Editor's Note: The de-escalation strategy for axillary management in breast cancer has been a consistent research focus in breast surgery. Last year, the SOUND study explored whether certain low-risk patients undergoing breast-conserving surgery could avoid sentinel lymph node biopsy (SLNB). At the 2024 San Antonio Breast Cancer Symposium (SABCS), the INSEMA study, a similar investigation, was presented. Oncology Frontier invited Dr. Yiding Chen from The Second Affiliated Hospital of Zhejiang University School of Medicine to provide an in-depth analysis of the INSEMA study.

01. Oncology Frontier:

What innovative aspects of the INSEMA study design stand out to you, especially regarding its 1:4 randomization ratio? How does this impact the study’s efficiency and interpretation?

Dr. Yiding Chen:During the oral presentation at this year’s SABCS, we reviewed the results of the INSEMA study, which closely mirrors the SOUND study. Both studies aim to investigate whether sentinel lymph node biopsy (SLNB) can be omitted for certain low-risk patients. Currently, SLNB is the standard approach for axillary lymph node management, particularly for patients without evidence of axillary metastasis. Researchers hope to determine if some patients can safely forego SLNB, further simplifying breast cancer surgical procedures.

Although the INSEMA and SOUND studies share similarities, their clinical designs differ. INSEMA utilized a 1:4 randomization ratio—meaning for every one patient allocated to the non-SLNB group, four were assigned to the SLNB group. This design might seem questionable due to the larger sample size required and the risk that some positive findings may not reach statistical significance.

However, a closer look reveals a clever design aimed at addressing two key questions:

1. Can omitting SLNB in low-risk patients achieve non-inferiority compared to standard SLNB? This was discussed in the morning session.
2. For patients with 1–3 positive SLNs, would omitting axillary lymph node dissection (ALND) result in outcomes comparable to those who undergo standard ALND? These patients were later randomized in a 1:1 ratio for this comparison.

Ultimately, the INSEMA study seeks to answer both questions. This dual-focused design offers two important insights: whether SLNB can be omitted for select patients and whether patients with 1–3 positive SLNs can avoid axillary dissection. This innovative design provides new perspectives on standard axillary lymph node management in breast cancer.

02. Oncology Frontier:

The study results show that omitting SLNB is non-inferior to SLNB regarding invasive disease-free survival (iDFS). How do you think this finding impacts clinical practice, particularly for low-risk, hormone receptor-positive (HR+)/HER2-negative early-stage invasive breast cancer patients? Is omitting axillary surgery now a safe and feasible option for these patients?

Dr. Yiding Chen:As mentioned earlier, the SOUND study generated significant debate, primarily due to its inclusion of older patients with small tumors (≤2 cm, T1 stage). Compared to SOUND, the INSEMA study allowed the enrollment of T1 and T2 tumors (≤5 cm). However, over 90% of enrolled patients had tumors ≤2 cm. Additionally, more than 95% of participants in both studies were HR+/HER2-. Though the INSEMA study allowed patients under 50 years old, they only accounted for about 10% of the participants. Despite a broader inclusion criterion, the INSEMA patient population closely resembled that of the SOUND study.

For these low-risk patients, the 5-year iDFS was 91.7% in the SLNB group and 91.9% in the non-SLNB group, meeting the study’s goal of demonstrating non-inferiority for omitting SLNB. This finding offers valuable clinical insights, especially as more breast cancer cases are diagnosed at early stages, with many being HR+/HER2-.

Subsequent commentary highlighted the need for axillary ultrasound evaluation in this patient group. Traditionally, ultrasound was not mandatory in SLNB studies if no enlarged lymph nodes were detected during physical exams. However, for this patient population—characterized by tumors ≤2 cm, HR+/HER2- status, and a small proportion under 50 years old—ultrasound assessment should be prioritized.

Thus, for patients over 50 with tumors ≤2 cm, no axillary abnormalities on preoperative ultrasound or physical exam, and confirmed HR+/HER2- status, omitting SLNB in clinical practice appears both safe and feasible.

03. Oncology Frontier:

Based on the INSEMA trial results, which areas should future research focus on regarding the omission of axillary surgery? Are there unresolved issues or challenges that require further investigation, such as evaluating the safety of omitting SLNB in patients after neoadjuvant chemotherapy?

Dr. Yiding Chen:During this morning’s presentation, I was deeply impressed by the significant progress made in the de-escalation of treatment for early-stage breast cancer patients, particularly in surgical de-escalation. Prior to the release of the INSEMA study, we already had joint analyses from two studies—NRG Oncology/RTOG 9804 and ECOG-ACRIN E5194—exploring the omission of radiotherapy and endocrine therapy in patients with ductal carcinoma in situ (DCIS). For invasive breast cancer, axillary assessment remains critical, though it now primarily informs postoperative treatment strategies rather than serving as direct treatment.

For early-stage HR+/HER2-negative breast cancer patients with positive sentinel lymph nodes, current intensified adjuvant therapy studies like NATALEE and monarchE recommend CDK4/6 inhibitors combined with endocrine therapy. Previously, we worried that omitting SLNB might result in missing patients who could benefit from CDK4/6 inhibitors. However, findings from the NATALEE study showed that even intermediate- to high-risk and node-negative patients might still be eligible for CDK4/6 inhibitor therapy, alleviating this concern.

Therefore, surgeons should begin considering the omission of SLNB as a viable option—but only after rigorous patient selection. Specifically, patients should ideally be over 50 years old, have tumors ≤2 cm, and be confirmed preoperatively as HR-positive and HER2-negative through immunohistochemical testing.

Additionally, avoiding axillary dissection after SLNB in patients who have undergone neoadjuvant therapy is an emerging focus. With the intensification of systemic neoadjuvant treatments, it is worth exploring whether surgical de-escalation can be achieved in this context. Since axillary surgery primarily provides prognostic information and guides postoperative therapy rather than serving as direct treatment, research into omitting axillary dissection after a positive SLNB in post-neoadjuvant settings will likely expand.

Surgical de-escalation aligns with the broader trend toward personalized treatment in surgery. It aims to cure the disease while promoting both physical and psychological recovery, reducing complications such as upper limb mobility issues, lymphedema, and excessive surgical trauma. This goal is shared by all surgeons.

With the publication of the INSEMA study, we also anticipate more research on SLNB in the post-neoadjuvant setting. Although studies on isolated tumor cells (ITCs) have been conducted, questions remain about whether patients with micrometastases, macrometastases, or varying numbers of positive lymph nodes can safely avoid axillary dissection. We look forward to more research addressing these questions.

Based on current evidence, I believe that for breast-conserving surgery patients who meet the aforementioned criteria, omitting SLNB can be confidently implemented. For patients post-neoadjuvant therapy, we await further clinical research to optimize axillary management strategies.

Dr. Yiding Chen

• Chief Physician, Director of Breast Surgery, and Doctoral Supervisor
• Second Affiliated Hospital of Zhejiang University School of Medicine
• Executive Member, Breast Cancer Committee, Chinese Anti-Cancer Association
• Executive Member, Hereditary Tumor Committee, Chinese Anti-Cancer Association
• Member, Breast Cancer Expert Committee, Chinese Society of Clinical Oncology (CSCO)
• Executive Member, Breast Disease Branch, Chinese Medical Promotion Association
• Vice Chair, Breast Tumor Committee, Zhejiang Medical Doctor Association
• Chair-Elect, Breast Cancer Committee, Zhejiang Anti-Cancer Association