Author: Rodrigo Arrangoiz MS, MD, FACS, FSSO

• The intergroup Radiation Therapy Oncology Group (RTOG 91–11) trial for advanced larynx cancer established:
  • Concurrent bolus cisplatin with radiation as a standard of care
• I mentioned that the study was open to patients with squamous cell carcinoma of the glottic or supraglottic larynx:
  • Patients with T1 disease or large-volume T4 disease were excluded
• Patients were randomly assigned to one of three larynx preservation strategies:
  • Induction cisplatin plus 5-FU followed by radiotherapy
  • Radiotherapy with concurrent cisplatin
  • Radiotherapy alone
• I mentioned that the dose of radiotherapy to the primary tumor and clinically positive nodes was:
  • 70 Gy in all treatment groups
• Severe or life-threatening mucositis in the radiation field was:
  • Almost twice as common in the concurrent treatment group compared with either the radiotherapy alone group or the sequential treatment group
• The primary endpoint of the study was:
  • Preservation of  the larynx
• The rate of laryngeal preservation was:
  • 84% for patients receiving radiotherapy with concurrent cisplatin versus 72% or patients receiving induction chemotherapy followed by radiation and 67% for patients receiving radiation therapy alone:
    • At a median follow-up of 3.8 years
• Distant metastases were reduced:
  • In patients who received either concurrent chemoradiotherapy or induction chemotherapy followed by radiotherapy compared with patients who received radiotherapy alone
• Overall survival:
  • Was not significantly different among the three treatment groups
• The lack of an overall survival difference between the three groups:
  • May be due to the contribution of salvage laryngectomy in all groups, as well as a 2% increase in the incidence of death that may have been related to treatment in the concurrent chemoradiotherapy group compared with the other two treatment groups:
    • It is important to recognize that the primary endpoint of the study was larynx preservation:
      • Not overall survival
• The current standard of care for larynx preservation remains:
  • Concurrent high-dose cisplatin and radiation for patients who fit the eligibility criteria that were used in RTOG 91–11

• Perhaps one of the most striking advances in breast cancer management and understanding:
  • Came with the molecular profiling of breast cancer:
    • Characterizing four distinct subtypes:
      • Based on the landmark paper by Perou et al., in 2000
• These define tumor biology and correlate with outcome and are broadly described as:
  • Luminal A, luminal B, human epidermal growth factor receptor 2 (HER2)-enriched, and basal like:
    • According to the most common profiles for each subtype:
      • However, not all tumors within each subtype contain all features
• The estrogen receptor (ER), progesterone receptor (PR), and HER2 receptor:
  • Are used as surrogates to approximate these subtypes and guide clinical care and management decisions
• Luminal A:
  • Most (80% to 85%) of breast cancers express the estrogen receptor (ER-positive) and / or the progesterone receptor (PR+) (75% to 80%) but not HER2:
    • These cancers tend to be more indolent than other subtypes
  • Luminal A tumors are associated with the most favorable prognosis:
    • Particularly in the short term:
      • In part because expression of hormone receptors:
        • Is predictive of a favorable response to hormonal therapy
• Luminal B:
  • These breast cancers are ER-positive and / or PR+:
    • They are further defined by either:
      • HER2 amplification, or high Ki-67 (an indicator of cellular proliferation)
  • They tend to have higher grade and more aggressive features than luminal A breast cancers
• HER2-enriched:
  • These breast cancers produce excess HER2 and do not express hormone receptors
  • These cancers tend to grow and spread more aggressively than other breast cancers and are associated with poorer short-term prognosis compared to ER-positive breast cancers:
    • However, the recent widespread use of targeted therapies for HER2-positive cancers:
      • Has reversed much of the adverse prognostic impact of HER2 overexpression:
        • With 40% to 70% of women achieving a pathologic complete response to combination chemotherapy and targeted anti-HER2 therapies
• Basal like:
  • These tumors are more biologically aggressive:
    • They are typically characterized by the lack of the ER, PR, and HER2 receptor
  • These cancers are often found in:
    • Premenopausal women
    • Those with a BRCA1 gene mutation
  • They are nearly two times more common:
    • In Black women than White women in US
  • The majority (> 70%) of triple negative breast cancers:
    • Fall into the basal-like subtype
  • Triple negative breast cancers:
    • Have a poorer short-term prognosis than other breast cancer types:
      • In part because there are currently no targeted therapies for these tumors:
        • However, a proportion of these tumors are very chemosensitive, exhibiting a pathologic complete response in up to a third of patients
    • Furthermore, several molecular subtypes of triple negative breast cancer have been described:
      • These may provide further insights into the varying biologic response and assist in development of therapeutic targets in addition to chemotherapy

• Design and Arms:
  • Population: 
    • 547 patients with stage III to IV (cT2 bulky to cT4) resectable squamous cell carcinoma of the larynx(supraglottic or glottic):
      • Who were candidates for total laryngectomy
• Randomization (3 arms):
  • Induction PF → RT (Control): 
    • Three cycles cisplatin 100 mg / m² day 1 + 5-FU 1 g/m²/day × 5, followed by definitive RT (66 to 76 Gy) for responders
  • Concurrent CRT: 
    • RT (70 Gy) + cisplatin 100 mg / m² q3wk ×3
  • RT Alone: 
    • 70 Gy definitive radiation
• Primary endpoint: 
  • Laryngectomy-free survival (LFS) and larynx preservation without loss of overall survival (OS)

• Interpretation:
  • Concurrent cisplatin-RT produced the highest larynx-preservation rate and superior laryngectomy-free survival compared with both RT alone and induction PF
  • No OS advantage for any arm:
    • Survival curves overlapped
• Long-Term and Late Toxicities (Forastiere et al., JCO 2013 update):
  • Non–cancer deaths:
    • Cardiopulmonary, treatment-related:
      • More frequent in the concurrent CRT arm after year 5
  • Late swallowing dysfunction and chronic aspiration:
    • Higher with CRT
  • Highlights need for lifelong surveillance and aggressive supportive care:
    • Speech / swallow therapy
    • Pulmonary monitoring
• Clinical Application:
  • Standard of care for organ preservation:
    • Definitive RT + high-dose cisplatin (100 mg / m² q3wk ×3):
      • For patients who are surgical candidates but wish to avoid total laryngectomy and are cisplatin-eligible
      • Requires baseline audiogram, renal function, and performance status assessment
  • Alternatives:
    • For cisplatin-ineligible patients:
      • Cetuximab-RT or carboplatin-based CRT:
        • With the understanding of lower organ-preservation rates

• Cisplatin-ineligible unresected disease:
  • Most guideline-concordant RT partner:
    • Cetuximab
• Anchor trials and what they show:
  • Proof that EGFR antibody + RT beats RT alone:
    • Establishes cetuximab as a curative RT partner
  • Bonner et al., NEJM 2006; 5-yr update 2010:
    • In locoregionally advanced, unresected HNSCC, adding cetuximab to definitive RT over RT alone improved:
      • Locoregional control:
        • Median 24.4 months vs 14.9 months:
          • HR 0.68, p=0.005 over RT alone
      • Overall survival:
        • Median 49.0 months vs 29.3 months:
          • HR 0.74, p=0.03 over RT alone
      • This occured without excess severe mucositis
    • This is the randomized dataset that legitimized cetuximab as a radiosensitizer when chemotherapy can’t be given:
      • New England Journal of Medicine+3PubMed+3New England Journal of Medicine+3
  • Proof that substituting cetuximab for cisplatin is harmful in HPV+ OPSCC:
    • So only use when truly ineligible
    • Trials:
      • RTOG-1016 (Lancet 2019): 
        • RT + cetuximab failed non-inferiority vs RT + cisplatin
        • It produced worse OS and PFS in HPV-positive OPSCC
        • Investigators conclude cisplatin remains the standard for eligible patients:
          • oralcancerfoundation.org+3PubMed+3The Lancet+3
      • De-ESCALaTE HPV (Lancet 2019): 
        • Similarly showed inferior OS and higher recurrence with cetuximab – RT vs cisplatin – RT:
          • Ending the practice of “de-escalation by substitution” 
            • The Lancet
  • Attempts to replace cetuximab in the cisplatin-ineligible setting haven’t beaten it:
    • NRG-HN004 (2024): 
      • In patients contraindicated for cisplatin, RT + durvalumab:
        • Did not improve outcomes over RT + cetuximab:
          • Cetuximab – RT remained the reference:
            • PubMed+2The Lancet+2
• Guideline through-line (how this translates to practice):
  • NCCN (2025): 
    • For definitive management when cisplatin is contraindicated:
      • For example:
        • Renal dysfunction, grade ≥ 2 SNHL, significant neuropathy
      • RT + cetuximab is a listed option:
        • Substitution for convenience or “de-escalation”;
          • Is not recommended given RTOG-1016 / De-ESCALaTE trials;
            • JNCCN
• Practical takeaways for your pathway:
  • Most guideline – concordant partner when cisplatin is off the table:
    • Cetuximab with RT:
      • Supported by the only randomized trial showing benefit over RT alone (Bonner) PubMed
  • Do not swap out cisplatin in HPV+ disease unless truly ineligible:
    • Expect worse survival with substitution PubMed+1
  • If cetuximab isn’t feasible:
    • Severe infusion reactions:
      • Some centers use carboplatin – based CRT (often AUC 1–2 weekly ± partner):
        • But high-level randomized evidence with RT is limited relative to cetuximab:
          • Data are mainly retrospective / phase II (Guideline nuances vary by site and risk) Cancer Treatment Reviews
• Bottom line: 
  • In cisplatin-ineligible, unresected HNSCC:
    • RT + cetuximab remains the most evidence-based, guideline-aligned radiosensitizer:
      • Chosen because it improves outcomes vs RT alone:
        • While trials show it must not replace cisplatin in eligible HPV+ patients

• Diffusely invasive carcinoma:
  • Has a mammographic appearance of diffuse architectural distortion:
    • Usually involving a large area, often larger than a lobe:
      • With no central tumor mass and no calcifications:
      • • It sometimes has the appearance of a “spider’s web” as shown in the Image

• The diffusely infiltrating cancer:
  • Forms concave contours with the surrounding fat in a manner similar to normal fibroglandular tissue (Images)

• The imaging findings of diffusely infiltrating breast cancer are strikingly different:
  • From the imaging findings of breast cancers originating either from the terminal ductal lobular units (TDLUs) or the lactiferous ducts:
  • • Suggesting that it may have a different site of origin

• It has been recently proposed that diffusely infiltrating breast cancers:
  • May originate from mesenchymal stem cells (progenitors):
    • Through a complex process of both:
      • Epithelial-mesenchymal transformation and more frequently, mesenchymal-epithelial transformation

• The clinical presentation:
  • Is typically a recently detected, extensive, firm lesion:
    • Often appearing as an interval cancer following a previous mammogram which was interpreted as normal

• On clinical breast examination:
  • The cancer does not have a distinct tumor mass or focal skin retraction seen in other cancers:
    • But rather an indistinct “thickening” and eventually a shrinkage of the breast.

• In order to make the diagnosis before the development of a palpable mass and a decrease in size of the breast:
  • The radiologist and breast surgeon must have a high level of suspicion and a thorough knowledge of the underlying pathophysiology

• The subgross (3D) histopathology images show how growth of the mesenchymal tissue:
  • Distorts the normal, harmonious connective tissue framework:
    • By causing nonuniform thickening of the fine sheets of connective tissue (Images):

• The predominance of mesenchyme in the diffusely infiltrating breast malignancy:
  • Allows it to be imaged with greater sensitivity by ultrasound than by mammography:

• • • The thin sheets or veils of tissue reflect the ultrasound waves:
      • But are relatively easily penetrated by x-rays

• • The structural / architectural distortion:
  • • While difficult to detect mammographically:
      • Is readily detectable on 2-mm thick coronal sections of automated breast ultrasound (Image)

• The 2-mm thick multi-slice series demonstrate the extensive architectural distortion, corresponding to the 3D histology:

• The hypoechoic changes can also usually be seen on hand held ultrasound, Image:

• The growth pattern and cell type of diffusely invasive breast cancer:
  • Is very similar to that of diffuse gastric carcinoma (linitis plastica), and both of these diseases can be associated with:
    • A deleterious mutation in the CDH1 gene:
      • Which is located on chromosome 16q22 and codes for e-cadherin protein (Image):

• CDH1 was initially known as a susceptibility gene for diffuse gastric cancer (linitis plastica)

• The histopathologic characteristics of diffuse gastric cancer:
  • Show similarities with e-cadherin negative:
    • Diffusely infiltrating breast cancer (infiltrating “lobular” carcinoma)
  • The neoplastic cells permeate the mucosa and wall as scattered individual signet-ring cells or small clusters of cells in an infiltrative growth pattern

• Since there are no TDLUs in the stomach:
  • If the similar cells in both conditions associated with CDH1 have a common origin, it could not be a TDLU:
  • • Raising the possibility that they could result from mesenchymal cell transformation in both organs

👉Rodrigo Arrangoiz MS, MD, FACS, FSSO cirujano oncology y cirujano de mamá de en Mount Sinai Medical Center:

• Es experto en el manejo del cáncer de mama

 👉Es miembro de la American Society of Breast Surgeons:

Training:

• General surgery:

• Michigan State University:

• 2004 al 2010

• Surgical Oncology / Head and Neck Surgery / Endocrine Surgery:

• Fox Chase Cancer Center (Filadelfia):

• 2010 al 2012

• Masters in Science (Clinical research for health professionals):

• Drexel University (Filadelfia):

• 2010 al 2012

• Surgical Oncology / Head and Neck Surgery / Endocrine Surgery:

• IFHNOS / Memorial Sloan Kettering Cancer Center:

• 2014 al 2016

#Arrangoiz

#Surgeon

#Cirujano

#SurgicalOncologist

#CirujanoOncologo

#BreastSurgeon

#CirujanodeMama

#CancerSurgeon

#CirujanodeCancer

• When to perform sentinel lymph node mapping and biopsy?
  • cT1N0, 65 y, HR+/HER2–, tumor 1.5 cm, negative axillary US, breast-conserving surgery (BCS). SLNB or omit?
    • Omission of SLNB is reasonable per ASCO 2025 criteria:
      • Low-risk, ≥ 50 years, HR+ / HER2-, ≤ 2 cm, negative pre-op axillary imaging, BCS:
        • After shared decision-making
  • Same patient as #1 but undergoing mastectomy. SLNB?
    • Perform SLNB:
    • Even if cN0, mastectomy removes future SLNB opportunity:
      • Most guidelines advises SLNB at mastectomy in case invasive disease or nodal information will alter RT /systemic therapy
  • Define the standard indications for SLNB in invasive cT1 to T2, cN0 disease:
    • SLNB is standard for staging in clinically node-negative invasive cancers:
      • Exceptions include specific low-risk cohorts where omission is now endorsed
      • Omission is reasonable per ASCO 2025 criteria:
        • Low-risk, ≥ 50 y, HR+/HER2–, ≤ 2 cm, negative pre-op axillary imaging, BCS, after shared decision-making
  • Pure DCIS having lumpectomy – do you stage the axilla?
    • No:
      • Pure DCIS treated with BCS does not need SLNB
  • DCIS requiring mastectomy – do you add SLNB?
    • Yes:
      • Perform SLNB at mastectomy because later mapping is unreliable and occult invasion risk exists
  • Role of pre-op axillary ultrasound (US) before SLNB?
    • US triages patients:
      • If suspicious nodes, biopsy to confirm cN+:
        • If negative and tumor low-risk, supports SLNB omission in ASCO-defined cohorts
  • SOUND trial bottom line for small tumors with negative axillary US:
    • In cT1 ≤ 2 cm, cN0 with negative US, no axillary surgery was non-inferior to SLNB for 5-year distant DFS
  • INSEMA trial bottom line (NEJM 2025):
    • Among cT1 to cT2, cN0 undergoing BCS, omitting axillary surgery was non-inferior to SLNB for invasive DFS, with less morbidity
  • Does NCCN acknowledge de-escalation of axillary surgery in select early-stage cases?
    • Yes – NCCN endorses risk-adapted axillary management; details in current NCCN Breast Cancer Guideline
  • Key counseling points when considering SLNB omission
    • Ensure negative axillary imaging, small HR+ / HER2-tumor, BCS with adjuvant therapy, and that nodal information won’t change systemic / RT plans; use shared decision-making
• Omission of SLNB in Early Breast Cancer – ASCO 2025 / SOUND / INSEMA Trials;
  • ASCO 2025 Guideline Update (“Sentinel Lymph Node Biopsy in Early-Stage Breast Cancer”) provides formal recommendations to omit routine SLNB in select patients:
    • The criteria include:
      • Age ≥ 50 and postmenopausal status 
      • HR positive
      • HER2 negative
      • Tumor grade 1 to 2
      • ≤ 2 cm size 
      • Clinically node negative (by exam)
      • Negative on preoperative axillary ultrasound (or a suspicious node that is benign on biopsy) 
      • Undergoing breast-conserving therapy with whole-breast irradiation (WBRT) ideally (for patients < 65; for older patients there is more flexibility) 
  • Trials supporting this omission:
    • SOUND trial – randomized patients with T1 (≤ 2 cm), cN0 breast cancer and negative axillary ultrasound to SLNB vs no axillary surgery:
      • At 5 years, distant disease-free survival was similar in both arms
    • INSEMA trial – included clinically node-negative invasive breast cancer ≤ 5 cm undergoing BCS:
      • This trial found omission of axillary surgery was non-inferior to SLNB in terms of invasive disease-free survival
  • Morbidity / Quality of life data:
    • In the INSEMA trial, omitting SLNB led to lower rates of persistent lymphedema:
      • ~ 1.8% in omission vs 5.7% in SLNB group
      • Other arm morbidity measures like restricted shoulder / arm movement and pain were significantly less in the omission group
      • These differences are clinically significant, especially considering the trade-off between morbidity and marginal gain in prognostic information in low-risk patients
  • Risks / caveats:
    • Even in SOUND and INSEMA trials, almost all patients still got radiotherapy (WBRT) which likely contributed to controlling any microscopic nodal disease
    • The longer follow-up is needed to ensure late recurrences in HR+ disease are not missed:
      • ASCO guidelines recognize that. 

• Positive sentinel nodes: who still needs ALND?
  • Z0011 scenario:
    • BCS + whole-breast RT, 1 to 2 positive SLNs (no gross ECE). ALND needed?
      • No. Omit ALND – no OS / DFS detriment at 10 years
  • IBCSG 23-01:
    • Micromets (≤ 2 mm) in SLN – ALND?
      • No:
        • Omit ALND; 10-year outcomes show safety
  • AMAROS take-home when SLN positive (mostly macromets):
    • Axillary RT provides comparable regional control to ALND with less lymphedema – a de-escalation option
  • Does Z0011 apply to mastectomy?
    • No:
      • Z0011 included lumpectomy + whole-breast RT only
      • If mastectomy and SLN+, decisions differ:
        • ALND or nodal radiation often considered
  • > 2 positive SLNs at upfront surgery – what’s recommended?
    • ALND or nodal RT (RNI) typically indicated
      • Z0011 criteria not met
  • Gross extranodal extension (ENE) in SLN on pathology – management?
    • Generally ALND (or comprehensive RNI) considered:
      • Most de-escalation trials excluded gross ENE
  • Under-coverage RT plans (no low-axilla tangents) but 1 to 2 SLN+ after BCS – omit ALND
    • Be cautious:
      • Z0011 assumed tangential fields. If axilla not covered, many favor ALND or add nodal RT
  • Inflammatory breast cancer – axillary staging approach?
    • ALND indicated:
      • SLNB is unreliable
  • cT3 / cT4 tumors but cN0, BCS planned – Z0011 applicable?
    • Z0011 enrolled T1 to T2:
      • Extrapolation to T3 / T4 is not evidence-based – individualize, often favor completion treatment
  • Do isolated tumor cells (ITCs) in SLN mandate ALND?
    • No; ITCs (pN0[i+]) do not require ALND
• ACOSOG Z0011 – ALND vs No ALND when SLNs positive
  • Population and design:
    • Women with clinical T1 or T2 invasive breast cancer, no palpable axillary adenopathy, 1 to 2 sentinel lymph nodes positive by hematoxylin and eosin stain
    • All underwent lumpectomy + WBRT + adjuvant systemic therapy
    • Median follow-up ~ 9.3 years

• Hazard Ratios / Noninferiority:
  • The study had a prespecified noninferiority margin of HR = 1.3 for OS:
    • The observed HR was 0.85 (SLND alone vs ALND) for OS; P = .02 for noninferiority
  • DFS had HR 0.85 (95% CI 0.62-1.17), i.e. no statistically significant difference
• Applicability limits (i.e. external validity constraints):
  • Excluded patients with > 2 positive SLNs, gross extranodal extension, patients undergoing mastectomy without RT, or those not getting WBRT tangents as per protocol:
    • So results apply only to those meeting Z0011 criteria
• Additional / Supporting Data and Real-World Observations:
  • Risk of lymphedema:
    • ALND is associated with significantly higher rates of lymphedema, shoulder mobility limitations, and arm pain than SLNB alone
    • Studies show that lymphedema incidence after SLNB is much lower (e.g., single digits) compared to ALND (where rates may be 20% to 30+% depending on patient, RT, etc.)
    • The SOUND / INSEMA omission studies show ~ 5% to 6% lymphedema in SLNB arm vs ~1% to 2% when SLNB omitted
    • Ultrasound negative imaging correlate:
      • In ASCO guideline and supporting articles, it’s noted that when axillary US is negative preoperatively in low-risk patients, ~85% of the time the SLNB is also negative
      • So negative US is a strong predictor and helps avoid unnecessary SLNB in selected patients.
    • Long-term axillary recurrence rates:
      From Z0011:
      • Regional recurrence was < 1% over the 10 years in SLNB alone group
    • Real-world data (e.g. from NSABP, other cohorts) confirm similar low regional recurrence in patients meeting Z0011 criteria with SLNB alone
• Putting It All Together: Key Data-Driven Pearls:
  • For a patient meeting Z0011 criteria (T1 to T2, cN0, 1 to 2 SLNs positive, lumpectomy + WBRT + systemic therapy):
    • Omitting ALND results in noninferior OS and DFS at 10 years, with very low regional recurrence (< 1%)
  • In the ASCO 2025 SLNB omission group (SOUND, INSEMA), for low-risk patients (≤2 cm, HR+/HER2-, grade 1-2, ≥ 50 y, negative US):
    • Omission of SLNB is noninferior in invasive disease–free or distant disease-free survival at 5 years
    • Also, nodal positivity on SLNB in these patients is relatively uncommon
    • The trade-off:
      • Small absolute increase in risk of occult nodal disease vs measurable reduction of morbidity (lymphedema, pain, mobility)
      • For many patients, quality of life gains are meaningful

• Carriers of the BRCA1 deleterious mutation:
  • Are more likely than both controls and carriers of the BRCA2 mutation to have:
    • High-grade, receptor-negative tumors (and, in particular, triple-negative tumors):
      • Containing necrosis, with higher mitotic counts and shorter tumor-doubling times
  • Carriers of the BRCA1 mutation have lesions that are more likely to have:
    • Pushing margins and that are less likely to be spiculated:
      • Making them harder to detect on mammography and more likely to be detected by MRI than mammography
• Women with a strong family history of both early-onset breast cancer and ovarian cancer in first-degree relatives:
  • Is consistent with hereditary breast and ovarian cancer syndrome:
    • The presence of triple-negative disease is most consistent with the history and diagnosis for a carrier of the BRCA1 deleterious mutation
• Although few studies have evaluated preoperative breast MRI in BRCA carriers after breast cancer has already been diagnosed:
  • Breast MRI has been shown to have a survival benefit in the high-risk screening setting:
    • The lifetime risk of cancer developing in the contralateral breast (which can also be mammographically occult) is nearly 40% in this population
  • Breast MRI is a reasonable preoperative option to evaluate the contralateral breast if the woman has:
    • Dense breasts, risk of being a BRCA carrier, and consequent risk of disease being present or developing in the contralateral breast:
      • However, for patients who opt for bilateral mastectomy:
        • Breast MRI preoperatively is not mandatory
• Although genetic testing has become more widespread and easier to perform in recent years:
  • Performing a genetic test without counseling by someone who has genetic training and expertise is not appropriate
• As some BRCA mutations are known to be deleterious, others are variants of undetermined significance:
  • This means, as the name suggests, that it is unclear whether the patient is at any greater risk of cancer, and if so, by how much:
    • This must be part of the discussion because 5% to 10% of mutations are these variants of undetermined significance, and patient perceptions of their own risk in that setting are high, mandating proper education
• Although women with BRCA mutations have bilateral mastectomy as an option to treat a known cancer and prevent a contralateral one:
  • The American Society of Clinical Oncology / Society of Surgical Oncology consensus statement on prophylactic mastectomy:
    • Considers a significant family history an appropriate indication for prophylactic mastectomy:
      • Even in the absence of a diagnosed mutation
• Women who have a diagnosed deleterious mutation and those who have not been tested but have a strong family history:
  • Are also considered appropriate for risk-reducing surgery.
• References:
  • Guillem JG, Wood WC, Moley JF, et al. ASCO/SSO review of current role of risk-reducing surgery in common hereditary cancer syndromes. Ann Surg Oncol. 2006;13:1296-1321.
  • Kaas R, Kroger R, Peterse JL, Hart AA, Muller SH. The correlation of mammographic and histologic patterns of breast cancers in BRCA1 gene mutation carriers, compared to age-matched sporadic controls. Eur Radiol. 2006;16:2842-2848.
  • Lakhani SR, Reis-Filho JS, Fulford L, et al. Prediction of BRCA1 status in patients with breast cancer using estrogen receptor and basal phenotype. Clin Cancer Res. 2005;11:5175-5180.
  • Murray ML, Cerrato F, Bennett RL, Jarvik GP. Follow-up of carriers of BRCA1 and BRCA2 variants of unknown significance: variant reclassification and surgical decisions. Genet Med. 2011;13:998-1005.
  • Plevritis SK, Kurian AW, Sigal BM, et al. Cost-effectiveness of screening BRCA1/2 mutation carriers with breast magnetic resonance imaging. JAMA. 2006;295:2374-2384.

• Among breast cancer patients:
  • It is estimated that 2% to 6%:
    • Carry a BRCA1 / BRCA 2 mutation
• Among epithelial ovarian cancer patients:
  • It is estimated that 10% to 15%:
    • Carry a BRCA1 / BRCA 2 mutation
• The lifetime risk of breast cancer for BRCA1 / BRCA2 mutation carriers:
  • Is approximately 45% to 80%
• The lifetime ovarian cancer risk is:
  • 45% to 60% for BRCA1 mutation carriers
  • 11% to 35% for BRCA2 mutation carriers
• BRCA1 mutation carriers:
  • Tend to be diagnosed with ovarian cancer at a younger age:
    • Than BRCA2 mutation carriers or sporadic cases
• BRCA-linked ovarian cancers:
  • Are associated with improved survival and longer disease-free interval:
    • Compared to patients with sporadic ovarian cancer
• To date, there is no reliable screening method to detect early ovarian cancer:
  • The prognosis of advanced ovarian cancer:
    • Is poor
• Risk-reducing bilateral salpingo-oophorectomy (RRSO):
  • Is associated with an 80% relative risk reduction:
    • For the development of ovarian and fallopian tube cancers
  • BSO causes a decrease in estrogen production:
    • Which is thought to lead to a 50% risk reduction in the development of future breast cancer:
      • Particularly among BRCA2 mutation carriers
• National Comprehensive Cancer Network (NCCN) guidelines recommend:
  • That BRCA1 mutation carriers be offered RRSO between the ages of 35 and 40
  • BRCA2 mutation carriers are recommended to undergo RRSO between the ages of 40 and 45
• A recent meta-analysis, which included three prospective studies of BRCA patients undergoing RRSO:
  • Found that this procedure salpingo-oophorectomy was associated with a decreased ovarian cancer risk, and decreased all-cause mortality:
    • With the largest risk reduction seen among BRCA1 mutation carriers
  • RRSO is associated with premature menopause, osteoporosis, cardiovascular disease, in addition to other medical issues which can impact quality of life:
    • Patients wishing to undergo RRSO should be counseled regarding these risks
• References:
  • Bougie O, Weberpals JI. Clinical Considerations of BRCA1- and BRCA2-mutation carriers: a review. Int J Surg Oncol. 2011;2011:374012.
  • National Comprehensive Cancer Network. Genetic/familial high risk assessment: breast and ovarian, Version 1.2020 https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf Accessed February 23, 2023.
  • Domchek SM, Friebel TM, Singer CF, Evans DG, Lynch HT, Isaacs C, et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA. 2010;304(9):967-975.
  • Kauff ND, Domchek SM, Friebel TM, Robson ME, Lee J, Garber JE, et al. Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study. J Clin Oncol. 2008;26(8):1331-1337.
  • Finch AP, Lubinski J, Moller P, Singer CF, Karlan B, Senter L, et al. Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation. J Clin Oncol. 2014;32(15):1547-1553.
  • Marchetti C, De Felice F, Palaia I, Perniola G, Musella A, Musio D, et al. Risk-reducing salpingo-oophorectomy: a meta-analysis on impact on ovarian cancer risk and all cause mortality in BRCA 1 and BRCA 2 mutation carriers. BMC Womens Health. 2014;14:150.

• Neoadjuvant chemotherapy (NAC) and the axilla:
  • Biopsy-proven cN1 starting NAC – what to do before therapy?
    • Clip / mark the positive node to enable targeted axillary dissection (TAD) after NAC
  • After NAC, exam / US cN0 – can SLNB be used? Main concern?
    • Yes:
      • But false-negative rate (FNR) is the issue
    • Use techniques to reduce FNR:
      • Dual tracers
      • ≥ 2 to 3 SLNs
      • Retrieval of the clipped node
  • Z1071 FNR headline and mitigation strategies:
    • Overall FNR about:
      • 12% to 13%
    • ≥ 3 SLNs, dual tracers, and removal of the clipped node lower FNR
  • SENTINA insights:
    • Identification and FNR vary by timing:
      • SLNB after NAC in initially node-positive patients has higher FNR unless optimized
    • SN-FNAC findings:
      • With rigorous pathology (IHC) and adequate technique, FNR can be ≈ 8% to 13%:
        • Still requires careful selection
  • What is TAD and why use it post-NAC?
    • TAD = SLNB + removal of the clipped metastatic node:
      • Improves accuracy and lowers FNR versus SLNB alone
  • If post-NAC axilla remains cN+ clinically or by imaging / biopsy – management?
    • ALND (and consideration of RNI) remains standard
  • Subtype and nodal pCR expectations after NAC:
    • HER2+ and TNBC have higher nodal pCR, supporting de-escalation strategies when cN1→cN0 with optimized technique
  • Do you routinely perform SLNB before NAC in cN0 to “bank” nodes?
    • Not routinely; most proceed with SLNB after NAC in cN0, reserving pre-NAC SLNB for select scenarios
  • If the clipped node is not retrieved at surgery post-NAC but SLNs are negative – what now?
    • Higher FNR concern; many advocate completion ALND or targeted re-localization to ensure the clipped node is removed
• Radiation interfaces (ASTRO-ASCO-SSO; PMRT/RNI):
  • How do PMRT / RNI guidelines intersect with axillary surgery choices?
    • Updated ASTRO-ASCO-SSO PMRT guidance:
      • Chest wall / breast plus regional nodes (including axilla) are addressed based on pathologic and clinical risk
      • In some SLN+ cases axillary RT may substitute for ALND
      • Z0011 vs regional nodal irradiation (RNI) big picture:
        • Z0011 patients had excellent outcomes with tangents; comprehensive nodal RT can also control axilla but with different toxicity trade-offs
  • After mastectomy with 1 to 3 positive nodes – axillary management?
    • Often PMRT with RNI is recommended
    • ALND may be performed depending on surgical/RT plan and extent of disease
  • Can axillary RT replace ALND for SLN+ in BCS patients (AMAROS principle)?
    • Yes – axillary RT offers comparable control with less lymphedema vs ALND
  • Does omission of SLNB (SOUND / INSEMA) change systemic therapy decisions?
    • In properly selected low-risk cohorts, nodal information rarely changes systemic therapy, enabling safe omission
• Practical technique and pathology:
  • Minimum SLN count to reduce FNR post-NAC?
    • Try to retrieve ≥ 2 to 3 SLNs:
      • More is better for accuracy
  • Mapping agents: single vs dual tracer?
    • Dual tracer (radioisotope + blue dye / ICG) reduces FNR:
      • Especially post-NAC
  • What to do with ITCs (pN0[i+]) post-NAC?
    • Treat as node-negative for surgical decision-making
    • Escalate RT / systemic therapy only if other factors indicate
  • How do micrometastases (pN1mi) affect ALND decisions in upfront BCS
    • Per IBCSG 23-01:
      • ALND can be omitted with micrometastases
  • Grossly matted / fixed nodes at presentation (cN2 to N3) – initial surgical plan?
    • These patients generally need systemic therapy and ALND (with RNI), not SLNB
• Special scenarios:
  • Pregnancy and SLNB – allowed?
    • Yes, with Tc-99m only (avoid blue dye anaphylaxis risk; methylene blue contraindicated in 1st trimester):
      • Institutional policies vary. (ASBrS technique guidance)
  • Prior breast / axillary surgery – impact on SLN mapping?
    • Prior surgery / radiation can alter drainage:
      • SLNB still feasible but may have lower identification rates:
        • Consider imaging aid
  • Local recurrence after previous SLNB – repeat SLNB?
    • Possible in selected cases; mapping may identify alternate basins; MDT discussion is key
  • Male breast cancer – apply same axillary algorithms?
    • Generally yes:
      • SLNB for cN0 invasive disease, with similar de-escalation logic when applicable
  • Medullary-like or tubular carcinoma – special SLNB rules?
    • No unique rules:
      • Follow general cN0 invasive management:
        • SLNB unless low-risk omission criteria met
• Gray zones and decision-making:
  • If genomic assay selection might hinge on nodal status, should you still omit SLNB?
    • If nodal status would alter systemic therapy decisions (e.g., chemotherapy indication):
      • Perform SLNB
    • Omission is for cases where nodal information won’t change therapy
  • How do you counsel about lymphedema risk when comparing SLNB vs ALND vs axillary RT:
    • Lymphedema risk:
      • ALND > axillary RT > SLNB > omission
    • AMAROS shows less lymphedema with RT vs ALND
  • If SLN is positive and patient is not a candidate for whole-breast RT (e.g., declines RT) after BCS – omit ALND
    • Z0011 required WBRT; without RT coverage, many favor ALND
  • Clinically negative axilla but suspicious single node on imaging with benign core biopsy – proceed with SLNB or omit?
    • Proceed with SLNB (or omission only if fully meeting SOUND / ASCO criteria and MDT agrees imaging is truly negative / safe)
• Bottom line:
• When is ALND still clearly indicated today?
  • Inflammatory breast cancer
  • Persistent cN+ after NAC
  • >2 SLNs positive in upfront BCS /mastectomy
  • Gross ENE
  • When RT plans won’t cover low axilla
  • Nodal information is needed

• Diffusely invasive carcinoma:
  • Has a mammographic appearance of:
    • Diffuse architectural distortion:
      • Usually involving a large area, often larger than a lobe:
        • With no central tumor mass and no calcifications
  • It sometimes has the appearance of a “spider’s web” as shown in Image

• The diffusely infiltrating cancer:
  • Forms concave contours with the surrounding fat in a manner similar to normal fibroglandular tissue (Images Above)
• The imaging findings of diffusely infiltrating breast cancer:
  • Are strikingly different from the imaging findings of breast cancers originating either from the terminal ductal lobular units (TDLUs) or the lactiferous ducts:
    • Suggesting that it may have a different site of origin
• It has been recently proposed that diffusely infiltrating breast cancers:
  • May originate from mesenchymal stem cells (progenitors):
    • Through a complex process of both:
      • Epithelial-mesenchymal transformation and more frequently, mesenchymal-epithelial transformation
  • The clinical presentation is typically a:
    • Recently detected, extensive, firm lesion:
      • Often appearing as an interval cancer following a previous mammogram which was interpreted as normal
    • On clinical breast examination:
      • The cancer does not have a distinct tumor mass or focal skin retraction seen in other cancers:
        • But rather an indistinct “thickening” and eventually a shrinkage of the breast
      • In order to make the diagnosis before the development of a palpable mass and a decrease in size of the breast:
        • The radiologist and breast surgeon must have a high level of suspicion and a thorough knowledge of the underlying pathophysiology
• The subgross (3D) histopathology images:
  • Show how growth of the mesenchymal tissue distorts the normal, harmonious connective tissue framework:
    • By causing nonuniform thickening of the fine sheets of connective tissue
• The predominance of mesenchyme in the diffusely infiltrating breast malignancy:
  • Allows it to be imaged with greater sensitivity by ultrasound than by mammography
• The thin sheets or veils of tissue reflect the ultrasound waves:
  • But are relatively easily penetrated by x-rays
• The structural / architectural distortion, while difficult to detect mammographically:
  • Is readily detectable on 2-mm thick coronal sections of automated breast ultrasound
• The hypoechoic changes:
  • Can also usually be seen on hand-held ultrasound
• The growth pattern and cell type of diffusely invasive breast cancer is very similar to that of diffuse gastric carcinoma (linitis plastica):
  • Both of these diseases can be associated with a deleterious mutation in the CDH1 gene:
    • Which is located on chromosome 16q22 and codes for e-cadherin protein
• References:
  • Hansford S, Kaurah P, Li-Chang H, Woo M, Senz J, Pinheiro H, et al. Hereditary diffuse gastric cancer syndrome: CDH1 mutations and beyond. JAMA Oncol. 2015;1(1):23-32.
  • Tot T. The diffuse type of invasive lobular carcinoma of the breast: morphology and prognosis. Virchows Arch. 2003;443(6):718-724.
  • Tot T. Diffuse invasive breast carcinoma of no special type. Virchows Arch. 2016;468(2):199-206.