Axillary dissection should not be performed in breast cancer patients with limited nodal disease to determine abemaciclib candidacy

In patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR⁺/HER2⁻) breast cancer, the use of adjuvant cyclin-dependent kinase 4/6 (CDK4/6) inhibitors has been implemented in the adjuvant setting for patients at high risk for relapse with the goal of prolonging disease-free survival (DFS) for early-stage breast cancer. The first trial to evaluate CDK4/6 inhibitors in this setting was monarchE, which investigated the benefit of adding abemaciclib to standard endocrine therapy (ET) (1). Patients enrolled in the monarchE trial were considered high risk if they were found to have 4 or more positive axillary lymph nodes (+LNs) or 1–3 +LNs with at least one additional high-risk feature (HRF): (I) tumor size ≥5 cm; (II) grade 3 disease; and (III) Ki67 >20%. At 5 years, this study found a significant improvement in invasive DFS [hazard ratio (HR): 0.680; 95% confidence interval (CI): 0.599–0.772] and distant relapse-free survival (HR: 0.675; 95% CI: 0.588–0.774) when comparing 2 years of abemaciclib treatment and ET to ET alone (2).

These promising data have made adjuvant abemaciclib a standard-of-care treatment option for patients with high-risk early-stage HR⁺/HER2⁻ breast cancer. The inclusion criteria of this study, however, created a predicament for multidisciplinary breast cancer teams. The American College of Surgeons Oncology Group Z0011 (Z0011) found that axillary lymph node dissection (ALND) could be safely omitted in patients undergoing upfront partial mastectomy with clinical negative nodes when only one or two positive sentinel lymph nodes (+SLNs) were found (3). The European After Mapping of the Axilla: Radiotherapy or Surgery (AMAROS) trial, which included 17% of patients who underwent mastectomy, extended this same paradigm to mastectomy cases as well (4). Patients with 1–3 +SLNs who have no additional HRF do not qualify for adjuvant abemaciclib, though may qualify if ALND results in ≥4 total +LNs. While it is standard-of-care to perform ALND in patients with 3 +SLNs, those with 1–2 +SLNs do not require additional axillary surgery based on data from the Z0011 and AMAROS trials. This raises the question of whether ALND should be performed to determine candidacy for adjuvant abemaciclib in patients with 1–2 +SLNs without other HRF.

We have previously examined this question by performing a retrospective review of 1,578 female patients from the National Cancer Database who underwent upfront surgery for nonmetastatic HR⁺/HER2⁻ breast cancer and had 1–2 +SLNs and no other HRFs (5). We found that overall, only 13% of patients who received ALND were found to have ≥4+ LNs and thus would meet criteria for abemaciclib. When stratified by number of +SLNs, 10% of those with 1 +SLN and 24% of those with 2 +SLNs would meet criteria for abemaciclib after ALND. In two smaller retrospective reviews, there was a similar incidence (11% and 12%) of patients who newly qualified for adjuvant abemaciclib after ALND (6,7). These studies comment on the significant morbidity associated with this intervention and question the appropriateness of ALND to identify candidacy for abemaciclib given the relatively low yield of newly diagnosed high-risk patients. The major limitation of these studies is that, since the performance of ALND is not routine for patients with 1–2 +SLNs, there is unquantifiable selection bias inherent in the analyses.

Recently, a post-hoc analysis of the data from the SENOMAC trial added to the growing data suggesting limited utility of ALND in this population (8). The SENOMAC trial was a prospective randomized, phase 3 non-inferiority trial comparing ALND to no additional axillary surgery after sentinel lymphadenectomy (SLNB) in patients with T1–3 breast cancer and one or two sentinel-lymph node macrometastases (8). At 5 years, the recurrence-free survival was comparable in the two study arms (ALND: 88.7% vs. SLNB alone: 89.7%), as was the regional recurrence rates (ALND: 0.5% vs. SLNB alone: 0.4%), confirming the results of previous trials.

In their follow-up analysis, de Boniface et al. further analyzed a subset of patients from the SENOMAC trial with T1–2, grade 1–2, HR⁺/HER2⁻ breast cancer—who would only meet criteria for adjuvant abemaciclib if they were found to have ≥4 +LNs on ALND (9). Like the retrospective analyses, they found that only 13% (101/802) of patients had ≥4 +LNs after ALND and thus would be eligible for adjuvant abemaciclib. As part of their evaluation, they also assessed the morbidity related to surgical treatment by examining patient-reported impairment of physical arm function 1 year after surgery. Of the 82.4% patients who responded to the quality-of-life survey, 84/634 (13%) in the ALND group and 30/708 (4%) in the SNLB alone group had severe or very severe impairment of their arm function at 1 year.

de Boniface et al.’s analysis of a prospective randomized trial adds to the evidence that effectively argues against the use of ALND as a diagnostic tool to determine candidacy for adjuvant abemaciclib therapy. This study is the first to examine this question using prospectively collected data in patients randomized to undergo ALND or no additional surgery, effectively eliminating selection bias. The authors again found a low proportion of patients who newly qualify for adjuvant abemaciclib following ALND (13%), consistent with the results seen in previous retrospective analyses (11–13%).

A major strength of the study is to confirm that this limited benefit comes with the cost of substantial morbidity, with three times as many patients who underwent ALND reporting severe or very severe arm symptoms at 1 year. These findings are consistent with prior work quantifying the morbidity of axillary surgery. For example, Che Bakri et al. performed a meta-analysis of 67 studies that compared lymphedema after ALND vs. SLNB alone (10). The difference between lymphedema prevalence with ALND was 16.5% at <12 months, 24.6% at 12–24 months, and 23.6% at more than 24 months vs. 7.5%, 3.7%, and 5.9% at the same time frames with SLNB alone (all P<0.0005). Another systematic review and meta-analysis of breast-cancer-related lymphedema similarly found a pooled estimate for arm lymphedema of 16.6% (95% CI: 13.6–20.2%) in women with breast cancer, but the incidences in ALND cases were almost four times higher than in SLNB alone (19.9% vs. 5.6%) (11). These incidences increased with time up to 2 years from diagnosis or surgery, after which they appeared to decrease.

While ALND seems to constitute surgical overtreatment in most patients with 1–2 +SLNs without additional HRFs, de Boniface et al. sought to quantify the medical benefit of abemaciclib use among those who would meet criteria for its use. Using their findings, and the invasive DFS data from monarchE, they calculate that 104 patients would need to undergo ALND to avoid just one invasive DFS event at 5 years, and that nine patients would experience severe or very severe impairment of physical arm function 1 year after surgery to avoid one invasive DFS event at 5 years. Outside the low proportion of patients who even qualify for consideration of adjuvant abemaciclib therapy, this analysis shows a stark contrast between its estimated long-term benefit and the risk of ALND. And while this study assessed arm morbidity specifically, the sequelae of ALND are many, including diminished quality of life (12) and the cost of additional surgery (which is not just material, and involves time away from work for recovery). Financial toxicity is also a concern when it comes to those who ultimately qualify for abemaciclib since these medications carry a great cost and can be problematic for patients who serve to only gain a small oncologic benefit (13).

Since the publication of this study, an additional factor makes ALND even less relevant in the discussion of adjuvant CDK4/6 inhibition. The NATALEE trial compared 3 years of adjuvant ribociclib with ET to ET alone and has led to the recent approval of ribociclib for adjuvant therapy for early-stage HR⁺/HER2⁻ breast cancer (14). Importantly, the inclusion criteria for this trial differed from those of monarchE: all anatomical stage IIB and stage III patients were included regardless of nodal status and (somewhat like monarchE), stage IIA patients were eligible if they had a least 1 +LN or, if node-negative, had a tumor grade ≥2 or Ki67 ≥20%. Overall, 28% (1,431/5,101) of patients enrolled in NATALEE were node negative. At 3 years, patients treated with ribociclib were found to have an invasive DFS benefit (90.4% vs. 87.1%, P=0.003). While there are additional considerations regarding dosing and adverse effects between abemaciclib and ribociclib, patients for whom ALND had previously been considered to make a determination about candidacy for adjuvant CDK4/6 inhibitors now have an option for additional adjuvant therapy without taking on added surgical morbidity.

de Boniface et al.’s analysis of the SENOMAC trial adds convincing prospective evidence that the excess risk of ALND in determining candidacy for adjuvant abemaciclib does not outweigh the possible benefit of increased DFS in patients with limited nodal disease.

Acknowledgments

None.

Footnote

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

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-178/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-178/coif). M.M. receives consulting fees from AstraZeneca. A.W. receives consulting fees from Elucent Medical. The other authors have 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.

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