SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 310,720 new cases of female breast cancer will be diagnosed in 2024, and about 42,250 individuals will die of the disease, largely due to metastatic recurrence.
Axillary lymph node status is a significant prognostic factor in patients with operable primary breast cancer, and is the most important predictor of recurrence and survival. Axillary lymph node dissection is used for staging of breast cancer and treatment of the axilla, if necessary. It is estimated that approximately 20-25% of women will have positive axillary lymph nodes when their breast cancer is detected through screening, whereas those with symptomatic early breast cancer have a 30-40% chance of having positive axillary nodes.
Axillary lymph node dissection is indicated for patients with proven axillary disease preoperatively or with a positive sentinel node biopsy. However, the landscape of breast cancer management has undergone significant evolution in recent years, particularly regarding the role of axillary surgery in node-negative disease. Among patients with clinically node negative breast cancer and 1-2 sentinel node metastases undergoing breast-conserving surgery and whole-breast radiation therapy, studies have shown that omission of axillary lymph node dissection did not have an impact on Overall Survival. However, questions remained about the necessity of completion axillary lymph node dissection in cases of sentinel-node metastases.
The SENOMAC trial was conducted in a large cohort of patients, to validate results from previous trials by comparing sentinel-node biopsy only with completion axillary lymph node dissection, in patients with clinically node-negative breast cancer and sentinel-lymph-node metastases. This study specifically focused only on patients with sentinel node macrometastases and extended eligibility criteria to include underrepresented subgroups such as those patients undergoing mastectomy, those with sentinel-node extracapsular extension or T3 tumors (tumor size more than 5 cm in the largest dimension), and men, thus broadening its applicability and relevance to real-world clinical scenarios.
In this ongoing, Phase III, international, randomized, non-inferiority trial which included 2540 patients (N=2540) from 5 European countries, 1335 had been assigned to undergo sentinel-node biopsy only with no further axillary surgery and 1205 to undergo completion axillary lymph node dissection (dissection group). Eligible patients had clinically node-negative breast cancer, with a tumor stage of T1, T2, or T3 (tumor size, T1, 2 cm or less; T2, 2-5 cm; and T3, more than 5 cm in greatest dimension) and one or two sentinel-node macrometastases (metastasis size, more than 2 mm in the greatest dimension). Patients who had suspicious but nonpalpable axillary lymph nodes on ultrasonography were eligible even if metastasis was confirmed by fine-needle aspiration. Adjuvant treatments and radiation therapy were administered in accordance with national guidelines, ensuring consistency in the approach to postoperative care across study participants. Whole-breast radiation therapy after breast-conserving surgery was mandatory, and radiation therapy including nodal target volumes was administered to 89.9% in the sentinel node biopsy-only group and to 88.4% in the dissection group. The median patient age was 61 yrs, approximately 64% had breast conserving surgery, 36% had mastectomy and 6% had T3 tumors. The Primary end point was Overall Survival (OS), and prespecified Secondary end points were Recurrence-Free Survival (RFS), Breast Cancer-Specific Survival, and Patient-Reported Outcomes. The median follow-up was 46.8 months.
Results from the trial demonstrated that the omission of completion axillary lymph node dissection was noninferior to the more extensive surgery in terms of Recurrence-Free Survival (RFS), and the estimated 5-year Recurrence-Free Survival was similar in the two treatment groups. The estimated 5-year RFS was 89.7% in the sentinel-node biopsy-only group and 88.7% in the dissection group, with a country-adjusted HR for recurrence or death of 0.89, which was significantly below the prespecified noninferiority margin (P<0.001).
These findings align with previous trials such as ACOSOG Z0011 and AMAROS, which also questioned the necessity of completion axillary lymph node dissection in certain patient populations. Yet, the SENOMAC trial offers distinct contributions. It included patients with T3 tumors and allowed for mastectomy, thus addressing gaps in previous research. Furthermore, the trial enrolled a substantial number of older patients, enhancing the generalizability of its results. Additionally, the trial adds to the growing body of evidence questioning the necessity of axillary surgery in diverse clinical scenarios, particularly in the era of advanced diagnostic imaging and tailored adjuvant therapies.
While the study has limitations, such as variations in radiation therapy practices and the predominantly luminal subtype of breast cancer among enrolled patients, its robust methodology and outcomes provide valuable insights. The results support the notion that axillary surgery may be unnecessary for certain patients with early-stage breast cancer and sentinel-node metastases, especially when combined with appropriate adjuvant therapies.
The researchers concluded that the omission of complete axillary lymph node dissection was noninferior to the more extensive surgery in patients with clinically node-negative breast cancer who had sentinel-node macrometastases, most of whom received nodal radiation therapy. The SENOMAC trial represents a significant milestone in advancing the evidence base and shaping clinical guidelines for the management of early-stage breast cancer with sentinel-node metastases.
Omitting Axillary Dissection in Breast Cancer with Sentinel-Node Metastases. de Boniface J, Tvedskov TF, Rydén L, et al. For the SENOMAC Trialists Group. N Engl J Med 2024;390:1163-1175.
