Rodrigo Arrangoiz MS, MD, FACS, FSSO

Breast Cancer Risk Factors

October 15, 2025October 14, 2025 Rodrigo Arrangoiz MS, MD, FACS, FSSO

Atypical ductal hyperplasia (ADH):
- Proliferative breast lesions:
  - Such as ADH confer a substantial increase in breast cancer risk of:
    - 4 to 5-fold when compared to the general population (RR 3.7-5.3)
In post-menopausal women a higher BMI and / or peri-menopausal weight gain:
- Is associated with a higher risk of breast cancer
- In the Nurses’ Health Study:
  - Women who gained 10 kg or more after menopause had a greater risk of developing breast cancer compared to those who maintained their weight (RR 1.18, 95% CI 1.03-1.35)
After an average of 10 years of follow-up in the Women’s Health Study:
- Higher daily alcohol consumption was associated with an increase in invasive breast cancer risk (RR 1.43, 95% CI 1.02-2.02 for ≥ 30g alcohol (2 to 3 drinks vs. none)
Based on epidemiological data from 52 studies, risk ratios for breast cancer increase with the number of affected first-degree relatives:
- 1.8 (99% CI 1.7-1.9), 2.9 (2.4-3.6), and 3.9 (2.0-7.5) respectively for one, two, and three or more affected relatives vs. none
There is no definitive evidence that caffeine intake is associated with breast cancer risk
References
- Smart CE, Furnival CM, Lakhani SR. Chapter 17: High-Risk Lesions: ALH/LCIS/ADH. In: Kuerer HM, ed. Kuerer’s Breast Surgical Oncology. New York, NY: McGraw-Hill; 2010.
- Eliassen AH, Colditz GA, Rosner B, Willett WC, Hankinson SE. Adult weight change and risk of postmenopausal breast cancer. JAMA. 2006;296(2):193-201.
- Zhang SM, Lee IM, Manson JE, Cook NR, Willett WC, Buring JE. Alcohol consumption and breast cancer risk in the Women’s Health Study. Am J Epidemiol. 2007;165(6):667-676.
- Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58,209 women with breast cancer and 101,986 women without the disease. Lancet. 2001;358(9291):1389-1399.
- Ganmaa D, Willett WC, Li TY, et al. Coffee, tea, caffeine and risk of breast cancer: a 22-year follow-up. Int J Cancer. 2008;122(9):2071-2076.

#Arrangoiz #BreastSurgeon #Surgeon #CancerSurgeon

SOUND and INSEMA Trials for Omitting Sentinel Lymph Node Biopsy in Breast Cancer

October 14, 2025September 22, 2025 Rodrigo Arrangoiz MS, MD, FACS, FSSO

Recent high-quality randomized trials have provided strong evidence supporting the:
- Omission of sentinel lymph node biopsy (SLNB) in select patients with:
  - Early-stage, clinically node-negative breast cancer
The SOUND and INSEMA trials both demonstrated that:
- In patients with small tumors (≤ 2 cm in SOUND; ≤ 5 cm in INSEMA) and negative axillary imaging:
  - Omission of SLNB is noninferior to SLNB in terms of:
    - Invasive disease-free survival (INSEMA) and distant disease-free survival (SOUND):
      - With very low rates of axillary recurrence and improved quality of life due to fewer surgical complications such as lymphedema and reduced arm mobility
Guidelines from the American Society of Clinical Oncology (ASCO) and Ontario Health (Cancer Care Ontario):
- Now recommend omitting SLNB in women aged 70 or older with:
  - Clinically node-negative, hormone receptor–positive, HER2-negative tumors who will receive endocrine therapy:
    - As supported by the Society of Surgical Oncology Choosing Wisely campaign
- For younger or higher-risk patients:
  - SLNB remains standard unless ongoing or future trials further expand the eligible population
According to a study published in JAMA Oncology, the following conclusion was reached:
- In this randomized clinical trial, omission of axillary surgery was noninferior to SLNB in patients with small breast cancer (BC) and a negative result on ultrasonography of the axillary lymph nodes
- These results suggest that patients with these features can be safely spared any axillary surgery whenever the lack of pathological information does not affect the postoperative treatment plan
In summary:
- Omission of SLNB is now supported for older women with low-risk, node-negative breast cancer and for select patients with small tumors and negative axillary imaging, provided that the lack of nodal pathological information does not alter adjuvant therapy decisions
- Ongoing trials:
  - BOOG 2013-08, NAUTILUS:
    - Will further clarify the boundaries of safe omission
References:
- Axillary Surgery in Breast Cancer — Primary Results of the INSEMA Trial. Reimer T, Stachs A, Veselinovic K, et al. The New England Journal of Medicine. 2024;. doi:10.1056/NEJMoa2412063.
- Sentinel Lymph Node Biopsy vs No Axillary Surgery in Patients With Small Breast Cancer and Negative Results on Ultrasonography of Axillary Lymph Nodes: The SOUND Randomized Clinical Trial. Gentilini OD, Botteri E, Sangalli C, et al. JAMA Oncology. 2023;9(11):1557-1564. doi:10.1001/jamaoncol.2023.3759.
- Management of the Axilla in Early-Stage Breast Cancer: Ontario Health (Cancer Care Ontario) and ASCO Guideline. Brackstone M, Baldassarre FG, Perera FE, et al. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2021;39(27):3056-3082. doi:10.1200/JCO.21.00934.
- Omitting Axillary Staging in Selected Patients: Rationale of Choosing Wisely in Breast Cancer Treatment. Grossi S, Le J, Armani A. Surgery. 2023;174(2):413-415. doi:10.1016/j.surg.2023.03.023.

High Dose vs Low Dose Cisplatin in Concurrent Chemoradiation for Locally Advanced Head and Neck Squamous Cell Carcinomas

October 13, 2025October 5, 2025 Rodrigo Arrangoiz MS, MD, FACS, FSSO

ConCERT Phase III Trial (ASCO 2022):
- Design:
  - Randomized, multicenter, definitive treatment of locally advanced HNSCC
- Findings:
  - Weekly 40 mg/m² was non-inferior to 100 mg/m² every 3 weeks in 2-year locoregional control:
    - 60.9% vs 57%, within a 10% non-inferiority margin
  - Better tolerance:
    - Fewer severe toxicities
    - Fewer hospitalizations
    - Fewer treatment interruptions with the weekly regimen
  - No significant differences in OS or PFS after ~ 26 months follow-up
Earlier Small Randomized and Retrospective Studies:
- Tsan et al. (2012) (Phase III, ~ 55 patients):
  - 100 mg/m² every 3 weeks had higher compliance (more patients achieved ≥ 200 mg/m² cumulative dose) and lower acute toxicity than weekly 40 mg/m²
- Mashhour et al. (2020):
  - Compared weekly 30 mg/m² vs 100 mg/m² every 3 weeks:
    - Weekly arm:
      - Less acute toxicity
      - Improved compliance
      - However, loco‑regional control was lower in weekly arm (57.6% vs 72.8%)
- Singh et al. (2022, retrospective):
  - 3‑weekly arm achieved better OS and DFS, higher completion of cumulative dose:
    - But had more toxicities and treatment breaks
- Meta‑Analysis and Cumulative Dose Importance
  Pooled analysis (Canada / Italy):
  - Higher cumulative cisplatin exposure (≥ 200 mg/m²) correlated with significantly better overall survival, especially in HPV-negative HNSCC:
    - 3-year OS:
      - 72% vs 60% vs 52%, p < 0.001
- Ongoing and Investigational Trials:
  - NRG‑HN009 (Phase II/III, recruiting):
    - Comparing toxicity and non-inferiority in OS between weekly 40 mg/m² vs 100 mg/m² every 3 weeks, stratified by HPV status
  - CISLOW Trial (Netherlands, protocol published 2023):
    - Focuses on patients with low skeletal muscle mass, comparing compliance and
      Cisplatin Dose-Limiting Toxicity (CDLT) risk between weekly and triweekly regimens
  - Fractionated cisplatin schedules (2024) are also being explored, e.g., splitting 100 mg/m² over 4 days to improve tolerability

Bottom Line (as of August 2025):
- High-dose (100 mg/m² q 3weeks):
  - Remains the standard based on long-term efficacy, especially where achieving ≥ 200 mg /m² is feasible and toxicities can be managed
- Weekly 40 mg/m² has emerged as a viable alternative:
  - Not inferior in locoregional control per ConCERT, with better tolerability, particularly for patients with comorbidities or reduced treatment tolerance
- Maintaining an adequate cumulative cisplatin dose (≥ 200 mg/m²) is crucial for optimal oncologic outcomes
Ongoing randomized trials (e.g., NRG-HN009, CISLOW) should provide clearer guidance soon

Support for Omitting SLNB in Some Early Breast Cancers

October 13, 2025September 22, 2025 Rodrigo Arrangoiz MS, MD, FACS, FSSO

Sentinel Lymph Node Biopsy Omission in Early Breast Cancer:
- Insights from the INSEMA Trial
Recent findings from the INSEMA trial offer robust evidence supporting the omission of sentinel lymph node biopsy (SLNB) in select patients with low-risk, early-stage invasive breast cancer undergoing breast-conserving surgery (BCS).
Presented by Toralf Reimer, PhD, at the 2024 San Antonio Breast Cancer Symposium (SABCS) and published in the New England Journal of Medicine, the trial demonstrates no significant compromise in survival outcomes when SLNB is omitted in these patients.
Among clinically node-negative women with stage T1 or T2 breast cancer, the 5-year invasive disease-free survival (DFS) rates were comparable:
- 91.9% in patients omitting SLNB and 91.7% in those who underwent SLNB (HR: 0.91; 95% CI: 0.73–1.14).
Overall survival (OS) rates were also similar, estimated at 98.2% without SLNB and 96.9% with SLNB.
Trial Design and Key Results:
- The INSEMA trial enrolled 5,502 patients with clinically node-negative, hormone receptor-positive, HER2-negative invasive breast cancer (T1 / T2, tumor size ≤ 5 cm). Following BCS and whole-breast irradiation, patients were randomized to SLNB or no axillary surgery.
  • Median follow-up: 73.6 months
  • Axillary recurrence:
  - Slightly higher in the no-SLNB group (1.0% vs. 0.3%):
    - Though the absolute numbers were low
  - Distant relapse rates:
    - Identical at 2.7% in both groups
  - Morbidity:
    - Omitting SLNB significantly reduced rates of lymphedema (5.7% vs. 1.8%), arm mobility restrictions (3.5% vs.
      and pain with arm or shoulder movement (4.2% vs. 2.0%).
      - Context Within Ongoing De-Escalation Trials
        
        The INSEMA trial is one of four ongoing studies exploring the omission of axillary surgery in select patients with early-stage breast cancer. These include:
        • SOUND trial: Published results demonstrated no difference in 5-year DFS or OS between patients undergoing or omitting axillary surgery for small (≤ 2 cm) breast tumors.
        • BOOG 2013-08 and NAUTILUS trials: Expected to further validate and refine patient selection criteria for omitting axillary surgery.
        
        Clinical Implications
        
        The INSEMA trial strengthens the case for omitting SLNB in carefully selected patients, particularly for tumors ≤ 2 cm. However, the continued role of SLNB as a staging tool in certain patients and the need for shared decision-making with multidisciplinary teams.
        
        This trial represents a key milestone in an ongoing paradigm shift, aligning with earlier data (e.g., Danish Breast Cancer Cooperative Group studies from the 1980s) that suggested no survival benefit from extensive axillary node removal.
        
        Conclusion:
        
        The findings from the INSEMA trial provide compelling evidence supporting deescalation of axillary surgery in early-stage breast cancer, with a significant reduction in morbidity and no compromise in survival outcomes.
        
        Further results from ongoing trials such as BOOG 2013-08 and NAUTILUS will likely cement this strategy as standard practice for patients with low axillary disease burden.

SOUND Trial Summary

October 12, 2025September 23, 2025 Rodrigo Arrangoiz MS, MD, FACS, FSSO

Title:
- Axillary Surgery in Breast Cancer Patients With Negative Axillary Ultrasound: The SOUND Randomized Clinical Trial
Published:
- 2023 in JAMA Oncology
  - ClinicalTrials.gov ID: NCT02167490
Location:
- Italy, Spain, Switzerland, Chile (18 hospitals)
Study Objective:
- To evaluate whether sentinel lymph node biopsy (SLNB):
  - Can be safely omitted in women:
    - With early-stage, clinically node-negative breast cancer with negative axillary ultrasound (AUS), without compromising oncologic outcomes
Patient Population:
- Women with:
  - Unifocal invasive breast cancer:
    - Tumor ≤ 2.0 cm (cT1)
  - Clinically and ultrasound-negative axilla
  - Undergoing breast-conserving surgery
  - No neoadjuvant therapy
- Tumor types:
  - Majority were hormone receptor-positive, HER2-negative
Study Design:
- Randomized, phase 3, non-inferiority trial
- Two arms:
  - SLNB group:
    - Underwent sentinel lymph node biopsy
  - Observation group:
    - No axillary surgery
- Primary endpoint:
  - 5-year distant disease-free survival (DDFS)
- Secondary endpoints:
  - Overall survival (OS)
  - Disease-free survival (DFS)
  - Axillary recurrence
  - Quality of life

Non-inferiority was met for the primary endpoint (DDFS)
Clinical Implications:
- In women with small tumors (≤ 2 cm) and negative axillary ultrasound:
  - SLNB can be omitted without compromising distant disease-free or overall survival
- Supports a less invasive approach and aligns with the de-escalation of axillary surgery trend in breast cancer care
Leads to fewer surgical complications:
- Lymphedema, seroma, pain
Limitations:
- Results apply only to women with:
  - Negative axillary ultrasound and early-stage, low-risk tumors
- Not applicable to:
  - Mastectomy patients
  - Multifocal tumors
  - Patients receiving neoadjuvant therapy
Conclusion:
- The SOUND trial confirms that routine sentinel lymph node biopsy can be safely omitted in selected patients with early-stage breast cancer and negative axillary ultrasound:
  - Supporting a shift toward minimally invasive surgical strategies in modern breast cancer management

SENOMAC Trial in Breast Cancer

October 11, 2025October 4, 2025 Rodrigo Arrangoiz MS, MD, FACS, FSSO

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
  - 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
  - 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
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
  - They still report 5-yr OS estimates:
    - ≈ 92.9% vs 92.0%
- Reported prespecified secondary endpoint:
  - RFS; NI margin HR upper bound < 1.44
- Median follow-up:
  - 46.8 months
Results (per-protocol)
- 5-yr RFS:
  - 89.7% (SLNB) vs 88.7% (cALND):
    - HR 0.89 (95% CI 0.66–1.19) → non-inferior
- 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
Toxicity / PROs:
- At 1 year:
  - Randomized SENOMAC PRO analysis:
    - SLNB-only patients reported less arm pain / symptoms and better function than cALND
- 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
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
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
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
- 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

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

October 10, 2025September 23, 2025 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:
    - 98.2% (SLNB) vs 98.4% (No surgery), P=0.72 JAMA Network
  - Regional control (events are rare):
    - 5-year cumulative axillary recurrence = 0.4% in each arm (Gray P=0.91)
  - Locoregional relapse:
    - 1.7% (SLNB) vs 1.6% (No surgery) JAMA Network
  - 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:
  - Omission was non-inferior with lower arm morbidity – reinforcing the SLNB – omission strategy for selected cN0 BCT candidates New England Journal of Medicine+2PubMed+2
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:
      - Longer follow-up always helpful JAMA Network
- 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:
    - Avoid extrapolating JAMA Network
- 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:
        
        SLNB may remain reasonable JAMA Network
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:
    - Cite SOUND + INSEMA JAMA Network+1]
- 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):
    - Median f/u 5.7 yrs. JAMA Network
  - 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:
    - 0.6% JAMA Network
  - 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

In p16+ Oropharyngeal Squamous Cell Carcinoma (OPSCC) – Does any Efficacy Endpoint Favor Cetuximab-RT over Cisplatin-RT?

October 9, 2025September 19, 2025 Rodrigo Arrangoiz MS, MD, FACS, FSSO

In p16+ OPSCC, does any efficacy endpoint favor cetuximab-RT over cisplatin-RT?
- Best answer:
  - No
- Why:
  - Neither OS, PFS, nor LRC improved with cetuximab:
    - All favored cisplatin PubMed+1
- When to deviate:
  - Only with absolute cisplatin ineligibility PMC:
    - Discuss RT + cetuximab (Bonner) or altered-fractionation RT
- Pitfalls:
  - Extrapolating the Bonner 2006 RT + cetuximab vs RT-alone result:
    - To cisplatin-eligible patients is incorrect New England Journal of Medicine
    - Bonner:
      - 5-yr OS 45.6% with RT + cetuximab vs 36.4% RT alone:
        
        Not a comparison to cisplatin
  - Under-discussing ototoxicity / renal toxicity risks with cisplatin:
    - Document shared decision-making when deviating
- Numbers:
  - RTOG – 1016 (NI trial, Lancet 2019):
  - De-ESCALaTE HPV (Lancet 2019):

Rodrigo Arrangoiz, MD (Oncology Surgeon)

HPV Positive Oropharyngeal Squamous Cell Carcinoma (OPSCC)

October 8, 2025September 19, 2025 Rodrigo Arrangoiz MS, MD, FACS, FSSO

HPV Positive Oropharyngeal Squamous Cell Carcinoma (HPV⁺ OPSCC):
- Radiation therpay (RT) + cetuximab vs RT + cisplatin (why substitution fails)
Clinical rule:
- In cisplatin-eligible HPV⁺ oropharynx cancer:
  - Do not replace cisplatin with cetuximab:
    - To “de-intensify”
- Two large phase III trials showed:
  - Worse survival and control with cetuximab
- RTOG-1016 (Lancet 2019; non-inferiority trial):
  - Design:
    - RT + cetuximab vs RT + cisplatin 100 mg / m² × 2 in HPV⁺ OPSCC
    - Primary endpoint OS:
      - Non-Inferiority (NI) margin HR 1.45
  - Results (median f/u ~ 4.5 y):
    - 5-yr OS:
      - 77.9% cetuximab vs 84.6% cisplatin:
        
        HR 1.45 → non-inferior criterion failed:
        
        Inferior with cetuximab
    - PFS:
      - HR 1.72:
        
        Worse with cetuximab
    - Locoregional failure:
      - HR 2.05:
        
        Higher with cetuximab
    - Acute / late grade ≥ 3 toxicity:
      - Overall similar rates (different profiles):
        
        So efficacy — not toxicity — drives the choice PubMed+1
- De-ESCALaTE HPV (Lancet 2019; “low-risk” HPV⁺):
  - Design:
    - RT + cetuximab vs RT + cisplatin
    - Primary end point:
      - Severe toxicity
  - Efficacy (≈ 2 y):
    - OS:
      - 97.5% cisplatin vs 89.4% cetuximab:
        
        HR ~ 5.0:
        
        Significantly worse with cetuximab
    - Recurrence:
      - 6.0% cisplatin vs 16.1% cetuximab:
        
        HR ~ 3.4
    - Severe toxicity:
      - Similar overall rates
      - More sever adverse effects (SAEs) with cisplatin:
        
        But not enough to offset the clear efficacy loss with cetuximab The Lancet+2Taylor & Francis Online+2
- Reinforcing data:
  - ARTSCAN III (mixed HNSCC, HPV- subset reported):
    - Concurrent cisplatin outperformed cetuximab with RT:
      - Mature results reiterate inferior outcomes with cetuximabPMC+1
  - Guidelines:
    - NCCN and contemporary reviews state that RT + cisplatin remains standard for eligible HPV⁺ OPSCC:
      - Cetuximab – RT is reserved for:
        
        True cisplatin ineligibility:
        
        CrCl < 50 mL / min, grade ≥ 2 SNHL / neuropathy) JNCCN
How to use this at tumor board:
- Eligible for cisplatin?
  - RT + cisplatin:
    - q3-weekly 100 mg / m² × 2 to 3, or weekly in appropriate settings:
      - To achieve ≥ 200 mg/m² cumulative if feasible (De-escalation ≠ drug substitution) PubMed
  - Cisplatin-ineligible?
    - RT + cetuximab (or institutionally accepted alternatives) with explicit counseling that efficacy:
      - Is inferior to cisplatin in HPV⁺ disease:
        
        Use only because platinum cannot be given JNCCN

Step-by-Step Expansion of Leukocyte Recruitment

October 7, 2025September 17, 2025 Rodrigo Arrangoiz MS, MD, FACS, FSSO

Tethering and Rolling (milliseconds–seconds):
- What happens:
  - Fast blood flow makes first contact fleeting:
    - Cells need “molecular Velcro” that works under shear.
  - Selectins on endothelium:
    - E-selectin:
      - Induced by TNF-α / IL-1
    - P-selectin:
      - Rapidly mobilized from Weibel–Palade bodies
      - Also on platelets
  - Ligands on leukocytes:
    - PSGL-1 and other sialyl-Lewis^x (sLe^x):
      - Decorated glycoproteins
    - L-selectin (CD62L) is on leukocytes:
      - Not endothelium:
        
        It helps secondary capture / rolling:
        
        Leukocyte–leukocyte interactions
        
        Binds Peripheral Node Addressin on High Endothelial Venules (PNAd on HEVs)
    - Mechanics:
      - “Catch bonds” let cells roll, sampling endothelium for activating cues
    - ✅ Fix to your line:
      - Rolling is mainly:
        
        E-selectin / P-selectin (endothelium) ↔ sLe^x/PSGL-1 (leukocyte)
      - L-selectin:
        
        Is leukocyte-borne:
        
        It augments rolling
      - P-selectin:
        
        Is not on neutrophils
Chemokine-Triggered Integrin Activation (“inside-out”):
- What happens:
  - Endothelial-bound chemokines (on heparan sulfates:
    - For example:
      - CXCL8 /IL-8 (neutrophils), CCL2 / MCP-1(monocytes):
        
        Bind GPCRs (CXCR1/2, CCR2…), engaging Gαi → Rap1 → talin / kindlin:
        
        To flip integrins into high-affinity and clustered states
  - Key integrins switched on:
    - β2 family:
      - LFA-1 (αLβ2; CD11a/CD18)
      - Mac-1 (αMβ2; CD11b/CD18).
    - β1 family:
      - VLA-4 (α4β1):
        
        Prominent in monocytes / lymphocytes
Firm Arrest and Adhesion Strengthening (seconds–minutes):
- Counter-receptors on endothelium:
  - ICAM-1 / ICAM-2 ↔ LFA-1 / Mac-1 (β2)
  - VCAM-1 ↔ VLA-4 (β1)
- Outside-in signaling:
  - Through engaged integrins stiffens the cytoskeleton (actin remodeling via Rho / Rac / Cdc42) and spreads the cell, locking it in place
Intraluminal Crawling:
- Arrested leukocytes crawl “upstream” under shear to junctions, mainly using Mac-1 ↔ ICAM-1:
  - This helps them find permissive exit sites
Diapedesis (Transendothelial Migration):
- Two routes:
  - Paracellular (most common):
    - Through junctions
  - Transcellular:
    - Through individual endothelial cells
- Adhesion molecules guiding the crossing:
  - PECAM-1 (CD31), JAM-A/B/C, CD99, ESAM:
    - Mostly homophilic interactions at junctions
  - Transient loosening of VE-cadherin adherens junctions (kinase signaling) opens a path
- Basement membrane and pericytes:
  - Leukocytes use integrins (e.g., α6β1, αvβ3) and proteases (MMP-2/-9, elastase) to breach matrix and pericyte sheaths, aiming for naturally “low-expression regions” of laminins / collagens
- Interstitial Chemotaxis → Focus of Infection / Injury:
  - Once in tissue, cells follow gradients of:
    - Chemokines:
      - CXCL8 (neutrophils), CCL2 (monocytes), CCL19/21 (lymphocyte homing)
    - Lipid mediators:
      - LTB4, PGE₂ (context-dependent)
    - Complement & danger cues:
      - C5a, fMLP from bacteria

Exam pearls
Sequence to memorize:
- Selectin-mediated rolling → chemokine GPCR signal → integrin activation → firm adhesion → crawling → diapedesis → chemotaxis
Inside-out vs outside-in:
- Chemokines activate (inside-out) integrins
- Integrin engagement stabilizes and signals (outside-in)
Platelets matter:
- Platelet P-selectin can recruit leukocytes to thrombi (immunothrombosis)
Tissue tropism:
- VLA-4 ↔ VCAM-1 is big for monocytes / lymphocytes
- Neutrophils lean on β2 integrins

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