SOUND Trial – Comprehensive Journal Club Q&A (Study Guide)

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • Framing the Question:
    • Clinical question:
      • In women with invasive breast cancer ≤ 2 cm, clinically node-negative and axillary ultrasound (AUS) negative:
        • Is omitting axillary surgery non-inferior to sentinel lymph node biopsy (SLNB):
          • For 5-year distant disease-free survival (DDFS)? JAMA Network
    • Why this matters now:
      • ACOSOG Z0011:
        • Showed no therapeutic benefit for ALND over less surgery (SLNB alone):
          • The next logical step tests whether staging itself (SLNB) can be omitted:
            • When it won’t change adjuvant plans:
              • Reducing morbidity without compromising oncologic safety JAMA Network
  • Study Design Essentials:
    • Design:
      • Prospective, multicenter, phase 3 non-inferiority RCT:
        • 1:1 randomization to:
          • No axillary surgery vs SLNB
      • Primary endpoint:
        • 5-yr distant disease free survival (DDFS) (ITT)
      • Secondary:
        • Disease free survival (DFS)
        • Overal survival (OS)
        • Cumulative incidence of distant and axillary recurrences, and adjuvant treatment recommendations JAMA Network
    • Setting and timeline:
      • 18 hospitals in:
        • Italy, Spain, Switzerland, and Chile
      • Enrollment Feb 2012 to Jun 2017
      • Analysis 2022 to 2023 JAMA Network
    • Eligibility (PICO):
      • Women of any age
      • Tumor ≤ 2 cm
      • cN0 by exam
      • Negative AUS:
        • Suspicious nodes required cytology to exclude metastasis
      • Breast-conserving surgery (BCS) common, with radiotherapy permitted:
        • Including partial breast and IORT
      • ITT N = 1,405:
        • SLNB 708
        • Omit 697
      • Median age 60
      • Median tumor 1.1 cm
      • ~ 88% ER+ / HER2 –  JAMA Network
    • AUS as a triage tool:
      • Despite variable sensitivity in literature:
        • Negative AUS in the SOUND trial effectively ruled out heavy nodal burden:
          • SLNB arm had 13.7% any nodal metastasis but only 0.6% had ≥ 4 positive nodes
          • Axillary recurrence 0.4% at 5 years in both arms JAMA Network
  • Statistics You Should Know:
    • Non-inferiority setup:
      • Primary analysis ITT:
        • NI margin 2.5% for 5-year DDFS; HR with 90% CI and one-sided NI P-value
        • Assumed 5-year DDFS ≈ 96.5%:
          • Observed outcomes were higher, increasing power to show NI if risks are truly similar JAMA Network
    • Follow-up:
      • Median follow-up for disease assessment 5.7 years in both arms JAMA Network
  • Results (with absolute numbers):
    • Primary endpoint (DDFS):
      • 5-year DDFS: 
        • 97.7% (SLNB) vs 98.0% (No surgery):
          • HR 0.84, 90% CI 0.45–1.54; P for non-inferiority = 0.02:
            • Two-arm difference not significant by log-rank (P=0.67) JAMA Network
    • Secondary endpoints:
      • 5-year DFS: 
        • 94.7% (SLNB) vs 93.9% (No surgery), P=0.30.
      • 5-year OS: 
      • Regional control (events are rare):
        • 5-year cumulative axillary recurrence = 0.4% in each arm (Gray P=0.91)
      • Locoregional relapse: 
      • Absolute event counts:
        • SLNB: 
          • 13 distant metastases (1.8%), 21 deaths (3.0%).
        • No surgery: 
          • 14 distant metastases (2.0%), 18 deaths (2.6%) JAMA Network
      • Adjuvant therapy impact:
        • No material differences in systemic therapy or RT use between arms:
          • Supporting that, in this AUS-negative group:
            • Pathologic nodal information didn’t drive adjuvant decisions JAMA Network
        • Radiotherapy details:
          • All RT options allowed, including partial breast / IORT
          • Notably, 114 patients (16.3%) in the no-surgery arm received ELIOT (full-dose or boost)
          • Despite this heterogeneity:
            • Axillary failures stayed 0.4% at 5 years in both arms JAMA Network
    • How often was SLNB positive?
      • 13.7% had any nodal metastasis in the SLNB arm (micro + macro metasteses)
      • Heavy burden (≥ 4 nodes) was 0.6% JAMA Network
  • Interpretation and External Context:
    • Plain-English bottom line:
      • For AUS-negative, ≤ 2 cm, cN0 tumors planned for BCS + RT:
        • Skipping SLNB is non-inferior for 5-yearr DDFS:
          • With no increase in axillary failures and no detectable survival trade-off – and you avoid the morbidity of axillary surgery JAMA Network
  • How does the SOUND trial line up with INSEMA trial (NEJM 2024/2025)?:
    • INSEMA broadened to T1 to T2 ≤ 5 cm BCT patients and used invasive DFS as the primary endpoint:
  • Generalizability – who are “SOUND-like” in clinic?
    • Mostly small (T1 / ≤ 2 cm), HR+ / HER2 –  tumors, negative AUS, upfront BCS + RT:
      • Adjuvant decisions unlikely to change with nodal micrometastatic information:
        • Authors estimate ~ 25% of all breast cancer (BC) cases may fit these criteria JAMA Network
  • Potential practice impact:
    • With ~ 2.3 M new BC cases / year, ~ 500,000 patients globally could avoid axillary surgery:
      • Improving early arm function and reducing lymphedema risk without oncologic compromise JAMA Network
  • Limitations and Caveats:
    • Low-risk enrichment:
      • Mostly small, ER+ / HER2- tumors:
        • Short-to-mid-term risk low:
    • Adjuvant therapy analysis not powered:
      • Differences in systemic / RT nuances might be too small to detect:
        • Adjuvant-recommendation analysis was secondary JAMA Network
    • Late trial registration noted:
      • Registered after enrollment began; protocol / statistical plan were peer-review-published, and authors state no interim looks occurred; still worth acknowledging JAMA Network
    • Radiation heterogeneity (including IORT):
      • Permissive RT techniques (e.g., ELIOT) could theoretically influence local / axillary outcomes:
        • Nonetheless axillary failure remained 0.4% in both arms JAMA Network
    • Not for neoadjuvant or mastectomy:
      • SOUND trial did not test patients planned for neoadjuvant systemic therapy or mastectomy without conventional whole-breast RT:
    • Young HR+ / HER2- patients (Rx-PONDER context):
      • In some premenopausal HR+ / HER2- patients:
        • Nodal positivity can still influence chemo or endocrine therapy type / duration:
          • If nodal information truly changes systemic therapy:
  • Apply in Clinic” Checklist (What to document):
    • Who qualifies for omission (SOUND-style)?
      • Tumor ≤ 2 cm
      • cN0 on exam
      • Negative AUS (suspicion cleared by cytology)
      • Upfront BCS + RT planned
      • Adjuvant plan won’t change with nodal micro-staging
      • Document shared decision-making:
    • Who should still get SLNB?
      • Neoadjuvant candidates (different evidence base)
      • Mastectomy without standard whole-breast RT
      • Cases where nodal status alters chemotherapy / Endocrine therapy decisions:
        • Younger HR+ / HER2-
      • AUS positive / suspicious nodes not cleared by cytology JAMA Network
    • How to counsel about risk:
      • Explain that with negative AUS, the chance of heavy nodal disease is very low (≥ 4 nodes 0.6% in SLNB arm), and axillary recurrence at 5 years ~ 0.4% without surgery – the same as with SLNB JAMA Network
    • Quick Numbers Box:
      • ITT N=1,405 (708 SLNB; 697 No surgery):
      • 5-yr DDFS: 
        • 97.7% vs 98.0% (HR 0.84; 90% CI 0.45–1.54; NI P=0.02) JAMA Network
      • 5-yr DFS: 
        • 94.7% vs 93.9% (P=0.30)
      • 5-yr OS: 98.2% vs 98.4% (P=0.72) JAMA Network
      • Axillary recurrence (5 yrs): 
        • 0.4% vs 0.4%
      • SLN+ (any):
        • 13.7%
      • ≥ 4 nodes:
      • RT nuance: 
        • 16.3% of omission arm received ELIOT (full-dose / boost) JAMA Network
  • Discussion Starters:
    • Endpoint choice: 
      • Was DDFS the best primary endpoint versus iDFS or regional failure:
        • SOUND chose DDFS to reflect oncologic safety independent of local RT nuances JAMA Network
    • Imaging vs surgery: 
      • Does negative AUS sufficiently replace pathologic staging in 2025 clinics, especially with modern systemic therapy selection? JAMA Network
    • RT heterogeneity: 
      • Could permissive RT (including IORT) have “rescued” regional control?
        • If so, why are axillary failures identically rare in both arms? JAMA Network
    • Younger HR+ / HER2- patients: 
      • Where do you draw the line for still doing SLNB given Rx-PONDER-type considerations? JAMA Network
    • Global impact: 
      • How would your clinic operationalize AUS-triaged omission (workflow, sonographer QA, documentation templates)? JAMA Network
    • How SOUND Aligns with INSEMA (one-paragraph takeaway):
      • INSEMA (NEJM 2024/2025) randomized cN0 BCT patients (T1 to T2 ≤ 5 cm) to omission vs SLNB:
        • Invasive DFS primary outcome was non-inferior, with less arm morbidity in the omission group
      • Together with SOUND (DDFS primary, ≤ 2 cm, AUS-negative), these trials support AUS-triaged omission of SLNB in carefully selected early breast cancers planned for BCS + RT New England Journal of Medicine+2PubMed+2

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Published by Rodrigo Arrangoiz MS, MD, FACS, FSSO

My name is Rodrigo Arrangoiz I am a breast surgeon/ thyroid surgeon / parathyroid surgeon / head and neck surgeon / surgical oncologist that works at Center for Advanced Surgical Oncology in Miami, Florida. I was trained as a surgeon at Michigan State University from (2005 to 2010) where I was a chief resident in 2010. My surgical oncology and head and neck training was performed at the Fox Chase Cancer Center in Philadelphia from 2010 to 2012. At the same time I underwent a masters in science (Clinical research for health professionals) at the University of Drexel. Through the International Federation of Head and Neck Societies / Memorial Sloan Kettering Cancer Center I performed a two year head and neck surgery and oncology / endocrine fellowship that ended in 2016. Mi nombre es Rodrigo Arrangoiz, soy cirujano oncólogo / cirujano de tumores de cabeza y cuello / cirujano endocrino que trabaja Center for Advanced Surgical Oncology en Miami, Florida. Fui entrenado como cirujano en Michigan State University (2005 a 2010 ) donde fui jefe de residentes en 2010. Mi formación en oncología quirúrgica y e n tumores de cabeza y cuello se realizó en el Fox Chase Cancer Center en Filadelfia de 2010 a 2012. Al mismo tiempo, me sometí a una maestría en ciencias (investigación clínica para profesionales de la salud) en la Universidad de Drexel. A través de la Federación Internacional de Sociedades de Cabeza y Cuello / Memorial Sloan Kettering Cancer Center realicé una sub especialidad en cirugía de cabeza y cuello / cirugia endocrina de dos años que terminó en 2016.

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