In the field of surgical treatment for breast cancer, the trend of "de-escalation" in axillary management has become a consensus. Although studies such as ACOSOG Z011 and AMAROS have laid the foundation for exempting axillary lymph node dissection (ALND) in patients with positive sentinel lymph nodes (SLN), controversy remains in clinical practice regarding whether it is safe to exempt ALND for patients undergoing total mastectomy, patients with large tumors (T3), and those with macrometastases. At this conference, Professor Jana de Boniface from Karolinska Institutet and Capio St. Göran Hospital in Sweden presented the highly anticipated latest results of the SENOMAC trial, a randomized controlled study focusing on survival data and patient-reported arm complications after exempting ALND in patients with SLN macrometastases.Main Content
01 Background and Challenges: Bottlenecks in the Era of Axillary Management
“Subtraction” Over the past few decades, one of the core themes in breast cancer surgical treatment has been how to minimize postoperative complications while ensuring oncological safety. Professor Jana de Boniface pointed out at the beginning of her speech that although traditional completion axillary lymph node dissection (ALND) provides precise pathological staging, the resulting upper limb lymphedema, chronic pain, and functional impairment significantly affect patients’ quality of life. Although the early ACOSOG Z011 and AMAROS studies proved that omitting ALND does not affect survival in SLN-positive patients receiving breast-conserving surgery and radiotherapy, these studies have obvious limitations: first, insufficient statistical power; second, the exclusion of a large number of mastectomy patients; and third, very minimal coverage of large tumor populations such as T3. Therefore, there is an urgent clinical need for a Phase III randomized controlled trial that includes mastectomy patients, covers a wider range of tumor stages, and possesses sufficient statistical power.
02 Study Design: The Rigorous Layout of the SENOMAC Trial
The SENOMAC study (NCT02240472) is a multinational, multicenter, randomized non-inferiority Phase III clinical trial designed to verify the safety of exempting ALND in breast cancer patients with SLN macrometastases. • Inclusion Criteria: Patients with invasive breast cancer, clinical stage cT1-T3, clinically node-negative (cN0) axilla; sentinel lymph node biopsy (SLNB) confirming the presence of 1-2 macrometastases. • Exclusion Criteria: Patients who previously received neoadjuvant therapy, have distant metastasis, or have a history of previous ipsilateral breast/axillary surgery. • Randomization: Patients were randomly assigned in a 1:1 ratio to either the ALND group (completion axillary lymph node dissection) or the ALND-exempt group (SLNB only). • Treatment Plan: Patients in both groups received standard adjuvant therapy after surgery, including radiotherapy and systemic therapy (such as endocrine therapy, chemotherapy, targeted therapy, etc.). Notably, the study allowed the enrollment of mastectomy patients, which addressed the shortcomings of the Z011 study. • Endpoint Settings: The primary endpoint was overall survival (OS), with a preset non-inferiority margin of 2.5%, meaning the upper limit of the 95% confidence interval (CI) for the hazard ratio (HR) must be below 1.44. Secondary endpoints included recurrence-free survival (RFS), breast cancer-specific survival (BCSS), and patient-reported outcomes (PROs). The study was launched in 2015 and completed recruitment in December 2021, enrolling a total of 2,766 intent-to-treat (ITT) patients, with a total of 2,540 patients in the per-protocol (PP) population.
03 Baseline Characteristics: Covering More Challenging Clinical Subgroups
Professor Jana de Boniface analyzed the baseline characteristics of the PP population in detail. The median age of the subjects was 61 years (range 20-94 years). The study successfully included subgroups that were less represented in previous studies: • T Stage: 6% (n=147) of patients had T3 tumors, which is the highest proportion in similar studies to date. • Surgical Method: 36% (n=919) of patients underwent total mastectomy, providing excellent representation. • Pathological Type: The ratio of ductal to lobular carcinoma was consistent with clinical distribution. • Molecular Subtype: 87% were ER-positive, HER2-negative Luminal-type breast cancer. • Lymph Node Status: 85% of patients had only 1 SLN macrometastasis, and 34.3% of patients had extracapsular extension (ENE). In the ALND group, the median number of lymph nodes dissected was 15, while in the exempt group, it was only 2. The results showed that 34.5% of patients in the ALND group were found to have additional non-sentinel lymph node metastases, of which 12.5% had a high lymph node burden (≥4 positive lymph nodes).
04 Oncological Safety Data: Highly Overlapping Survival Curves
The results of the primary endpoint OS analysis were encouraging. The median follow-up time reached the required standard (203 deaths recorded, satisfying the requirement of 190 cases for statistical power). • OS Data: The 5-year OS rate was 93.4% in the ALND group and 94.4% in the ALND-exempt group. • Statistical Evaluation: The hazard ratio (HR) was 0.89 (95% CI: 0.68-1.17). The upper limit of the HR confidence interval, 1.17, was far below the preset non-inferiority margin of 1.44, confirming the non-inferiority of exempting ALND compared to standard ALND. • Subgroup Analysis: Whether in the T3 tumor subgroup or the mastectomy subgroup, the HR values showed excellent consistency, with no negative safety signals observed. Regarding secondary survival endpoints: • RFS Data: The 5-year RFS rates for the ALND and exempt groups were 90.2% and 90.8%, respectively (HR 0.93). • BCSS Data: The 5-year BCSS was 97.2% and 97.9%, respectively. There was no statistical difference between the two groups in terms of local recurrence, regional recurrence, and distant metastasis rates. Professor Jana de Boniface pointed out that although about 13% of patients in the exempt group might have left behind untreated non-sentinel positive lymph nodes, these potential lesions did not translate into an actual survival disadvantage. This may benefit from the coverage provided by modern radiotherapy techniques and potent systemic therapy.
05 Quality of Life and Arm Complications: Intuitive Manifestation of Patient Benefit
A major highlight of the SENOMAC study is its detailed collection of patient-reported outcomes (PROs). The study used scales such as EORTC QLQ-C30, B23, and LymICF to evaluate patients at multiple time points: early postoperatively, 1 year, 3 years, and 5 years, with response rates as high as 81%-83%. • Global Health Status and Quality of Life: In the early postoperative period and at year 3, the scores of the ALND-exempt group were significantly better than those of the ALND group (P<0.05). • Upper Limb Symptom Scores: The difference between the two groups was most pronounced here. Higher scores represent more severe symptoms. The ALND group consistently scored at least 10 points higher than the exempt group during follow-up. This difference persisted through 1 year and 5 years post-surgery, with no trend toward relief. • Proportion of Severe Symptoms: Five years after surgery, 12.6% of patients in the ALND group reported severe or very severe arm problems, compared to only 3.6% in the exempt group. These data strongly demonstrate that exempting ALND is not only oncologically safe but also possesses a decisive advantage in long-term functional recovery and reduction of iatrogenic injury.
06 Expert Comments and Clinical Practice Recommendations
In her summary, Professor Jana de Boniface emphasized that the SENOMAC study provides the highest level of evidence-based medical support for the de-escalation of axillary management in patients with SLN macrometastases, especially for mastectomy and T3 patients. However, clinical application should follow these boundary conditions:
- Synergy with Regional Radiotherapy: Most patients in this study received standard adjuvant radiotherapy. The safety prerequisite for exempting ALND is the “safety net” provided by high-quality radiotherapy and systemic therapy.
- Exclusion of Neoadjuvant Therapy: It must be clarified that the study population consisted of primary patients undergoing direct surgery. For patients who turn node-negative (ycN0) after neoadjuvant therapy, axillary management strategies should refer to other studies (such as S1207, etc.).
- Future Exploration: The research team is currently conducting the SENOMAC-Ultra trial to further explore the possibility of axillary de-escalation in clinically node-positive (cN+) patients after systemic therapy. Additionally, whether ALND and axillary radiotherapy can be omitted simultaneously after mastectomy still requires answers from follow-up studies such as T-REX.
Conclusion
The release of the SENOMAC study marks another major victory for “minimalism” in breast cancer axillary surgery. The data accurately answer clinical doubts: in the case of 1-2 sentinel lymph node macrometastases, omitting ALND will not reduce the 5-year survival rate of patients but will significantly improve upper limb function. This is not only a change in surgical approach but also the practice of the “patient-centered” medical philosophy.
