Should abemaciclib candidacy be an indication for ALND?—commentary on SENOMAC post-hoc analysis

Modern treatment of early-stage breast cancer centers on multimodal individualized treatment that considers tumor- and patient-specific factors within the context of a multidisciplinary team. Evidence-based personalized treatment not only improves survival but also minimizes morbidity without compromising oncologic outcomes (1). This approach is most notably demonstrated by changes in axillary nodal management over the past two decades, resulting in sentinel lymph node biopsy (SLNB) becoming standard for surgical axillary staging in patients with clinically node-negative (cN0) disease, while indications for axillary lymph node dissection (ALND) have decreased (1).

Surgical axillary staging provides prognostic information and can influence adjuvant therapy recommendations (2), but the extent of axillary surgery does not alter survival (3-6). In patients with cT1–2 cN0 invasive breast cancer with low volume axillary disease (<3 positive nodes) on SLNB, the American College of Surgeons Oncology Group (ACOSOG) Z0011 and After Mapping of the Axilla: Radiotherapy or Surgery (AMAROS) trials showed that SLNB combined with either whole breast or regional-nodal radiation was non-inferior in terms of overall survival (OS) and offered comparable locoregional control compared to completion ALND (cALND) in patients undergoing breast-conserving surgery (BCS) and mastectomy (5-7). Though impactful, Z0011 and AMAROS were limited by variations in radiation fields and eligibility criteria, including tumor size (cT1–2), patient sex, presence of extranodal extension, and the low number of patients undergoing mastectomy in AMAROS (8). Thus, the sentinel node-macrometastasis (SENOMAC) trial was designed to validate these findings within a broader patient population (8).

SENOMAC was a prospective randomized phase-3 non-inferiority trial conducted at 67 European hospitals from January 2015 to December 2021 that enrolled 2,766 women and men with cT1–3cN0 invasive breast cancer who were found to have 1–2 SENOMAC on SLNB. They were randomized to cALND or omission of ALND (i.e., SLNB alone). All patients underwent adjuvant systemic and radiation therapy. After a median of 46.8 months, the estimated 5-year recurrence-free survival was 89.7% [95% confidence interval (CI): 87.5–91.9] with SLNB alone vs 88.7% (95% CI: 86.3–91.1) with ALND, demonstrating that ALND omission was non-inferior to cALND (8). These findings support that SLNB alone is a reasonable option for patients with early-stage invasive breast cancer and low-volume axillary disease. However, a recently published post-hoc analysis of the SENOMAC trial investigated the utility of cALND in providing an indication for the use of novel adjuvant cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors in patients with hormone-receptor positive (HR⁺) human epidermal growth factor 2 (HER2) negative (HER2⁻) disease (1).

Oral CDK4/6 inhibitors (i.e., abemaciclib, ribociclib, palbociclib) can be used in addition to endocrine therapy (ET) in the treatment of HR⁺/HER2⁻ breast cancer. CDK4/6 inhibitors improve progression-free survival when used in combination with ET in the metastatic setting (9), and their utility in extending OS in patients with high-risk early-stage breast cancer is under investigation in the monarchE and NATALEE trials (10,11). While the addition of CDK4/6 inhibitors to standard ET has shown an absolute reduction in invasive distant recurrence (11) and invasive disease-free survival for women with high-risk HR⁺/HER2⁻ early breast cancers (10,11), the final endpoint of OS has not yet matured. A recent post-hoc analysis of the SENOMAC trial sought to elucidate benefit versus harm in performing cALND in select patients with HR⁺/HER2⁻ disease to identify patients who may be eligible for adjuvant abemaciclib. SENOMAC patient-reported outcome (PRO) data regarding arm dysfunction and AMAROS data regarding clinical signs and treatment of lymphedema were used to determine the expected rate of arm impairment and lymphedema after cALND (1). These data, in combination with 5-year invasive disease-free survival results from the monarchE trial, were used to calculate 3 values in the post-hoc analysis: (I) number needed to treat (i.e., number of patients who need to receive adjuvant abemaciclib to avoid one invasive disease-free survival event), (II) number needed to diagnose (i.e., number of cALNDs needed to perform to identify ≥4 nodal metastases and thus provide an indication for adjuvant abemaciclib per monarchE criteria); and (III) number needed to harm (i.e., number of patients needing to undergo cALND in order to have one additional report of either severe or very severe arm impairment or clinical signs or treatment of lymphedema) (1).

MonarchE was an open-label randomized trial investigating the impact of adjuvant abemaciclib in addition to standard ET alone on outcomes in patients at high-risk of distant recurrence with HR⁺/HER2⁻ breast cancer (11). The only indication for adjuvant abemaciclib for monarchE cohort 1 [patients who were ≥18 years with estrogen receptor positive (ER⁺)/HER2⁻, pT1–2, grade 1–2 breast cancer with 1–2 SLN(s) macrometastases] was the presence of ≥4 axillary nodal metastases, which would theoretically only be known if patients received a cALND (1). Thus, the SENOMAC post-hoc analysis explored the potential impact of cALND on patients enrolled in SENOMAC who also matched the criteria for cohort 1 of monarchE and could potentially become eligible for adjuvant abemaciclib after cALND if ≥4 axillary nodal metastases were identified.

Sixty-seven percent (n=1,705) of SENOMAC trial patients met eligibility criteria for the post-hoc analysis (1). Of these patients, 802 (47%) underwent cALND and 903 (53%) had SLNB alone. There were similar survey response rates for the PRO arm function questionnaire in both groups (83% cALND vs. 82% SLNB alone). After a median follow-up of 45.2 months, there was an increase of severe or very severe arm dysfunction in patients undergoing cALND compared to those undergoing SLNB alone [84/634 (13%) vs. 30/708 (4%); P<0.001]. They calculated that 104 patients would need to undergo cALND in order to avoid one invasive disease-free survival event at 5 years with 2 years of adjuvant abemaciclib treatment. Of those 104 patients, 9 would develop severe or very severe arm impairment, 13 would develop clinical signs of lymphedema, and 17 would require lymphedema treatment (1). The authors conclude that, given this significant risk of arm impairment and no known OS benefit from adjuvant abemaciclib, performing cALND to identify patients with ≥4 nodal metastases should not be routinely performed.

The authors’ recommendation against routine performance of cALND in this patient population reflects the overall trend in de-escalation of axillary surgery for breast cancer patients. Since Z0011 and AMAROS, SLNB has been adopted as the standard for surgical axillary staging in clinically node negative (cN0) patients. The Choosing Wisely and American Society of Clinical Oncology (ASCO) Guidelines recommend against the routine use of SLNB in women ≥70 years of age with HR+ invasive breast cancer (12). More recently, the Sentinel Node vs Observation After Axillary Ultra-Sound (SOUND) and Intergroup-Sentinel-Mamma (INSEMA) trials used pre-operative axillary ultrasound to stage the axilla in patients with early-stage disease. Short-term results demonstrate that SLNB can safely omitted in patients with cT1–2 cN0 breast cancer and a negative pre-operative axillary ultrasound (13,14). Long-term results await maturation and additional ongoing studies will further provide data to inform SLNB omission (15,16). As data continues to support omission of surgical nodal staging, the notion that patients with favorable tumor biology should undergo ALND to inform use of adjuvant abemaciclib is a difficult argument for surgeons and patients. While the burden of additional nodal disease can be identified by further surgery (i.e., cALND), several nomograms exist that can calculate the probability of non-sentinel lymph node (SLN) metastases and potentially spare patients further surgery (17,18). Use of these nomograms can support identifying patients who are likely to have ≥4 axillary nodal metastases and are thereby eligible for adjuvant abemaciclib without performing cALND. However, for patients with clinically node positive (cN+) disease who undergo upfront surgery, ALND remains standard of care. Other indications for ALND include patients with inflammatory breast cancer, patients found to have more than ≥3 positive SLNs, those who are not suitable radiation therapy candidates, and residual nodal disease after neoadjuvant chemotherapy (2).

The size of SLN metastases is an independent predictor of the presence of non-SLN metastases (17,18). While the presence of any residual axillary disease after neoadjuvant chemotherapy has been an indication for cALND (19), recent data support the omission of cALND in patients with only isolated tumor cells (ITCs) in the SLN(s) after neoadjuvant chemotherapy (20). Additionally, the results of Alliance A11202, which investigates the use of axillary radiation alone rather than cALND with axillary radiation in patients with residual nodal disease after chemotherapy, will further inform the utility of cALND in the neoadjuvant setting. While size of SLN metastases is understood as an important factor for predicting total burden of axillary disease and performance of cALND, the definition of lymph node positivity (i.e., whether macrometastases, micrometastases, or ITCs) was not specified in monarchE (11) and should be carefully considered in treatment recommendations.

While the use of oral abemaciclib in addition to standard ET in high-risk patients with HR⁺/HER2⁻ breast cancer provides some benefits, there are several important considerations. Advocating for more aggressive axillary surgery without a clear OS advantage for those who receive abemaciclib should be approached cautiously, especially in the setting of adding morbidity. Abemaciclib itself can result in morbidity. Common side effects of abemaciclib include hematologic and liver enzyme derangements, diarrhea, interstitial lung disease, and fatigue (11). When comparing abemaciclib plus ET to the ET alone in monarchE, there were more grade ≥3 adverse events and serious adverse events in patients receiving abemaciclib (49.9% abemaciclib vs. 16.9% ET alone) (11). Adverse events caused interruption of abemaciclib in 61.7% of patients, and 43.6% of patients required abemaciclib dose-reduction due to side effects (11). While there were similar deaths due to adverse events while on treatment in both groups, 2 (2/15) deaths in the abemaciclib group were assessed as possibly directly related to study treatment, while none of the deaths in the ET group were thought to be treatment related (11).

The morbidity of ALND is well-established. Patients who receive SLNB alone have less arm morbidity and improved quality of life compared to those who undergo ALND (21). Breast cancer-related lymphedema (BCRL) is one of the most dreaded outcomes of axillary surgery, as it is often a lifelong condition with substantial physical and psychological impact on patients (21). Extent of axillary surgery is associated with increased rates of BCRL—25–30% of patients develop lymphedema after ALND compared to about 8–11% of patients after SLNB (22). Body mass index (BMI) is a well-established risk factor for BCRL (22,23). There have also been racial/ethnic disparities noted with higher rates of BCRL in Black and Hispanic individuals, though the biological basis for this is unknown (23,24). Patient BMI, race, and ethnicity were not reported in the post-hoc analysis, though these factors could be informative given reported differences in BCRL rates. Though no gold standard exists for the evaluation or treatment of BCRL, patient-reported symptoms taken together with physical exam and quantitative metrics, including linear circumference and volumetric and bioimpedance measures, can aid in diagnosis (21). However, patient perception does not always correlate with objective measurements. Patients have been shown to both over- and underreport perception of BCRL symptoms. In a study including 120 patients undergoing either SLNB or ALND followed for 12 months with both PRO of arm function and arm volume measurements, 12% of patients reported a sensation of arm swelling with no change in arm volume while 5% of patients were found to meet volume criteria for lymphedema without any subjective arm dysfunction (25). Arm volumes were also found to fluctuate over the study period, underscoring the need for longitudinal follow-up (25). Because of these known limitations in the diagnosis of BCRL, longitudinal quantitative measures of arm volumes in addition to PRO data would have strengthened the post-hoc analysis.

With no data on an OS benefit with adjuvant abemaciclib for patients with non-metastatic HR⁺/HER2⁻ breast cancer and the increased morbidity of ALND, we agree with the authors of the SENOMAC post-hoc analysis that routine cALND should not be routinely performed for patients with cT1–2N0, HR⁺/HER2⁻ breast cancer found to have 1–2 positive SLN(s). While axillary surgery can provide prognostic information, its utility is becoming increasingly reduced for patients with HR⁺/HER2⁻ disease due to genomic assays and recent data revealing that omission of SLNB in select patients does not influence OS. Increasing breast cancer morbidity with more extensive axillary surgery to inform the use of oral systemic therapy that may not result in an OS benefit is overtreatment and not currently warranted.

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-2025-38/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-2025-38/coif). C.S.C. is supported by the National Institutes of Health (NIH) under Award Number 5K08CA276706-02 (PI: Cortina), PCORI EA25591 (PI: Cortina), and Advancing a Healthier Wisconsin AHW 04698 (PI: Cortina). In addition to support of research activities, support has also included annual meeting registration for attending the American Society of Breast Surgeons annual meeting in 2024 and 2025. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. 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/.

References

1. de Boniface J, Appelgren M, Szulkin R, et al. Completion axillary lymph node dissection for the identification of pN2-3 status as an indication for adjuvant CDK4/6 inhibitor treatment: a post-hoc analysis of the randomised, phase 3 SENOMAC trial. Lancet Oncol 2024;25:1222-30. [Crossref] [PubMed]
2. Burstein HJ, Curigliano G, Thürlimann B, et al. Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021. Ann Oncol 2021;32:1216-35. [Crossref] [PubMed]
3. Hersh EH, King TA. De-escalating axillary surgery in early-stage breast cancer. Breast 2022;62:S43-9. [Crossref] [PubMed]
4. Fisher B, Jeong JH, Anderson S, et al. Twenty-five-year follow-up of a randomized trial comparing radical mastectomy, total mastectomy, and total mastectomy followed by irradiation. N Engl J Med 2002;347:567-75. [Crossref] [PubMed]
5. Donker M, van Tienhoven G, Straver ME, et al. Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS): a randomised, multicentre, open-label, phase 3 non-inferiority trial. Lancet Oncol 2014;15:1303-10. [Crossref] [PubMed]
6. Giuliano AE, Ballman KV, McCall L, et al. Effect of Axillary Dissection vs No Axillary Dissection on 10-Year Overall Survival Among Women With Invasive Breast Cancer and Sentinel Node Metastasis: The ACOSOG Z0011 (Alliance) Randomized Clinical Trial. JAMA 2017;318:918-26. [Crossref] [PubMed]
7. Bartels SAL, Donker M, Poncet C, et al. Radiotherapy or Surgery of the Axilla After a Positive Sentinel Node in Breast Cancer: 10-Year Results of the Randomized Controlled EORTC 10981-22023 AMAROS Trial. J Clin Oncol 2023;41:2159-65. [Crossref] [PubMed]
8. de Boniface J, Filtenborg Tvedskov T, Rydén L, et al. Omitting Axillary Dissection in Breast Cancer with Sentinel-Node Metastases. N Engl J Med 2024;390:1163-75. [Crossref] [PubMed]
9. Wang X, Zhao S, Xin Q, et al. Recent progress of CDK4/6 inhibitors' current practice in breast cancer. Cancer Gene Ther 2024;31:1283-91. [Crossref] [PubMed]
10. Slamon D, Lipatov O, Nowecki Z, et al. Ribociclib plus Endocrine Therapy in Early Breast Cancer. N Engl J Med 2024;390:1080-91. [Crossref] [PubMed]
11. Johnston SRD, Toi M, O'Shaughnessy J, et al. Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): results from a preplanned interim analysis of a randomised, open-label, phase 3 trial. Lancet Oncol 2023;24:77-90. [Crossref] [PubMed]
12. Brackstone M, Baldassarre FG, Perera FE, et al. Management of the Axilla in Early-Stage Breast Cancer: Ontario Health (Cancer Care Ontario) and ASCO Guideline. J Clin Oncol 2021;39:3056-82. [Crossref] [PubMed]
13. Gentilini OD, Botteri E, Sangalli C, et al. Sentinel Lymph Node Biopsy vs No Axillary Surgery in Patients With Small Breast Cancer and Negative Results on Ultrasonography of Axillary Lymph Nodes: The SOUND Randomized Clinical Trial. JAMA Oncol 2023;9:1557-64. [Crossref] [PubMed]
14. Reimer T, Stachs A, Nekljudova V, et al. Restricted Axillary Staging in Clinically and Sonographically Node-Negative Early Invasive Breast Cancer (c/iT1-2) in the Context of Breast Conserving Therapy: First Results Following Commencement of the Intergroup-Sentinel-Mamma (INSEMA) Trial. Geburtshilfe Frauenheilkd 2017;77:149-57. [Crossref] [PubMed]
15. van Roozendaal LM, Vane MLG, van Dalen T, et al. Clinically node negative breast cancer patients undergoing breast conserving therapy, sentinel lymph node procedure versus follow-up: a Dutch randomized controlled multicentre trial (BOOG 2013-08). BMC Cancer 2017;17:459. [Crossref] [PubMed]
16. Jung JG, Ahn SH, Lee S, et al. No axillary surgical treatment for lymph node-negative patients after ultra-sonography [NAUTILUS]: protocol of a prospective randomized clinical trial. BMC Cancer 2022;22:189. [Crossref] [PubMed]
17. van la Parra RF, Ernst MF, Bevilacqua JL, et al. Validation of a nomogram to predict the risk of nonsentinel lymph node metastases in breast cancer patients with a positive sentinel node biopsy: validation of the MSKCC breast nomogram. Ann Surg Oncol 2009;16:1128-35. [Crossref] [PubMed]
18. Van Zee KJ, Manasseh DM, Bevilacqua JL, et al. A nomogram for predicting the likelihood of additional nodal metastases in breast cancer patients with a positive sentinel node biopsy. Ann Surg Oncol 2003;10:1140-51. [Crossref] [PubMed]
19. Cavalcante FP, Millen EC, Zerwes FP, et al. Role of Axillary Surgery After Neoadjuvant Chemotherapy. JCO Glob Oncol 2020;6:238-41. [Crossref] [PubMed]
20. Montagna G, Laws A, Ferrucci M, et al. Nodal Burden and Oncologic Outcomes in Patients With Residual Isolated Tumor Cells After Neoadjuvant Chemotherapy (ypN0i+): The OPBC-05/ICARO Study. J Clin Oncol 2025;43:810-20. [Crossref] [PubMed]
21. Marchica P, D'Arpa S, Magno S, et al. Integrated Treatment of Breast Cancer-related Lymphedema: A Descriptive Review of the State of the Art. Anticancer Res 2021;41:3233-46. [Crossref] [PubMed]
22. Naoum GE, Roberts S, Brunelle CL, et al. Quantifying the Impact of Axillary Surgery and Nodal Irradiation on Breast Cancer-Related Lymphedema and Local Tumor Control: Long-Term Results From a Prospective Screening Trial. J Clin Oncol 2020;38:3430-8. [Crossref] [PubMed]
23. Montagna G, Barrio AV. Managing the Morbidity: Individualizing Risk Assessment, Diagnosis, and Treatment Options for Upper Extremity Lymphedema. Surg Oncol Clin N Am 2023;32:705-24. [Crossref] [PubMed]
24. Montagna G, Zhang J, Sevilimedu V, et al. Risk Factors and Racial and Ethnic Disparities in Patients With Breast Cancer-Related Lymphedema. JAMA Oncol 2022;8:1195-200. [Crossref] [PubMed]
25. McLaughlin SA, Bagaria S, Gibson T, et al. Trends in risk reduction practices for the prevention of lymphedema in the first 12 months after breast cancer surgery. J Am Coll Surg 2013;216:380-9; quiz 511-3. [Crossref] [PubMed]