In a randomised, controlled SENOMAC study, the estimated 5-year recurrence-free survival (RFS) after sentinel-node biopsy only was noninferior to that after completion axillary lymph node dissection among patients with breast cancer and one or two sentinel-node macrometastases. Most of the patients, regardless of study group assignment, received adjuvant systemic treatment and radiation therapy, including nodal target volumes.
This study provides robust evidence that the omission of completion axillary lymph node dissection was safe in patients with clinically node-negative T1, T2, or T3 breast cancer and one or two sentinel-node macrometastases, who received adjuvant systemic treatment and radiation therapy, according to Dr. Jana de Boniface of the Breast Center, Department of Surgery, Capio St. Göran’s Hospital in Stockholm, Sweden and colleagues who published the findings on 3 April 2024 in The New England Journal of Medicine.
The ACOSOG Z0011study showed the safety of the omission of completion axillary lymph node dissection among patients with clinically node-negative breast cancer undergoing breast-conserving surgery and whole-breast radiotherapy in whom sentinel-lymph-node biopsy had revealed one or two metastases. Since then, the use of completion axillary lymph node dissection has been steadily decreasing. However, in some countries, the adaptation of guidelines has been slow, owing mainly to underrecruitment in the ACOSOG Z0011 and the premature closure of that study in combination with a large noninferiority margin, short follow-up, and uncertainties regarding irradiated nodal volumes and any consequences for adjuvant therapies.
In AMAROS study, completion axillary lymph node dissection was replaced with axillary radiation therapy. Mastectomy was not an exclusion criterion, but only 248 such patients (17.4%) underwent randomisation. Although neither of these studies reached statistical power for endpoints, no benefit of completion axillary lymph node dissection was observed after 10 years of follow-up. Signs of lymphoedema, however, were twice as common after completion axillary lymph node dissection than after axillary radiation therapy in the AMAROS study.
In 2015, the researchers from Northern Europe opened the SENOMAC study for enrolment. The aim of this study was to validate results from previous studies in a sufficiently large cohort focused only on patients with sentinel-node macrometastases and to extend eligibility criteria to include important underrepresented subgroups like patients undergoing mastectomy, those with sentinel-node extracapsular extension or T3 tumours, and men.
SENOMAC is a noninferiority study in which patients with clinically node-negative primary T1 to T3 breast cancer with one or two sentinel-node macrometastases (metastasis size >2 mm in the largest dimension) were randomly assigned in a 1:1 ratio to completion axillary lymph node dissection or its omission (sentinel-node biopsy only). Adjuvant treatment and radiation therapy were used in accordance with national guidelines. The primary endpoint was overall survival.
The SENOMAC researchers report the per-protocol and modified intention-to-treat analyses of the prespecified secondary endpoint of RFS. To show noninferiority of sentinel-node biopsy only, the upper boundary of the confidence interval for the hazard ratio for recurrence or death had to be below 1.44.
Between January 2015 and December 2021, a total of 2766 patients were enrolled across five countries. The per-protocol population included 2540 patients, of whom 1335 were assigned to undergo sentinel-node biopsy only and 1205 to undergo completion axillary lymph node dissection (dissection group). Radiation therapy including nodal target volumes was administered to 1192 of 1326 patients (89.9%) in the sentinel-node biopsy–only group and to 1058 of 1197 (88.4%) in the dissection group. The median follow-up was 46.8 months (range, 1.5 to 94.5).
Overall, 191 patients had recurrence or died. The estimated 5-year RFS was 89.7% (95% confidence interval [CI] 87.5 to 91.9) in the sentinel-node biopsy–only group and 88.7% (95% CI 86.3 to 91.1) in the dissection group, with a country-adjusted hazard ratio for recurrence or death of 0.89 (95% CI 0.66 to 1.19), which was significantly (p < 0.001) below the prespecified noninferiority margin.
Although the SENOMAC study differs from earlier studies in several aspects, the current results are in line with those of the ACOSOG Z0011 and AMAROS studies, which enrolled patients in the periods of 1999–2004 and 2001–2010. The use of radiation therapy followed national guidelines, which led to a high proportion of patients undergoing nodal field irradiation, which is the standard care in Sweden and Denmark. Thus, the results of the SENOMAC study are comparable with those of the AMAROS and OTOASOR rather than with those of the POSNOC, SINODAR-ONE, and ACOSOG Z0011.
The authors wrote that a common problem in clinical trials is the underrepresentation of older patients. Only SINODAR-ONE had an age limit for enrolment, the reported populations in previous trials have had mean ages between 54 years and 56 years, which is lower than in a typical breast cancer population. SENOMAC study enrolled a substantial number of older patients, and the median ages of 65 years in the Swedish breast cancer population and 62 years in the Danish breast cancer population support the external validity of study results.
Other prospective randomised trials evaluating the omission of completion axillary lymph node dissection have been initiated. The BOOG 2013-07 study in the Netherlands was closed prematurely owing to slow enrolment. The second randomisation of the INSEMA study in Germany had not met the target enrolment when the study closed enrolment in 2019, when its first randomisation, in which patients were assigned to sentinel-node biopsy or its omission, had reached full enrolment. The results of the POSNOC study in the UK, in which 1900 patients with clinically node-negative breast cancer with a tumour stage of T1 or T2 were randomly assigned either to axillary treatment (completion axillary lymph node dissection or axillary radiation therapy) or to no axillary treatment, are awaited.
The study was previously presented in part at the San Antonio Breast Cancer Symposium in San Antonio, TX, US on 7 December 2023.
The study was supported by grants from the Swedish Research Council, the Swedish Cancer Society, the Nordic Cancer Union, and the Swedish Breast Cancer Association.
Reference
de Boniface J, Tvedskov TF, Rydén L, et al. for the SENOMAC Trialists’ Group. Omitting Axillary Dissection in Breast Cancer with Sentinel-Node Metastases. N Engl J Med 2024;390:1163-1175.