Tari A. King, MD, FACS, FSSO, FASCO
Research advances are reshaping axillary management in breast cancer by showing that select patients with higher-risk features but limited nodal involvement can safely avoid lymph node dissection, according to Tari A. King, MD, FACS, FSSO, FASCO.
“How we approach the axilla in a patient who has disease in the lymph nodes [includes asking]: What is the molecular subtype of the breast cancer?” King said in an interview with OncLive®. “Is it the subtype that will respond well to preoperative chemotherapy? If yes, should we use preoperative chemotherapy? If it’s not the type of breast cancer that we expect to have a good response to preoperative chemotherapy, then we also want to understand the burden of disease to determine whether we can apply some of the strategies that have been performed in clinical trials that tell us that in patients with limited volume of nodal disease, it’s safe to avoid lymph node dissection.”
In the interview, King discussed factors that influence locoregional breast cancer management strategies, as well as how findings from the SENOMAC trial (NCT02240472) built on standards set in the phase 3 ACOSOG Z0011 trial (NCT00003855) regarding the safety of avoiding axillary lymph node dissection in patients with only 1 or 2 positive nodes.
King is chief surgical officer for the cancer service line and codirector of the Glenn Family Breast Center at Winship Cancer Institute of Emory University and Emory Healthcare in Atlanta, Georgia; as well as a professor and chief of the Division of Breast Surgery in the Department of Surgery at Emory University School of Medicine.
OncLive: What factors do you consider when deciding which patients with locoregional disease can be candidates for treatment de-escalation?
King: When we’re evaluating a patient with breast cancer, if it’s clear that they have regional—or nodal—disease, which is disease in the lymph nodes, then we need to assess whether there’s an opportunity to downstage her axilla—or eradicate that nodal disease—with an option of preoperative chemotherapy. We don’t manage all breast cancers as one disease. The molecular subtype of the breast cancer—whether it’s hormone receptor [HR] positive, HER2-positive, or triple negative—factors into our decision-making as to whether a patient would be a reasonable candidate for preoperative therapy and whether we would expect the nodal disease to be downstaged by the therapy.
For example, patients with HER2-positive breast cancer are excellent candidates to receive preoperative therapy if they have disease in their lymph nodes, because approximately 70% to 80% of the time, that disease will be eradicated with preoperative therapy. We can take them to the operating room and perform an axillary staging procedure, which is called either sentinel lymph node mapping and biopsy, or targeted axillary dissection. If we can demonstrate that the nodal basin is free of disease with one of these staging procedures, then we can avoid a complete lymph node dissection. However, if there is still disease remaining in the lymph nodes, then the standard of care is to perform a complete lymph node dissection in that setting. When patients present with nodal disease or regional disease, we ask ourselves: Is there an opportunity to use preoperative therapy to eradicate that disease so we can de-escalate axillary surgery?
[Nevertheless], for example, in patients with HR-positive breast cancer, preoperative chemotherapy doesn’t result in the same excellent rates of downstaging as it does in HER2-positive disease. In a patient with HR-positive disease, we only expect their nodal basin to be cleared approximately 20% to 25% of the time. Those patients are still more likely to receive a lymph node dissection after preoperative therapy.
Having said that, if a patient has limited nodal involvement preoperatively—if we’re evaluating them in the clinic and perhaps radiographically, it only looks like they have 1 abnormal lymph node—if they have HR-positive disease, we may then choose to take that patient to the operating room and perform the sentinel lymph node staging procedure, which removes the first set of nodes that drain the breast, [including] presumably the 1 node that looked abnormal or that was positive in an individual patient. However, typically, we find 2 to 3 sentinel nodes. If we remove those sentinel nodes, send them to pathology, and can demonstrate that only 1 or 2 of them are positive, then those patients can often also be afforded the opportunity to avoid a lymph node dissection based on a large body of clinical data demonstrating that patients who have 1 or 2 positive sentinel nodes can safely forego axillary lymph node dissection in the setting of appropriate postoperative systemic therapy and radiation therapy.
What were the rationale and design of the SENOMAC trial?
The SENOMAC trial was an upfront surgery trial that extended the results of the landmark Z0011 trial, which was the first trial that demonstrated for us as surgeons that patients who are clinically node negative—meaning we cannot feel any nodes under their arm, [also known as] T1 and T2 breast cancers, [which are] tumors 5 cm [or less] in size—we would take to upfront surgery and perform the sentinel lymph node mapping and biopsy procedure. Among women found to have 1 or 2 positive nodes only, Z0011 demonstrated that it was safe to avoid lymph node dissection with no differences in rates of axillary recurrence, disease-free survival [DFS], or overall survival [between patients] undergoing lymph node dissection vs those having just their axilla observed. Even though that landmark trial made a huge difference for patients and opened the door for de-escalation of therapy, there were concerns that the trial perhaps enrolled a population of lower-risk patients, primarily postmenopausal women.
Most of the patients had smaller tumors. Even though the study allowed T1 and T2 tumors, most were T1, HR-positive, and HER2-negative. That left lingering questions as to how broadly the results of Z0011 could be applied and how safe it is to omit lymph node dissection in a more heterogeneous group of patients.
The SENOMAC trial expanded its eligibility criteria to patients with up to T3 tumors—bigger than 5 cm—and allowed for 1 or 2 positive nodes, but specified that those nodes needed to be involved with macrometastatic disease. Another criticism of Z0011 was that a lot of the patients had micrometastases, not true macrometastases. SENOMAC also enrolled patients undergoing mastectomy, whereas Z0011 was limited to patients having breast conservation. Similarly, [SENOMAC enrolled] male patients and more patients with lobular breast cancers.
[Overall, SENOMAC studied a] broader patient population with higher-risk features and was asking the same question [as Z0011]: Can patients who are clinically node negative—even though they might have other higher-risk features—be taken to the operating room if found to have 1 or 2 positive sentinel nodes? Is it safe to avoid lymph node dissection? This was a randomized, prospective trial. Patients were randomly assigned intraoperatively to either undergo the lymph node dissection or not.
What were the key findings from SENOMAC?
What we learned from that trial was that the burden of nodal disease in the patients undergoing a lymph node dissection was higher than we saw in Z0011. In Z0011, 27% of patients [with axillary lymph node disease] had additional, [nonsentinel] nodal disease, whereas in SENOMAC, [this rate was] 34.5%, [so those patients were] more likely to have disease in the axilla beyond the sentinel node.1,2 However, [in SENOMAC], the population of patients who did not undergo a lymph node dissection did not have increased rates of axillary failure and did not have differences in DFS compared with those who did undergo axillary dissection. [SENOMAC demonstrated] that it is safe to avoid lymph node dissection in a broader, more heterogeneous population of patients undergoing upfront surgery if they’re found to have only 1 or 2 positive sentinel nodes.
References
- 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(10):918-926. doi:10.1001/jama.2017.11470
- 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(13):1163-1175. doi:10.1056/NEJMoa2313487