Navigating the future of axillary surgery in HER2⁺ breast cancer: insights and opportunities for change

Breast cancer (BC) with overexpression of human epidermal growth factor receptor 2 (HER2) oncogene is positive in approximately 20% of primary cancers (1). Advances in systemic therapy, particularly HER2-targeted therapy, have significantly improved outcomes for these patients (2,3). This has led to increased use of neoadjuvant therapy (NAT) in HER2⁺ patients (4), now recommended for metastatic lymph node disease (cN+) and for tumors larger than 2 cm (T2) (5). Pathologic complete response (pCR) rates following NAT for HER2⁺ BC have been reported in at least 40% (6) and up to 67% in patients with HER2 overexpression of 3+ in the immunohistochemistry (7). The advent of conjugated HER2-targeting drugs has ushered in a new era of treatment options, now indicated for metastatic patients (8) and those with post-NAT residual disease (9).

Axillary staging following NAT depends on the axillary staging at presentation. Sentinel lymph node biopsy (SLNBx) is recommended for patients who were cN0 prior to NAT. Patients who are found to have metastatic spread to lymph nodes (cN1) are treated with targeted axillary surgery (TAS) (10). TAS includes some or all of the following features: use of dual tracer techniques, retrieval of preoperative positive nodes (clipped node), and sampling of at least three nodes. According to guidelines (5), when metastatic lymph nodes are found post-NAT, axillary lymph node dissection (ALND) is recommended.

Given the possible short- and long-term complications of axillary surgery, efforts are made to omit axillary surgery when possible. Such efforts have already been widely adopted for hormone positive HER2 negative early cancer in older women (11) and those with ultrasound showing no suspicious lymph nodes (12). Complications of axillary surgery may include long-term shoulder and arm morbidity, including pain, sensitivity, numbness, swelling, and reduced range of motion (13).

The study titled “Axillary Nodal Response to Neoadjuvant T-DM1 Combined with Pertuzumab in a Prospective Phase II Multi-Institution Clinical Trial” (14) offers a new pathway to potentially limit axillary surgery. The authors examined 158 patients with cN0 and cN1 HER2-enriched BC who completed novel NAT regimen with six cycles of neoadjuvant trastuzumab-emtansine (T-DM1) plus pertuzumab. They reported that all patients with breast pCR following NAT had no nodal involvement, regardless of axillary stage at diagnosis, cN0 or cN1 (30 and 48 patients respectively). Patients without breast pCR had 16% (7/44) nodal disease in cN0 and 53% (19/36) in cN1. This is consistent with the 0–5% rate of residual nodal disease reported for cN0 HER2-positive patients achieving a breast pCR (15-18). Notably, however, those studies have reported residual nodal disease in 5–52% of initial cN1 patients achieving a breast pCR.

Several recent studies support omission of axillary surgery in patients with limited residual nodal disease who are projected to receive radiation therapy (19,20). These data rise to the question as to whether we can omit axillary surgery in patients following NAT in order to avoid the known complications of axillary surgery, especially in selected patients where the rate of extensive nodal disease is very low. However, omission of accurate axillary staging in HER2 positive disease is not an easy decision as the information this provides is critical for making adjuvant therapy decisions. It has been shown that adjuvant treatment, in patients who did not achieve pCR, reduces the risk of recurrence or invasive disease or death by 50% (9). Hence the necessity of detecting residual disease may be of higher importance.

This study utilized data gathered as part of a phase two clinical trial examining a chemotherapy regimen; thus, it has a limited sample size and lacks randomization. Additionally, the study may be subject to selection bias, as patients enrolled in clinical trials often have different characteristics compared to the general population. There is also the potential for confounding variables that were not controlled for, which could influence the outcomes. The relatively short follow-up period may not capture long-term recurrence and survival data, limiting the ability to fully assess the durability of the findings. Furthermore, the innovative NAT protocol used in this study may not be widely available or applicable to all clinical settings, which can affect the generalizability of the results. Despite these limitations, this research provides further impetus to advance ongoing randomized clinical trials. These trials aim to explore the feasibility and safety of omitting SLNBx following NAT in patients with HER2⁺ or triple-negative BC who receive NAT (21,22). The findings from this study not only underscore the need for continued investigation but also highlight the potential benefits and challenges associated with modifying axillary staging strategies in this specific patient population. This ongoing research will be crucial for informing clinical practice guidelines and optimizing treatment approaches for these patients.

Several questions continue to linger regarding the optimal method for determining cN0 status at presentation. Should it rely solely on physical examination, or should diagnostic tools such as axillary ultrasound, magnetic resonance imaging, or positron emission tomography-computed tomography be incorporated, either individually or in combination, to enhance accuracy? Additionally, the accurate determination of a complete response in the breast following NAT is crucial. This information serves as a cornerstone in making informed decisions about the potential omission of axillary surgery. However, in scenarios where residual breast disease is only identified postoperatively, the necessity for axillary surgery becomes more complex. Such situations may necessitate additional surgical interventions, or in cases where mastectomy is performed, the success of axillary surgery might be compromised. Thus, resolving these uncertainties is essential for refining treatment strategies and optimizing patient outcomes in the management of BC.

Acknowledgments

Funding: 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.

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References

1. Patel A, Unni N, Peng Y. The Changing Paradigm for the Treatment of HER2-Positive Breast Cancer. Cancers (Basel) 2020;12:2081. [Crossref] [PubMed]
2. Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 2011;365:1273-83. [Crossref] [PubMed]
3. Trastuzumab for early-stage, HER2-positive breast cancer: a meta-analysis of 13 864 women in seven randomised trials. Lancet Oncol 2021;22:1139-50. [Crossref] [PubMed]
4. Cobain EF, Hayes DF. Expanding the reach of HER2-targeted therapies: transformation of an historical paradigm. J Clin Invest 2022;132:e166384. [Crossref] [PubMed]
5. NCCN guidelines. 2024. Available online: https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf
6. Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 2012;13:25-32. [Crossref] [PubMed]
7. Krystel-Whittemore M, Xu J, Brogi E, et al. Pathologic complete response rate according to HER2 detection methods in HER2-positive breast cancer treated with neoadjuvant systemic therapy. Breast Cancer Res Treat 2019;177:61-6. [Crossref] [PubMed]
8. Hurvitz SA, Kim SB, Chung WP, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer patients with brain metastases from the randomized DESTINY-Breast03 trial. ESMO Open 2024;9:102924. [Crossref] [PubMed]
9. von Minckwitz G, Huang CS, Mano MS, et al. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. N Engl J Med 2019;380:617-28. [Crossref] [PubMed]
10. Dux J, Habibi M, Malik H, et al. Impact of axillary surgery on outcome of clinically node positive breast cancer treated with neoadjuvant chemotherapy. Breast Cancer Res Treat 2023;202:267-73. [Crossref] [PubMed]
11. Heidinger M, Maggi N, Dutilh G, et al. Use of sentinel lymph node biopsy in elderly patients with breast cancer - 10-year experience from a Swiss university hospital. World J Surg Oncol 2023;21:176. [Crossref] [PubMed]
12. 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]
13. Verbelen H, Gebruers N, Eeckhout FM, et al. Shoulder and arm morbidity in sentinel node-negative breast cancer patients: a systematic review. Breast Cancer Res Treat 2014;144:21-31. [Crossref] [PubMed]
14. Weiss A, Jin Q, Waks AG, et al. Axillary Nodal Response to Neoadjuvant T-DM1 Combined with Pertuzumab in a Prospective Phase II Multi-Institution Clinical Trial. J Am Coll Surg 2024;238:303-11. [Crossref] [PubMed]
15. Barron AU, Hoskin TL, Day CN, et al. Association of Low Nodal Positivity Rate Among Patients With ERBB2-Positive or Triple-Negative Breast Cancer and Breast Pathologic Complete Response to Neoadjuvant Chemotherapy. JAMA Surg 2018;153:1120-6. [Crossref] [PubMed]
16. Tadros AB, Yang WT, Krishnamurthy S, et al. Identification of Patients With Documented Pathologic Complete Response in the Breast After Neoadjuvant Chemotherapy for Omission of Axillary Surgery. JAMA Surg 2017;152:665-70. [Crossref] [PubMed]
17. Choi HJ, Ryu JM, Kim I, et al. Prediction of axillary pathologic response with breast pathologic complete response after neoadjuvant chemotherapy. Breast Cancer Res Treat 2019;176:591-6. [Crossref] [PubMed]
18. Zhu J, Li J, Fan Z, et al. Association of higher axillary pathologic complete response rate with breast pathologic complete response after neoadjuvant chemotherapy. Ann Transl Med 2020;8:992. [Crossref] [PubMed]
19. Boughey JC, Yu H, Dugan CL, et al. Changes in Surgical Management of the Axilla Over 11 Years - Report on More Than 1500 Breast Cancer Patients Treated with Neoadjuvant Chemotherapy on the Prospective I-SPY2 Trial. Ann Surg Oncol 2023;30:6401-10. [Crossref] [PubMed]
20. Montagna G, Laws A, Ferrucci M, et al. Abstract GS02-02: Are nodal ITCs after neoadjuvant chemotherapy an indication for axillary dissection? The OPBC05/EUBREAST-14R/ICARO study. Cancer Res 2024;84:GS02-02. [Crossref]
21. Reimer T, Glass A, Botteri E, et al. Avoiding Axillary Sentinel Lymph Node Biopsy after Neoadjuvant Systemic Therapy in Breast Cancer: Rationale for the Prospective, Multicentric EUBREAST-01 Trial. Cancers (Basel) 2020;12:3698. [Crossref] [PubMed]
22. Avoiding Sentinel Lymph Node Biopsy in Breast Cancer Patients After Neoadjuvant Chemotherapy (ASICS). 2020. Available online: https://clinicaltrials.gov/study/NCT04225858#collaborators-and-investigators