Axillary surgery for breast cancer: evolving approaches

Introduction

In patients with early-stage breast cancer, the involvement of axillary lymph nodes is a major contributor to staging and oncologic outcomes. The role and extent of axillary surgery have continued to evolve over time in response to efforts to optimize oncologic outcomes while striving to improve the quality of life for patients with breast cancer. Recently, there has been significant de-escalation in the extent of axillary surgery with fewer patients requiring axillary lymph node dissection (ALND), with the implementation of tailored indications for sentinel lymph node biopsy (SLNB) and strategies, such as targeted ALND, intended to provide less morbid options for patients. With advancements in breast cancer imaging techniques, radiation therapy, and systemic therapy, progress in further defining the scope and role of axillary surgery continues forward. In this review, we will discuss the current oncologic approach for axillary surgery, including of current strategies and techniques that are employed to prevent the development of lymphedema in patients undergoing surgery for breast cancer.

History of axillary staging

At the beginning of the 20^th century, the Halsted radical mastectomy, which included the removal of the entire breast, pectoralis muscles, and ipsilateral axillary nodes, was the standard of care operation for patients with breast cancer diagnoses. After recognition of surgical morbidity and oncologic equivalence, the modified radical mastectomy, which spares the pectoralis muscles and level 3 nodes, became the gold standard in the 1970’s. In an effort to investigate the effectiveness of less extensive breast surgery, randomized prospective clinical trials were conducted. One of the most influential trials was the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-04 trial in 1971, which randomized clinically node-negative women to radical mastectomy, total mastectomy plus axillary radiation, or total mastectomy alone with delayed axillary dissection for patients who subsequently developed positive nodes. This trial demonstrated that there was no significant difference with respect to disease-free survival, distant disease-free survival, or overall survival for patients with clinically node-negative disease among the three treatment arms (1). Notably, this trial showed that the rate of axillary recurrence was 20% for the patients that had a total mastectomy alone and ≤3% for patients that had a radical mastectomy or total mastectomy with radiation (1). The median time to axillary recurrence was 14.8 months. This study supported the paradigm shift to less invasive surgery for breast cancer patients with clinically node-negative axilla.

Role of axillary surgery in patients who are clinically node negative

Given the recognized increased morbidity associated with ALND, efforts towards the de-escalation of axillary intervention persisted throughout the mid-1980’s (2). During this time, there was an increased emphasis on local and systemic therapy to limit disease progression, which ultimately has allowed for a less invasive approach to axillary staging.

In the 1990’s, SLNB began to be explored as an alternative to ALND for clinically node negative patients. Multiple randomized control trials have compared SLNB to ALND and have demonstrated that there was similar overall survival, reduced morbidity, lower risk of lymphedema, and improved quality of life following SLNB when compared with ALND (2,3). One of the largest trials to compare these procedures was the NSABP-B32 trial which accrued clinically node-negative patients with pathologically negative sentinel nodes from 1999 to 2004. Patients were randomized to SLNB alone versus SLNB plus ALND (4). This study found that there were no statistical differences in terms of overall survival, disease-free survival, and regional control between patients that underwent an ALND versus SLNB. A similar randomized controlled trial found that 10-year survival was similar between patients who had undergone SLNB plus complete ALND versus SLNB followed by ALND only if the sentinel nodes were metastatic, as well as had a low rate of axillary recurrence (5). Given the results of these trials SLNB alone became the accepted standard of care for patients undergoing surgery for breast cancer with clinically negative lymph nodes.

Recently there has been a push to avoid SLNB completely for certain patient populations. Axillary lymph node evaluation has not been associated with improved survival outcomes for women over the age of 70 with early-stage hormone receptor positive (HR⁺) breast cancer who have received endocrine therapy (6-8). In 2012, the American Board of Internal Medicine (ABIM) published the Choosing Wisely recommendations for axillary management, recommending that surgeons “Don’t routinely use sentinel node biopsy in clinically node-negative women ≥70 years of age with early-stage hormone receptor-positive, HER2-negative invasive breast cancer” (9,10). These guidelines were later endorsed by the Society of Surgical Oncology (SSO) in 2016 and The American Society of Breast Surgeons (ASBrS) in 2018 (10,11). However, it is important to note that these guidelines remain a debatable topic given that nodal status might affect adjuvant treatment decisions for certain patients within this patient population. Some studies report that SLNB provides important information that may allow for the omittance of radiotherapy for elderly HR⁺ patients that are found to have a negative sentinel lymph node (12). Another National Cancer Database (NCDB) study developed a clinical rule that combines tumor stage and grade to classify breast cancer patients ≥70 years with HR⁺ invasive breast cancer into low-risk and high-risk groups of having a positive lymph node status (13). This clinical rule can then be used to guide clinicians on which patients would benefit from following the Choosing Wisely recommendations for axillary management. As a result, the decision to pursue sentinel node biopsy in clinically node negative women ≥70 years of age with early-stage HR⁺, HER2⁻ negative invasive breast cancer should remain a multidisciplinary decision as not all patients within this patient population are the same.

Role of ALND for patients who are clinically node negative with positive sentinel lymph nodes

Previous standard practice required that patients with breast cancer who are found to have metastatic lymph node involvement on SLNB went on to receive a completion ALND. However, significant axillary surgery de-escalation occurred in response to the American College of Surgeons Oncology Group Z0011 clinical trial (ACOSOG Z0011) trial, which accrued patients from 1999 to 2004. In this randomized controlled trial, breast cancer patients who had early-stage clinically node-negative breast cancer with limited pathologic metastatic lymph node involvement (≤2 positive sentinel lymph nodes) were treated with breast-conserving surgery (BCS) and randomized to ALND or SLNB alone (14). This was followed by whole breast radiation (WBI). Of note, the tangential radiation fields were not recorded and were not standardized for this study which could have resulted in variations in the outcomes. Decisions regarding systemic therapy were left to the discretion of the patient’s oncologist. The 10-year outcomes of this study showed that there was no statistically significant difference in axillary recurrence rates and distant disease-free survival rates for patients who underwent ALND versus SLNB with adjuvant breast radiation therapy (15). This study also found that overall survival for ALND compared with SLNB was non-inferior. Further, those who were allowed to omit ALND benefitted from reduced morbidity and a lower risk of lymphedema. One retrospective cohort study examined the impact of the ACOSOG Z0011 trial and found that the incidence of lymphedema for patients that had undergone ALND was 19.2% compared to 5.1% for patients that had undergone SLNB (P=0.0001) and subsequently the lymphedema referrals had been reduced by 20% (P=0.001) (16). These findings informed the current standard of care, that omission of ALND is appropriate for clinically node-negative patients with one or two positive sentinel lymph nodes.

The ASBrS and the American Society of Clinical Oncology (ASCO) endorsed the findings of the Z0011 trial in 2014 (17,18). Following these endorsements, the most recent National Comprehensive Cancer Network (NCCN) guidelines do not recommend completion ALND for clinically node-negative patients with a positive sentinel lymph that fall into the following criteria: T1 or T2 tumor, one or two positive sentinel lymph nodes, undergoing BCS, planned to receive WBI, and did not receive neoadjuvant chemotherapy (NAC) (19).

Beyond Z0011, further opportunity for axillary management progress has occurred in the role of radiation therapy. Axillary radiation has been evaluated as a less invasive alternative to ALND for patients with positive sentinel lymph nodes. The European Organization for Research and Treatment of Cancer (EORTC) conducted the After Mapping of the Axillary Radiotherapy Or Surgery (AMAROS) trial, accruing patients from 2001 to 2010, to assess if axillary radiation provides comparable regional control of the axilla and compared side effects to ALND. This was a phase III randomized control trial in which women with T1–2 clinically node-negative breast cancer with positive sentinel lymph nodes were randomized to undergo completion ALND or axillary radiation (20). A majority of patients underwent BCS for both patient groups, however a small subset of patients underwent mastectomy. The mastectomy patients that had a positive sentinel node underwent postmastectomy radiotherapy (PMRT). Five-year axillary recurrence was 0.43% and 1.19% after ALND versus axillary radiation, respectively. Lymphedema in the ipsilateral arm was noted significantly more often after ALND than after axillary radiation at 5-year follow-up, 23% versus 11% respectively (P<0.0001). These results demonstrate that clinically node-negative patients with a positive sentinel node or nodes can achieve comparable axillary control after undergoing axillary radiation or ALND. It is important to note that the effects of radiation toxicity for the patients that underwent axillary radiation and PMRT may take several years to manifest and as a result the differences in rates of lymphedema between the different patient groups may have not been correctly evaluated yet. All in all, the results of these trials suggest that completion ALND may not result in additional oncologic benefit for breast cancer patients with limited metastatic disease. Also, the use of adjuvant treatment such as axillary radiation can play a significant role in axillary control in these patients.

Axillary management in patients who are clinically node positive

ALND can now be avoided for patients with negative sentinel lymph nodes and patients with one or two positive sentinel lymph nodes receiving breast or axillary radiation, but it remains the gold standard for patients that are clinically node-positive in the up-front surgery setting. However, this approach subjects clinically node-positive patients treated with NAC and nodal pathological complete response (pCR) to the complications and increased morbidity associated with ALND. Given these risks, multiple trials evaluated the use of SLNB in patients who are clinically node positive and were administered NAC. Four major prospective studies have assessed the use of SLNB after NAC in clinically node-positive patients. The ACOSOG Z1071 trial included patients with clinical T0–T4, N1–N2 breast cancer who received NAC and underwent both SLNB and ALND (21). This study showed that the false negative rate (FNR) of SLNB after NAC in patients with cN1 breast cancer was 12.6% for patients with at least two sentinel nodes removed. The SENTINA trial enrolled both patients with clinically node-negative and node-positive disease before NAC (22). This study found that the sentinel node identification rate was 80.1% and the FNR was 14.2% for patients who initially presented with clinically positive lymph nodes and ultimately converted to a clinically negative axillary status (arm C). The sentinel node biopsy following neoadjuvant chemotherapy (SN FNAC) study included patients with biopsy-proven node-positive breast cancer who received NAC and were subsequently found to have a sentinel node identification rate of 87.6% and FNR of 8.4% (23). The GANEA2 study evaluated women with early-stage breast cancer after NAC and had a FNR rate of 11.9% ultimately concluding that a negative SLNB post-NAC can allow breast surgeons to safely avoid ALND (24). A recent meta-analysis found that there is an inverse relationship between the FNR and number of nodes removed (25). This meta-analysis found that the FNR rate decreased from 20% to 12% and 4% with the removal of 1, 2, and 3 or more nodes, respectively. These studies indicate that SLNB after NAC in patients with node-positive breast cancer is accurate and it is possible to effectively identify those with nodal response who are ultimately eligible for the omission of ALND. It is also important to note that these trials did not evaluate the oncological safety of omitting ALND, but instead only noted the accuracy and feasibility of performing SLNB after NAC. However, studies have shown that NAC has the potential to achieve a pCR of up to 40% of patients (26,27). Currently, patients who are found to be clinically node-positive at the time of diagnosis often undergo neoadjuvant systemic therapy to reduce the burden of disease in the breast and/or axilla, minimize the scale of surgical intervention, and to assess response to therapy, to inform future medical intervention and for prognostic purposes.

Given the standard use of NAC for clinically node-positive patients and the concerns about the FNR, targeted axillary dissection (TAD) was developed to improve the reliability of axillary assessment at surgery. For patients who undergo NAC with known lymph node involvement, a clip is placed in the positive axillary lymph node. The clip is preferably one that is easily identifiable post-NAC response, such as a VISION clip or SAVI Scout. After the patient completes NAC, axillary staging is repeated, the marker clip is identified, the clipped lymph node is localized, and the clip is confirmed in the excised specimen. This is performed in combination with radioactive injection (also known as dual mapping) to identify additional sentinel lymph nodes. This procedure allows clinicians to confirm sampling of the biopsy-proven lymph node to improve the assessment of residual nodal disease after chemotherapy (28).

A prospective study that was conducted at MD Anderson evaluated patients with biopsy-confirmed node-positive disease. A marker clip was placed in the biopsied node and after NAC, axillary ultrasound was repeated and an ¹²⁵I-labelled radioactive seed was placed in the node with the marker clip. Patients then underwent SLNB with removal of the clipped node followed by formal ALND. The FNR for SLNB was 10.1% and adding the evaluation of the clipped node reduced the FNR to 1.4% (29). Another prospective study used the MARI (Marking Axillary Lymph Nodes with Radioactive Iodine ¹²⁵I Seeds) procedure which is a minimally invasive approach to assess the pathological response of nodal metastases after NAC. Patients had an ¹²⁵I seed placed in a previously proven metastatic axillary lymph node (also known as the MARI node) and a ¹²⁵I seed was placed in the breast tumor. The MARI node was identified by using a radiation detector and subsequently removed followed by an ALND. This study found that the identification rate of the MARI node was 97% and the FNR of the MARI procedure was 7% (30). The use of TAD provides clinicians with additional assurance that there is no additional axillary disease after the completion of NAC and SLNB. The concept of eliminating ALND is being explored further in the phase III randomized controlled trial, Alliance 11202, which randomly assigned women with clinically node-positive disease after NAC to ALND and nodal radiation therapy versus axillary and nodal radiation therapy alone. We continue to await the results of this trial.

Surgical techniques to minimize the morbidity of ALND

SLNB is the standard approach for patients with clinically node-negative breast cancer given that it reduces the risk of arm lymphedema and postoperative morbidity when compared to ALND. However, some studies have found that SLNB does not completely eliminate the risk of lymphedema. One study found that there is still a 7% chance of developing lymphedema after SLNB only (31). Given the risk of lymphedema associated with ALND and SLNB, the axillary reverse mapping (ARM) technique was developed to map and protect the arm lymphatic drainage during ALND and/or SLNB. The ARM procedure is based on the theory that the lymphatic pathway draining the breast maybe distinct from the nodes draining the arm; therefore, preserving the axillary nodes draining the arm may prevent lymphedema (32).

The ARM technique was first described in the United States by Klimberg in 2007. In this study, 220 patients underwent SLNB with or without ALND. Sentinel lymph nodes were identified with a radioactive tracer and a blue dye was used to map the ARM lymphatics. This study found that hot sentinel lymph nodes were found in 214 of 220 axillae (97.2%) and of those axillae, 40 (18.7%) had metastases and were followed by ALND. ARM lymphatics were near the sentinel lymph node field in 40.6% of patients. This study found that 2.8% of patients had a common channel at the level of the sentinel lymph node and 5.6% of patients had low-lying ARM lymphatics that were separate but juxtaposed lymphatic channels. This study provided evidence that patients undergoing SLNB continue to have a significant risk of lymphedema given that approximately 40% of patients had the blue ARM lymphatics identified near the hot sentinel lymph nodes (33). Factors that may influence the success of ARM include the experience of the operating surgeon, the impact of NAC on lymphatic fibrosis and a decrease in ARM node identification, varying volumes of the blue dye that is used, and the location of the ARM nodes during ALND versus SLNB (34). Currently there is a phase III randomized controlled trial, Alliance A221702, that is enrolling patients to evaluate the occurrence of lymphedema in patients with T1–3, N0–3, M0 breast cancer that have undergone the ARM procedure versus patients that have undergone SLNB followed but ALND if their sentinel lymph node is positive (35). Further studies are needed to determine the success of ARM in reducing lymphedema before it is accepted as a standard procedure in axillary management for breast cancer patients, but its use in both SLNB and ALND is compelling to clinicians.

Lymphatic Microsurgical Preventive Healing Approach (LYMPHA) is another surgical technique performed at the time of lymph node dissection with the goal of preventing lymphedema in patients undergoing ALND. This procedure involves the prophylactic bypass of one or more lymphatics transected at the time of lymph node dissection with anastomosis to nearby venous outflow tracts. One meta-analysis showed a lymphedema incidence of 14.1% after ALND without LYMPHA and 2.1% after ALND with LYMPHA (36). Another study reported that 40% of patients who underwent ALND developed lymphedema while only 12.5% of patients who underwent ALND with LYMPHA developed transient LYMPHA (37). Simplified Lymphatic Microsurgical Preventing Healing Approach (SLYMPHA) is another surgical procedure that can be performed by the operating breast surgeon and creates lymphatic venous anastomoses without the use of an operating microscope. One study found that SLYMPHA resulted in a 16% rate of lymphedema compared to a rate of 32% for patients that did not have SLYMPHA (P=0.01) (38). LYMPHA and SLYMPHA are safe surgical techniques that have resulted in a significantly lower incidence of lymphedema and should be considered when performing an ALND.

Although the LYMPHA procedure has been demonstrated to prevent lymphedema for high-risk patients, there are several barriers to implementation of this procedure. For example, insurance coverage remains inconsistent. Additionally, the procedure requires specialized training and equipment that may not be available at all institutions. Finally, this procedure requires close coordination between the breast surgeon performing the lymph node dissection and the plastic surgeon performing the LYMPHA procedure. SLYMPHA avoids the need for a plastic surgeon and the need for an operating microscope, providing breast surgeons with a safe and simple method to decrease the incidence of lymphedema in breast cancer patients. Further randomized controlled trial studies will need to be conducted to compare LYMPHA to SLYMPHA versus no lymphatic restorative procedures to clearly highlight the benefits in minimizing the morbidity of axillary staging surgery.

More recent trials are now assessing breast cancer recurrence and survival outcomes in women with early-stage breast cancer who have omitted axillary surgery. The Sentinel Node Vs Observation After Axillary Ultra-souND (SOUND) trial was launched in 2012 in Milan to evaluate distant disease-free survival in patients of any age with T1 cN0 breast cancer who have undergone BCS without axillary staging surgery (39). Similar trials have been initiated in Germany, the Intergroup-Sentinel-Mamma (INSEMA) trial, and in The Netherlands, the BOOG 2013-08 trial, in which women 18 and older with T1–2 cN0 breast cancer who have undergone BCS are evaluated for invasive disease free-free survival and regional recurrence rate, respectively (40,41). The results of these trials will provide valuable information regarding recurrence and survival outcomes for patients with early-stage breast cancer that have forgone axillary staging surgery.

Although there has been great emphasis on eliminating ALND, we may find that ALND is beneficial in certain circumstances to help make adjuvant treatment decisions for patients. For instance, the RxPonder trial found that post-menopausal women with HR⁺, HER2⁻ negative breast cancer with 1–3 positive axillary lymph nodes and a recurrence score of <26 did not benefit from adjuvant chemotherapy (42). However, this trial did not include patients with 4 or more positive axillary lymph nodes. Perhaps performing an ALND for patients with 1–3 positive axillary lymph nodes will provide clinicians with more information regarding the benefit of adjuvant chemotherapy for this patient population. The Monarch trial is another recent study that involves the use of abemaciclib, a cyclin-dependent kinase inhibitor, in combination with standard adjuvant endocrine therapy for high-risk post-menopausal women with node-positive, early-stage HR⁺, HER2⁻ negative breast cancer, but requires patients to have at least 4 positive axillary lymph nodes and a Ki-67 of >20% and may require patients to undergo an ALND to qualify for the study (43). Many studies have shown that axillary staging adds no benefit for cancer recurrence and patient survival outcomes, however there are certain patient populations who may benefit from axillary surgery to make decisions regarding adjuvant therapy.

Conclusions

Axillary staging has been an evolving field within the surgical and oncologic management of breast cancer patients. There has been a continued effort to de-escalate surgical techniques used for clinically node-negative and positive patients and patients with minimal nodal disease. There has also been a significant improvement in sentinel lymph node identification and removal for clinically node-positive patients who have received NAC. Current studies have shifted their focus to the primary prevention of lymphedema using ARM and LYMPHA and forgoing axillary staging surgery in certain patient populations. The use of axillary staging has been questioned for elderly women with early-stage breast cancer that have shown no evidence of improved survival outcomes. Finally axillary surgery may be beneficial for certain patient populations despite the risks associated with lymphedema. Decisions regarding axillary surgery should remain a multidisciplinary decision as all breast cancer patients cannot be treated the same.

Acknowledgments

Funding: None.

Footnote

Peer Review File: Available at https://abs.amegroups.com/article/view/10.21037/abs-23-9/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://abs.amegroups.com/article/view/10.21037/abs-23-9/coif). The series “Breast Cancer-related Lymphedema” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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