Axillary surgery in the cyclin-dependent kinase 4/6 inhibitors era: no time to move backward

Introduction

In the era of molecular biology, assessing the extent of axillary lymph node involvement remains a key prognostic factor in breast cancer. Historically, axillary staging relied on systematic axillary lymph node dissection (ALND), a procedure associated with significant and often long-lasting impairment of quality of life in a substantial proportion of patients. Over recent decades, multiple de-escalation trials have allowed a progressive reduction in surgical morbidity without compromising essential prognostic or therapeutic information. This shift began with the introduction of sentinel lymph node biopsy (SLNB) as the standard axillary staging technique, and later with the omission of axillary dissection in selected patients with limited nodal involvement undergoing primary surgery.

In line with this evidence, major international guidelines [National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO)] recommend omission of ALND in clinically node-negative (cN0) patients who meet ACOSOG-Z0011 or SENOMAC criteria. Overall, they prioritize minimizing morbidity while maintaining oncologic safety, providing the clinical framework within which the findings of the monarchE trial should be interpreted.

In parallel with these surgical de-escalation strategies, genomic profiling tools such as Oncotype DX and MammaPrint have increasingly influenced adjuvant treatment decisions in luminal-human epidermal growth factor receptor 2 (HER2)-negative early breast cancer. By providing individualized estimates of recurrence risk independent of nodal burden, these assays can help identify patients who may safely forgo chemotherapy and, in some cases, mitigate the need for more extensive axillary staging. Their growing integration into clinical practice further reinforces the trend toward minimizing axillary morbidity while maintaining precision in systemic therapy selection.

At a time when omission of routine ALND as a staging procedure is widely accepted, the publication of the monarchE trial (1) has introduced a new dilemma: should we reconsider axillary dissection to identify patients with four or more positive lymph nodes who may be eligible for treatment with abemaciclib?

MonarchE trial and abemaciclib

Abemaciclib is a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor used to reduce the risk of early recurrence in the adjuvant setting for patients with hormone receptor-positive, HER2-negative breast cancer who present high-risk features such as nodal involvement, large tumor size, and intermediate-to-high histologic grade (Figure 1).

Figure 1 Mechanism of action of CDK4/6 inhibitors. AI, aromatase inhibitors; CDK4/6, cyclin dependent kinase 4/6; ER, estrogen receptor.

The monarchE trial (1) is a phase III study that enrolled more than 5,000 pre- and postmenopausal women with node-positive, hormone receptor-positive breast cancer, who may have received adjuvant or neoadjuvant chemotherapy. The primary objective was to determine whether adding abemaciclib for two years to standard endocrine therapy improved invasive disease-free survival (IDFS). Two cohorts were analyzed: Cohort 1 included patients with ≥4 positive lymph nodes, or 1–3 positive nodes combined with either grade 3 histology or tumor size >5 cm (approximately 60% of this cohort had ≥4 positive nodes); a second exploratory cohort included patients with 1–3 positive nodes and Ki-67 ≥20%. The trial demonstrated a clear absolute benefit in IDFS of 7.6% at five years of follow-up (Figure 2). These findings have led to the approval of abemaciclib in combination with endocrine therapy for patients who meet these criteria.

Figure 2 Schematic representation of the monarchE trial. C, cancer; ET, endocrine therapy; G, histologic grade; HER2, human epidermal growth factor receptor 2; IDFS, invasive disease-free survival; M, metastasis; N, node; NAC, neoadjuvant chemotherapy; R, randomization ratio; T, tumor.

It is important to note that the trial does not specify the type of axillary surgery performed or the timing of the procedure; therefore, it includes patients who underwent SLNB without axillary dissection, provided they met the previously described criteria, as well as those in whom these criteria were fulfilled after axillary dissection. Furthermore, the extent of nodal burden may be identified either in the context of primary surgery or after neoadjuvant therapy, resulting in a highly heterogeneous cohort in terms of treatment sequence.

Discussion

The main question raised by the recent findings of the monarchE trial (1,2) is whether we should reconsider performing completion ALND when 1–2 sentinel nodes are found to be positive for metastasis. This approach would allow identification of patients with four or more positive nodes who could benefit from the addition of abemaciclib in terms of IDFS, albeit at the cost of increased morbidity due to lymphedema.

It is important to note that the monarchE trial did not analyze outcomes according to the type of axillary surgery performed, nor did it specify whether patients underwent completion ALND or SLNB alone. This methodological limitation introduces substantial heterogeneity in nodal assessment and prevents any direct inference regarding the optimal extent of axillary surgery. Explicitly acknowledging this constraint is essential to avoid overinterpreting the trial’s findings in the context of surgical decision‑making.

Currently, in cN0 patients with luminal phenotype, even when 1 or 2 positive sentinel nodes are detected, axillary dissection is not performed if ACOSOG-Z0011 (2), AMAROS (3), or SENOMAC (4) criteria are met, as completion dissection has not been shown to improve disease-free or overall survival. Data from the National Cancer Data Base [2018–2019] indicate that among 1,578 patients undergoing primary surgery with 1 or 2 positive sentinel nodes and no additional risk factors, the probability of harboring four or more positive nodes is approximately 13% (5), a figure consistent with control groups in ACOSOG-Z0011(2) and AMAROS (3) trials.

Importantly, not all patients would lose eligibility for abemaciclib; only those who do not meet high-risk criteria—such as tumors of grade 1–2 or Ki-67 <20%—would be excluded. Moreover, if these patients are molecularly classified as low risk, the benefit of therapy may be limited. Similarly, a post-hoc analysis of the SENOMAC trial (6) estimated that 104 axillary dissections would be required to prevent one recurrence at five years, with at least nine patients developing lymphedema. In other words, most patients would undergo a procedure associated with increased morbidity without deriving any meaningful benefit.

Further supporting this trend toward axillary de-escalation, the SOUND and INSEMA trials demonstrated that routine SLNB—and certainly ALND—may be safely omitted in most postmenopausal patients with small, grade 1–2, estrogen receptor (ER)-positive/HER2-negative tumors without compromising oncologic outcomes. In parallel, a recent systematic review by Albuainain et al. (7) concluded that indications for adjuvant CDK4/6 inhibitors should not be modified based on the omission of axillary surgery. Together, these findings reinforce that neither SLNB nor ALND is required to determine eligibility for CDK4/6 inhibition, further supporting the rationale for minimizing axillary intervention in this population.

These observations are also consistent with the real‑world data reported by Heidinger et al. (8), who demonstrated that omission of SLNB in SOUND/INSEMA-eligible patients results in a very small proportion of missed CDK4/6 inhibitor indications and a negligible estimated impact on recurrence risk. Their findings provide quantitative confirmation that axillary surgery contributes minimally to CDK4/6i decision-making in early luminal breast cancer and therefore should not drive more aggressive axillary staging.

Fortunately, this debate may soon come to an end with the promising results of the NATALEE trial (9). This study demonstrated an improvement in IDFS when ribociclib (another CDK4/6 inhibitor) was added to endocrine therapy in patients with stage II or III hormone receptor-positive, HER2-negative breast cancer, including those with 1–3 positive nodes or node-negative disease with additional risk factors. Consequently, Ribociclib would be indicated for all pN1 patients who are not eligible for abemaciclib, offering a survival benefit comparable to that observed in the monarchE trial.

Conclusions

The monarchE trial was not designed to determine the optimal approach to axillary staging; therefore, no direct conclusions can be drawn in this regard. Based on previous studies evaluating the need for axillary dissection in specific scenarios, and considering the recent SENOMAC trial, the benefit of performing axillary dissection to increase the number of patients eligible for abemaciclib in addition to standard endocrine therapy appears questionable. This strategy would expose patients to a 13–14% risk of lymphedema in exchange for an IDFS benefit of approximately 7.6% at best, without clear evidence that such benefit would apply to cases lacking high-risk molecular features.

Finally, the recently published 5-year results of the NATALEE trial confirm a sustained IDFS benefit with ribociclib, reinforcing its potential to end this debate by offering adjuvant therapy to all pN1 patients not included under monarchE criteria.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-2025-1-76/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-2025-1-76/coif). M.I.G. reports support for attending meetings and/or travel from Astra-Zeneca, Roche, and Novartis; and participation on the Data Safety Monitoring Boards or Advisory Boards of Astra-Zeneca, Roche, Novartis, Gilead, and Lilly. J.I.S.M. reports honoraria for lectures from Novartis. 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.

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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