Selection of Breast Cancer Patients for Omission of Axillary Lymph Node Surgery

Jenny Bui, MD, MPH¹; S. David Nathanson, MD¹; Christine Joliat, MD¹; Jessica Bensenhaver, MD, MS¹; Theresa L. Schwartz, MD, MS¹; Lindsay Petersen, MD¹; Anna Lehrberg, DO¹; Laura Dalla Vecchia, MD¹

1. Department of Surgery, Henry Ford Health, Detroit, Michigan

OPEN ACCESS

PUBLISHED:30 October 2024

CITATION: Bui, J., et al., 2024. Selection of Breast Cancer Patients for Omission of Axillary Lymph Node Surgery.
Medical Research Archives, [online] 12(10).
https://doi.org/10.18103/mra.v12i11.5861

COPYRIGHT:© 2024 European Society of Medicine. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

DOI: https://doi.org/10.18103/mra.v12i11.5861

ISSN: 2375-1924

 

ABSTRACT

Accurate axillary lymph node dissection (CALND), defined as the removal of all lymph nodes from levels I and II, has been the standard for clinically confirmed lymph node (LN) metastases, or prophylactic for clinically negative LNs, and was once a routine part of the standard surgical management for patients with breast cancer (BC). In 1977, the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-04 trial called into question the therapeutic value of CALND in early BC with clinically negative ALNs. In this landmark trial, patients were randomized to radical mastectomy, total mastectomy with LN irradiation, or the mastectomy without any surgical intervention. The ultimate goal is to eliminate axillary surgery altogether in some patients. However, some patients’ outcomes depend upon excision of the axilla. This review aims to summarize the current recommendations for the omission of axillary lymph node surgery.

Keywords

breast cancer, axillary lymph node dissection, sentinel lymph node biopsy, metastasis, surgical management

Introduction

Complete axillary lymph node dissection (CALND), defined as the removal of axillary lymph nodes (ALNs) from levels I and II, either therapeutic for clinically confirmed lymph node (LN) metastases, or prophylactic for clinically negative LNs was once a routine part of the standard surgical management for patients with breast cancer (BC). In 1977, the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-04 trial called into question the therapeutic value of CALND in early BC with clinically negative ALNs.¹ In this landmark trial, patients were randomized to radical mastectomy, total mastectomy with LN irradiation, or total mastectomy with delayed CALND if nodal disease developed. After 25 years of follow-up, it was shown that there were no survival differences among the groups. In the observation arm, only 18.5% of patients developed axillary recurrence, despite a calculated likelihood that 40% would have had nodal metastases, suggesting that in more than 50% of the cases the LN metastases did not progress.¹

These studies demonstrated success in improvement in locoregional control by adjuvant systemic therapies compared to surgery alone. In the NSABP B-14 trial, endocrine therapy with Tamoxifen significantly lowered the locoregional recurrence rate in estrogen receptor–positive women from 14.7% to 4.3%.² Similarly, the NSABP B-13 trial showed that chemotherapy reduced locoregional recurrence in estrogen receptor–negative women from 13.4% to 2.6%.³ This trend was further confirmed in the NSABP B-31 trial, where combining the anti-HER2/neu antibody trastuzumab with chemotherapy in HER2/neu-overexpressing BC patients led to enhanced local control.⁴

Other advances in adjuvant therapies confirmed the hypothesis that LN metastases can be eradicated without surgery.⁵ ⁶ Following the introduction of sentinel lymph node biopsy (SLNB) as a diagnostic rather than a therapeutic procedure in the 1990s, the CALND has been largely replaced.⁷ ¹² While SLNB is less invasive and poses fewer complications compared to CALND, there is a growing trend toward de-escalation of axillary management in BC treatment. The ultimate goal is to eliminate axillary surgery altogether in select patients. However, some treatment decisions still depend upon excision of the SLNs.⁷–¹⁰ ¹³ In addition, there are some patients with more advanced BCs with LN metastases that still warrant CALND.⁷ ¹⁰ ¹⁴ ¹⁵

In an age where each BC patient deserves a careful personalized plan of management that conforms to the current guidelines, the type of ALN surgery is an important area of investigation. The selection of the type of LN surgery should include accounting for surgical morbidity, demographics, the patient’s quality of life, the expected treatment outcomes, molecular subtype, pathological factors, a deeper understanding of tumor biology, and improved means of evaluating the tumor status of regional LNs.

In this paper, we will discuss recent advances in the detection of LN metastases by imaging modalities (IM), the indications and outcomes of omitting SLNB, the rationale behind these decisions, and the potential impact on patient outcomes. By focusing on evidence-based practices and recent clinical trials, we provide an overview of this evolving aspect of BC management, ultimately contributing to more effective and less invasive treatment pathways for patients.

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Nonsurgical Evaluation of Ipsilateral Axillary Lymph Nodes

Nonsurgical evaluation of ipsilateral ALNs in BC patients adds accuracy to preoperative staging and treatment planning. Techniques such as ultrasound (US), magnetic resonance imaging (MRI), positron emission tomography (PET), and computed tomography (CT) are increasingly used to assess LN involvement.¹⁶–²¹

Ultrasound, often combined with fine-needle aspiration biopsy (FNAB) or core needle biopsy (CNB), allows for real-time imaging and cytological/histological evaluation.¹⁷ Ultrasound combined with elastography enhances the specificity of the imaging.

enabling clinicians to not only identify suspicious LNs, but also to possibly justify the avoidance of invasive surgery.²³

Ultrasound is the preferred ALN imaging modality for primary BC while MRI, PET and CT may be reserved for staging purposes or in cases where more extensive disease is suspected. Compared with clinical examination, axillary US has a significantly higher negative predictive value (76%–84% for US vs. 50%–62% for clinical examination).²⁴ Sonographic criteria of possible LN metastatic disease include cortical thickening greater than 3 mm, loss of the fatty hilum, changed LN shape, increased vascularity, and irregular cortical bulges.²⁵ ²⁶ Ipsilateral axillary US is commonly performed when LNs appear abnormal on mammogram, when ipsilateral invasive BCs are larger than 2 centimeters, for clinically palpable nodes, or for meeting the SOUND trial criteria for deferring SLNB²⁷ (patient aged greater than 50 years old, tumor size less than 2 cm, hormone receptor positive, and more than 2 mm).²⁷

Breast MRI is effective in assessing the size and anatomical extent of ipsilateral ALNs while allowing for immediate comparison with the opposite side. However, its specificity in diagnosing LN metastases is low, which limits its accuracy. Furthermore, the potential discomfort and high costs associated with MRIs make them less practical for routine clinical use, especially when other less invasive and more cost-effective diagnostic methods are available. For these reasons, despite its imaging capabilities, MRI might not always be the most suitable option for evaluating LNs in clinical settings.¹⁸ ¹⁹

PET with or without CT scans can be valuable for identifying metabolic activity in ALNs, offering insights into the possibility that enlarged nodes harbor malignant tumors. However, they have limitations in differentiating between malignant tumors and benign conditions that also cause increased metabolic activity. These conditions include lymphoproliferative responses due to tumor in the primary breast site, recent surgical intervention, inflammation, vaccination, immunotherapy, or infection.²⁰ ²¹ Therefore, while PET-CT is useful in evaluating ALNs, observed abnormalities must be interpreted with caution and often need confirmation through additional diagnostic methods like tissue biopsy.

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Axillary Imaging as an Alternative to Axillary Lymph Node Surgery

Although not currently an absolute guideline, axillary US is selectively recommended for patients with BC to evaluate ALN status preoperatively. The SOUND trial has shown that negative axillary US in small early BCs is noninferior to performing a SLNB. Other studies have demonstrated that some sonographic features of breast lesions, such as tumor size, margin morphology, and location might be associated with BC nodal metastases and thus can help predict ALN status.²⁶ ²⁸ Risk models have also been developed for predicting ALN metastases in patients with BC.²⁹–³² As imaging modalities improve and more nomograms are developed, US and other imaging modalities may help to further de-escalate ALN surgery.

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Confirming the Diagnosis of Clinically Positive Lymph Nodes

Neoadjuvant systemic therapy, including chemotherapy (NAC), anti-HER2/neu or other targeted therapy, immunotherapy or hormonal therapy is often used in patients with proven LN metastases. In BC patients with clinically or radiologically suspicious LNs, the choice between FNAB and CNB for cytological proof of LN metastases is an important consideration that can impact treatment decisions and patient outcomes.

Fine needle aspiration biopsy is a quick, minimally invasive procedure that involves using a thin, hollow needle to extract a small sample of cells from the LN. However, FNAB provides only cellular material and may not yield enough tissue for comprehensive histopathological evaluation, particularly for determining receptor (hormone receptors and HER2/neu) status. It may also have a higher false-negative rate compared to CNB.³³ ³⁴ Core needle

biopsy offers more comprehensive diagnostic information. Core needle biopsy uses a larger, hollow needle to obtain a tissue core from the LN, allowing for a more detailed pathological analysis, including receptor status and tumor grade. Of note, whenever a LN is biopsied, it is important to leave a metal clip in the node as a guide for the surgeon for future removal by targeted axillary dissection.³⁵

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Current Recommendations for Axillary Lymph Node Surgery

EARLY CLINICALLY cN0 INVASIVE BREAST CANCER
The National Comprehensive Cancer Network, American Society of Clinical Oncology, American Society of Breast Surgeons, and Society of Surgical Oncology recommend eligible patients with early-stage BC undergo an operative axillary evaluation to determine the presence of LN metastasis.⁷–¹⁰ Clinically node-negative patients (cN0) should be offered axillary evaluation by SLNB (Figure 1). If SLNs exhibit metastatic BC in less than 3 LNs and without extra-nodal invasion, clinical studies support avoiding CALND,³⁶ ³⁸ provided that regional radiation and systemic therapies are also added as appropriate (Figure 2).

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Figure 1. Summary of Axillary Lymph Node Management for Breast Cancer

• Sentinel lymph node biopsy (SLNB) is the preferred method. ⁷ ¹⁰

• Level III dissection only when there is gross tumor in level II or III nodes.

• See Figures 2 and 3 for indications for complete axillary lymph node dissection.

• Optional criteria for omission of SLNB:

  • Pathologically favorable tumors

  • Selection of systemic and/or radiation is unlikely to be affected

  • ≥ 70 years of age³⁹

  • Serious comorbid conditions

  • The SOUND criteria (> 50 years of age, hormone receptor positive, ≤ 2 cm in size, Ki 67 < 20%, and negative axillary US)²⁷

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Figure 2. Management of clinically negative ipsilateral axillary nodes in breast cancer.

⁸ Abbreviations: CALND, complete axillary lymph node dissection; LN micromets, lymph node micrometastases; NAC, neoadjuvant chemotherapy; RT, radiation therapy; SLNB, sentinel lymph node biopsy

 

Molecular/Genetic Markers that Could Make Sentinel Node Biopsy Redundant

Apart from the special conditions for avoiding SLNB already described above, we can imagine the following 3 situations where surgical excision of ALNs would be redundant:

1. molecular or genetic tests done on BC tumor cells provide enough prognostic and predictive information that supersedes the information obtained from accurate pathologic documentation of metastases in the SLN;

2. BC tumor cells directly invade intra- or peri-tumoral blood vessels but not lymphatics; and

3. BC tumor cells do not directly invade lymphatics or blood vessels and therefore are not capable of metastasizing to either regional LNs or systemic sites.**

Molecular markers, such as hormone receptors, HER2/neu and Ki67, are routinely performed on BCs. When combined with demographic features (such as age at diagnosis) and pathologic characteristics (such as tumor size, grade, and the presence of lymphovascular invasion), the likelihood of LN and systemic metastases can be calculated and appropriate systemic treatment selected.⁶³While assessments of standard clinical and pathological features have been used to determine the use of adjuvant systemic therapy with early-stage BC, the challenge of accurately identifying those patients that will benefit from adjuvant therapies remains challenging. Gene expression assays can guide treatment for early-stage BC. The Oncotype DX test (Exact Sciences, Madison, WI), based upon the expression of 16 functional and 5 control genes, is usually done on the primary BC after lumpectomy or mastectomy in selected patients, where SLNB has already been performed.⁶⁴ The results are commonly used to advise adjuvant therapy. Several other commercially available genomic assays continue to be clinically validated.⁶⁵ These assays can be done on needle biopsy specimens prior to surgical treatment and such a practice, if it were to become routine, might be as valuable as SLNB.Even in the age of molecular medicine, the presence or absence of BC in regional LNs remains the strongest predictor of systemic metastases.⁶⁶ LNs thus act as a highly efficient bioassay for identifying metastasis-competent cells. If we knew that BC tumor cells were able to invade directly into intra- or peri-tumoral blood vessels and metastasize to systemic sites, and bypass LNs, we could avoid SLNB. Molecular evidence of distinct parental subclones of cells that bypass regional LNs has been shown in both breast and colorectal cancer.⁶⁷,⁶⁸ Similarly, it is conceivable that we could identify by molecular means tumors where neither lymphatic nor blood vessel invasion is likely. Unfortunately, such assays are not yet available.

Other advances that allowed de-escalation of axillary nodal surgeryDe-escalation of axillary node surgery did not occur in a vacuum. At the beginning of the modern age, BC was managed predominantly by surgeons. Successful management of BC, including the avoidance of axillary node surgery, developed because of the multidisciplinary approach to the disease in its many manifestations. Each stage of diminished axillary node surgery has been supported by countless revolutionary changes in many disciplines that interact directly or indirectly in the management of BC (Figure 4). Each discipline played a necessary role in how we can now confidently select to omit excision of ALNs.

We anticipate a further decrease in axillary node surgery with developing technologies in axillary imaging and by incorporating clinicopathological and molecular/genetic predictors of LN metastases. Innovative imaging techniques, such as US, MRI, and molecular imaging, may offer a more precise, personalized approach to BC management.⁵⁸,⁶⁹ However, challenges persist, including the need for standardized imaging protocols, consistent interpretation, and large-scale clinical validation of emerging methods. As BC management continues to evolve, multidisciplinary clinical and translational research collaboration is essential to balance accurate

Figure 4. Advances that contributed to development of safe, selective omission of axillary lymph node surgery in breast cancer

• Research and development

  ○ Government, pharmaceutical, university, and private funded research programs

• Biological understanding

  ○ Improved awareness of the biology and progression of BC⁷⁰

  ○ Increased understanding of patterns and sites of metastasis⁶⁹

• Imaging and diagnostics

  ○ Advances in the imaging of the breast, LNs and systemic sites¹⁶–²¹

  ○ Needle biopsy of primary and metastatic BCs³³–³⁵

• Therapeutic advances

  ○ Discoveries of new chemotherapeutic drugs, targeted therapies, endocrine therapy, and immunotherapy⁴

  ○ Development of successful adjuvant therapies⁷¹

  ○ Radiation technologies and research⁷²

• Sub-specialization in oncology

  ○ Subspecialization of BC oncologists

  ○ Superspecialized breast surgeons⁷

• Pathology and molecular subtyping

  ○ BC pathological subtypes reclassification⁷³

  ○ BC molecular subtypes recognized⁷⁴

  ○ Molecular/genetic aids for selection of adjuvant therapy⁴⁴

• Patient empowerment and awareness

  ○ Breast cancer awareness

  ○ Women taking charge – change at political and cultural level

  ○ Increasing awareness propagated through schools, churches, and social gatherings

• Clinical decision support

  ○ National and international guidelines⁸

  ○ Advances in mathematical outcome prediction models⁷⁵

  ○ High-risk and genetic counselors⁷⁶

  ○ Tumor boards⁷⁷

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Conclusion

The evaluation of ALNs in BC patients continues to evolve. De-escalation of ALN surgery has historically been the clinical pattern starting from the Halstedian dogma of levels I, II, and III LN dissection in all BC patients, regardless of whether LNs were clinically suspicious or not. The carefully controlled era of SLNB is still the standard of care in most cases. The morbidity of nodal surgery while markedly decreased with SLNB has not completely disappeared. Recently, the trend has turned to selective complete avoidance of all axillary nodal surgery. During these historic times the accompanying belief in the therapeutic value of CALND has largely evaporated, justifying removal of LNs for staging and treatment planning purposes in some cases. As the genetic/molecular era leads us to better predictive and prognostic tests, we anticipate a time when axillary nodal surgery may disappear completely.

Conflicts of Interest:

The authors have no conflicts of interest to declare.

Acknowledgement:

This review was supported by the Nathanson/Rands Chair in Breast Cancer Research, Detroit, Michigan, and by the Team Angels, Sterling Heights, Michigan.

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