Research gaps in sentinel lymph node biopsy in breast cancer

This commentary focuses on 5 questions that need to be answered when considering sentinel lymph node biopsy in breast cancer, aiming to highlight these issues and provide researchers with ideas to resolve.

Sentinel lymph node biopsy (SLNB) in breast cancer is now exceeding its known role as the standard of care in axillary lymph node (LN) staging to replace standard axillary lymph node dissection (ALND) in selected cases of node-positive breast cancer.This role is expanding year by year and the threshold to perform SLNB has become steadily lower, and the restrictions looser.It is now clear that the goal of axillary surgery is mainly diagnostic rather than therapeutic.][3][4] Despite answering many questions regarding its efficacy and safety, there are still gray zones and points that need further research to be illuminated.
In this commentary, I focus on 5 questions that still need to be answered, aiming to highlight these issues and provide researchers with ideas to help fill the knowledge gaps.

What should the breast surgeon do if he has positive one out of one or 2 out of 2 sentinel nodes?
The ACOSOG Z0011 trial was a practice-changing study that paved the way to limiting the role of ALND in patients who met all of the following criteria: only one or 2 positive sentinel nodes, small tumors, did not receive neoadjuvant therapy, and underwent breast-conserving therapy with planned postoperative axillary irradiation. 5,6Recently, the guidelines were expanded to include patients who underwent mastectomy as well. 7,8][11] However, breast surgeons may face ambiguous situations with no clear answers based on existing evidence, eg, what if a patient has positive one out of one or 2 out of 2 dissected sentinel nodes?Should the surgeon stick literally to the Z0011 criteria and omit ALND accepting the risk that there could be additional positive axillary nodes, or should he pursue ALND carrying the risk that all the excised LNs may be negative for malignancy and exposing the patient to unnecessary complications of ALND?Further research should be conducted to include this category of patients and compare the surgical and oncological outcomes in patients with 1/1 or 2/2 positive LNs on SLNB when they undergo completion versus omission of ALND.

What should the decision regarding ALND be in patients who received neoadjuvant therapy with nodal conversion in institutions lacking radioactive materials or in patients in whom pretreatment lymph node clipping was not performed and the retrieved sentinel nodes are less than 3?
The management of the axilla after neoadjuvant therapy has witnessed many paradigm shifts, especially in those who converted from node-positive to node-negative disease and especially in the last decade.Because the main concern is the relatively high false negative rate in these patients, some prerequisites are usually advised to ensure the oncological safety of performing sentinel node biopsy rather than ALND.These prerequisites include the use of a dual mapping technique (radioactive isotope + blue dye), retrieval of 3 or more lymph nodes, and targeted axillary dissection, which entails clipping of the positive nodes before neoadjuvant therapy then removal of the sentinel nodes in addition to the clipped nodes at the time of surgery. 7,12n practice, nuclear medicine facilities are not available in all institutions worldwide, especially in the Eastern world. 13,14Also, the surgeon may meet a patient with positive nodes before treatment who did not undergo clipping.Last, retrieval of 3 sentinel nodes at the time of surgery does not usually occur.The options here are either SLNB, which carries the risk of a relatively high false-negative rate or ALND, depriving these patients of the benefit of nodal downstaging achieved by neoadjuvant therapy.
6][17] Further supporting studies are needed to allow updating international guidelines.

Is it always practical to clip all positive lymph nodes before neoadjuvant therapy?
Another issue related to targeted axillary dissection is lymph node clipping before neoadjuvant therapy. 18If the initial radiologic evaluation reveals 3 or more malignant-looking lymph nodes, is it practical or even possible to put a clip in all the malignant-looking lymph nodes?If a patient has 5 malignant-looking axillary lymph nodes, should we clip them all?Will the cost of the titanium clips and the radiologists' capabilities all over the world support such a strategy?And even if it were possible, should we remove all these lymph nodes in addition to the sentinel nodes after neoadjuvant therapy?This may cause lymphatic damage equal to that caused by ALND.

Should we proceed to ALND in N2-3 patients even after an excellent clinical response?
It is accepted as of this writing that patients with heavy nodal infiltration before neoadjuvant therapy (N2-3) should undergo ALND regardless of the response to treatment. 19,20owever, this may be an unfair practice, especially for patients with triple negative disease or HER2-positive disease receiving neoadjuvant chemotherapy and dual anti-HER2 therapy, respectively, in which a nodal complete pathological response is more likely to be achieved. 21,22urther research should be conducted with a special focus on this category of patients who are usually considered a high-risk group for regional recurrence and distant metastasis.

How should the breast surgeon proceed after neoadjuvant therapy in the initially nodepositive axilla with post-treatment axillary nodes having indeterminate sonographic criteria?
Regardless of the axillary staging procedure used after neoadjuvant therapy in those with initially node-positive disease, breast surgeons repeatedly face a confusing situation when the axillary lymph nodes show indeterminate ultrasonographic criteria that cannot lead to a certain decision whether the lymph nodes are still malignant or not. 23ntil now, the standard of care for node-positive disease that remains positive after neoadjuvant therapy is ALND.For those who converted to negative nodes, 15,18 the standard is targeted axillary dissection (or SLNB).But what about those who have an uncertain nodal status after neoadjuvant therapy?Should the surgeon proceed with ALND, or should he consider the nodes to be negative?Or should surgery be postponed for an ultrasound-guided biopsy from the most significant lymph node?
These 5 questions represent gaps that lack sharp answers to frequently faced situations in surgical oncology practice.The optimal oncological philosophy is that which aims to achieve the best survival outcomes and improve quality of life without affecting oncological safety or putting patients at risk.