially chemoresistant disease.^6,41,42 Rates of non-SLN positivity in patients with residual disease in the SLNs post NAC range from 61% to 72%,^42-44 far higher than the 20% typically seen in the up-front surgery setting. Importantly, there are limited retrospective data on nodal recurrence in patients with residual disease in the SLNs treated without ALND, with small numbers of patients included and variable nodal recurrence rates ranging from 0% to 22%.^45-48 Although randomized trials evaluating nodal RT vs ALND in patients with a positive SLN post NAC are ongoing (ie, Alliance A011202 [NCT01901094] and TAXIS),^28,49 outside of a clinical trial, ALND remains standard in patients with residual disease in the SLNs post NAC.

An exception to this is patients with residual isolated tumor cells (ITCs) alone in the SLNs post NAC, as these patients were not included in the randomized trials. Residual ITCs are identified in less than 3% of patients after NAC and comprise a small minority of past studies, resulting in variable surgical practices for this subset.⁵⁰ In the recent multicenter ICARO study (NCT06464341), Montagna et al⁵¹ evaluated patients with T1 to T3 N0 to N3 disease who underwent NAC with ITCs detected in the SLNs by either hematoxylin and eosin staining or immunohistochemistry. Of the 583 patients, 182 underwent ALND, and 401 had no ALND. Among those who underwent ALND, 30% had additional positive nodes, with 18% having additional ITCs only, 7% with additional micrometastases, and 5% with macrometastasis. When comparing those treated with ALND with those treated without, there was no difference in 5-year axillary recurrence (1.7%, ALND; 1.1% no ALND; P = .7) or any invasive recurrence (16%, ALND; 19%, no ALND; P = .13), respectively. These findings suggest a very low likelihood of clinically significant residual nodal burden among those with ITCs after NAC and do not support routine ALND in this setting.

Radiotherapy Considerations After pCR to NAC

Improvements in neoadjuvant systemic therapies are increasing the rates of pCR and facilitating surgical de-escalation; they may facilitate RT de-escalation as well. Historically, nodal RT has been recommended for most patients with cN+ disease at presentation, irrespective of response to NAC, which is due to a presumed higher locoregional recurrence rate associated with an initial heavier nodal burden.

However, prognosis is strongly linked to response to NAC, suggesting that nodal RT may be overtreating a subset of patients with cN+ disease and who achieve nodal pCR. In a combined analysis of the NSABP B-18 and B-27 neoadjuvant trials, which included 3088 patients who did not receive nodal RT or PMRT, the 10-year cumulative incidence of locoregional recurrence was significantly lower among those with a nodal pCR as compared with those without, regardless of surgery type (10%-12% with nodal pCR vs 15%-20% without nodal pCR).⁵² This observation raised the question of whether RT may be de-escalated among patients who achieve a nodal pCR after NAC. The omission of nodal RT in patients with cN+ disease who achieved nodal pCR was evaluated in the NRG Oncology/NSABP-B-51/RTOG 1304 trial (NCT01872975); 5-year results were presented at the 2023 San Antonio Breast Cancer Symposium. Investigators evaluated patients with cT1 to 3N1 disease with biopsy-proven nodal metastasis who underwent NAC with pathologically negative lymph nodes at surgery (SLNB or ALND) and were randomly assigned 1:1 to standard RNI (n = 820) or no RNI (n = 821). There was no difference in the 5-year invasive breast cancer recurrence-free interval (91.8%, no RNI; 92.7%, RNI; P = .51) or the isolated locoregional recurrence-free interval (98.4%, no RNI; 99.3%, RNI; P = .088) between the groups, suggesting that patients who achieve a nodal pCR with NAC may avoid RNI without a compromise in oncologic outcomes.⁵³ While formal publication of the NSABP B-51 trial and long-term outcomes are awaited, these compelling early findings support a nuanced, multidisciplinary discussion and consideration of de-escalation of RNI for eligible patients who achieve a nodal pCR.

Impact of Surgical De-escalation on Systemic Therapy Decisions

Early data from SOUND and INSEMA showed low rates of pN2 disease in their cohorts, suggesting minimal impact on systemic chemotherapy decisions with SLNB omission in postmenopausal patients. However, the introduction of CDK 4/6 inhibitors in the adjuvant setting for early-stage HR+/HER2− breast cancer has raised concerns about potential undertreatment with SLNB omission because a small subset of eligible patients with positive nodes would be missed. Results from the phase 3 monarchE trial (NCT03155997) demonstrated a significant improvement in iDFS with the addition of abemaciclib to endocrine therapy (absolute iDFS benefit was 7.6% at 5 years) for patients with luminal breast cancer who have 4 or more positive nodes, or 1 to 3 positive nodes and a tumor size of 5 cm or greater, or histologic grade 3 disease.⁵⁴ Although the likelihood of pN2-3 disease is exceedingly low among patients with early-stage cN0 HR+/HER2− disease, it may be reasonable to continue axillary staging among those with high-risk features such as high tumor grade to avoid missing patients with even 1 positive node who may be eligible for abemaciclib.

Another controversy is whether patients with luminal cancer and 1 or 2 positive SLNs and no additional high-risk features should undergo ALND to identify those with at least 4 positive nodes who qualify for abemaciclib. A recent publication by de Boniface et al⁴ addressed this question by performing a post hoc analysis of the randomized SENOMAC trial including patients 18 years or older with HR+/HER2−, grade 1 to 2, cT1-2N0 breast cancer with 1 or 2 positive SLNs. Among 1705 patients, and using data extracted from the monarchE and AMAROS trials,^2,54 the authors calculated that ALND would need to be performed in 104 patients to avoid
1 iDFS event at 5 years after 2 years of treatment with abemaciclib, with 9 patients experiencing severe or very severe arm morbidity.⁵⁵ Given the limited benefit of this approach, ALND is not justified for patients with luminal breast cancer, 1 or 2 positive SLNs, and otherwise low-risk features.

Although abemaciclib is currently the only FDA-approved CDK 4/6 inhibitor for patients who are node-positive in the adjuvant setting, early data show promise for the use of ribociclib in a broader population of patients with node-negative and node-positive luminal cancer. Initial results from the phase 3 NATALEE trial (NCT03701334) demonstrated a 3.3% absolute iDFS benefit at
3 years with the addition of ribociclib to endocrine therapy.⁵⁶ Moving forward, decisions for CDK 4/6 inhibitor eligibility should be based on the nodal information available and avoid unnecessary surgical escalation when the benefit is limited.

Conclusion

Axillary management continues to evolve as multimodality therapies permit de-escalation without compromising oncologic outcomes. Avoiding ALND and SLNB omission in select patients with early-stage breast cancer, when appropriate, decreases the burden of cancer treatment and improves survivors’ quality of life. Recent trial results highlight the scope for continued de-escalation of axillary surgery among patients with low-risk disease and likely minimal nodal disease burden, along with great promise for surgical and RT de-escalation in excellent responders to neoadjuvant therapy. Ongoing research will be essential to refine treatment strategies in this era of multidisciplinary treatment.

Disclosures

AVB reports speaking honorarium from Novartis and Merck Sharp & Dhome.

Corresponding Author

Aditya Bagrodia, MD

Associate Professor, Department of Urology

University of California San Diego

Suite 1-200, 9400 Campus Point Drive

La Jolla, CA 92037, US

Phone: (858) 657-7876

Email: Bagrodia@health.ucsd.edu

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