- Design and who was included:
- Multicenter randomized contral trial (RCT):
- Setting:
- Sweden, Denmark, Germany, Greece, Italy
- Patients:
- cN0, cT1 to cT3 tumors with 1 to 2 SLN macrometastases:
- BCS or mastectomy allowed
- Extra capsular extension (ECE) and cT3 permitted
- SENOMAC did allow patients who had SLNB before neoadjuvant systemic therapy (NAST) to be enrolled if cN0 and with ≤ 2 SLN macrometastases:
- Randomization was recommended before starting NAST
- cN0, cT1 to cT3 tumors with 1 to 2 SLN macrometastases:
- Randomized SLNB only vs cALND:
- Adjuvant therapy and radiation therapy (RT) per national guidelines
- Size and surgery type:
- N=2766 enrolled:
- Per-protocol N=2540:
- SLNB 1335
- cALND 1205
- Mastectomy ≈ 36% in each arm:
- SLNB 490 / 1335
- cALND 430 / 1205
- Per-protocol N=2540:
- N=2766 enrolled:
- Radiation usage (key to applicability):
- RT including nodal volumes given to ~ 90% in both arms:
- SLNB 89.9%; cALND 88.4%
- Quality assessment (QA) check showed:
- 99.3% concordance for breast / chest-wall fields and 96.6% for nodal targets
- RT including nodal volumes given to ~ 90% in both arms:
- Setting:
- Multicenter randomized contral trial (RCT):
- Endpoints and follow-up:
- Primary endpoint = OS (pending):
- In 2020 the Data and Safety Monitoring Board (DSMB):
- Switched the primary endpoint to overall survival (OS):
- To declare non-inferiority on OS, the trial needs 190 deaths:
- At last analysis there weren’t enough events:
- So OS is not yet formally tested
- At last analysis there weren’t enough events:
- To declare non-inferiority on OS, the trial needs 190 deaths:
- Switched the primary endpoint to overall survival (OS):
- They still report 5-yr OS estimates:
- ≈ 92.9% vs 92.0%
- In 2020 the Data and Safety Monitoring Board (DSMB):
- Reported prespecified secondary endpoint:
- RFS; NI margin HR upper bound < 1.44
- Median follow-up:
- 46.8 months
- Primary endpoint = OS (pending):
- Results (per-protocol)
- 5-yr RFS:
- 89.7% (SLNB) vs 88.7% (cALND):
- HR 0.89 (95% CI 0.66–1.19) → non-inferior
- 89.7% (SLNB) vs 88.7% (cALND):
- 5-yr OS:
- 92.9% (SLNB) vs 92.0% (cALND)
- Breast cancer (BC)-specific survival:
- 97.1% (SLNB) vs 96.6% (cALND)
- Regional recurrences were rare:
- Axilla alone in 3 patients
- Axilla + infraclavlavicular 2 patients
- Supraclavicular / infraclavicualar, internal mammary nodes (IMN), parasternal 1 each (locations unknown in 4)
- Local and distant events similar between arms
- Stage migration:
- Among primary-surgery patients,:
- cALND upstaged more often (pN2 – 9.9%, pN3 – 3.0%) vs SLNB-only (pN2 – 0.5%):
- Without outcome benefit
- Additional non-SLN metastasis on cALND in 34.5% overall:
- If 1 SLN macrometatases:
- 31.3% had more positive nodes
- If 2 macrometastases:
- 51.3% had more positive nodes
- If 1 SLN macrometatases:
- cALND upstaged more often (pN2 – 9.9%, pN3 – 3.0%) vs SLNB-only (pN2 – 0.5%):
- Among primary-surgery patients,:
- 5-yr RFS:
- Toxicity / PROs:
- At 1 year:
- Randomized SENOMAC PRO analysis:
- SLNB-only patients reported less arm pain / symptoms and better function than cALND
- Randomized SENOMAC PRO analysis:
- Post-hoc (Lancet Oncol 2024):
- Focused on abemaciclib eligibility:
- To prevent 1 iDFS event at 5 yrs via identifying ≥ pN2-pN3 with cALND:
- ~ 104 cALNDs would be needed:
- Causing severe / very severe arm dysfunction in ~ 9 / 104 at 1 year:
- Discourages ALND purely to find pN2-pN3 for CDK4/6 indication
- Causing severe / very severe arm dysfunction in ~ 9 / 104 at 1 year:
- ~ 104 cALNDs would be needed:
- To prevent 1 iDFS event at 5 yrs via identifying ≥ pN2-pN3 with cALND:
- Focused on abemaciclib eligibility:
- At 1 year:
- Why it matters (esp. mastectomy):
- ≈ 36% mastectomy:
- With comprehensive nodal RT common:
- Omitting cALND preserved control and survival and minimized arm morbidity:
- Supports SLNB-only + RNI / PMRT for 1 to 2 SLN macrometastases after mastectomy
- Omitting cALND preserved control and survival and minimized arm morbidity:
- With comprehensive nodal RT common:
- ≈ 36% mastectomy:
- One-liner:
- SENOMAC shows that in cN0 patients with 1 to 2 SLN macrometastases including mastectomy cases:
- SLNB – only with planned nodal RT is non-inferior to cALND for oncologic outcomes and substantially reduces arm morbidity
- SENOMAC shows that in cN0 patients with 1 to 2 SLN macrometastases including mastectomy cases:
- Summary:
- Why this trial had what it adds:
- Prior trials (ACOSOG Z0011, AMAROS) had power / RT-field uncertainties and underrepresented subgroups
- SENOMAC purposely broadened eligibility (included mastectomy, ECE, T3, and men) to validate omission of cALND in a larger, more representative cohort
- Consistency with prior evidence:
- Findings align with AMAROS and OTOASOR (no oncologic advantage to cALND; morbidity higher with ALND)
- Ongoing / related trials (e.g., POSNOC; INSEMA’s second randomization) are noted for context
- Generalizability:
- Age distribution mirrors real-world Nordic populations, supporting external validity
- Inclusion of substantial mastectomy volume improves applicability beyond BCS-only settings
- RT practice in the trial:
- Adjuvant RT followed national guidelines:
- ~ 90% received nodal RT
- Data entry matched actual RT plans well (good concordance):
- Though granular nodal-level dose / field details were not yet available at reporting
- Adjuvant RT followed national guidelines:
- Limitations called out by authors:
- Shorter follow-up relative to late-recurring luminal cancers
- Very few men enrolled (n≈10), limiting sex-specific analyses
- Trial under-enrolled vs target:
- But event counts and narrow CIs yield precise estimates for NI
- Higher withdrawal in the ALND arm, though unlikely to affect conclusions given size and balance
- Bottom line :
- For cN0 cT1 to cT3 patients with 1 to 2 SLN macrometastases who receive modern systemic therapy and (typically) comprehensive nodal RT:
- Omitting cALND maintains disease control with less arm morbidity
- Results support replacing routine cALND with SLNB ± RNI / PMRT:
- While acknowledging the need for longer follow-up and more granular RT-field reporting
- For cN0 cT1 to cT3 patients with 1 to 2 SLN macrometastases who receive modern systemic therapy and (typically) comprehensive nodal RT:
- Why this trial had what it adds:
Rodrigo Arrangoiz MS, MD, FACS, FSSO 