Upfront axillary surgical management—a commentary on previously underrepresented patient groups and how the SENOMAC trial righted this wrong

Introduction

The most common location of metastasis in breast cancer is the axillary lymph nodes. As such, standard of care used to include removing all axillary lymph nodes via an axillary lymph node dissection (ALND) both for local control and staging purposes. However, this predated our use of effective systemic therapies; as these therapies have improved, so has our ability to de-escalate axillary surgical interventions. The use of completion ALND (cALND) for breast cancer has been decreasing significantly since publication of clinical trials like American College of Surgeons Oncology Group (ACOSOG) Z0011 and radiotherapy (RT) or surgery of the axilla after a positive sentinel lymph node (SLN) (EORTC 10981-22023 AMAROS) (1,2). Although practice changing, the broad applicability of these trials is questioned for a few reasons. ACOSOG Z0011 was meant to compare ALND to no further axillary treatment after SLN biopsy (SLNB) among patients with clinical (c) T1–2N0 breast cancer with 1–2 positive SLNs; however, many patients received RT to the nodal basins (3). The trial ended early, not meeting its primary endpoint due to a lack of events; although this is a reassuring finding, critics have cited this as a limitation. Furthermore, ACOSOG Z0011 included only cT1–2 patients treated with breast conservation therapy, thus excluding patients with larger tumors, and those who underwent mastectomy. Additionally, patients with lobular carcinoma were poorly represented. AMAROS included patients with cT1–2N0 breast cancer found to have positive SLNs and compared ALND to regional nodal irradiation (RNI). It, too, was underpowered for the primary noninferiority endpoint due to few events, and though it included patients who underwent mastectomy, this patient population comprised only 17% of the total study cohort. Despite these limitations, patients treated with RNI experienced significantly less lymphedema compared to those treated with ALND (11% versus 23% at 5 years, P<0.001), thus motivating surgical and radiation oncologists to employ RNI in place of ALND in proper patients, striving to find data to broaden applicability.

The recent publication, “Omitting Axillary Dissection in Breast Cancer with Sentinel-Node Metastases” or SENOMAC, compared SLNB alone versus cALND in a large, inclusive cohort including male and female patients with cT1–3 breast cancer treated with breast conserving therapy (BCT) or mastectomy, with 1–2 SLNB-confirmed macrometastases including extracapsular extension (ECE) (4). Herein we will review important knowledge gaps that SENOMAC has addressed as well as discuss future directions.

Weaknesses of the existing data

Patients who undergo mastectomy and are found to have positive SLNs are a poorly studied patient population. Although patients undergoing mastectomy were included in the International Breast Cancer Study Group’s 23-01 clinical trial which compared SLNB without further axillary treatment to ALND among patients with SLN micrometastasis, they made up only 9% of each treatment arm (5). These in addition to 8% of patients enrolled to AATRM 048/13/2000 and 17% of patients enrolled to Optimal Treatment of the Axilla “OTOASOR” make the total sample size of mastectomy patients 434, which is relatively small (6,7). Despite this, providers and patients have been motivated to eliminate ALND from patients’ care plans; more specifically, most feel it is important to avoid overtreatment in the form of both ALND and post-mastectomy radiation (PMRT, typically including RNI) in patients who very likely have small volumes of lymph node disease, as high rates of lymphedema have been reported in this patient population (2,8). In a National Cancer Database (NCDB) study of patients treated with mastectomy found to have 1–2 positive SLNs, ALND rates decreased from 47% in 2006 to 23% in 2014 (AMAROS publication year), PMRT increased from 8% to 27%, and SLNB-only rates remained relatively stable at 34–37% (9). The use of SLNB alone appears high in this population, especially considering that AMAROS included RNI, though errors in data collection for large population-based datasets like NCDB should be considered. A survey study of Alliance for Clinical Trials in Oncology cooperative group members specializing in breast cancer was conducted to examine how breast cancer providers may or may not be extrapolating results from ACOSOG Z0011 to other patient groups; a total of 45–55% provider respondents reported that they routinely turn to multi-disciplinary discussion to decide axillary management of mastectomy patients with 1–2 positive SLNs (10). This is similar to a single institution protocol that nearly eliminated intraoperative lymph node assessment to minimize intraoperative decision-making to encourage bringing pathology results to multi-disciplinary tumor board to decide the best course of action (8). Taken together, these studies indicate there is tremendous effort aimed at deciphering the nuanced axillary management of mastectomy patients, where a clinical trial including more mastectomy patients would aid in clinical decision making of medical, surgical and radiation oncologists.

Patients with invasive lobular carcinoma (ILC) have also been underrepresented on trials evaluating the omission of ALND. It is a widely held belief that patients with ILC tend to have more involved lymph nodes, as evidenced by low accrual rates of patients with ILC to ACOSOG Z0011 at about 7%, despite ILC making up about 15% of breast tumors (1). However, a large series out of Memorial Sloan Kettering Cancer Center proved the difference may not be as striking as once thought (11). Out of a total of 813 Z0011-eligible patients (i.e., cT1–2N0 undergoing BCT), 104 with pure or mixed ILC histology and 709 with invasive ductal carcinoma (IDC) were treated strictly according to Z0011 and underwent ALND if their pathology revealed ECE (>2 mm) or ≥3 positive SLNs. Despite higher rates of macrometastatic disease in the lymph nodes of ILC patients (81.7% ILC versus 69.4% IDC; P=0.01) and more patients with >2 mm of ECE (30.8% ILC versus 19.5% IDC; P=0.03), ILC patients had equivalent rates of 3 or more total positive lymph nodes (14.4% ILC versus 9.9% IDC; P=0.2). This supports the application of the ACOSOG Z0011 trial results to patients with ILC; however, strongly held beliefs are difficult to nullify and ILC histology is an independent predictor of ALND (12). More data supporting SLNB alone in this population was needed.

The presence ECE has also led to controversy. ACOSOG Z0011 excluded patients with “matted nodes or gross extranodal disease”, which has been widely misinterpreted as microscopic ECE, and the presence of ECE was not reported in AMAROS (1,2). As such, ECE became an indication for many to treat with ALND. This may be based on studies like this single institution series examining a historic dataset of patients who underwent ALND but were Z0011-eligible, with T1–2 tumors undergoing BCT with <3 positive SLNs (13). Among 778 patients without ECE, 3% had ≥4 positive lymph nodes, and among 331 patients with ECE, 20% had ≥4 positive lymph nodes at cALND (P<0.0001); furthermore, size of ECE mattered with 33% of the 151 patients whose ECE measured >2 mm having ≥4 positive nodes and 9% in the 180 patients with <2 mm (P<0.0001). ECE >2 mm was the strongest predictive factor of ≥4 positive lymph nodes with an odds ratio of 14.2. Patients with ECE remain controversial and are frequently discussed at multi-disciplinary tumor boards, oftentimes with differing management opinions. The debate is not whether additional positive lymph nodes exist, but the volume of that nodal disease and whether standard doses of RNI can control this regional disease.

The necessity of RNI in patients with low volume axillary disease treated with SLNB is also an active area of investigation. Classic studies of RNI have shown a survival benefit, even in low volume axillary disease (14-16). These classic studies were conducted with suboptimal axillary staging techniques, RT, and systemic therapies, bringing into question whether they are relevant in modern practice. Both Z0011 and AMAROS were surgical studies in the modern era investigating the utility of ALND in cN0 patients; however, protocol-specified RT varied among these studies. The Z0011 protocol specified that patients were randomized to ALND versus no further axillary-specific intervention after SLNB, specifically not permitting RNI with a third nodal field. However, among patients with detailed RT records, approximately 50% were treated with “high tangents”, which includes the low axilla, and 19% received RNI with 3+ fields (3). This brings to question whether SLNB alone is adequate in patients with axillary nodal metastases or if RNI is necessary, as the majority of patients included in Z0011 had at least the low axilla treated with RT. AMAROS investigated the role of ALND versus RNI (including all three levels of the axilla and the medial supraclavicular fossa) in patients with a positive SLN. Canadian Cancer Trials Group (CCTG) MA.20 and EORTC 22922 are RT-specific trials conducted in the modern era to evaluate the benefit of RNI in patients with early-stage breast cancer (17,18). MA.20 included patients who underwent BCT with SLNB or ALND and had pN1 disease or were “high-risk” without axillary nodal involvement. Patients were randomized to whole breast irradiation (WBI) versus WBI with RNI (including the internal mammary, supraclavicular, and axillary lymph nodes). Although there was no difference in overall survival between cohorts, patients receiving RNI had significantly improved disease-free survival and distant disease-free survival at 10 years. EORTC 22922 evaluated the utility of RNI in patients with centrally or medially located primary tumors irrespective of axillary involvement or externally located tumors with axillary involvement treated with BCT or mastectomy with either SLNB or ALND. Patients were randomized to WBI or chest wall irradiation plus or minus RNI. Again, there was no difference in overall survival; however, there was significantly improved disease-free survival and distant disease-free survival at 10 years. These endpoints lost significance at 15 years; however, patients treated with RNI had significantly lower rates of breast cancer death at 15 years.

Another area of debate is the treatment of patients with ultrasound-detected lymph node disease. Dedicated axillary imaging was not needed for enrollment to ACOSOG Z0011. Among the 1,425 patients enrolled to AMAROS with a positive SLN, 859 (60%) underwent dedicated axillary imaging (2). The National Comprehensive Cancer Network (NCCN) guidelines allow for the application of Z0011 principles to patients with ultrasound-detected lymph node disease, even if a lymph node is biopsy-proven to contain disease, provided that the patients only have 1–2 positive SLNs (19). This guidance is based on several single-institution retrospective series of patients who all underwent ALND. One such study reported that of 225 patients with axillary ultrasound-detected, biopsy-proven, positive lymph node disease, 99 (44%) had only 1–2 positive lymph nodes total (20). Thus, many argue that axillary ultrasound-detected disease does not obligate an ALND, especially as one might deduce that patients enrolled to Z0011 may have had ultrasound-detected disease had they undergone ultrasound. Anecdotally, this practice is being implemented widely, and technical maneuvers being employed to accurately quantify the burden of disease before proceeding straight to ALND, despite a lack of rigorous clinical trial data supporting this practice.

SENOMAC

The SENOMAC trial was an international multi-institutional noninferiority trial of SLNB alone versus the addition of cALND in 2,540 patients with cT1–3 node-negative breast cancer found to have 1–2 positive lymph nodes on SLNB. The lymph nodes had to have macrometastases, whereas many (~40%) Z0011 and AMAROS patients had micrometastases only, and additional metastases in non-SLNs removed during surgery (totaling >1–2 positive lymph nodes) were not considered exclusion criteria. Additional micrometastases on SLNB were also allowed, thus 49 patients had three metastatic SLNs and an additional 3 patients had four. Most patients received adjuvant systemic and radiation therapy including RNI. At a median follow-up of 46.8 months, the 5-year recurrence-free survival after SLNB-only was noninferior to that after cALND [89.7% (95% CI: 87.5% to 91.9%) and 88.7% (95% CI: 86.3% to 91.1%), respectively; P<0.001].

SENOMAC had more relaxed inclusion criteria than ACOSOG Z0011 and AMAROS resulting in higher risk patients being enrolled, providing data to support the omission of ALND for several of the aforementioned patient groups. Patients with larger tumors, cT3, were included and one-third of patients enrolled underwent mastectomy. Twenty percent of patients had ILC, 28% had lymphovascular invasion, and about one-third had ECE. Lastly, cN0 disease was defined as non-palpable. Pre-operative axillary ultrasound was required and patients with suspicious lymph nodes, even biopsy-proven positive, could be included as long as their nodal disease was non-palpable. This trial adds to the growing body of literature proving the omission of ALND is safe, which is a clinically meaningful finding for patients and providers alike.

Limitations and future directions

Many of the underrepresented, often contested, patient groups may now safely avoid ALND because of the SENOMAC clinical trial results. However, the trial is not without limitations. Most patients in SENOMAC had hormone receptor-positive (HR⁺) disease, potentially limiting its applicability for patients with HER2-positive or triple-negative breast cancer. Nearly 90% of patients in both SENOMAC treatment arms received RT, leaving the non-inferiority of ALND omission compared to more extensive axillary surgery in patients who do not receive RT an unanswered question. Additionally, data on race and ethnicity were not reported, which may also limit its generalizability. Although patients with cT3 tumors were included, they comprised only ~5% of the trial population. While this is an improvement over the single cT3 patient enrolled to AMAROS and median tumor sizes of 1.7 cm in both AMAROS and Z0011, the best axillary treatment for patients with larger tumors is still unclear.

Another eligible patient group, though underrepresented, were patients whose axillary lymph nodes were clinically nonpalpable but were suspicious on axillary ultrasound, even biopsy-proven to contain metastatic disease. Including these patients was a tremendous step forward and has the potential to support the axillary surgery strategy that is presented by the NCCN guidelines, and may already be widely practiced, i.e., attempting SLNB for patients with ultrasound-detected lymph node disease and only dissecting if 3 or more lymph nodes are positive. However, only 13.3% of the SLNB group had suspicious lymph nodes detected by axillary ultrasound and only 1.3% were biopsy-proven positive, and 14.1% of the ALND group were suspicious with only 1.5% biopsy-proven. Thus, it remains cautionary to omit ALND in this patient population and more data is needed. A logical future clinical trial might include only patients with clinically positive, biopsy-proven metastatic lymph nodes, which would allow a higher number of positive SLNs to be randomized to further axillary surgery versus SLNB with RNI.

A current question in breast cancer practice is if RNI is necessary in patients with low volume axillary disease who undergo SLNB in the modern era, especially because Z0011 did not permit RNI per protocol, although most of the enrolled patients received RT to at least the low axilla. Patients on SENOMAC were treated according to national RT guidelines (Sweden, Denmark, Germany, Greece, and Italy) and 88–90% of patients received adjuvant axillary radiation, but we are awaiting detailed RT volumes and doses used. CCTG MA.39 TAILOR RT (NCT03488693) is currently enrolling to answer this question in patients with estrogen receptor positive, biomarker low-risk (defined by Oncotype DX score <25), node-positive breast cancer. Included patients may have 1–2 positive nodes on SLNB or 3 positive nodes if they undergo ALND. Patients who undergo BCT are randomized to WBI with or without RNI, and those who undergo mastectomy are randomized to no adjuvant RT versus PMRT (including chest wall and RNI). This trial will hopefully answer if any axillary treatment is necessary beyond surgical staging with SLNB in this biologically favorable patient cohort.

In summary, SENOMAC provides crucial data to broaden the patient population who may benefit from ALND omission, now providing evidence of its clinical equipoise in patients with larger tumors, SLN macrometastases, ECE, and ILC, in a cohort of patients who mostly received systemic therapy and axillary RT. This trial has the potential to prevent unnecessary overtreatment, which can lead to lymphedema and impact patient quality of life.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-151/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-151/coif). K.R.G. reports honoraria from Empire State Hematology & Oncology Society, and serves as co-chair of the Survivorship Committee of National Consortium of Breast Centers. A.W. reports research funds from Myriad Laboratories, consulting fees from Merck and Myriad Laboratories, honoraria from Society of Breast Imaging, MJH Lifesciences, Breast Cancer Foundation New Zealand; and also serves on the Advisory Board of Merck and Myriad Laboratories; and also receives food and beverage from Endomag. The other author has no 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.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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