In a prospective, randomised, noninferiority Intergroup Sentinel Mamma (INSEMA) study that involved patients with early-stage, clinically node-negative (cN0), T1 or T2 invasive breast cancer (90% of whom had clinical T1 cancer), omission of surgical axillary staging was noninferior to sentinel lymph node biopsy after a median follow-up of approximately 6 years.
This de-escalation concept may be suitable for patients 50 years of age or older who present with low-risk (grade 1 or 2), HR-positive, HER2-negative invasive breast cancer and clinical T1 tumours according to Dr. Toralf Reimer of the Department of Obstetrics and Gynecology, University of Rostock in Rostock, Germany and colleagues, who presented the primary outcome data at the San Antonio Breast Cancer Symposium along with a simultaneous publication in The New England Journal of Medicine on 12 December 2024.
The authors wrote in the background that ACOSOG Z0011 study provided the basis for the design and funding of several de-escalation trials of the omission of axillary surgery in the treatment of early-stage breast cancer. Four prospective, randomised trials (SOUND, INSEMA, BOOG 2013-08, and NAUTILUS) are investigating the omission of axillary sentinel lymph node biopsy in patients with cN0 breast cancer who undergo upfront breast-conserving surgery.
Recently, primary results from the SOUND study showed that omission of axillary surgery was noninferior to sentinel lymph node biopsy in patients with small breast cancers up to 2 cm. Primary outcome results of the BOOG study are expected to be reported in 2025. Later, in 2027, data from the NAUTILUS study are expected.
A preplanned central quality assurance review process for radiotherapy planning and axillary contouring was included in the INSEMA protocol, and the findings of the review were published in 2020. Recent analysis of patient-reported outcomes showed differences between the groups with respect to scores on a quality-of-life assessment of breast symptoms and arm symptoms, with better scores among patients who did not undergo sentinel lymph node biopsy than among those who did. In the assessment of arm symptoms, patients who underwent sentinel lymph node biopsy had significantly higher scores (indicating worse symptoms) for symptoms including pain, arm swelling, and impaired mobility at all postoperative visits.
The goal of the INSEMA study is to show that complete omission of axillary surgery in early-stage breast cancer treated with breast-conserving surgery is noninferior to sentinel lymph node biopsy with respect to invasive disease-free survival (iDFS). To show the noninferiority of the omission of axillary surgery, the 5-year iDFS rate had to be at least 85%, and the upper limit of the confidence interval for the hazard ratio (HR) for invasive disease or death had to be below 1.271.
The study was conducted at 142 sites in Germany and 9 sites in Austria after obtaining approval from local independent review boards. The study was designed by the University Medicine Rostock in cooperation with the German Breast Group.
A total of 5502 eligible patients (90% with clinical T1 cancer and 79% with pathological T1 cancer) underwent randomisation in a 1:4 ratio. The per-protocol population included 4858 patients; 962 were assigned to undergo treatment without axillary surgery (the surgery-omission group), and 3896 to undergo sentinel lymph node biopsy (the surgery group). The median follow-up was 73.6 months.
The estimated 5-year iDFS rate was 91.9% (95% confidence interval [CI] 89.9 to 93.5) among patients in the surgery-omission group and 91.7% (95% CI 90.8 to 92.6) among patients in the surgery group, with HR of 0.91 (95% CI 0.73 to 1.14), which was below the prespecified noninferiority margin.
The analysis of the first primary outcome events (occurrence or recurrence of invasive disease or death from any cause), which occurred in a total of 525 patients (10.8%), showed apparent differences between the surgery-omission group and the surgery group in the incidence of axillary recurrence (1.0% versus 0.3%) and death (1.4% versus 2.4%).
The safety analysis indicates that patients in the surgery-omission group had a lower incidence of lymphoedema, greater arm mobility, and less pain with movement of the arm or shoulder than patients who underwent sentinel lymph node biopsy.
The authors commented that the 5-year iDFS in INSEMA is consistent with the results of the SOUND trial. The study provides important information with regard to patient selection for the omission of sentinel lymph node biopsy. Approximately 90% of patients in the study were 50 years of age or older, and 95% presented with a luminal intrinsic tumour subtype (HR-positive and HER2-negative); patients with the combination of these two characteristics can be considered to be eligible for the omission of sentinel lymph node biopsy. The study included few patients with tumours larger than 2 cm, and the results for this subgroup had wide confidence intervals, which precludes definitive conclusions.
In an accompanied editorial article, Dr. Monica Morrow of the Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center in New York, NY, US wrote that successful de-escalation of any therapeutic approach requires multidisciplinary consideration of the effects on the entire treatment plan. INSEMA and SOUND data provide a strong foundation for consideration of how to incorporate the elimination of sentinel lymph node biopsy into practice.
At present, patients with grade 1 or 2, cT1 tumours are ideal candidates for this approach. If surgical pathological examination reveals a larger T2 tumour, a high-grade tumour, or lymphovascular invasion (factors that increase the likelihood of nodal metastases and are indicative of worse prognosis) patients can then undergo sentinel lymph node biopsy. This approach will avoid axillary surgery for the majority while minimising undertreatment. Patient-reported outcomes are needed to determine which therapies patients prefer to de-escalate.
The study was supported by grants from the German Cancer Aid, Bonn, Germany.
References
- Reimer T, Stachs A, Veselinovic K, et al. Axillary Surgery in Breast Cancer — Primary Results of the INSEMA Trial. NEJM; Published online 12 December 2024. DOI: 10.1056/NEJMoa2412063
- Morrow M. Sentinel-Lymph-Node Biopsy in Early-Stage Breast Cancer — Is It Obsolete? NEJM; Published online 12 December 2024. DOI: 10.1056/NEJMe2414899